+EARLY CHILDHOOD ADVERSE EXPERIENCES

4 chapter 4

early childhood adverse experiences

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Don’t blame the drowning for drowning

Or

Be very careful of a broken heart

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I started my research because I knew that my own heart felt like it was breaking and I could not stop it.  I wanted to know exactly what this pain was coming from.  I learned that the consequence that mattered the most is that the development of my brain was altered from the abuse I suffered from birth.

I thought that fact was a major discovery.  Yes, it was.  But now many months later I am discovering through my studies that a very similar consequence can happen to people through no direct obvious maltreatment at the hands of either parent.  It can happen, and is happening, because hormonal alterations in a mother’s body, present even at the instant of conception, can signal to the developing fetus that the world is a dangerous place and the fetus needs to prepare to live in a hostile, toxic, malevolent world.

Stress talks.  Stress chemical change women’s hormones, and those hormones talk to the fetus and tell it to get ready for a hard life.  A little stress for the mother is not going to destroy her offspring’s health and hope for happiness.  But it doesn’t take a lot of stress in the mother’s body to change the course of development for the fetus on all levels, particularly true with the effects on the male fetus.

It makes me so sad to realize how pervasive these conditions can be and nobody realizes it.  All the children being born depressed, born with PTSD, attention and learning and memory problems, ADHD.  Stress for the mother can be as harmful as drug or alcohol consumption, and nobody knew it.  The research is coming out fast and furious right now.

How do we reach back in time and give mother’s back security and relative peace while they are carrying children?  How do we take back women’s lib, women’s rights, feminism, by telling the truth about the dangers of chronic stress on mothers as they carry and birth their babies?  How do we restore the natural balance so that babies are not being born in bodies prepared to meet the conditions of the worst kind of worlds?  And we will most likely discover that the alterations made in the infant’s DNA mechanisms will be passed down to their offspring right down the generations to come.

To find out now that it doesn’t take a crazy madwoman of a mother to nearly equal the damage to her offspring as violence and abuse.  I had no idea I was going to end up looking back so far, or that I would discover what I am discovering.  I’m stunned, scared, and full of sorrow.

Because of my own experience, because I now know that it was the changes in my developing brain, nervous system, and immune system due to the chronic abuse that happened to me that matter more in the long run than all the horrible things my mother did to me per se, I appreciate how devastating the epigenetic alterations in a person’s life will be throughout their entire lifespan.

These levels of abuse do not merely take away our childhoods.  They do not destroy only our capacity for intimacy and a chance at true well being.  This level of alterations take our bodies away from us.  They take away our true personalities.  They take away our chance from birth, from conception even, to life a fully happy, healthy, productive life.  It’s not unlike aborting us and still leaving us alive.  And then blaming us forever more for not being like “everyone else,” for not being able to react normally, to learn normally, to remember normally, to respond normally, to plan for our futures, to make fantastic choices and decisions, to avoid addictions, to stay healthy – to NOT be mentally ill.

These words feel so shallow and ordinary to me.  Yet these new research studies I am discovering make what used to be earth shaking news to me from Teicher’s article that we get evolutionarily altered brains from child abuse.  It alters our entire bodies!  It changes the way our DNA manifests for the rest of our lives.  And this damage can happen in the womb simply due to a mother being too stressed while she carries her baby, even from when she conceives it.  Even when no direct abuse is intended or accomplished against the child.  It is happening accidentally.  Add to those accidental in utero baby changes the consequences of direct abuse post birth, and then wonder what’s wrong with babies, children and people down the road?  THAT is nuts.

Maybe I need to make a distinction between what I experienced and how I experienced it.  The specific what of the abuse change the how I experience my entire life.

With prenatal stress damage, the mother is experiencing the what of whatever is happening in her life that is causing her stress, and her what is changing her baby’s how for the rest of its life.

What happens to us tell our genes how to manifest themselves.  In the womb, it is the mother’s what that is telling the infant’s genes how to manifest as the tiny body is developing from start to birth.

This is also the reason why twin studies are not giving true answers to the true questions.  Those fetuses are sharing the same environment in the womb, perhaps with one of the twins receiving more nutrition than the other, but if the mother is stressed, if her hormones are telling her babies that the world is toxic, they will both be altered on the genetic manifestation level.  The how is only now being discovered.

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Cicchetti & Toth 2005

Abstract – Mt. Hope Family Center, Rochester, New York 14608, USA. MHFC@netacc.net

Child maltreatment.

Child maltreatment exemplifies a toxic relational environment that poses significant risks for maladaptation across biological and psychological domains of development.

Research on child maltreatment can inform developmental theory, but more importantly, it can enhance the quality of clinical, legal, and policy-making decisions for maltreated children. This chapter addresses definitional, epidemiological, and etiological aspects of child maltreatment. A developmental psychopathology perspective is directed toward the discussion of the psychological and neurobiological sequelae of child maltreatment. Implications for prevention, intervention, and social policy are discussed, and recommendations for future research are proffered.

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Any discussion of the development of dissociation in maltreated children ties in directly with my chapter “Remembering the Self.”  Remembering of a self should be a normal natural process starting from before birth, but when maltreatment enters the infant’s life, all the rules are changed – and so are the outcomes – one way or the other.

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Macfie, Cicchetti & Toth 2001

Abstract – Mt. Hope Family Center, University of Rochester, USA. macfie@email.unc.edu

The development of dissociation in maltreated preschool-aged children.

Dissociation reflects disruptions in the integration of memories, perception, and identity into a coherent sense of self, and may develop following childhood maltreatment.

The preschool years were identified as an important period for the development of dissociation.

However, prior research has not examined the development of dissociation during this time. In order to address this gap, evidence of dissociation in 45 maltreated children, assessed for sexual abuse, physical abuse, and neglect, was compared with dissociation in 33 nonmaltreated children.

Rather than depend on adult observer reports of behavior, the study sought to gain an understanding of dissociation from the child’s own point of view. Because self-reports have limitations with such young children, a measure of dissociation evidenced in children’s narrative story-stem completions was utilized.

Maltreated children, especially physically abused children and sexually abused children, demonstrated more dissociation than did nonmaltreated children. Moreover, during the preschool period maltreated and nonmaltreated children followed different trajectories such that dissociation increased for maltreated children but did not do so for nonmaltreated children.

Findings suggest that although the self is normatively integrated during the preschool period, it becomes increasingly fragmented for some maltreated children.

Results are discussed in terms of cascading effects of maltreatment throughout development, and the importance of developmentally sensitive interventions.

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Valentino et al 2008

Abstract – University of Rochester, USA. kristin.valentino@yale.edu

True and false recall and dissociation among maltreated children: the role of self-schema.

The current investigation addresses the manner through which trauma affects basic memory and self-system processes. True and false recall for self-referent stimuli were assessed in conjunction with dissociative symptomatology among abused (N=76), neglected (N=92), and nonmaltreated (N=116) school-aged children.

Abused, neglected, and nonmaltreated children did not differ

in the level of processing self-schema effect

or in the occurrence and frequency of false recall.

Rather, differences in the affective valence of false recall emerged as a function of maltreatment subtype and age. Regarding dissociation, the abused children displayed higher levels of dissociative symptomatology than did the nonmaltreated children.

Although abused, neglected, and nonmaltreated children did not exhibit differences in the valence of their self-schemas, positive and negative self-schemas were related to self-integration differently among the subgroups of maltreatment.

Negative self-schemas were associated with increased dissociation among the abused children,

whereas positive self-schemas were related to increased dissociation for the neglected children.

And if a child was both abused and neglected, what happened then?

Thus, positive self-schemas displayed by the younger neglected children were related to higher dissociation,

suggestive of defensive self-processing.

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Macfie, Cicchetti & Toth 2001b

Abstract – Mt. Hope Family Center, University of Rochester, NY, USA.

Dissociation in maltreated versus nonmaltreated preschool-aged children.

Dissociation is linked to the experience of child maltreatment for adults and for school-aged children. The goals of the current paper were: First, to extend existing research and examine the link between child maltreatment and preschool-aged children; and second, to examine which subgroups of maltreated preschoolers are most likely to evidence dissociation. METHOD: A well-validated measure of dissociation in children, The Child Dissociative Checklist (CDC; Putnam, Helmers, & Trickett, 1993), was utilized in a sample of low SES maltreated and nonmaltreated preschoolers (N = 198). A measure of internalizing and externalizing symptoms was also utilized. The maltreated children were assessed for sexual abuse, physical abuse, neglect, and also for severity, chronicity, and multiple subtypes of maltreatment.

RESULTS: The sexually abused, physically abused, and neglected groups each demonstrated more dissociation than did the nonmaltreated group. Dissociation in the clinical (psychopathological) range was associated with physical abuse. Moreover, maltreatment severity, chronicity, multiple subtypes, and internalizing and externalizing symptomatology were each related to dissociation.

CONCLUSIONS: Child maltreatment is a factor in dissociation in preschool-aged children as it is in older children and in adults. Sexual abuse, physical abuse, neglect, severity, and chronicity are all implicated. Developmentally sensitive interventions that look beyond comorbidity with behavioral symptoms for dissociative preschool-aged children are needed.

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Silberg 2000

Abstract – Sheppard Pratt Health System, 6501 N. Charles Street, P.O. Box 6815, Baltimore, MD 21285-6815, USA. jlsilberg@aol.com

Fifteen years of dissociation in maltreated children: where do we go from here?

Controversies have centered on the prevalence of dissociative symptoms and disorders in children and adolescents, recommended treatment approaches, and the potential effects of suggestive interpersonal influences. Convergence among diverse practitioners describing dissociative children and adolescents with similar symptoms and maltreatment histories supports the occurrence of these symptom patterns. Although prevalence information has not been well studied, dissociative symptoms may be found in children from a variety of settings across a continuum of severity. There is not yet agreement on exact treatment protocols, but successful treatment outcomes have been reported. A challenge for future research is to develop assessment protocols that are derived from multiple sources of data, and to incorporate the latest developmental research findings into theory development that addresses psychobiological, family, and cultural factors.

The study of dissociation in children and adolescents has the potential to clarify some puzzling child and adolescent presentations and to identify a process by which some children respond and adapt to traumatic environments.

Disorganized/disoriented attachment, even avoidant attachment patterns demonstrate dissociation.

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Haugaard 2004 — get this article

Abstract – Cornell University, NY, USA.

Recognizing and treating uncommon behavioral and emotional disorders in children and adolescents who have been severely maltreated: dissociative disorders.

Children who have experienced severe maltreatment may use dissociation as a strategy to cope with the ongoing trauma of their maltreatment. Although dissociation may help children cope with maltreatment, it can become maladaptive if it is used in other contexts.

For the most part, I adamantly disagree with this evaluation of dissociation.  Certainly when it begins in early childhood, even in infancy, it should be perfectly obvious that it is NOT a defense or a strategy to cope with trauma.  It is a neurological process that has developmentally been built into the brain.

Any attempt to change these patterns must first be based on an understanding that neural circuits are altered in dissociation, and change requires that new circuits be established in the brain, if possible.

The evolutionarily altered brain that Teicher describes possesses within itself, I believe, multiple options for dissociation.  Any brain processes that work in tandem, cooperatively, in conjunction with one another, those that share circuitry and overlap during part of their processes are examples, to me, of where dissociation can develop from birth.

I believe that dissociation is a memory and processing disorder, not a “defense.”

I am talking about false memories.  That is outside the scope of this book.  I am talking about how I, based on my own experiences of chronic severe abuse from birth, do not have a sense of self – or a coherent life story – related to my disorganized/disoriented attachment —

This article explores the symptoms of dissociate disorders and the ways that maladaptive dissociation can develop in maltreated children. Strategies for distinguishing dissociative disorders from other disorders in children are reviewed and treatment strategies for children and adolescents with maladaptive dissociation, and their families, are explored.

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Howe, Cicchetti & Toth 2006

Abstract – Lancaster University, Department of Psychology, UK. mark.howe@lancaster.ac.uk

Children’s basic memory processes, stress, and maltreatment.

Building upon methods and research utilized with normative populations, we examine extant assumptions regarding the effects of child maltreatment on memory. The effects of stress on basic memory processes is examined, and potential neurobiological changes relevant to memory development are examined.

The impact of maltreatment-related sequelae (including dissociation and depression) on basic memory processes as well as false memories and suggestibility are also outlined. Although there is a clear need for additional research, the investigations that do exist reveal that maltreated children’s basic memory processes are not reliably different from that of other, nonmaltreated children.

Research would need to be carefully designed to disentangle the facts related to this last statement.  What do the authors mean by basic memory processes?  The processes might not be different for most maltreated children, but it has to be different for those who experience dissociation.  In my case, I do not believe that anyone could have gone through what I did in the way I did and not end up with a dissociative brain as a result.

We assume that a brain develops in an orderly, predictable, stable fashion.  But it literally internalizes the experiences that build it.  So if the experiences are anything but stable, etc., a different brain results from those interactional experiences.

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Eisen et al 2007

Abstract – Department of Psychology, California State University, Davis CA 95616,USA. ggoodman@ucdavis.edu

Maltreated children’s memory: accuracy, suggestibility, and psychopathology.

Memory, suggestibility, stress arousal, and trauma-related psychopathology were examined in 328 3- to 16-year-olds involved in forensic investigations of abuse and neglect. Children’s memory and suggestibility were assessed for a medical examination and venipuncture.

Being older and scoring higher in cognitive functioning were related to fewer inaccuracies. In addition,

cortisol level and trauma symptoms in children who reported more dissociative tendencies were associated with increased memory error,

whereas cortisol level and trauma symptoms were not associated with increased error for children who reported fewer dissociative tendencies.

Sexual and/or physical abuse predicted greater accuracy. The study contributes important new information to scientific understanding of maltreatment, psychopathology, and eyewitness memory in children.

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Valentino et al 2008b

Abstract – University of Rochester, USA. kristin.valentino@yale.edu

Memory, maternal representations, and internalizing symptomatology among abused, neglected, and nonmaltreated children

A depth-of-processing incidental recall task for maternal-referent stimuli was utilized to assess basic memory processes and the affective valence of maternal representations among abused (N = 63), neglected (N = 33), and nonmaltreated (N = 128) school-aged children (ages 8-13.5 years old). Self-reported and observer-rated indices of internalizing symptoms were also assessed.

Abused children demonstrated impairments in recall compared to neglected and nonmaltreated children.

  1. Although abused, neglected, and nonmaltreated children did not differ in valence of maternal representations, positive and negative maternal schemas related to internalizing symptoms differently among subgroups of maltreated children.   Did researchers determine if the mother was the abuser or not?

Valence of maternal schema was critical in differentiating those with high and low internalizing symptomatology among the neglected children only.

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Toth, Cicchetti & Kim 2002

Abstract – Mt. Hope Family Center, University of Rochester, New York 14608, USA. s.toth@worldnet.att.net

Relations among children’s perceptions of maternal behavior, attributional styles, and behavioral symptomatology in maltreated children.

This investigation examined relations among perceptions of mothers, attributional style, and counselor-rated behavior problems in 187 school age children (88 maltreated, 99 nonmaltreated). Hypotheses regarding the presence of higher levels of internalizing and externalizing behavior problems in maltreated children were confirmed.

Attributional style was found to function as a moderator of externalizing behavior problems, suggesting that attributional style exerts a protective role against the harmful effect of child maltreatment.

Perceptions of mothers were found to operate as a mediator of both internalizing and externalizing symptomatology, with maltreated children with less positive perceptions of their mothers exhibiting greater internalizing and externalizing behavior problems.

These findings advance knowledge of how cognitive processes contribute to behavior problems in maltreated children and possess implications for prevention and intervention efforts.

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Price & Glad 2003

Abstract – Department of Psychology, San Diego State University, San Diego, California 92120-4913, USA.

Hostile attributional tendencies in maltreated children.

The hostile attributional tendencies of maltreated children in elementary school across key relationship figures (i.e., parents, teachers, and peers), the relation between children’s hostile attributional tendencies and the frequency and severity of maltreatment, and the role of children’s hostile attributions of their parents in mediating the relation between maltreatment and children’s hostile attributions of unfamiliar peers were examined. The sample consisted of 44 maltreated and 56 nonmaltreated children (females = 51) of mixed ethnicity. Subjects were administered a 20-item measure of attributional processes. The results indicated that

relative to nonmaltreated children, physically abused boys were more likely to attribute hostile intentions to a variety of relationship figures, including their parents, an unfamiliar teacher, their best friend, and unfamiliar peers.

A positive relation was also found between the frequency of physical abuse and hostile attributional tendencies among males.

Finally, support was found for the role of children’s hostile attributions of their mothers in mediating the relation between physical abuse and children’s hostile attributions of unfamiliar peers.

The results support a link between physical abuse and hostile attributional tendencies in children in early elementary school.

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Yehuda 2005 – get this article

Abstract – naamayehuda@aol.com

The language of dissociation.

Three case studies of inner-city elementary school children illustrate the connection between speech-language disorders and dissociative disorders in children who have known or suspected trauma histories.

The role of speech language pathologists in identifying and responding to dissociative symptoms in children is explored. Lack of adequate training concerning the impact of trauma and scarce literature on the communication profiles of dissociative children contributes and greatly impacts the diagnosis, referral, and treatment of these children. The case studies demonstrate how unusual speech and language symptoms and awareness of dissociative features may aid in identifying trauma-related problems and instituting effective treatment.

Grounding techniques and specific language interventions can assist children in acquiring the vocabulary needed for communicating both their daily experiences and traumatic histories.

The nature of the relationship between dissociation and communication disorders is explored, and the importance of future research, interdisciplinary collaboration, and trauma training in the speech-language curriculum is emphasized

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Cicchetti & Rogosch 1997

Abstract – Mt. Hope Family Center, University of Rochester, NY 14608, USA.

The role of self-organization in the promotion of resilience in maltreated children.

The dynamic nature of resilience necessitates that children from high-risk backgrounds who are functioning adaptively despite experiences of adversity must be examined over time.

Be very careful not to assume that these resiliency factors are entirely or even primarily located within the child itself.  The role of attachment in forming the brain and reaction to all stress requires that adequate social support be present in the child’s universe, and this social support mediates all aspects of the child’s resilience, including the modulation of genetics.

In the current investigation, the adaptation of school-age maltreated and nonmaltreated socioeconomically disadvantaged children was examined over 3 consecutive years. In accord with predictions, a higher percentage of nonmaltreated children than of maltreated children were found to be resilient.

Moreover, a higher percentage of maltreated than of nonmaltreated children were shown to exhibit functioning consistently in the low adaptive range

. Differential predictors of resilience were found in maltreated and nonmaltreated children.

Specifically, for maltreated children, positive self-esteem, ego resilience, and ego overcontrol predicted resilient functioning, whereas

relationship features were more influential for nonmaltreated children. This is an interesting finding, and not necessarily in agreement with research done after 1997.  Children’s self-esteem and ego resilience are consequences to the largest extent of their interactions with early caregivers.  I would have to call in this article to even see what ages they are reviewing here, and if they even looked at the birth-2 relationships of the child

These findings are discussed in relation to the unfolding of resilient self-organizational strivings in maltreated and nonmaltreated children.

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Flores, Cicchetti & Rogosch 2005

Abstract – Mt. Hope Family Center, University of Rochester, 187 Edinburgh Street, Rochester, NY 14608, USA. eaflores@psych.rochester.edu

Predictors of resilience in maltreated and nonmaltreated Latino children.

To date, few studies have sought to investigate the effects of child maltreatment and processes influencing maladaptation and resilience in Latino children. In the current investigation, multiple aspects of functioning, personal resources, and relationship features were examined in school-age maltreated and nonmaltreated Latino children.

Maltreated Latino children were found to have

fewer areas of resilient functioning.

Ego-resiliency and ego-control, as personal resources,

and the ability to form a positive relationship with an adult figure outside of the immediate family

predicted resilience.

However, certain aspects of interpersonal functioning were differentially related to resilience for maltreated and nonmaltreated Latino children. These findings have implications for understanding how resilience can be promoted in maltreated and nonmaltreated Latino children.  Again, I don’t have the article to find out what they noted here.

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Ayoub et al 2006

Abstract – Harvard Graduate School of Education, Cambridge, MA 02138, USA.

Cognitive and emotional differences in young maltreated children: a translational application of dynamic skill theory.

Through a translational approach, dynamic skill theory enhances the understanding of the variation in the behavioral and cognitive presentations of a high-risk population-maltreated children. Two studies illustrate the application of normative developmental constructs from a dynamic skills perspective to samples of young maltreated and nonmaltreated children. Each study examines the emotional and cognitive development of maltreated children with attention to their developing world view or negativity bias and cognitive skills.

Across both studies, maltreated children demonstrate negativity bias when compared to their nonmaltreated counterparts. Cognitive complexity demonstrated by the maltreated children is dependent upon a positive or negative context. Positive problem solving is more difficult for maltreated children when compared to their nonmaltreated counterparts. Differences by maltreatment type, severity, timing of the abuse, and identity of the perpetrator are also delineated, and variation in the resulting developmental trajectories in each case is explored. This translation of dynamic skill theory, as applied to maltreated children, enhances our basic understanding of their functioning, clarifies the nature of their developmental differences, and underscores the need for early intervention.

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Haskett et al 2006

Abstract – Department of Psychology, North Carolina State University, Raleigh, NC 27695, USA. mary_haskett@ncsu.edu

Diversity in adjustment of maltreated children: factors associated with resilient functioning

Many decades of research indicate that physical abuse and neglect are associated with substantial risk for maladaptation across many developmental tasks of childhood, adolescence, and adulthood.

Recent investigations, however, indicate that in spite of elevated risk for negative outcomes, some abused and neglected children demonstrate relatively positive adjustment and success in developmental tasks.

An overview of studies of resilient functioning among maltreated children is provided, and results indicate that although a proportion of maltreated children do appear to be resilient to harsh and inadequate caretaking, resilient functioning might be short-lived and/or limited to single areas of functioning.

A summary of factors associated with resilient functioning among abused and neglected children is provided.

Such factors include individual child characteristics (e.g., self-regulatory processes), self-regulation is a consequence of early brain formation interactions with caregivers and does not just happen automatically – these influences must be considered features of the child’s family context (e.g., supportive parenting), and experiences in the broader environment (e.g., close friendships).

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Jaffee et al 2007

Abstract – Department of Psychology, University of Pennsylvania, 3720 Walnut Street, Philadelphia, PA 19104, USA.

Individual, family, and neighborhood factors distinguish resilient from non-resilient maltreated children: a cumulative stressors model.

OBJECTIVE: Children who are physically maltreated are at risk of a range of adverse outcomes in childhood and adulthood, but some children who are maltreated manage to function well despite their history of adversity. Which individual, family, and neighborhood characteristics distinguish resilient from non-resilient maltreated children? Do children’s individual strengths promote resilience even when children are exposed to multiple family and neighborhood stressors (cumulative stressors model)? [i.e. allostatic load]METHODS: Data were from the Environmental Risk Longitudinal Study which describes a nationally representative sample of 1,116 twin pairs and their families. Families were home-visited when the twins were 5 and 7 years old, and teachers provided information about children’s behavior at school. Interviewers rated the likelihood that children had been maltreated based on mothers’ reports of harm to the child and child welfare involvement with the family. RESULTS: Resilient children were those who engaged in normative levels of antisocial behavior despite having been maltreated.

Boys (but not girls) who had above-average intelligence and whose parents had relatively few symptoms of antisocial personality were more likely to be resilient versus non-resilient to maltreatment.

Children whose parents had substance use problems and who lived in relatively high crime neighborhoods that were low on social cohesion and informal social control were less likely to be resilient versus non-resilient to maltreatment.

Consistent with a cumulative stressors model of children’s adaptation, individual strengths distinguished resilient from non-resilient children under conditions of low, but not high, family and neighborhood stress.

CONCLUSION: These findings suggest that for children residing in multi-problem families, personal resources may not be sufficient to promote their adaptive functioning.

These conditions do not magically go away when a person reaches adulthood.  They follow us in all sorts of ways.

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DuMont, Widom & Czaja 2007

Abstract – Bureau of Evaluation & Research, New York State Office of Children & Family Services, Rensselaer, NY, USA.

Predictors of resilience in abused and neglected children grown-up: the role of individual and neighborhood characteristics.

PURPOSE: This paper examines individual, family, and neighborhood level predictors of resilience in adolescence and young adulthood and describes changes in resilience over time from adolescence to young adulthood in abused and neglected children grown up. METHOD: We use documented cases of childhood physical and sexual abuse and neglect (n=676) from a Midwestern county area during the years 1967-1971 and information from official records, census data, psychiatric assessments, and self-reports obtained through 1995. Analyses involve logistic regressions, replicated with Mplus to test for possible contextual effects.

RESULTS: Almost half (48%) of the abused and neglected children in adolescence and nearly one-third in young adulthood were resilient. Is the glass half empty or half full?  I don’t have the article to find out what they use for measures of resiliency.

Over half of those who were resilient in adolescence remained resilient in young adulthood, whereas 11% of the non-resilient adolescents were resilient in young adulthood.

Females were more likely to be resilient during both time periods.

Being white, non-Hispanic decreased [something missing in sentence here?] and growing up in a stable living situation increased the likelihood of resilience in adolescence, but not in young adulthood.

Stressful life events and a supportive partner promoted resilience in young adulthood.

Neighborhood advantage did not exert a direct effect on resilience, but moderated the relationship between household stability and resilience in adolescence and between cognitive ability and resilience in young adulthood.

CONCLUSIONS: Ecological factors appear to promote or interfere with the emergence and stability of resilience following childhood maltreatment.

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McGloin & Widom 2001

Abstract – Rutgers University, USA.

Resilience among abused and neglected children grown up.

Although an extensive literature has accumulated documenting the maladaptive outcomes associated with childhood victimization, a limited body of knowledge addresses resilience.

This paper sought to operationalize the construct of resilience across a number of domains of functioning and time periods and to determine the extent to which abused and neglected children grown up demonstrate resilience. Substantiated cases of child abuse and neglect from 1967 to 1971 were matched on gender, age, race, and approximate family social class with nonabused and nonneglected children and followed prospectively into young adulthood. Between 1989 and 1995. 1,196 participants (676 abused and neglected and 520 controls) were administered a 2-hr in-person interview, including a psychiatric assessment.

Resilience

requires meeting the criteria for success across six of eight domains of functioning: employment, homelessness, education, social activity, psychiatric disorder, substance abuse, and two domains assessing criminal behavior (official arrest and self-reports of violence).

Results indicate that 22% of abused and neglected individuals meet the criteria for resilience.

More females met the criteria for resilience and females were successful across a greater number of domains than males.

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Haskett et al 2006

Abstract – Department of Psychology, North Carolina State University, Raleigh, NC 27695, USA. mary_haskett@ncsu.edu

Where did I put this article?

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Kaplow & Widom 2007

Abstract – Department of Psychiatry, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, NJ, USA. jkaplow@jjay.cuny.edu

Age of onset of child maltreatment predicts long-term mental health outcomes.

The authors tested the hypothesis that children who are maltreated earlier in life are at greater risk for poor psychological functioning in adulthood than those maltreated later in life. Age of onset of maltreatment was assessed with 3 classifications: (a) continuous (ages 0-11 years); (b) dichotomous (early [ages 0-5 years] vs. later [ages 6-11 years]); and (c) developmental (infancy [ages 0-2 years], preschool [ages 3-5 years], early school age [ages 6-8 years], and school age [ages 9-11 years]). Individuals with documented cases of physical and sexual abuse and neglect prior to age 12 (N=496) were followed up and assessed in adulthood.

Results indicated that an earlier onset of maltreatment, measured dichotomously and developmentally,

predicted more symptoms of anxiety and depression in adulthood,

while controlling for gender, race, current age, and other abuse reports.

Later onset of maltreatment, measured continuously or developmentally, was predictive of

more behavioral problems in adulthood.

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Jaudes & Mackey-Bilaver 2008

Abstract – University of Chicago, Illinois Department of Children and Family Services, La Rabida Children’s Hospital, East 65th Street at Lake Michigan, Chicago, IL 60649, USA.

Do chronic conditions increase young children’s risk of being maltreated?

OBJECTIVE: To examine whether and to what extent specific chronic health conditions place young children at risk of maltreatment. METHODS: The study used a sample of Illinois children (born between January 1990 and March 1996) who were through age 3 continuously enrolled in Medicaid, a public health insurance program for low-income families. The study used “paid claims” data and ICD-9-CM health codes to identify children with one or more of three chronic conditions: chronic physical illness, developmental delay/mental retardation (dd/mr), and behavior/mental health conditions (b/mh). The analysis used Cox proportional hazard models to estimate the risk of substantiated child maltreatment that each of these health conditions confer on children under age 6.

RESULTS: Among children under age 6, 24.1% had chronic physical health conditions, 6.1% had b/mh conditions, and 4.2% had dd/mr. Among the children, 11.7% were maltreated (abused or neglected).

Children with b/mh conditions were 1.95 times more likely than children without such conditions to be victims of child abuse or neglect. Children with chronic physical health conditions were 1.1 time more likely to be maltreated (p<or=.001). In contrast, children with dd/mr were not at an increased risk of maltreatment.

Further, if the child had a prior history of abuse or neglect before age 3 and was also diagnosed with a behavioral health condition, that child was 10 times more likely to be maltreated again (relative risk of 9.2, p<or=.0001).

CONCLUSIONS: Behavioral/mental health conditions placed low-income children under age 6 at the highest risk of abuse or neglect. Developmental delay/mental retardation, however, did not appear to increase the risk of maltreatment, while chronic physical health conditions increased the risk slightly among this group of children. Therefore, identified behavior/mental health in young, low-income children should be considered a risk factor for potential abuse [I doubt it’s so much a risk factor as a symptom due to chronic abuse and neglect] to pediatricians and other health professionals. Child protection agencies should be trained to identify behavioral/mental health conditions of children. PRACTICE IMPLICATIONS: Chronic behavioral/mental health conditions place young children at heightened risk of abuse or neglect. Early detection of mental or psychosocial health conditions is mandated by the Individuals with Disabilities Education Act (IDEA), a federal law that governs how state and public agencies provide services to children with disabilities. Given the higher risk of abuse and neglect among children with behavioral/mental health conditions, clinicians should give added scrutiny to these children. Child protection agencies should also be trained to identify behavioral/mental health conditions, and more states should record disability status in their abuse records.

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Silva, Mallozi & Ferrari 2007

Abstract – Universidade Estadual Paulista, Botucatu, SP, Brazil. igorlopes@uol.com.br

Salivary cortisol to assess the hypothalamic-pituitary-adrenal axis in healthy children under 3 years old.

OBJECTIVE: To establish reference concentration intervals for salivary cortisol in healthy children, in the morning and in the afternoon, investigating factors that interfere with the concentration measured and the possibility that circadian rhythms are present. METHODS: A controlled observational study was carried out with 91 children aged 45 days to 36 months, selected at random and living in Santo André, state of São Paulo, Brazil. Inclusion criteria were: healthy, well-nourished, free from fever and corticoid use, subdivided by age group (five subsets) at 6-month intervals. Saliva was collected during home visits in the morning and afternoon. Cortisol was radioimmunoassayed with cortisol 3-oxime-bovine albumin antiserum. RESULTS: The five subsets exhibited higher cortisol concentration during the morning than in the afternoon (p < 0.001), and this difference passed 30% from 1 year of age onwards. Mean concentrations, in nmol/L, were 557.86 (morning) and 346.36 (afternoon). A negative linear correlation was observed between morning concentrations and hours’ sleep and frequency of meals (p < 0.05), and in the afternoon with anthropometric measurements (p < 0.05). CONCLUSIONS:

Reference values for normal salivary cortisol in healthy children were established. At 45 days it was possible to observe circadian rhythms, which reached maturity at 12 months of life. Sleep and food deprivation increased morning cortisol levels.

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Fogaca et al 2005

Abstract – Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo, Brazil.

Salivary cortisol as an indicator of adrenocortical function in healthy infants, using massage therapy.

CONTEXT AND OBJECTIVE: The evaluation of adrenocortical function with the use of therapeutic massage has been little studied in Brazil. The purpose of this study was to evaluate the salivary cortisol levels before and after Shantala massage therapy on healthy infants. DESIGN AND SETTING: Prospective case series, in a public nursery, in São Paulo. METHODS: Saliva was obtained from 11 infants at the times of 8:00-9:00 a.m. and 4:00-5:00 p.m. in a nursery and 9:00-10:00 p.m. at home. They received a 15-minute therapeutic massage on two consecutive days, and saliva was collected before and after the massage. The procedure was repeated after a one-week interval. Cortisol values (intra-assay < 5%; inter-assay < 10%) at different times of the day were compared by ANOVA. RESULTS: The mean cortisol values (nmol/l +/- SD) on the first day were: morning (M) = 14.1 +/- 5.7, afternoon (A) = 8.3 +/- 2.7, night (N) = 3.3 +/- 1.1; after two consecutive days of therapeutic massage: M = 22.3 +/- 13.5, A = 13.4 +/- 6.0, N = 5.8 +/- 3.5; after a one-week interval: M = 15.8 +/- 7.7, A = 14.3 +/- 7.7, N = 3.4 +/- 2.0. CONCLUSION:

There was a modification in the salivary cortisol values

following massage,

thus reflecting possible adaptation of the hypothalamic-pituitary-adrenal axis.

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Cicchetti & Rogosch 2007

Abstract – Institute of Child Development, University of Minnesota, Minneapolis, MN 55455, USA.

Personality, adrenal steroid hormones, and resilience in maltreated children: a multilevel perspective.

In this multilevel investigation, resilience in adaptive functioning among maltreated and nonmaltreated low-income children (N = 677) was examined in relation to the regulation of

two stress-responsive adrenal steroid hormones,

cortisol and dehydroepiandrosterone (DHEA),

as well as the personality constructs of ego resiliency and ego control.

Maltreatment status was not related to differences in average levels of morning or afternoon cortisol or DHEA. However,

lower morning cortisol

was related to higher resilient functioning, but only in

nonmaltreated children.

In contrast, among physically abused children,

high morning cortisol was related to higher resilient functioning.

Morning and afternoon DHEA was negatively related to resilient functioning.

Although diurnal change in cortisol was not related to resilience, for DHEA, maltreated children with high resilience showed an atypical rise in DHEA from morning to afternoon.

Morning and afternoon cortisol/DHEA ratios [for both groups?] were positively related to resilient functioning, but did not interact with maltreatment status.

Ego resiliency and ego control strongly differentiated maltreated and nonmaltreated children, and the personality variables were substantially predictive of resilience.

I much prefer to think in terms of SELF rather than in terms of ego.

When considered together, demonstrated

effects of personality, cortisol, and DHEA

maintained independent contributions

in predicting resilience among high-risk youth.

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Cicchetti & Rogosch 2001

Abstract – Mt Hope Family Center, University of Rochester, NY 14608, USA.

Diverse patterns of neuroendocrine activity in maltreated children.

Cortisol regulation was investigated in a sample of school-aged maltreated (n = 175) and demographically comparable low-income nonmaltreated (n = 209) children in the context of a day camp research program. Overall group differences between maltreated and nonmaltreated children were not found for average morning or average afternoon cortisol levels. However,

significant variations were found that were based on the subtypes of maltreatment that the children had experienced. Maltreated children who had been both physically and sexually abused (as well as neglected or emotionally maltreated) exhibited substantial elevations in morning cortisol levels;

children who had high (>1 SD) cortisol levels in both the morning and afternoon were also overrepresented in the multiple abuse group.

Developmental timing of maltreatment did not account for these group differences, whereas the severity of sexual abuse was implicated.

In contrast to the multiple abuse group, a subgroup of physically abused children showed evidence of a trend toward lower morning cortisol relative to nonmaltreated children with a significantly smaller decrease in cortisol levels from morning to afternoon.

The findings are discussed in terms of the diversity of atypical cortisol regulation patterns that are exhibited among maltreated children.

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Gunnar & Vazquez 2001

Abstract – Institute of Child Development, University of Minnesota, Minneapolis 55455, USA.

Low cortisol and a flattening of expected daytime rhythm: potential indices of risk in human development.

Since the work of Hans Selye,

stress has been associated with increased activity of the

limbic-hypothalamic-pituitary-adrenocortical (LHPA) axis.

Recently, a number of studies in adults have shown that this neuroendocrine axis may be hyporesponsive in a number of stress-related states.

Termed hypocortisolism,

the paradoxical suppression of the LHPA axis

under conditions of trauma and prolonged stress presently challenges basic concepts in stress research.

Adverse conditions that produce elevated cortisol levels

early in life are hypothesized to contribute to the

development of hypocortisolism in adulthood.

However, as reviewed in this paper, hypocortisolism also may be a common phenomenon early in human childhood. Although preliminary at this point, the ubiquity of these findings is striking.

We argue that developmental studies are needed that help explicate the origins of low cortisol and to determine whether the development of hypocortisolism is, in fact, preceded by periods of frequent or chronic activation of the LHPA axis.

We also argue that developmental researchers who incorporate measures of salivary cortisol into their studies of at-risk populations need to be aware of the hypocortisolism phenomenon.

Lower than expected cortisol values should not necessarily be relegated to the file drawer because they contradict the central dogma that stress must be associated with elevations in cortisol.

Lastly, we note that evidence of low cortisol

under adverse early life conditions in humans

adds to the importance of understanding the implications of hypocortisolism for health and development.

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Gunnar & Quevedo 2008

Abstract – Institute of Child Development, University of Minnesota, Minneapolis, MN 55455, USA. gunnar@umn.edu

Early care experiences and HPA axis regulation in children: a mechanism for later trauma vulnerability.

Post-traumatic stress disorder (PTSD) is associated with functional abnormalities of the hypothalamic-pituitary-adrenocortical (HPA) axis.

Emerging evidence suggests that

failures in social regulation of the HPA axis in young children manifested as neglectful or abusive care

may play a role in shaping cortico-limbic circuits involved in processing experiences threatening experiences encountered later in life.

Low cortisol levels, particularly near the peak of the diurnal rhythm, have been reported in abused, neglected and deprived children.

Thus early imprinting effects of parenting quality on the HPA system regulation may be one of the mechanisms causing heightened risk of PTSD in responses to later trauma.

However there is also evidence that the altered patterns of cortisol production seen in the context of early adverse care are not permanent, and remit once the care children receive improves.

These interventions must occur EARLY – in time for the imprinting to be altered, in time for the manifestation of genetic disturbances to be altered.  We must also realize that it is not only brain development, nervous system development that is being altered – also impacts development of the immune system, which is itself in the process of detecting the threat and danger of abuse as it occurs.

What awaits study is whether

periods of atypical cortisol levels and altered HPA function

early in life, even if transient,

impact brain development in ways that heighten vulnerability to PTSD in response to traumas experienced later.

Research would also be implicating the role of handedness in this risk.

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Tarullo & Gunnar 2006

Abstract – Institute of Child Development, 51 East River Road, University of Minnesota, Minneapolis, Minnesota, USA.

Child maltreatment and the developing HPA axis.

The developing HPA axis

is under strong social regulation in infancy and early childhood and is vulnerable to perturbation in the absence of sensitive, responsive caregiving.

Child maltreatment has complex, long-term influences both on basal cortisol levels and on HPA responsivity to pharmacological and psychological stressors, depending on current psychiatric status, current life adversity, age, and most likely, genetic factors.

Among the more consistent findings,

maltreated children with internalizing problems have

elevated basal cortisol most often detected in early AM concentrations, whereas adults maltreated as children often exhibit low basal cortisol levels and elevated ACTH response to psychological stressors.

To disentangle these complicated interactions, future research must take the above qualifiers into account, study the transition to puberty, explore the moderating role of candidate genes, and utilize animal models and pharmacological challenges, when ethical, to localize changes in the HPA axis. Post-institutionalized children may provide a model to separate early adverse care histories from current adversity.

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Shea et al 2005

Abstract – Women’s Health Concerns Clinic, St Joseph’s Healthcare, 50 Charlton Avenue East, Hamilton, Ont., Canada.

Child maltreatment and HPA axis dysregulation: relationship to major depressive disorder and post traumatic stress disorder in females.

A history of child maltreatment

increases the vulnerability to the development of Major Depressive Disorder (MDD) and/or Posttraumatic Stress Disorder (PTSD), especially in females.

Both MDD and PTSD are associated with a dysregulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis.

Dysregulation of the HPA axis may be an important etiological link between child maltreatment and subsequent psychiatric disorder, yet little is known about the relationship between exposure and outcome. The aim of this review is to explore the role of HPA axis dysregulation in the link between child maltreatment and MDD/PTSD among women.

Studies of females with MDD frequently indicate a hyperactivity of the HPA axis, and contribute to our understanding of the underlying mechanisms involved in mood dysregulation.

Evidence for HPA axis dysregulation in PTSD is less convincing and suggests that timing of the stressful experience as well as the type of the trauma may influence the outcome.

The strongest evidence to date suggesting that the development of the HPA axis may be affected by early life stressful experiences comes from pre-clinical animal studies.

Together these studies add to our understanding of the role of the HPA axis in psychiatric disorders in relation to stress.

The literature on HPA axis function in both children and adults following child maltreatment

further highlights the potential relevance of early stress to later onset of major psychiatric disorders.

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Gunnar et al 2008

Abstract – Institute of Child Development, University of Minnesota, 51 East River Road, Minneapolis, MN 55455, United States.

Moderate versus severe early life stress: Associations with stress reactivity and regulation in 10-12-year-old children.

Early life stress (ELS) is expected to increase reactivity of the hypothalamic-pituitary-adrenocortical (HPA) axis; however, several recent studies have shown diminished cortisol reactivity among adults and children with ELS exposure.

The goal of this study was to examine cortisol activity in 10-12-year-old internationally adopted children to determine if moderate and severe ELS have different impacts on the HPA axis. Salivary cortisol and two measures of autonomic activity were collected in response to the Trier Social Stress Test for Children (TSST-C). Three groups reflecting moderate, severe, and little ELS were studied: early adopted children who came predominantly from foster care overseas (early adopted/foster care (EA/FC), n=44), later adopted children cared for predominantly in orphanages overseas (late adopted/post-institutionalized (LA/PI), n=42) and non-adopted (NA) children reared continuously by their middle- to upper-income parents in the United States (n=38).

They are not screening for direct abuse, direct intent to harm these children, which presents a direct threat to life, threat of death – specifically altering HPA function perhaps in different ways than what they are measuring here.

Diminished cortisol activity was noted for the EA/FC group (moderate ELS), while the LA/PI group (severe ELS) did not differ from the NA group. Overall, few children showed cortisol elevations to the TSST-C in any group. The presence/absence of severe growth delay at adoption proved to be a critical predictive factor in cortisol activity.

Regardless of growth delay, however, LA/PI children exhibited higher sympathetic tone than did NA children. These results suggest that moderate ELS is associated with diminished cortisol activity; however, marked individual differences in cortisol activity among the LA/PI children suggest that child factors modify the impact of severe ELS.

Lack of effects of severe ELS even for growth delayed children may reflect the restorative effects of adoption or the generally low responsiveness of this age group to the TSST-C.

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Gunnar et al 2001

Abstract – Institute of Child Development, University of Minnesota, Minneapolis, 55455, USA. Gunnar@tc.umn.edu

Salivary cortisol levels in children adopted from Romanian orphanages.

Six and a half years after adoption. 6- to 12-year-old children reared in Romanian orphanages for more than 8 months in their first years of life (RO. n = 18) had higher cortisol levels over the daytime hours than did early adopted (EA, < or = 4 months of age, n = 15) and Canadian born (CB, n = 27) children.

The effect was marked, with 22% of the RO children exhibiting cortisol levels averaged over the day that exceeded the mean plus 2 SD of the EA and CB levels.

Furthermore, the longer beyond 8 months that the RO children remained institutionalized the higher their cortisol levels.

Cortisol levels for EA children did not differ in any respect from those of CB comparison children.

This latter finding reduces but does not eliminate concerns that the results could be due to prenatal effects or birth family characteristics associated with orphanage placement. Neither age at cortisol sampling nor low IQ measured earlier appeared to explain the findings.

Because the conditions in Romanian orphanages at the time these children were adopted were characterized by multiple risk factors, including gross privation of basic needs and exposure to infectious agents, the factor(s) that produced the increase in cortisol production cannot be determined.

Nor could we determine whether these results reflected effects on the limbic-hypothalamic-pituitary-adrenal axis directly or were mediated by differences in parent-child interactions or family stress occasion by behavioral problems associated with prolonged orphanage care in this sample.

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Thomson 2007

Abstract – Paula-maurice@sbcglobal.net

“Down will come baby”: prenatal stress, primitive defenses and gestational dysregulation.

Knowledge of maternal stress and its direct influence on the developing embryo and fetus (prenate) can influence psychotherapeutic treatment decisions, especially when treating patients who are severely traumatized and dissociative.

Not only may maternal stress alter prenate

neurobiological attachment and stress systems

in the limbic-hypothalamus-pituitary-adrenal axis (LHPA)

and limbic-autonomic nervous system (L-ANS),

but it may also shape the development

of prenate ‘fixed action patterns’ built from primitive defensive reflex activation.

As a result, the offspring’s defensive,

mating and caregiving behavior

may all be biased towards survival in a threatening world and may be more readily transmitted to subsequent generations.

Including through epigenetic mechanisms

This theoretical article provides a prenatal relational model that outlines experience- dependent prenate development that is contingent on and concordant with maternal regulation and dysregulation. Not only anxiety, depression and anger, but also posttraumatic stress and dissociation in the mother, may affect the neurobiology of the prenate.

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Talge et al 2007

Abstract – Institute of Child Development, University of Minnesota, USA.

Antenatal maternal stress and long-term effects on child neurodevelopment: how and why?

We review a significant body of evidence from independent prospective studies that if a mother is stressed while pregnant, her child is substantially more likely to have emotional or cognitive problems, including an increased risk of attentional deficit/hyperactivity, anxiety, and language delay.

These findings are independent of effects due to

maternal postnatal depression and anxiety

We still do not know what forms of anxiety or stress are most detrimental, but research suggests that the relationship with the partner can be important in this respect.

The magnitude of these effects is clinically significant,

as the attributable load of emotional/behavioral problems

due to antenatal stress and/or anxiety

is approximately 15%.

Animal models suggest that activity of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis

and its hormonal end-product cortisol

are involved in these effects

in both mother and offspring.

The fetal environment can be altered

if stress in the mother changes her hormonal profile,

and in humans, there is a strong correlation between

maternal and fetal cortisol levels.

However, many problems remain in understanding the mechanisms involved in this interaction. For example, maternal cortisol responses to stress decline over the course of pregnancy, and earlier in pregnancy, the link between maternal and fetal cortisol is less robust.

It is possible that the effects of maternal anxiety and stress on the developing fetus and child are moderated by other factors such as a maternal diet (e.g., protein load).

It is suggested that extra vigilance or anxiety,

readily distracted attention,

or a hyper-responsive HPA axis

may have been adaptive in a stressful environment during evolution,

but exists today at the cost of vulnerability to neurodevelopmental disorders.

And adult onset disorders for the rest of the lifespan

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Brunton, Russell & Douglas 2008

Abstract – Laboratory of Neuroendocrinology, Centre for Integrative Physiology, Hugh Robson Building, University of Edinburgh, Edinburgh, UK.

Adaptive responses of the maternal hypothalamic-pituitary-adrenal axis during pregnancy and lactation.

Over the past 40 years, it has been recognized that the maternal hypothalamic-pituitary-adrenal (HPA) axis undergoes adaptations through pregnancy and lactation that might contribute to avoidance of adverse effects of stress on the mother and offspring.

The extent of the global adaptations in the HPA axis has been revealed and the underlying mechanisms investigated within the last 20 years.

Both basal, including the circadian rhythm, and stress-induced adrenocorticotrophic hormone and glucocorticoid secretory patterns are altered.

Throughout most of pregnancy, and in lactation, these changes predominantly reflect reduced drive by the

corticotropin-releasing factor (CRF) neurones

in the parvocellular paraventricular nucleus (pPVN).

An accompanying profound attenuation of HPA axis responses to a wide variety of psychological and physical stressors emerges after mid-pregnancy and persists until the end of lactation.

Certainly in light of the extreme sensitivity of the fetus to stress hormones during its development would mean that nature would lessen the risk of this happening – but it then must mean that whatever stresses the mother enough to release her stress hormones means that the environment is certain to be TOXIC – much so!

Central to this suppression of stress responsiveness

is reduced activation of the pPVN CRF neurones.

This is consequent on the reduced effectiveness of the stimulation of brainstem afferents to these

CRF neurones

(for physical stressors) and of

altered processing by limbic structures (for emotional stressors).

Emotional stressors – I am realizing that our emotions are immune system responses – and I think I am right.  This article is making my point right here.  Is it just the basic five emotions without their differentiations that are implicated here, because processing by the brain self and mind of the person influences emotional reactions, too?

Infants and children must have feelings, sensations, far before one learns what feelings are.  Is it a raw emotion in the body rather than a refined “feeling” that I am talking about here as an immune system response?

Emotions, like disgust certainly, tell us what is wrong in our environment so that we can react and act to protect and defend ourselves.

Look at it from a cellular level, how a cell has means to protect itself.  That would make the fight-flight-freeze response an immune system response.

And as social beings, the opioid system is implicated here

And hence the attachment system.

Perhaps Carl Jung would understand the difficulties I am experiencing right now at this stage of my research because perhaps I am approaching something that is numinous, as he would call it.  Am I standing at the point where soul, mind, spirit and body and its senses intersect with one another, and thus I sense this power, this intensity – and this fear – of rushing in where angels fear to tread – and nearly feel overwhelmed with the work?  Too bright, too big, like it will topple down on top of me.  Like every piece of research to this point has been a brick, and the wall is high now – and the faint of heart would turn away and be done with it – not to finish it now that the going is getting difficult and the roof is about to be put on.

This is requiring perseverance, dedication, and faith in the work – that there is good to come out of this, that it has meaning, that it can and will help people – though I cannot see how.  If I were a welder I would put the mask on now and not glare directly at the light, it is too bright, and I fear I will be incinerated –

like a Phoenix.

And there will be nothing left of me, of the work, of the book

But the ashes.

Is this what awe feels like?  This is the intensity that is so hard for me to regulate and modulate – that fact being what led me into the research in the first place – that my feelings are so intense, that they are so physical – that I cannot make them go away.

The mechanism of reduced CRF neurone responses to physical stressors in pregnancy is the suppression of noradrenaline release in the PVN by an

up-regulated

endogenous opioid mechanism,

which is induced by neuroactive steroid produced from progesterone.

By contrast, in lactation suckling the young

provides a neural stimulus that dampens the HPA axis circadian rhythm and reduces stress responses.

Reduced noradrenergic input activity

is involved in reduced stress responses in lactation,

although central prolactin action also appears important.

Such adaptations limit the adverse effects of excess glucocorticoid exposure on the foetus(es) and facilitate appropriate metabolic and immune responses.

In the fetus or in the mother during lactation?

This directly connects to the immune information in the well being chapter.

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Abe et al 2007

abstract – Division of Psychiatry, Department of Clinical Neuroscience, School of Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan. abehiro@med.miyazaki-u.ac.jp

Prenatal psychological stress causes higher emotionality, depression-like behavior, and elevated activity in the hypothalamo-pituitary-adrenal axis.

In humans, stressful events during pregnancy may raise the risk of psychiatric disorders in offspring, and

studies with rodents have found that physical prenatal stress can cause changes in the physiology, neurobiology, and behavior of offspring.

In the present study, we examined whether psychological prenatal stress with little physical stress could cause changes in the neurobiology and behavior of offspring in Sprague-Dawley rats, as physical prenatal stress did.

Dams received psychological stress by observing a rat being electrically shocked behind a transparent wall in the social communication box during the last trimester of gestation but were not exposed to any physical stress.

Male offspring from the dams exposed to psychological stress showed enhanced emotionality in an open field test, depression-like behavior in a forced swim test, and enhanced activity in the hypothalamo-pituitary-adrenal axis, compared with rats from untreated dams.

However, the prenatally stressed rats showed intact ability to acquire context conditioning. This is the first report that psychological prenatal stress in the communication box can cause changes in the neurobiology and behavior of offspring in rodents.

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Darnaudery & Maccari 2008

Abstract – Perinatal Stress Team, University of Lille 1, 59655 Villeneuve d’Ascq Cedex, France.

Epigenetic programming of the stress response in male and female rats by prenatal restraint stress.

Exposure to hostile conditions

results in a series of coordinated responses

aimed at enhancing the probability of survival.

The activation of the hypothalamo-pituitary-adrenocortical (HPA) axis plays a pivotal role in the stress response.

While the short-term activation of the HPA axis allows adaptive responses to the challenge, in the long run this can be devastating for the organism.

In particular, life events occurring during the perinatal period have strong long-term effects on the behavioral and neuroendocrine response to stressors.

In male and female rats exposed to prenatal restraint stress (PRS), these effects include a long-lasting hyperactivation

of the HPA response associated with

an altered circadian rhythm of corticosterone secretion.

Furthermore, male animals exhibit sleep disturbances.

In males,

these HPA dysfunctions have been reported

in infant, young, adult and aged animals,

thus suggesting a permanent effect of early stress.

Interestingly, after exposure to an intense inescapable footshock,

female PRS rats durably exhibit a blunted corticosterone secretion response to stress.

This would be closer to a PTSD response?

In male PRS rats exposed to an alcohol challenge, the HPA axis is similarly hyporesponsive.

Rats exposed to PRS also show behavioral disturbances.

Both male and female PRS rats show high anxiety levels and depression-like behavior during adulthood,

although some studies suggest that female PRS rats present low anxiety levels.

With ageing, male and female PRS rats

exhibit memory impairments in hippocampus-dependent tasks,

INTERESTING!

while female PRS rats improve their memory performance during adulthood.

The gender effect on behavior seems to be related to

a reduction in hippocampal plasticity in male PRS rats,

and an increase in female PRS rats.

Despite the permanent imprinting induced by early stress,

the dysfunctions observed after PRS

can be reversed by environmental or pharmacological strategies such as environmental enrichment or antidepressive and neurotrophic treatments.

So the imprinting remains but the “dysfunctions” can be altered?

Mechanisms underlying the effects of PRS on the offspring remain largely unknown.

However, previous studies have demonstrated that maternal glucocorticoids during pregnancy play an important role in the HPA disturbances reported in male offspring.

Finally, gestational stress has long-lasting effects

on the HPA axis and on behavior in the dams.

Stressed mothers do a worse job of mothering

Alterations in maternal behavior could thus also make a strong contribution to the long-term effects of PRS,

through epigenetic mechanisms.

They aren’t describing what these mechanisms are here

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Kapoor et al 2006

Abstract – Department of Physiology, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King’s College Circle, Toronto, Ontario, Canada.

Fetal programming of hypothalamo-pituitary-adrenal function: prenatal stress and glucocorticoids.

Prenatal stress (PS) and maternal exposure to exogenous glucocorticoids can lead to permanent modification of hypothalamo-pituitary-adrenal (HPA) function and stress-related behavior.

Both of these manipulations lead to increased fetal exposure to glucocorticoids.

Glucocorticoids are essential for many aspects

of normal brain development, but exposure of the fetal brain to an excess of glucocorticoids can have life-long effects on neuroendocrine function.

Both endogenous glucocorticoid and synthetic glucocorticoid exposure have a number of rapid effects in the fetal brain, including modification of neurotransmitter systems and

transcriptional machinery.

Such fetal exposure permanently alters HPA function in prepubertal, postpubertal and ageing offspring, in a sex-dependent manner.

Prenatal stress and exogenous glucocorticoid manipulation also lead to the modification of behavior, brain and organ morphology, as well as altered regulation of other endocrine systems.

It is also becoming increasingly apparent that the timing of exposure to PS or synthetic glucocorticoids has tremendous effects on the nature of the phenotypic outcome.

Permanent changes in endocrine function will ultimately impact on health in both human and animal populations.

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Richardson et al 2006

Abstract – Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California 92037, USA.

Exposure to repetitive versus varied stress during prenatal development generates two distinct anxiogenic and neuroendocrine profiles in adulthood.

Early life experiences can [it DOES shape it, for heaven’s sake!] shape brain function and behavior in adulthood. The present study sought to elucidate the effects of repetitive, predictable vs. varied, unpredictable prenatal stress on sexually dichotomous neuroendocrine and anxiety-related behavioral responses in adult offspring. Rat dams were exposed repeatedly during the last week of pregnancy to no stress, only restraint stress [prenatal stress (PS)-restraint], or a randomized sequence of varied stressors (PS-random), and several behavioral and endocrine measures were assessed in adult male and female offspring.

Repeated exposure to the same stressor (restraint) generated the most robust changes, including increased anxiety-related behaviors (both passive, measured on the elevated plus maze, and active, measured using defensive burying tests),

a delayed and prolonged hypothalamic-pituitary-adrenal (HPA) axis response to stress in female offspring.

Conversely, PS-restraint males showed no changes in anxiety-like behavior and had elevated basal ACTH and a blunted HPA response to stress; consistent with attenuated HPA responsivity

was an increase in glucocorticoid receptor immunoreactivity in the hippocampus, suggesting increased negative feedback on the HPA axis in these animals.

Prenatal exposure to a varied, unpredictable pattern of stressors did not have as much effect on HPA function, with most neuroendocrine measures residing intermediate to PS-restraint and control animals within each sex.

Gonadal steroids were altered independent of the type of prenatal stress, but changes were measurable

only in males (lower testosterone).

Interesting males become less aggressive!

The present data exemplify the differential sensitivity of the developing nervous and endocrine systems to stress, depending on not only gender but also the nature of the stressful experience endured by the mother during pregnancy.

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Matthews et al 2004

Abstract – Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. stephen.matthews@utoronto.ca

Fetal glucocorticoid exposure and hypothalamo-pituitary-adrenal (HPA) function after birth

The fetus may be exposed to increased endogenous glucocorticoid or synthetic glucocorticoid in late gestation. Indeed, 7-10% of pregnant women in Europe and North America are treated with synthetic glucocorticoid to promote lung maturation in fetuses at risk of preterm delivery. Such therapy is effective in reducing respiratory complications. However, very little is known about the mechanisms by which synthetic glucocorticoid or prenatal stress influence neurodevelopment in the human, or whether specific time windows of increased sensitivity exist.

Glucocorticoids are essential for many aspects of normal brain development. However, there is growing evidence that exposure of the fetal brain to excess glucocorticoid can have lifelong effects on neuroendocrine function and behavior. We have shown that both endogenous glucocorticoid and synthetic glucocorticoid exposure has a number of rapid effects in the fetal brain in late gestation, including modification of neurotransmitter systems and transcriptional machinery. Such fetal exposure permanently alters hypothalamo-pituitary-adrenal (HPA) function in prepubertal, postpubertal, and aging offspring, in a sex-dependent manner. These effects are linked to changes in central glucocorticoid feedback machinery after birth. Prenatal glucocorticoid manipulation also leads to modification of HPA-associated behaviors, brain and organ morphology, as well as altered regulation of other endocrine systems. Permanent changes in endocrine function will have a long-term impact on health, since elevated cumulative

exposure to endogenous glucocorticoid is linked to the premature onset of pathologies associated with aging.

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Weinstock 2005

Abstract – Department of Pharmacology, School of Pharmacy, Hebrew University Medical Centre Jerusalem, Israel. martar@md.huji.ac.il

The potential influence of maternal stress hormones on development and mental health of the offspring.

Recent studies in humans suggest that

alterations in the activity of the neuroendocrine system

mediate the effects of psychosocial stress

on fetal development and birth outcome.

Chronic maternal distress compromises the normal regulation of hormonal activity during pregnancy and elevates free circulating corticotrophin-releasing hormone (CRH), probably of placental origin, before the normal increase occurs at term.

Excess CRH, and other hormones like cortisol and met-enkephalin that pass through the placenta, could precipitate preterm labor, reduce birth weight and slow growth rate in prenatally stressed infants.

CRH and/or cortisol have also been associated with impaired fetal habituation to stimuli and temperamental difficulties in infants.

These changes may result from actions of the hormones

on their receptors in the fetal limbic system.

In the rat, gestational stress and excess maternal and fetal plasma corticosterone cause downregulation of fetal glucocorticoid (GR) and mineralocorticoid (MR) receptors and impair the feedback regulation of the hypothalamic-pituitary adrenal (HPA) axis in infancy and adulthood.

The impairment in HPA axis activity can be prevented by maternal adrenalectomy and mimicked by administration of glucocorticoids.

Gestational stress also increases CRH activity in the amygdala and the incidence of anxiogenic and depressive-like behavior in rats and non-human primates, which can be ameliorated by CRH antagonists.

Excess amounts of CRH and cortisol reaching the human fetal brain during periods of chronic maternal stress could alter personality and predispose to attention deficits and depressive illness through changes in neurotransmitter activity.

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Wadhwa 2002

Abstract – Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697-4260, USA. pwadhwa@uci.edu

Behavioral perinatology: biobehavioral processes in human fetal development.

Behavioral perinatology is as an interdisciplinary area of research

that involves conceptualization of theoretical models and conduct of empirical studies of the dynamic time-, place-, and context-dependent interplay between biological and behavioral processes in fetal, neonatal, and infant life using an epigenetic framework of development.

The biobehavioral processes of particular interest to our research group relate to the effects of maternal pre- and perinatal stress and maternal-placental-fetal stress physiology. We propose that behavioral perinatology research may have important implications for a better understanding of the processes that underlie or contribute to the

risk of three sets of outcomes:

prematurity, adverse neurodevelopment,

and chronic degenerative diseases in adulthood.

Based on our understanding of the ontogeny of human fetal development and the physiology of pregnancy and fetal development, we have articulated a neurobiological model of pre- and perinatal stress.

Our model proposes that chronic maternal stress may exert a significant influence on fetal developmental outcomes.

Maternal stress may act via one or more of three major physiological pathways: neuroendocrine, immune/inflammatory, and vascular.

We further suggest that

placental corticotropin-releasing hormone (CRH)

may play a central role in coordinating the effects

of endocrine, immune/inflammatory, and vascular processes

on fetal developmental outcomes.

Finally, we hypothesize that the effects of maternal stress are modulated by the nature, duration, and timing of occurrence of stress during gestation.

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Wadhwa 2005

Abstract – Behavioral Perinatology Research Program, Department of Psychiatry and Human Behavior, College of Medicine, University of California, Irvine, 92697-4260, USA. pwadhwa@uci.edu

Psychoneuroendocrine processes in human pregnancy influence fetal development and health.

Individual differences in psychoneuroendocrine function play an important role in health and disease.

Developmental models postulate that these individual differences evolve through a progressive series of dynamic time-, place- and context-dependent interactions between genes and environments in fetal, infant and adult life.

The effects of early experience have longer-lasting and more permanent consequences than those later in life.

Experimental studies in animals have provided convincing evidence to support a causal role for stress-related psychoneuroendocrine processes in negatively influencing critical developmental and health outcomes over the life span, and have also offered valuable insights into putative physiological mechanisms.

However, the generalizability of these findings from animals to humans may be limited by the existence of large inter-species differences in physiology and the developmental time-line.

We have initiated a program of research in behavioral perinatology and conducted studies over the past several years to examine the effects of stress-related psychoneuroendocrine processes in human pregnancy on fetal developmental and health outcomes.

Our findings support a significant and independent role

for maternal prenatal stress in the etiology

of prematurity-related outcomes,

and suggest that these effects are mediated, in part,

by the maternal-placental-fetal neuroendocrine axis,

and specifically by

placental corticotropin-releasing hormone.

Our findings also suggest that the use of a fetal challenge paradigm offers a novel way to quantify fetal neurobehavioral maturity in utero, and that the

maternal environment exerts a significant influence

on the fetal neurodevelopmental processes related to recognition, memory and habituation.

Finally, our findings provide preliminary evidence to support the notion that the influence of prenatal stress and maternal-placental hormones on the developing fetus may persist after birth, as assessed by measures of temperament and behavioral reactivity in the first few years of postnatal life.

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Kertes et al 2008

Abstract – Institute of Child Development, 51 East River Road, University of Minnesota, Minneapolis, MN 55455, USA.

Early deprivation and home basal cortisol levels: a study of internationally adopted children.

Animal studies reveal that early deprivation impairs regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis, potentially increasing vulnerability to stressors throughout life.

To examine early deprivation effects on basal HPA axis activity in humans, basal cortisol levels were examined in 164 internationally adopted children who had experienced varying degrees of preadoption deprivation. Duration of institutional care, age at adoption, and parent ratings of preadoption neglect indexed a latent factor of Deprived Care. Adoption measures of height and weight standardized to World Health Organization norms indexed a latent factor of Growth Delay that was viewed as another reflection of deprivation. Cortisol samples were collected 3.3-11.6 years postadoption (Md = 7.3 years) at home on 3 days approximately 30 min after wakeup and before bedtime. Both early a.m. levels and the decrease in cortisol across the day were examined. A structural equation model revealed that

preadoption Deprived Care predicted Growth Delay at adoption and Growth Delay predicted higher morning cortisol levels

and a larger diurnal cortisol decrease.

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Fernald, Burke & Gunnar 2008

Abstract – University of California, Berkeley, 50 University Hall, MC 7360, Berkeley, CA94720-7360, USA. fernald@berkeley.edu

Salivary cortisol levels in children of low-income women with high depressive symptomatology.

Children (N = 324 boys, 315 girls) between the ages of 2.5 and 6 (mean age = 3.63) were identified in a house to house survey in low-income areas (income <20th percentile nationally) of urban Mexico. The Center for Epidemiologic Studies-Depression Scale was administered to mothers of all children. Salivary cortisol samples were taken in children as a measure of hypothalamic-pituitary-adrenocortical (HPA) system activity at time of arrival (baseline, Time 0), 25 min after arrival (Time 1), and 50 min after arrival (Time 2). Between Time 0 and Time 1, children were administered several cognitive tests.

Results of hierarchical linear modeling analyses revealed that

higher levels of maternal depressive symptoms

were associated with lower baseline cortisol levels

in their children (p < .05),

while controlling for age, gender, and time since awakening.

Higher levels of maternal depressive symptoms were associated with less of an increase in salivary cortisol to the arrival of the experimenters and subsequent cognitive testing (p < .05).

All results were moderated by gender,

with enhanced cortisol response in girls and

no response in boys.

These results suggest that among very low-income families, high maternal depressive symptoms

are associated with hypoactivity of the HPA system in children, particularly boys.

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Burke et al 2005

Abstract – Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA. hburke@itsa.ucsf.edu

Depressive symptoms are associated with blunted cortisol stress responses in very low-income women.

The purpose of this study was to examine the association between depressive symptoms and salivary cortisol responses to stress in a high-risk population of very poor Mexican women. METHODS: Adult women (N = 1109) between the ages of 18 and 44 years (mean age, 29) were identified in a house-to-house survey in low-income areas (income <20th percentile nationally) of urban Mexico. An interview containing the Spanish version of the Center for Epidemiologic Studies–Depression Scale (CES-D) was administered to all women. The naturalistic stressor was defined as the unexpected arrival of a team of researchers at the participants’ homes followed by an in-depth interview and physical assessment, with saliva samples taken at time of arrival (baseline), 25 minutes, and 50 minutes after arrival.

RESULTS: The mean CES-D score was 19.42 (range, 0-53). Results of hierarchical linear modeling analyses revealed no effect of depressive symptoms on baseline salivary cortisol levels. However, a

significant depressive symptom by time interaction revealed that women with elevations in depressive symptoms (CES-D scores = 35) failed to exhibit a cortisol response to the stressor

. In contrast, in women with lower CES-D scores, cortisol levels significantly increased in response to the stressor.

CONCLUSION: Consistent with research on individuals with major depressive disorder, results of this study demonstrate that women with very high levels of depressive symptoms exhibit blunted cortisol responses to a naturalistic psychological stressor. Results also contribute to previous research by generalizing findings to a high risk, underserved population of women.

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Ashman et al 2002

Abstract – Department of Psychology, University of Washington, Seattle 98195, USA.

Stress hormone levels of children of depressed mothers.

Research suggests that disruptions in early caretaking can have long-term effects on the hypothalamic-pituitary-adrenal (HPA) axis, which mediates the stress response.

Children of depressed mothers are at increased risk for developing internalizing problems in part because of disruptions in their caretaking environment.

The present study investigated whether children of depressed mothers exhibit elevated salivary cortisol levels. Salivary cortisol samples were collected from 45 7- to 8-year-old children of mothers with a history of depression and 29 children of nondepressed mothers. Samples were collected soon after arrival to the laboratory and after a mild laboratory stressor and at home after wakeup and before bedtime.

Children who had elevated levels of intemalizing symptoms and whose mothers had a history of depression showed

elevated laboratory baseline cortisol levels.

Children who were reported to have clinically significant internalizing symptoms were also more likely to show an elevated stress response to a mild laboratory stressor.

When the longitudinal history of maternal depression was examined, matemal depression during the child’s first 2 years of life was the best predictor of elevations in baseline cortisol at age 7 years

. This study provides evidence that internalizing symptoms exist in conjunction with a more reactive hormonal stress system in children of depressed mothers.

This compares to the Mexican study where the depressed mothers showed a blunted response to stress – so the children are showing an opposite reaction?  Why would that be so?

The results also provide preliminary evidence that exposure to maternal depression in the first 2 years of life may be related to children’s cortisol levels later in life.

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Ashman, Dawson & Panagiotides 2008

Abstract – University of Washington, USA. sashman@u.washington.edu

Trajectories of maternal depression over 7 years: relations with child psychophysiology and behavior and role of contextual risks.

This study examines the relation between the longitudinal course of maternal depression during the child’s early life and children’s psychophysiology and behavior at age 6.5 years. One hundred fifty-nine children of depressed and nondepressed mothers were followed from infancy through age 6.5 years. Growth mixture modeling was used to identify classes of depressed mothers based on the longitudinal course of the mother’s depression.

School-aged children of chronically depressed mothers were found to have elevated externalizing behavior problems, decreased social competence, reduced frontal brain activation (EEG power), and higher respiratory sinus arrhythmia reactivity. Demonstrating involvement of the immune system?

Children of mothers with decreasing and stable mild depression were found to have increased hyperactivity and attention problems compared to children of nondepressed mothers.

Contextual risk factors were found to mediate the relation between maternal depression and child behavioral outcomes. I don’t have the article so don’t know what these contextual factors are – call it in.

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Sohr-Preston & Scaramella 2006

Abstract – University of New Orleans, New Orleans, Louisiana, USA.

Implications of timing of maternal depressive symptoms for early cognitive and language development.

Statistically, women, particularly pregnant women and new mothers, are at heightened risk for depression.

The present review describes the current state of the research linking maternal depressed mood and children’s cognitive and language development.

Exposure to maternal depressive symptoms,

whether during the prenatal period, postpartum period, or chronically, has been found to increase children’s risk for later cognitive and language difficulties.

The present review considers both the timing of maternal depression and the chronicity of mothers’ depression on children’s risk for cognitive and language delays. Infancy is frequently identified as a sensitive period in which environmental stimulation has the potential to substantially influence children’s cognitive and language development. However, children’s exposure to chronic maternal depression seems to be associated with more problematic outcomes for children, perhaps because depression interferes with mothers’ ability to respond sensitively and consistently over time.

Consistent with this expectation, interventions targeting parenting practices of depressed mothers have been found to increase children’s cognitive competence during early childhood. The current review provides a synthesis of the current state of the field regarding the association between maternal depression and children’s cognitive and language development during early childhood.

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Dubowitz et al 2001

Abstract – Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. hdubowitz@peds.umaryland.edu

Type and timing of mothers’ victimization: effects on mothers and children.

OBJECTIVES: There is mounting concern about how mothers’ own victimization experiences affect their children. This study examines the effects of mothers’ victimization on their own mental health and parenting and on their children’s behavior, development, and health. The effects of both timing and type of victimization are assessed. A related objective was to determine if there was a cumulative risk effect produced by victimization during both childhood and adulthood, or both physical and sexual. SETTING: Urban families in an eastern state and urban and rural families in a southern state. PARTICIPANTS: A total of 419 mothers and their children 6 to 7 years old were identified from 2 sites. The eastern sample was recruited in the first 2 years of life from 3 pediatric clinics: 1 for children at high risk for human immunodeficiency virus disease, 1 for children with failure to thrive, and a third providing pediatric primary care. The southern sample was derived from a cohort of children at risk for adverse health or developmental outcomes, plus a systematic sampling of controls, recruited from area hospitals. At age 4, a random sample of children from the original cohort who had been maltreated along with a matched comparison group of nonmaltreated children were selected.

RESULTS: In general, mothers victimized during both childhood and adulthood had poorer outcomes than mothers victimized during either childhood/adolescence or adulthood who in turn had worse outcomes than mothers with no history of victimization.

This manifested as more maternal depressive symptoms, harsher parenting, and more externalizing and internalizing behavior problems in their children.

There were no significant differences in maternal functioning or child outcomes between those abused in childhood and those abused in adulthood. These findings were similar for type of victimization. Mothers’ depression and harsh parenting were directly associated with their children’s internalizing and externalizing behavior problems.

CONCLUSIONS: Maternal victimization appears to be a highly prevalent problem in high-risk samples and is associated with harmful implications for mental health and parenting, as well as for the offspring.

Pediatricians need to consider past and current victimization of mothers. Routine screening for these problems, followed by appropriate evaluation and intervention may reduce maternal depression, improve parenting, and reduce the incidence of behavior problems in children.

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Caspi et al 2002

Abstract – UK  – violence

Large sample of male children studied from birth to adulthood to determine why some children who are maltreated grow up to develop antisocial behavior and others not

… “A functional polymorphism in the gene encoding the neurotransmitter-metabolizing enzyme monoamine oxidase A (MAOA) was found to moderate the effect of maltreatment.

Maltreated children with a genotype conferring high levels of MAOA expression were less likely to develop antisocial problems.

These findings may partly explain why not all victims of maltreatment grow up to victimize others, and they provide epidemiological evidence that genotypes can moderate children’s sensitivity to environmental insults.”

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Rosenberg et al 2006

Abstract – Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel. rozenber@tx.technion.ac.il

The association of DNA sequence variation at the MAOA genetic locus with quantitative behavioural traits in normal males.

Monoamine oxidase A (MAOA)

catalyses the oxidative deamination of biogenic amines including neurotransmitters,

mainly norepinephrine and serotonin in the brain and peripheral tissues.

A nonsense mutation in the gene was shown to be involved in a rare X-linked behavioural syndrome, which includes impaired impulse control, aggression and borderline mental retardation (Brunner syndrome).

Several recent studies have shown the association of genetic variation

of a VNTR in the gene promoter with various pathological behavioral traits.

In the present study the association of MAOA genetic variation with a large set of quantitative behavioral traits in normal individuals has been examined

DNA samples from 421 unrelated males were genotyped for 14 SNPs and for the promoter VNTR at the MAOA locus. An additional 16 SNPs were genotyped at apparently neutral loci across the X chromosome to serve as a genomic control for possible false positive associations due to population structure. Behavioral traits were measured using the NEO psychometric questionnaire, which is based on a 5-axis model of personality, and consists of 30 different quantitative traits

There was a robust association of the A2 (“straightforwardness”)

facet with common allelic variants at the promoter VNTR.

Most of the tested traits were not associated with the VNTR despite reasonable power, thus demonstrating that the VNTR influence on quantitative behavioral traits in normal males may be very specific

In contrast, several traits of the C

(“conscientiousness”)

axis were associated with less common SNP-defined haplotypes.

Hence, it appears that common genetic variation at the VNTR contributes to the behavioral attribute of

“straightforwardness”,

while rare haplotypes defined by SNPs downstream of the transcription start site may contribute to

“conscientiousness”.

This study is used to address the validation, interpretation and limitation of genetic association studies of quantitative behavioral traits.

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Huizinga et al 2006

Abstract – Institute of Behavioral Science, University of Colorado, Boulder, 80303, USA. huizinga@colorado.edu

Childhood maltreatment, subsequent antisocial behavior, and the role of monoamine oxidase A genotype.

A functional promoter polymorphism in monoamine oxidase A (MAOA) has been implicated as a moderating factor in the relationship between childhood maltreatment and later adolescent and adult antisocial behavior.

Despite wide interest in this hypothesis, results remain mixed from the few attempts at replication. METHODS: Regression-based analyses were conducted to test for a genotype-environment interaction using self-reported physical abuse and MAOA genotype to predict later antisocial behavior and arrests for violence by participants in the National Youth Survey Family Study. We also examined the interaction using a measure of violent victimization. The analysis sample included 277 Caucasian male respondents, aged 11-15 in 1976, who provided buccal swab DNA samples and who were successfully genotyped for the variable number tandem repeat (VNTR) in the MAOA promoter using polymerase chain reaction.

RESULTS: Maltreatment by a parent during adolescence was a risk factor for adolescent and adult antisocial and violence related behavioral problems.

Tests for the main effect of MAOA and a MAOA-maltreatment interaction were nonsignificant.

Similar results were obtained using the measure of adolescent violent victimization. CONCLUSIONS: Findings from this general population sample could not confirm the hypothesis that MAOA moderates the relationship between adolescent maltreatment and adolescent or adult antisocial behavior.

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Kim-Cohen et al 2006

Abstract – Department of Psychology, Yale University, New Haven, CT 06520, USA. julia.kim-cohen@yale.edu

MAOA, maltreatment, and gene-environment interaction predicting children’s mental health: new evidence and a meta-analysis.

Previous research on adults has shown that a functional polymorphism in the promoter region of the monoamine oxidase A (MAOA) gene moderates the impact of childhood maltreatment on risk for developing antisocial behavior.

Thus far, attempts to replicate this finding have been mixed. The current study (i) presents new data investigating this finding in a sample of 975 seven-year-old boys, and (ii) evaluates the extant data by conducting a meta-analysis of published findings.

We replicated the original finding by showing that the MAOA polymorphism moderates the development of psychopathology after exposure to physical abuse, we extended the finding to childhood closer in time to the maltreatment experience, and we ruled-out the possibility of a spurious finding by accounting for passive and evocative gene-environment correlation.

Moreover, meta-analysis demonstrated that across studies, the association between maltreatment and mental health problems is significantly stronger in the group of males with the genotype conferring low vs high MAOA activity.

These findings provide the strongest evidence to date suggesting that the MAOA gene influences

vulnerability to environmental stress, and that

this biological process can be initiated early in life

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Craig 2005

Abstract – Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, P082, De Crespigny Park, London, UK.

The role of monoamine oxidase A, MAOA, in the aetiology of antisocial behaviour: the importance of gene-environment interactions.

Reports from both human studies and animal models suggest that MAOA may have a key role in aggression.

Differences in the copy number of a repeat motif in the promoter of MAOA appear to regulate its activity.

We review the evidence that suggests activity levels of this enzyme may play a key role in modulating antisocial/aggressive behavioral outcomes.

Two common alleles in the human population have been identified which confer either high or low transcriptional functionality. The gene is X-linked and males can, therefore, be typed as ‘low’ or ‘high’ types.

A key feature that has emerged from both our own studies and replicated recently by others, is that high activity variants of the gene appear to confer a protective influence against maltreatment, such that maltreated males with a high-MAOA activity genotype were less likely to develop antisocial problems, an observation that may explain part of the variability in developmental outcomes associated with maltreatment.

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Widom & Brzustowicz 2006

Abstract – Department of Psychiatry, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, 07103, USA. widomca@umdnj.edu

MAOA and the “cycle of violence:” childhood abuse and neglect, MAOA genotype, and risk for violent and antisocial behavior.

Two recent studies with white males have shown that genotypes associated with high levels of monamine oxidase A (MAOA) protect against the impact of childhood maltreatment and adversity on the development of antisocial behavior and conduct disorder. METHODS: Participants in a prospective cohort design study involving court substantiated cases of child abuse and neglect and a matched comparison group were followed up into adulthood and interviewed (N = 802). Eighty-two percent consented to provide blood and 631 gave permission for DNA extraction and analyses. A composite index of violent and antisocial behavior (VASB) was created based on arrest, self-report, and diagnostic information.

RESULTS: No main effect was found for the relationship between MAOA genotype and VASB. Genotypes associated with high levels of MAOA activity buffered abused and neglected whites from increased risk of becoming violent and/or antisocial in later life.

This protective effect was not found for non-white abused and neglected individuals.

CONCLUSIONS: Possible explanations for this differential effect for whites and non-whites include differences in contextual factors (e.g., environmental stressors) and a question of the suitability of using the MAOA promoter VNTR polymorphism as a proxy for MAOA levels in non-white populations.

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Brunner 1996

Abstract – Department of Human Genetics, Nijmegen University Hospital, The Netherlands.

MAOA deficiency and abnormal behaviour: perspectives on an association.

We have recently described an association between abnormal behavior and monoamine oxidase A (MAOA) deficiency in several males from a single large Dutch kindred.

Affected males differed from unaffected males by borderline mental retardation and increased impulsive behavior (aggressive behavior, abnormal sexual behavior and arson). Nevertheless, a specific psychiatric diagnosis was not made in four affected males who had psychiatric examination.

Since MAOA deficiency raises 5-hydroxytryptamine (5-HT) levels, it provides an interesting exception to the low 5-HT paradigm of impulsive aggression.

Even if the possible relationship between MAOA deficiency and abnormal behavior is confirmed in other kindreds, the data do not support the hypothesis that MAOA constitutes an “aggression gene’. In fact, because genes are essentially simple and behavior is by definition complex, a direct causal relationship between a single gene and a specific behavior is highly unlikely. In the case of MAOA deficiency, some of the complexities are illustrated by the variability in the behavioural phenotype, as well as by the highly complex effects of MAOA deficiency on neurotransmitter function. Thus, the concept of a gene that directly encodes behavior is unrealistic.

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Craig 2007

Abstract – Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London PO82, De Crespigny Park, London SE5 8AF, UK. i.craig@iop.kcl.ac.uk

The importance of stress and genetic variation in human aggression.

Both genetic and environmental factors have key roles in determining aggressive tendencies. In particular, reaction to stress appears to be an important factor in precipitating aggressive episodes and individuals may vary in their ability to cope with stressful environments depending on their genetic make up.

Evidence from humans and primates indicates that

adverse rearing conditions may interact with variants in stress and neurotransmitter pathway genes leading to antisocial and/or violent behavior.

Common alleles of some serotonin pathway genes,

including those involved in its degradation

(monoamine oxidase A, MAOA),

or its re-uptake into pre-synaptic neurones

(serotonin transporter, SERT)

have been shown to confer functional variation.

Examination of the interaction between the alleles of such polymorphisms (in particular those affecting MAOA) and environmental stressors suggest that they may provide protection against, or increase sensitivity to, abusive upbringing; an observation that may explain part of the variability in developmental outcomes associated with maltreatment.

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Popova, Naumenko & Pliusina 2006

Abstract – Article in Russian

[The involvement of brain 5-HT(1A)-receptors in genetically determined aggressive behavior]

The hypothesis was tested that one of the critical mechanisms underlying genetically determined aggressiveness involves brain serotonin 5-HT(1A)-receptors.

The expression of 5-HT(1A)-receptor mRNA in brain structures and functional correlate for 5-HT(1A)-receptors identified as 8-OH-DPAT-induced hypothermia were studied in Norway rats bred over the course of 59 generations for the low and high affective (defensive) aggressiveness with respect to man and in MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (Tg8 strain). Considerable differences between the aggressive and the nonaggressive animals were shown.

Agonist of 5-HT(1A)-receptor 8-OH-DPAT (0.5 mg/kg for rats and 2.0 mg/kg for mice, i.p.) produced a distinct hypothermic reaction in nonaggressive rats and mice and did not affect significantly the body temperature in aggressive animals.

In aggressive rats, a significant reduction of the expression of 5-HT(1A)-receptor mRNA was found in the midbrain. In highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (Tg8 strain mice, 5-HT(1A)-receptor mRNA level was increased in the frontal cortex and amygdala and not changed in the hypothalamus and the midbrain. The results provide support for the idea that brain 5-HT(1A)-receptors contribute to the genetically determined individual differences in aggressiveness.

Does this mean that in some way antidepressants that work to increase the functioning of serotonin in brain are actually moving us, like a sliding volume control, closer toward aggression?  Only we are normally so nonaggressive that we don’t even notice it this way?

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Popova 2006

Abstract – Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia. npopova@bionet.nsc.ru

From genes to aggressive behavior: the role of serotonergic system.

Recent investigations in neurogenomics have opened up new lines of research into a crucial genetic problem-the pathway from genes to behavior.

This paper concentrates on the involvement of protein elements in the brain neurotransmitter serotonin (5-HT) system in the genetic control of aggressive behavior.

Specifically, it describes:

(1) the effect of the knockout of MAO A, the principal enzyme in 5-HT degradation,

(2) the association of intermale aggression with the polymorphism in the Tph2 gene encoding the key enzyme in 5-HT synthesis in the brain, tryptophan hydroxylase (TPH), and [which I would think is operating on the aggression mechanisms in part by regulating the release of vasopressin]

(3) the effect of selective breeding for nonaggressive behavior on 5-HT metabolism, TPH activity and 5-HT(1A) receptors in the brain.

The review provides converging lines of evidence that:

(1) brain 5-HT contributes to a critical mechanism underlying genetically defined individual differences in aggressiveness, and

(2) genes encoding pivotal enzymes in 5-HT metabolism

(TPH tryptophan hydroxylase and MAO A), 5-HT-transporter, 5-HT(1A) and 5-HT(1B) receptors belong to a group of genes that modulate aggressive behavior.

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Popova, Naumenko & Plyusina 2007

Abstract – Behavioral Neurogenetics Laboratory, Institute of Cytology and Genetics, Siberian Division, Russian Academy of Sciences, Novosibirsk. npopova@bionet.nsc.ru

Involvement of brain serotonin 5-HT1A receptors in genetic predisposition to aggressive behavior.

Experiments were performed on Norwegian rats selected over more than 59 generations for high and low levels of high-affective defensive aggressivity and on highly aggressive (offensive) Tg8 mice with irreversible monoamine oxidase A knockout.

There were significant differences in the functional state and expression of 5-HT(1A) receptors between highly aggressive and non-aggressive animals.

Functional activity assessed in terms of hypothermia [I’m unclear on how the measurement of hypothermia reflects aggression – I think hypothermia is in part regulated by the endocannabinoid system] evoked by a 5-HT(1A) agonist was significantly greater in non-aggressive rats and mice than in aggressive animals.

The high level of functional activity in non-aggressive rats coincided with a greater level of expression of 5-HT(1A) receptors in the midbrain.

The level of 5-HT(1A) receptor mRNA in aggressive mice was unchanged in the midbrain and hypothalamus and was increased in the frontal cortex and amygdaloid complex. These results led to the conclusion that 5-HT(1A) receptors play a significant role in the mechanisms of genetic predisposition to aggressive behavior.

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I would logically suppose that if levels regulated by the MAO A gene polymorphisms affect aggression, that they must be linked to the expression of vasopressin and oxytocin.  The following, though complicated, is an affirmation of my suspicions.  It would be reasonable, I would also suspect, to suspect that all of these interactions moderated by changes in the serotonin genes, would also be implicated with interactions with child abuse and violence.

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Alia-Klein et al 2008

Abstract – Medical Department, Brookhaven National Laboratory, Upton, New York 11973, USA. nellyklein@bnl.gov

Brain monoamine oxidase A activity predicts trait aggression.

The genetic deletion of monoamine oxidase A (MAO A),

an enzyme that breaks down the monoamine neurotransmitters norepinephrine, serotonin, and dopamine, [and tyramine]

produces aggressive phenotypes across species.

OK, so it breaks down all of the Big 3 plus tyramine, whatever that is!

Therefore, a common polymorphism in the MAO A gene (MAOA, Mendelian Inheritance in Men database number 309850, referred to as high or low based on transcription in non-neuronal cells) has been investigated in a number of externalizing behavioral and clinical phenotypes.

These studies provide evidence linking the low MAOA genotype and violent behavior

but only through interaction with

severe environmental stressors during childhood.

Here, we hypothesized that in healthy adult males the gene product of MAO A in the brain, rather than the gene per se, would be associated with regulating the concentration of brain amines involved in trait aggression.

Brain MAO A activity was measured in vivo in healthy nonsmoking men with positron emission tomography using a radioligand specific for MAO A (clorgyline labeled with carbon 11). Trait aggression was measured with the multidimensional personality questionnaire (MPQ).

Here we report for the first time that brain MAO A correlates inversely with the MPQ trait measure of aggression (but not with other personality traits) such that the lower the MAO A activity in cortical and subcortical brain regions, the higher the self-reported aggression (in both MAOA genotype groups) contributing to more than

one-third of the variability.

Because trait aggression is a measure used to predict antisocial behavior, these results underscore the relevance of MAO A as a neurochemical substrate of aberrant aggression.

One must consider aberrant aggression in light of survival – in earlier times, male aggression meant the survival of the species and without it we would likely not have made it thus far.  Thus malevolent versus benevolent contextual factors are related to how we perceive the nature of the aggression links.  That it is so moderated by early abuse ties its manifestations directly to the body preparing itself for a future in which there is likely to be a very great need for this increase in aggression for survival’s sake.

A “division of labor” among humans also probably meant that those highest in aggressive potential would do their thing, while still allowing those of us lower in aggression to excel at what we needed to do – to pay attention to the smaller detailed needs of our environment.  Hence, we did not ALL have to have high aggression – and perhaps in times of need those of us able to function well in the micro environment might have contributed what was needed for the species to survive under differing conditions.  Our genes allowed a wide range of abilities to endure – as well as opportunities along this spectrum to excel in one direction or the other as needed.

This aggression continuum was not necessarily always related to dominance within group, either.  Here is another context where high and low trait anxiety is not the appropriate one for consideration of assets within a tribe or within our species.  I mean, how aggressive would one need to be in order to detect, find, remember all the details around harvesting particular plants for food or medicine?

Remember the looming and fluttering analogy.  Subtle versus not so subtle.

See below where they refer to MAO A alterations as altered phenotypes – reverse true whether high or low – aggression and placidity variables?  So, we smoke to become more like the Big Bad Guys?

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Fowler et al 2007

Abstract – Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA. fowler@bnl.gov

Evidence that brain MAO A activity does not correspond to MAO A genotype in healthy male subjects.

A functional polymorphism in the promoter region of the monoamine oxidase A (MAO A) gene has two common alleles that are referred to as the high and low MAO A genotypes.

We report the first in vivo human study to determine whether there is an association between MAO A genotype and brain MAO A activity in healthy male subjects. METHODS: Brain MAO A activity was measured with positron emission tomography and [(11)C]clorgyline in 38 healthy adult male nonsmokers genotyped for MAO A polymorphism.

RESULTS: There was no significant difference in brain MAO A activity between the high (n = 26) and low (n = 12) MAO A genotypes.

CONCLUSIONS: The lack of an association between the high and low MAO A genotype and brain MAO A activity suggests that this polymorphism by itself does not contribute to differences in brain MAO A activity in healthy adult male subjects.

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Alia-Klein et al 2008b

Abstract – Medical Department, Brookhaven National Laboratory, Upton, New York, 11973, United States.

The MAO-A genotype does not modulate resting brain metabolism in adults.

Variation in the monoamine-oxidase-A (MAO-A) gene

has been associated with volumetric changes

in corticolimbic regions

with differences in their response

to relevant emotional tasks.

Here we show no changes in baseline regional brain metabolism as a function of genotype indicating that, unchallenged, corticolimbic activity is not modulated by the MAO-A genotype.

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Chen et al 2007b

Abstract – Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90089, USA.

Forebrain-specific expression of monoamine oxidase A reduces neurotransmitter levels, restores the brain structure, and rescues aggressive behavior in monoamine oxidase A-deficient mice.

Previous studies have established that abrogation of

monoamine oxidase (MAO) A expression

leads to a neurochemical, morphological, and behavioral specific phenotype

with increased levels of serotonin (5-HT), norepinephrine, and dopamine, loss of barrel field structure in mouse somatosensory cortex, and an association with increased aggression in adults.

Forebrain-specific MAO A transgenic mice were generated from MAO A knock-out (KO) mice by using the promoter of calcium-dependent kinase IIalpha (CaMKIIalpha). The presence of human MAO A transgene and its expression were verified by PCR of genomic DNA and reverse transcription-PCR of mRNA and Western blot, respectively.

Significant MAO A catalytic activity, autoradiographic labeling of 5-HT, and immunocytochemistry of MAO A were found in the frontal cortex, striatum, and hippocampus but not in the cerebellum of the forebrain transgenic mice.

Also, compared with MAO A KO mice, lower levels of 5-HT, norepinephrine, and DA and higher levels of MAO A metabolite 5-hydroxyindoleacetic acid were found in the forebrain regions but not in the cerebellum of the transgenic mice.

These results suggest that MAO A is specifically expressed in the forebrain regions of transgenic mice.

This forebrain-specific differential expression resulted in abrogation of the aggressive phenotype.

Furthermore, the disorganization of the somatosensory cortex [would this be where our sensitivities are tending to manifest?  Disorganization meaning what?] barrel field structure associated with MAO A KO mice was restored and became morphologically similar to wild type. Thus, the

lack of MAO A in the forebrain of MAO A KO mice may underlie their phenotypes.

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Owesson et al 2002

Abstract – Neurotransmission Laboratory, Academic Department of Anaesthesia and Intensive Care, Barts and The London School of Medicine and Dentistry, Alexandra Wing, Royal London Hospital, Whitechapel, London E1 1BB, UK.

Altered presynaptic function in monoaminergic neurons of monoamine oxidase-A knockout mice.

Monoamine oxidase-A knockout (MAO-A KO) mice have

elevated brain serotonin (5-HT) and noradrenaline (NA) levels,

and one would therefore anticipate increased monoamine release and compensatory changes in other aspects of presynaptic monoamine function. In this study we used voltammetry in brain slices from the locus coeruleus (LC), dorsal raphe (DRN) and striatum (CPu) in 7-week-old MAO-A KO and C3H control mice to measure stimulated monoamine efflux and its control by amine transporters and autoreceptors. In LC, peak NA efflux on stimulation (99 pulses, 100 Hz) was higher in MAO-A KO than C3H mice (938 +/- 58 nm cf. 511 +/- 42 nm; P < 0.001). The NA uptake half time (t(1/2)) was longer in MAO-A KO than in C3H mice (6.0 +/- 0.9 s cf. 1.9 +/- 0.3 s; P < 0.001) and the selective NA reuptake inhibitor desipramine (50 nm) had a smaller effect in MAO-A KO mice. NA transporter binding was significantly lower in the LC of MAO-A KO mice compared to C3H controls (P < 0.01) but not in the DRN. The alpha 2 agonist dexmedetomidine (10 nm) decreased stimulated NA efflux more in C3H than in MAO-A KO mice (73.3% cf. 29.6% inhibition, P < 0.001). In DRN, peak 5-HT efflux on stimulation (99 pulses, 100 Hz) was greater (P < 0.01) in MAO-A KO (262 +/- 44 nm) than C3H mice (157 +/- 16 nm). Moreover, 5-HT uptake t(1/2) was longer (P < 0.05) in MAO-A KO than in C3H mice (8.8 +/- 1.1 s cf. 4.9 +/- 0.6 s, P < 0.05) and the effect of citalopram (75 nm) was attenuated in MAO-A KOs. Serotonin transporter binding was also lower in both the DRN and LC of MAO-A KO mice. The 5-HT(1A) agonist 8-OH-DPAT (1 microm) decreased 5-HT efflux more in C3H than in MAO-A KO mice (38.3% inhibition cf. 21.6%, P < 0.001). In contrast, there were no significant differences between MAO-A KO and C3H mice in CPu dopamine efflux and uptake and the effect of the D(2/3) agonist quinpirole was similar in the two strains. In summary,

MAO-A KO mice show major dysregulation

of monoaminergic presynaptic mechanisms

such as autoreceptor control and transporter kinetics.

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Evrard et al 2002

Abstract – INSERM U288, Neuropsychopharmacologie Moléculaire, Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, 91 Boulevard de l’Hôpital, 75634 Paris Cedex 13, France. evrard@ext.jussieu.fr

Altered regulation of the 5-HT system in the brain of MAO-A knock-out mice

Genetic deficiency of monoamine oxidase-A (MAO-A)

induces major alterations of mood and behavior in human.

Because serotonin (5-HT) is involved in mood regulation, and MAO-A is responsible for the catabolism of 5-HT, we investigated 5-HT mechanisms in knock-out mice (2-month-old) lacking MAO-A, using microdialysis, electrophysiological, autoradiographic and molecular biology approaches.

Compared to paired wild-type mice, basal extracellular 5-HT levels were increased in ventral hippocampus (+202%), frontal cortex (+96%) and dorsal raphe nucleus (DRN, +147%) of MAO-A mutant mice.

Conversely, spontaneous firing rate of 5-HT neurons in the DRN (recorded under chloral hydrate anaesthesia) was approximately 40% lower in mutants.

Acute 5-HT reuptake blockade by citalopram (0.2 and 0.8 mg/kg i.v.) produced a much larger increase in extracellular 5-HT levels (by approximately 4 fold) and decrease in DRN neuronal firing (with a approximately 4.5 fold decrease in the drug’s ED50) in MAO-A knock-out mice, which expressed lower levels of the 5-HT transporter throughout the brain (-13 to -34% compared to wild-type levels). The potency of the 5-HT1A agonist 8-OH-DPAT to produce hypothermia and to reduce the firing of DRN serotoninergic neurons was significantly less in the mutants, indicating a desensitization of 5-HT1A autoreceptors.

This was associated with a decreased autoradiographic labeling of these receptors (-27%) in the DRN. Altogether, these data indicate that,

in MAO-A knock-out mice,

the enhancement of extracellular 5-HT levels

induces a down-regulation of the 5-HT transporter,

and a desensitization of 5-HT1A autoreceptors

which allows the maintenance of tonic activity of 5-HT neurons in the

dorsal raphe nucleus (DRN).

And this condition would lead to increased aggressive tendencies?  Does a reverse of this provide a “greased wheel” for tendency toward feeling low self esteem?  Is the reduction of MAO A as a genetic interacting factor with child abuse geared directly to the body taking over competency of active coping abilities in a hostile world?  Aggression versus passivity.

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Popova et al 2001

Abstract – Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia. npopova@bionet.nsc.ru

Regional serotonin metabolism in the brain of transgenic mice lacking monoamine oxidase A.

The effect of a lack of the gene encoding monoamine oxidase A (MAO A) in transgenic highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (Tg8 strain mice on the activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin (5-HT) biosynthesis, and on the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in the midbrain, hypothalamus, hippocampus, striatum, amygdala, and frontal cortex was studied. It was shown that mice with a genetic MAO A knockout

differed from mice of the initial C3H/HeJ strain in having a

higher level of 5-HT and a lower level of its metabolite, 5-HIAA,

in all brain regions but the frontal cortex,

where the changes were insignificant.

Although the 5-HIAA/5-HT ratio in various brain regions differed considerably, the decrease of the 5-HT oxidative deamination index in highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (Tg8 strain mice was similar in different brain regions (to 41-45% of control values), with the exception of the frontal cortex, where the decrease of the 5-HIAA/5-HT was somewhat smaller (to 54%). The presence of the remaining 45% +/- 1.9% of the control ratio value

indicates rather effective oxidative deamination of 5-HT in

MAO A knockout mice

and explains the lack of severe behavioral and pathological consequences in MAO A genetic deficiency.

Does this mean, when there is NOT an interaction with severe abuse in childhood – normally there would not be a severe behavioral and pathological consequence?  So the abuse might somehow interfere with this normally occurring effective oxidative deamination of 5-HT, whatever that means?

So the serotonin levels, though they differ, are being proportionately processed in a balanced way – like normal (when no abuse)?

An increase of TPH activity in mice lacking MAO A was found in the frontal cortex, hippocampus, and amygdala. No significant changes were found in the striatum, hypothalamus, and midbrain.

The data show an effect of the MAO A gene mutation on TPH and indicate a uniform decrease of 5-HT catabolism in different brain regions except for the frontal cortex, which is somewhat more resistant to the lack of MAO A than other brain structures.

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Kier, Han & Jacobson 2005

Abstract – Center for Neuropharmacology and Neuroscience, MS 501E, Albany Medical College, Mail Code 136, Albany, New York 12208, USA.

Chronic treatment with the monoamine oxidase inhibitor phenelzine increases hypothalamic-pituitary-adrenocortical activity in male C57BL/6 mice: relevance to atypical depression.

Atypical depression

has been linked to

low hypothalamic-pituitary-adrenocortical axis activity and exhibits physical and affective symptoms

resembling those of glucocorticoid deficiency.

Because atypical depression has also been defined by preferential responsiveness to monoamine oxidase inhibitors (MAO-I), we hypothesized that MAO-I reverse these abnormalities by interfering with glucocorticoid feedback and increasing hypothalamic-pituitary-adrenocortical activity. To test this hypothesis, we measured plasma hormones and ACTH secretagogue gene expression in male C57BL/6 mice treated chronically with saline vehicle or phenelzine, a representative MAO-I. Changes in glucocorticoid feedback were evaluated using adrenalectomized (ADX) mice with and without corticosterone replacement. Antidepressant efficacy was confirmed by decreased immobility during forced swim testing. Phenelzine significantly increased circadian nadir and postrestraint plasma corticosterone levels in sham-operated mice, an effect that correlated with increased adrenocortical sensitivity to ACTH. Phenelzine increased circadian nadir, but not poststress ACTH in ADX mice, suggesting that phenelzine augmented corticosterone secretion in sham-operated mice by increasing stimulation and decreasing feedback inhibition of hypothalamic-pituitary activity. Consistent with the latter possibility, phenelzine significantly increased plasma ACTH and paraventricular hypothalamus CRH mRNA in ADX, corticosterone-replaced mice. Phenelzine did not increase paraventricular hypothalamus CRH or vasopressin mRNA in ADX mice lacking corticosterone replacement. We conclude that chronic phenelzine treatment induces sustained increases in glucocorticoids by impairing glucocorticoid feedback, increasing adrenocortical responsiveness to ACTH, and increasing glucocorticoid-independent stimulation of hypothalamic-pituitary activity.

The resulting drive for adrenocortical activity could account for the ability of MAO-I to reverse endocrine and psychiatric symptoms of glucocorticoid deficiency in atypical depression.

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links between MAO-A and vasopressin and oxytocin – related to aggression

Vacher et al 2003

Abstract – Laboratoire de Neurobiologie des Signaux Intercellulaires, CNRS UMR 7101, Université Pierre et Marie Curie, Paris, France. Claire-Marie.Vacher@snv.jussieu.fr

Monoaminergic control of vasopressin and VIP expression in the mouse suprachiasmatic nucleus.

We studied the effects of serotonin and noradrenaline

on the expression of arginine-vasopressin (AVP)

and vasoactive intestinal peptide (VIP) in the suprachiasmatic nucleus (SCN).

We used transgenic highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (Tg8 strain mice knockout for the MAO-A (monoamine oxidase A) gene, which are characterized by increased amounts of serotonin and noradrenaline in brain compared to wild-type mice (C3H).

The MAO-A deficiency

caused an increase in AVP and VIP expression

I believe increased vasopressin is directly tied to increased aggression

(determined by immunohistochemistry, enzyme immunoassay, and in situ hybridization) compared to C3H mice. The number of peptidergic neurons was also increased.

Inhibiting serotonin or noradrenaline synthesis in highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (Tg8 strain mice by the administration of parachlorophenylalanine or alpha-methylparatyrosine, respectively, the amounts of AVP, VIP and their mRNAs were decreased, but not the number of peptidergic neurons.

This study indicates that serotonin and noradrenaline stimulate AVP and VIP expression, and could participate in the differentiation of the neurochemical phenotype in the mouse SCN.

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Vacher et al 2004

Abstract – Laboratoire de Neurobiologie des Signaux Intercellulaires, UMR CNRS 7101, Université Pierre et Marie Curie, 75252 Paris cedex 05, France. Claire-Marie.Vacher@unibas.ch

Postnatal regulation by monoamines of vasopressin expression in the neuroendocrine hypothalamus of MAO-A-deficient mice.

We studied the influence of noradrenaline (NA) and serotonin (5-HT) on arginine-vasopressin (AVP) expression in the mouse neuroendocrine hypothalamus during the postnatal period.

We used 11-day-old transgenic highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (Tg8 strain mice knock-out for the monoamine oxidase A gene, which are characterized by increased amounts of NA (two-fold) and 5-HT (nine-fold) in the brain compared with wild-type littermates.

AVP expression, determined by enzyme immunoassay and in situ hybridization, was increased in the suprachiasmatic nucleus (SCN), decreased in the supraoptic nucleus (SON), and unchanged in the paraventricular nucleus of highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (Tg8 strain mice compared with wild-types.

Inhibiting NA synthesis by injecting alpha-methylparatyrosine to highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (Tg8 strain mice, AVP levels were decreased in the SCN but increased in the SON. Moreover, the administration of parachlorophenylalanine, a 5-HT synthesis inhibitor, was associated with increased AVP contents in the SCN only.

these data show a marked region-specific sensitivity

of AVP expression to NA and 5-HT during the postnatal period

in the mouse

hypothalamus.

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Vacher et al 2002

Abstract – Laboratory of Neurobiology of Intercellular Signals, Unité Mixte de Recherche 7101, Centre National de la Recherche Scientifique, Pierre and Marie Curie University, 75252 Paris Cedex 05, France. Claire-Marie.Vacher@snv.jussieu.fr

Activation by serotonin and noradrenaline of vasopressin and oxytocin expression in the mouse paraventricular and supraoptic nuclei.

Noradrenaline and serotonin are known to control

arginine-vasopressin (AVP) and oxytocin (OT) secretion

in the systemic circulation.

The aim of the current study was to investigate whether these monoamines are also able to influence AVP and OT expression in the paraventricular (PVN) and supraoptic nuclei (SON). To test this hypothesis, we used the highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (Tg8 strain transgenic mice KO for the monoamine oxidase-A gene, which present high levels of noradrenaline and serotonin in the brain. AVP and OT expression were evaluated at peptide and mRNA levels by immunohistochemistry, enzyme immunoassay, and in situ hybridization. Compared with wild type, the amounts of AVP, OT, AVP mRNA, and OT mRNA were increased in the PVN and SON in highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (Tg8 strain mice. To distinguish the respective contributions of noradrenaline and serotonin to these modifications, we treated highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (Tg8 strain mice with a synthesis inhibitor of either catecholamines [alpha-methylparatyrosine (alpha-MPT)] or serotonin [parachlorophenylalanine (pCPA)].

Administration of alpha-MPT to highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (Tg8 strain mice induced a decline in the amounts of AVP, OT, and their mRNA in the PVN and SON. The pCPA treatment in highly aggressive (offensive) MAO A-knockout mice (highly aggressive (offensive) MAO A-knockout mice (Tg8 strain mice was also associated with a decrease in OT expression in the PVN and SON and in AVP expression in the PVN, but not in the SON. These results suggest that

noradrenaline may activate AVP and OT expression in the PVN and SON. Likewise,

serotonin is proposed to stimulate AVP and OT expression in the PVN and only OT expression in the SON.

More on vasopressin and oxytocin in other chapters

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Connected to this, it is interesting to see that MAO-A is connected to smoking.  Smokers get a reduction from smoking?  If higher levels are connected to less aggression, do lower levels give us more aggression from external sources?  How is nicotine reacting with which receptors? So it might make us feel more aggressive or be connected to a higher sense of being able to actively cope?  Does smoking give the timid more courage?

Fowler et al 1996

Abstract – Chemistry Department, Brookhaven National Laboratory, Upton, NY 11973-5000, USA. fowler@simbrain.chm.bnl.gov

Brain monoamine oxidase A inhibition in cigarette smokers.

Several studies have documented a strong association between smoking and depression. Because cigarette smoke has been reported to inhibit monoamine oxidase (MAO) A in vitro and in animals and because MAO A inhibitors are effective antidepressants, Hence giving us a closer link to aggression, less MAO A equally more serotonin and noradrenaline in the brain?  So we are self medicating with a form of an antidepressant?  Relate this also to the reduction in the sensitivity of the “gating response” to incoming stimuli, so that we screen it down – putting on the muscles and the sunglasses!  Neurochemically, no less!  This also puts sensitive youth who are depressed or not aggressive at higher risk for smoking in the first place, and makes it harder for those of us who are like this to quit later on.  We might be especially at risk in a culture that aims for the BIG – mostly in my book meaning the manufactured value of materialist objects – at a higher value than the sensitivities of the real person.

we tested the hypothesis that MAO A would be reduced in the brain of cigarette smokers. We compared brain MAO A in 15 nonsmokers and 16 current smokers with [11C]clorgyline and positron emission tomography (PET). Four of the nonsmokers were also treated with the antidepressant MAO inhibitor drug, tranylcypromine (10 mg/day for 3 days) after the baseline PET scan and then rescanned to assess the sensitivity of [11C]clorgyline binding to MAO inhibition. MAO A levels were quantified by using the model term lambda k3 which is a function of brain MAO A concentration.

Smokers had significantly lower brain MAO A than nonsmokers in all brain regions examined (average reduction, 28%). The mean lambda k3 values for the whole brain were 0.18 +/- 0.04 and 0.13 +/- 0.03 ccbrain (mlplasma)-1 min-1 for nonsmokers and smokers, respectively; P < 0.0003). Tranyl-cypromine treatment reduced lambda k3 by an average of 58% for the different brain regions.

Our results show that tobacco smoke exposure is associated with a marked reduction in brain MAO A, and this reduction is about half of that produced by a brief treatment with tranylcypromine.

This suggests that MAO A inhibition needs to be considered as a potential contributing variable in the high rate of smoking in depression and in the development of more effective strategies for smoking cessation.

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Fowler et al 2005

Abstract – Chemistry Department, Brookhaven National Laboratory, Upton, NY 11973, USA. fowler@bnl.gov

Comparison of monoamine oxidase a in peripheral organs in nonsmokers and smokers.

Smokers have reduced levels of brain monoamine oxidase A (MAO A) leading to speculation that MAO A inhibition by tobacco smoke may underlie some of the neurophysiologic effects of smoking.

I.e. its antidepressant effects.

Because smoking exposes peripheral organs as well as the brain to MAO A-inhibitory compounds, we determined whether smokers would also have reduced MAO A in peripheral organs. METHODS: We measured MAO A in peripheral organs in a group of 9 smokers and compared it with a group of nonsmokers studied previously. MAO A was measured using PET and serial scans with the MAO A-specific radiotracers (11)C-clorgyline and deuterium-substituted (11)C-clorgyline ((11)C-clorgyline-D2) using the deuterium isotope effect to assess binding specificity. The time course of radiotracer in the arterial plasma was also measured and data from the tissue time-activity curves and the arterial input function were analyzed using a 3-compartment model to estimate k(3), which represents the rate-limiting step for the irreversible binding of labeled clorgyline to MAO A. RESULTS: Tracer uptake at plateau was reduced with deuterium substitution for the heart, lungs, and kidneys, indicating specificity for MAO. There was no difference in organ uptake at plateau between nonsmokers and smokers though, for the smokers, the efflux of tracer from peak uptake to plateau was slower for the lungs. The area under the time-activity curve for the arterial plasma was also significantly reduced for smokers versus nonsmokers and the reduction occurred in the first few minutes after radiotracer injection. Smokers had an approximately 50% reduction in k(3) when compared with nonsmokers; however, k(3) did not differ for nonsmokers and smokers for the heart and the kidneys.

CONCLUSION: Because MAO A breaks down serotonin, norepinephrine, dopamine, and tyramine, and because the lung is a major metabolic organ in degrading some of these substances, reduced lung MAO A may contribute to some of the physiologic effects of smoking.

This study also revealed that the concentration of the radiotracers in the arterial plasma is significantly lower for the smoker versus the nonsmoker and that this appears to be caused in part by retention of the radiotracer in lungs. If this is generally true for other substances that are administered intravenously, then this needs to be considered as a variable that may contribute to different short-term behavioral responses to intravenously administered drugs for nonsmokers versus smokers.

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++++++++++++++++++++++++

I do not want this discussion of the impact and long term effects of severe abuse and neglect from birth, (or before) to be about the actual literal details of the experiences we lived through and endured.  This is not about my mother suffering a psychotic break while delivering me so that she thought the devil sent me to kill her through making me come into the world butt first.  It is not about the particulars of how she treated me with abhorrence and violence for the next 18 years because she was nuts and believed I was the devil’s child.

It is not about every screaming battering assault upon my tiny body, or the assaults upon that body that should have landed her in prison for no less than 15,000 years.  I will recount some of those “dramas” simply as the gravel layer underlying the pavement of the highway we are about to take our journey down.

What matters to me is the common ground that all of us who were so abused find ourselves walking upon as we attempt to live a “normal” life, or any life at all.  In learning about this common underlying layer of affect we can join our voices into a perfect single note that carries around the globe, through time, across individual experiences.  We can no more “put our childhoods behind us and get on with our lives” than we can flap our arms and fly.  Our bodies built themselves to include adaptations and adjustments to the literally toxic conditions our bodies were formed in and by from conception.  They changed how our genes operate and manifest.  The stress of trauma places an unbearable burden upon the body, and it will show itself.  There is a cost for such an allostatic load.  There is a price to pay.  It is far too late to wish it otherwise.

Imagine trying to build a house in the midst of a powerful earthquake, or trying to fly a fragile paper kite in the midst of hurricane winds and rain.  Our body, nervous system, brain, immune system, all had to continue building themselves under the horrible and horrifying conditions we were born into.  How could we NOT expect and anticipate that the expression of our genes would change?

One must remove the largest wreckage after a disaster to find the bodies, dead or alive, that might be buried there.  Moving past all the psycho-babble, the prescription recommendations, the popular attitudes about “mental illness” and psychiatric labeling, “dysfunctional behavior” and “codependency” down through the layers, into the body we each live in and with, lets us learn about the actual changes we had to make, the alternative pathways our bodies had to take in order to survive and endure the overwhelming impossible catastrophe that was many of our infanthood and childhood experience.

The mediating factor for all of the difficulties of our childhoods had to be “adequate social support.”  If that support was there for us from birth through relationships with early caregivers, the long term disastrous consequences of our abuse and neglect could have been moderated through these mediators.  If that support was not available, we were left in essence completely alone in a world we were in no way prepared to deal with – except with the options made available to us on the level of our genetic potential.  This is both on the level of the actual DNA contained within our genes, and on the level of the machinery and mechanisms that tell our DNA what to do, when and how.  The WHAT of our DNA means nothing without the HOW.

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Weinreb et al 2002

Abstract – Department of Family Medicine and Community Health. Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA. weinrebl@ummhc.org

OBJECTIVE: Hunger, with its adverse consequences for children, continues to be an important national problem. Previous studies that document the deleterious effects of hunger among children cannot distinguish child from family hunger and do not take into account some critical environmental, maternal, and child variables that may influence child outcomes. This study examines the independent contribution of child hunger on children’s physical and mental health and academic functioning, when controlling for a range of environmental, maternal, and child factors that have also been associated with poor outcomes among children. METHODS: With the use of standardized tools, comprehensive demographic, psychosocial, and health data were collected in Worcester, Massachusetts, from homeless and low-income housed mothers and their children (180 preschool-aged children and 228 school-aged children). Mothers and children were part of a larger unmatched case-control study of homelessness among female-headed households. Hunger was measured by a set of 7 dichotomous items, each asking the mother whether she has or her children have experienced a particular aspect of hunger during the past year–1 concerns food insecurity for the entire family, 2 concern adult hunger, and 4 involve child hunger. The items, taken from the Childhood Hunger Identification Project measure, are summed to classify the family and divided into 3 categories: no hunger, adult or moderate child hunger, or severe child hunger (indicating multiple signs of child hunger). Outcome measures included children’s chronic health condition count using questions adapted from the National Health Interview Survey, Child Health Supplement, and internalizing behavior problems and anxiety/depression, measured by the Child Behavior Checklist. Additional covariates included demographic variables (ie, age, gender, ethnicity, housing status, number of moves, family size, income), low birth weight, child life events (ie, care and protection order, out of home placement, abuse, severe life events count), developmental problems (ie, developmental delay, learning disability, emotional problems), and mother’s distress and psychiatric illness. Multivariate regression analyses examined the effect of child hunger on physical and mental health outcomes.

RESULTS: The average family size for both preschoolers and school-aged children was 3; about one third of both groups were white and 40% Puerto Rican. The average income of families was approximately $11 000. Among the school-aged children, on average 10 years old, 50% experienced moderate child hunger and 16% severe child hunger. Compared with those with no hunger, school-aged children with severe hunger were more likely to be homeless (56% vs 29%), have low birth weights (23% vs 6%), and have more stressful life events (9 vs 6) when compared with those with no hunger.

School-aged children with severe hunger scores had parent-reported anxiety scores that were more than double the scores for children with no hunger and significantly higher chronic illness counts (3.4 vs 1.8) and internalizing behavior problems when compared with children with no hunger.

There was no relationship between hunger and academic achievement.

Among preschool-aged children, who averaged 4 years of age, 51% experienced moderate child hunger and 8% severe child hunger. For preschoolers, compared with children with no hunger, severe hunger was associated with homelessness (75% vs 48%), more traumatic life events (8.5 vs 6), low birth weight (23% vs 6%), and higher levels of chronic illness and internalizing behavior problems.

Mothers of both preschoolers and school-aged children

who reported severe hunger

were more likely to have a lifetime diagnosis

of posttraumatic stress disorder.

For school-aged children, severe hunger was a significant predictor of chronic illness after controlling for housing status, mother’s distress, low birth weight, and child live events. For preschoolers, moderate hunger was a significant predictor of health conditions while controlling for potential explanatory factors. For both preschoolers and school-aged children, severe child hunger was associated with higher levels of internalizing behavior problems. After controlling for housing status, mother’s distress, and stressful life events, severe child hunger was also associated with higher reported anxiety/depression among school-aged children. CONCLUSION: This study goes beyond previous research and highlights the independent relationship between severe child hunger and adverse physical health and mental health outcomes among low-income children. Study findings underscore the importance of clinical recognition of child hunger and its outcomes, allowing for preventive interventions and efforts to increase access to food-related resources for families.

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Seckl 2008

Abstract – Endocrinology Unit, Centre for Cardiovascular Science, Queen’s Medical Research Institute, Edinburgh, UK. J.Seckl@ed.ac.uk

Early life environmental events have persisting effects on tissue structure and function, a phenomenon called ‘developmental programming’. Exposure to stress and its glucocorticoid hormone mediators may underpin many such effects. Indeed, studies in animal models and observations in humans suggest that prenatal stress/glucocorticoid overexposure causes permanent cardiometabolic, neuroendocrine and behavioural effects in offspring. Such effects appear mediated via tissue-specific changes in gene expression. Underlying epigenetic changes in target gene promoters may ensure persistence of altered transcription long after the initial challenge.

Posttraumatic stress disorder and other affective diseases may both act as environmental challenges if present in early life and may themselves be more likely in individuals made ‘vulnerable’ by early life stress.

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Meaney, Szyf & Seckl 2007

Abstract – McGill Program for Study of Genes, Environment and Health, McGill University, Montreal, Canada. michael.meaney@mcgill.ca

EPIGENETICS

Environmental effects on the materno-foetal interaction determine birth outcomes that predict health over the lifespan. Thus, maternal undernutrition or stress associate with low birth weight, leading to an increased risk of metabolic and cardiovascular illness in the offspring. We argue that these effects are, in part, mediated by direct and indirect effects on the hypothalamic-pituitary-adrenal (HPA) axis such that (i) the effect of maternal adversity on foetal growth is mediated by adrenal glucocorticoids and (ii) environmental adversity alters maternal physiology and behavior, which then programs HPA activity in the offspring.

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Zeh & Zeh 2008

Abstract – Department of Biology and Program in Ecology, Evolution and Conservation Biology, University of Nevada, Reno, NV, USA. jaz@unr.edu

Maternal inheritance, epigenetics and the evolution of polyandry.

Growing evidence indicates that females actively engage in polyandry either to avoid genetic incompatibility or to bias paternity in favor of genetically superior males.

Despite empirical support for the intrinsic male quality hypothesis, the maintenance of variation in male fitness remains a conundrum for traditional “good genes” models of sexual selection.

Here, we discuss two mechanisms of non-Mendelian inheritance, maternal inheritance of mitochondria and epigenetic regulation of gene expression, which may explain the persistence of variation in male fitness traits important in post-copulatory sexual selection.

The inability of males to transmit mitochondria

precludes any direct evolutionary response to selection

on mitochondrial mutations that reduce or enhance male fitness.

Consequently, mitochondrial-based variation in sperm traits is likely to persist, even in the face of intense sperm competition.

Indeed, mitochondrial nucleotide substitutions, deletions and insertions are now known to be a primary cause of low sperm count and poor sperm motility in humans.

Paradoxically, in the field of sexual selection, female-limited response to selection has been largely overlooked.

Similarly, the contribution of

epigenetics

(e.g., DNA methylation, histone modifications and non-coding RNAs)

to heritable variation in male fitness has received little attention from evolutionary theorists.

Unlike DNA sequence based variation,

epigenetic variation

can be strongly influenced

by environmental and stochastic effects

experienced during the lifetime of an individual.

Remarkably, in some cases, acquired

epigenetic

changes can be stably transmitted to offspring.

A recent study indicates that sperm exhibit particularly high levels of epigenetic variation both within and between individuals.

We suggest that such epigenetic variation may have important implications for post-copulatory sexual selection and may account for recent findings linking sperm competitive ability to offspring fitness.

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Kiefer 2007

Abstract – Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, Utah 84132, USA. jkiefer@neuro.utah.edu

It has become increasingly evident in recent years that

development is under epigenetic control.

Epigenetics is the study of heritable changes

in gene function that occur independently of alterations

to primary DNA sequence.

The best-studied epigenetic modifications are DNA methylation, and changes in chromatin structure by histone modifications, and histone exchange. An exciting, new chapter in the field is the finding that long-distance chromosomal interactions also modify gene expression.

Epigenetic modifications are key regulators of important developmental events, including X-inactivation, genomic imprinting, patterning by Hox genes and neuronal development. This primer covers these aspects of epigenetics in brief, and features an interview with two epigenetic scientists.

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Kubicek et al 2006

Abstract – Research Institute of Molecular Pathology, The Vienna Biocenter, Austria. kubicek@imp.univie.ac.at

Epigenetic mechanisms control eukaryotic [A single-celled or multicellular organism whose cells contain a distinct membrane-bound nucleus] development beyond DNA-stored information.

DNA methylation, histone modifications and variants, nucleosome remodeling and noncoding RNAs all contribute to the dynamic make-up of chromatin [mass of genetic material composed of DNA and proteins that condense to form chromosomes in eukaryotic cell division] under distinct developmental options.

In particular, the great diversity of covalent histone tail modifications has been proposed to be ideally suited for imparting epigenetic information. While most of the histone tail modifications represent transient marks at transcriptionally permissive chromatin, some modifications appear more robust at silent chromatin regions, where they index repressive epigenetic states with functions also outside transcriptional regulation. Under-representation of repressive histone marks could be indicative of epigenetic plasticity in stem, young and tumor cells, while committed and senescent (old) cells often display increased levels of these more stable modifications. Here, we discuss profiles of normal and aberrant histone lysine methylation patterns, as they occur during the transition of an embryonic to a differentiated cell or in controlled self-renewal vs pro-neoplastic or metastatic conditions. Elucidating these histone modification patterns promises to have important implications for novel advances in stem cell research, nuclear reprogramming and cancer, and may offer novel targets for the combat of tumor cells, potentially leading to new diagnostic and therapeutic avenues in human biology and disease.

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Feng, Fouse & Fan 2007

Abstract – Department of Human Genetics, David Geffen School of Medicine, University of California at Los Angeles, CA 90095, USA.

Epigenetic regulation of neural gene expression and neuronal function.

The development and function of the CNS requires accurate gene transcription control in response to proper environmental signals.

Epigenetic mechanisms, including DNA methylation, histone modifications, and other chromatin-remodeling events, are critically important in mediating precise neural gene regulation.

This review focuses on discussing the role of DNA methylation and histone modifications in neural lineage differentiation, synaptic plasticity and neural behavior.

We postulate that DNA methylation- and histone

modification-mediated gene regulation

is not only important for neural cell differentiation

but also crucial for high-order cognitive functions

such as learning and memory.

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Levenson & Sweatt 2006

Abstract – Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.

In this review we address the idea that

conservation of

epigenetic mechanisms for information storage

represents a unifying model in biology,

with epigenetic mechanisms being utilized for cellular memory at levels from behavioral memory

to development

to cellular differentiation.

Epigenetic mechanisms typically involve alterations

in chromatin structure,

which in turn regulate gene expression.

An emerging idea is that the

regulation of chromatin structure

through histone acetylation and DNA methylation

may mediate long-lasting behavioral change

in the context of learning and memory.

This sure has some implications regarding stress and trauma – learning and memory – like I’ve been saying, the body will not let go until it makes us if at all possible of every experience we have

We find this idea fascinating

because similar mechanisms are used for triggering and storing long-term ‘memory’ at the cellular level,

for example when cells differentiate.

An additional intriguing aspect of the

hypothesis of a role for epigenetic mechanisms

in information storage is that lifelong behavioral memory storage may involve lasting changes in the physical, three-dimensional structure of DNA itself.

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Again, it is nearly impossible to know at this point where to draw the line between topics of interest.  I want to put some of the epigenetic information in memory chapter, but epigenetics is not only about what happens “down the line,” but is also crucially important when looking at ontogeny.  EVERYTHING our body does to manifest DNA is about epigenetics, and epigenetics IS about memory.  It is about what our body deems necessary for survival one fraction of an instant to the next as we move through this stream that is our LIFE.

Do we only want to think about memory in terms of what our self, our “ego self” might be able to consciously recall?  I suspect that information is almost of mute importance to our existence.

So for the time being I will include epigenetics under childhood because, though happening long before we inhale and exhale our first breath, it is already operating to best prepare us for what lies ahead once we exit our mother’s womb.  In the end, epigenetics will probably need its own chapter….

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Miller & Sweatt 2007

abstract – Department of Neurobiology and the Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

DNA methylation is a covalent chemical modification of DNA catalyzed by DNA methyltransferases (DNMTs).

DNA methylation is associated with transcriptional silencing and has been studied extensively as a lifelong molecular information storage mechanism put in place during development.

Here we report that DNMT gene expression is upregulated in the adult rat hippocampus following contextual fear conditioning and that DNMT inhibition blocks memory formation.

In addition, fear conditioning is associated with rapid methylation and transcriptional silencing of the

memory suppressor gene PP1

and demethylation and transcriptional activation of the synaptic plasticity gene reelin,

indicating both methyltransferase and demethylase activity during consolidation.

DNMT inhibition prevents the PP1 methylation increase, resulting in aberrant transcription of the gene during the memory-consolidation period.

These results demonstrate that DNA methylation

is dynamically regulated in the adult nervous system

and that this cellular mechanism is a crucial step

in memory formation.

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Albalat 2008

Abstract – Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Av. Diagonal, 645, E-08028, Barcelona, Spain, ralbalat@ub.edu.

DNA methylation is an

epigenetic mark

associated with gene regulation and cell memory,

silencing of transposable elements,

genomic imprinting,

and repression of spurious transcription of duplicated sequences.

These roles have varied widely during animal evolution and

current functions depend on the specific methylation pattern of the species

under consideration.

The patterns of methylation are

established, maintained, and translated into

appropriate functional states

by the DNA-methylation machinery,

which includes three groups of methyltransferase enzymes,

Dnmt1,

Dnmt2 and

Dnmt3, and

five methyl-DNA binding proteins,

Mbd1, Mbd2, Mbd3, Mbd4, and MeCP2.

In this study, I have identified the members of the Dnmt and the Mbd gene families in the cephalochordate amphioxus (Branchiostoma floridae), the most basal extant chordate and one of the closest sister groups of vertebrates. Database searches, phylogenetic studies and protein domain analyses revealed the presence of the three major groups of Dnmt enzymes in the cephalochordate genome, whereas only two Mbd members, Mbd2/3 and Mbd4, were found. Analysis of the amphioxus methylation machinery suggested that the complexity and the structural organization of cephalochordate methyltransferases do not differ substantially from those of current vertebrate enzymes, while new Mbd proteins arose in vertebrates, which perhaps minimized certain collateral effects associated with the major genomic changes that occurred during the invertebrate-vertebrate transition.

Again, this is looking into the eyeglass and mouthpiece of genesis itself, looking both back into the far reaches of time as we can imagine it, and looking at the same time into the immediate present.  This is an inclusive-exclusive diorama of creation in progress, in process.  Genesis is an ongoing procedure present in all species even though they may appear to us presently with clear cut delineations.

Every species must consistently and continually remember who and what it is, defining and redefining its own boundaries – and these boundaries determine from the inside and to the outside, exactly what the particular species is.  Among humans, the genetic manifestations also determine who and what the individual is in terms of behavior from cellular transactions outwards – growing into larger and larger manifestations until we see the behavior of the entire body in action, participating in conscious choice to whatever degree is possible for that person.

In the end, this is all about expectation and anticipation.  The organism prepares itself for life by using all the genetic memory stored within its DNA, and within the powers of differentiation contained in its genetic memory that determines how its manifestation machinery can operate.  In the end, it is all about potential and possibilities.

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Papaleo et al 2008

Abstract – Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, Maryland 20892, USA.

The COMT (catechol-O-methyltransferase) gene

has been linked to a spectrum of human phenotypes,

including

cognition,

anxiety,

pain sensitivity and

psychosis.

Doubts about its clinical impact exist, however, because of the complexity of human COMT polymorphism and clinical variability. We generated transgenic mice overexpressing a human COMT-Val polymorphism (Val-tg), and compared them with mice containing a null COMT mutation.

Increased COMT enzyme activity in Val-tg mice

resulted in disrupted attentional set-shifting abilities, and

impaired working and recognition memory, but

blunted stress responses and pain sensitivity.

Conversely, COMT disruption

improved working memory, but

increased stress responses and pain sensitivity.

Does this tie in with “let’s hear it for the doves?”  Is this involved with the ability to pay very close, persistent and focused attention to whatever is happening or about to happen in the most minute detail in the near rather than the big, far, distant environment?

Amphetamine ameliorated recognition memory deficits in COMT-Val-tg mice but disrupted it in wild types, illustrating COMT modulation of the inverted-U relationship between cognition and dopamine. COMT-Val-tg mice showed increased prefrontal cortex (PFC) calcium/calmodulin-dependent protein kinase II (CaMKII) levels, whereas COMT deficiency decreased PFC CaMKII but increased PFC CaMKKbeta and CaMKIV levels,

suggesting the involvement of

PFC CaMK pathways in COMT-regulated

cognitive function and

adaptive stress responses.

Our data indicate a critical role for the

COMT gene

in an apparent evolutionary trade-off

between cognitive and affective functions.

Let me suggest that the sensitivities of the doves requires them to be able to feel, that is to recognize aspects of environmental interactions on the sensate level rather than detections based on thought or fore thought – which is, as we know, the slower way to both gain information and to react to it.

I would understand that early childhood adverse experiences further inform the dove end of the spectrum organisms that the environment is not only potentially dangerous, but certainly dangerous – based on experience as the teacher.

Here is epigenetics in process – experiential development – a skewing and amplification of possibilities and potential – an exaggeration of what can be the end result geared toward survival in the most flexible way possible – which unfortunately cannot retain at the same time enough flexibility to “change back again” in the future even if the environment were to change later on.

We can be as mad as we want about the limited flexibility abilities inherent within our species – and I mean that on the “innermost” level – into our cells themselves.  That we contain and retain enough flexibility to adapt to toxic and therefore dangerous environments in the first place is a miracle in itself.  But we are not made of play-do or silly putty!  Our plasticity, our “resiliency,” our protective factors can only reach so far.

In essence, this is who we are, right at the point of the intersection of our genesis, where IT is happening – the manifestation of our DNA on a continual, ongoing basis – to the limitations of our architecture and structure.

From this level the research moves up a notch and, to my thinking, loses its connection to the epigenetic factors in its consideration of actual polymorphisms in the genes themselves.  This level is not considering itself with the process of HOW the genes are expressing themselves and is more concerned with the genes and the polymorphisms in these genes.  I will include this information here and sort it out later….

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Smolka et al 2005

Abstract – Germany

Catechol-O-methyltransferase (COMT) degrades the catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine.

A functional polymorphism in the COMT gene (val158met) accounts for a fourfold variation in enzyme activity.

The low-activity met158 allele has been associated with

…………… improved working memory but with

……………higher risk for anxiety-related behaviors.

Using functional magnetic resonance imaging, we assessed the effects of COMT genotype on brain activation by standardized affective visual stimuli (unpleasant, pleasant, and neutral) in 35 healthy subjects.

…………..The analysis of genotype effects was restricted to brain areas with robust activation by the task. To determine genedose effects, the number of met158 alleles (0, 1, or 2) was correlated with the blood oxygen level-dependent (BOLD) response elicited by pleasant or unpleasant stimuli compared with neutral stimuli.

……..COMT genotype had no significant impact on brain activation by pleasant stimuli

………but was related to the neural response to unpleasant stimuli:

reactivity to unpleasant stimuli was significantly positively correlated with the

…….number of met158 alleles in the limbic system (left hippocampus, right amygdala, right thalamus), connected prefrontal areas (bilateral ventrolateral prefrontal cortex, right dorsolateral prefrontal cortex), and the visuospatial attention system (bilateral fusiform gyrus, left inferior parietal lobule).

Genotype explained up to 38% of interindividual variance in BOLD response elicited by unpleasant stimuli.

We conclude that

………..(1) genetic variations can account for a substantial part of interindividual variance in task-related brain activation and that

……… (2) increased limbic and prefrontal activation elicited by unpleasant stimuli in subjects with more met158 alleles might contribute to the observed lower emotional resilience against negative mood states.

Are there environmental conditions, particularly as the brain develops, that create this situation?  Not the genes themselves, obviously, but how we experience life with these genes?

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Drabant et al 2006

Abstract – MD —need to get this one

Catechol O-methyltransferase (COMT), the

….major enzyme determining cortical dopamine flux, has a

….common functional polymorphism (val(158)met) that

…affects prefrontal function and working memory capacity

….and has also been associated with

anxiety and emotional dysregulation.

OBJECTIVES: To examine COMT val(158)met effects on corticolimbic circuitry reactivity and functional connectivity during processing of biologically salient stimuli, as well as the relationship to the temperamental trait of novelty seeking.

DESIGN: Within-subject functional magnetic resonance imaging study. SETTING: National Institute of Mental Health, Genes, Cognition, and Psychosis Program, Bethesda, Md. Patients One hundred one healthy subjects of both sexes.

RESULTS: We found that the met allele was associated with a dose-dependent increase in hippocampal formation and ventrolateral prefrontal cortex activation during viewing of faces displaying negative emotion.

In met/met homozygotes, limbic and prefrontal regions showed increased functional coupling.

……….Moreover, in these same subjects, the magnitude of amygdala-orbitofrontal coupling was inversely correlated with novelty seeking,

……….an index of temperamental inflexibility.

CONCLUSIONS: Our results indicate that heritable variation in dopamine neurotransmission associated with the met allele of the COMT polymorphism results in heightened reactivity and connectivity in corticolimbic circuits.

This may reflect a genetic predisposition for inflexible processing of affective stimuli, a mechanism possibly accounting for aspects of arousal and behavioral control that contribute to emotional dysregulation previously reported in met/met individuals.

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Bertolino et al 2006

Abstract – Italy —call this article in

Functional polymorphisms in the catechol-O-methyltransferase (COMT) and the dopamine transporter (DAT) genes modulate dopamine inactivation,

…………..which is crucial for determining neuronal signal-to-noise ratios in prefrontal cortex during working memory.

We show that the COMT Met158 allele and the DAT 3′ variable number of tandem repeat 10-repeat allele are

………independently associated in healthy humans

………with more focused neuronal activity … in the working memory cortical network, including the prefrontal cortex.

Moreover, subjects homozygous for the COMT Met allele and the DAT 10-repeat allele

…………have the most

focused

response,

………whereas the COMT Val and the DAT 9-repeat alleles have the least.

These results demonstrate additive genetic effects of genes regulating dopamine signaling on specific neuronal networks subserving

working memory.

I can’t help but wonder about this combination.  This is one thing I know about myself – I can focus.  I have tied this into dissociation for myself because I can be so focused on my immediate task that short of a bomb exploding I cannot be distracted.  While in this state nothing else exists but whatever it is I am focusing on.

I have also wondered if my focusing ability is part of what keeps me so loyal for so long – and contributes to my inflexibility and rigidity about moving off in another direction if something is not good for me or is not “bearing fruit.”  It is a form of “stick-to-it-ness” that is a concentrated application of focused effort – no matter what.

It is certainly an ability that probably served me as a child.  There was no way out or around of my 18 years of abuse except to go through it to the end.  There were no alternatives available to me.  Perhaps I have this genetic combination they are talking about here – and I marshaled and honed my abilities far beyond the usual.

If so, then this combination (of course along with others) could keep a person from giving up.  A strong work ethic involving working memory that allows us to apply ourselves in spite of overwhelming obstacles – even on those occasions and in those situations when doing so is not in our best interest.  Maybe it’s the “Little Engine that Could” gene, that keeps us raising our children when that act takes a whole lot of courage and application of focused commitment.  Maybe it’s the gene that keeps some of us trying and trying and trying to make relationships work that have been all down hill from the start.  We will push that relationship UP and over the top if it kills us – and for us, that is within our working memory capacities.  Maybe we used this gene so hard in surviving our contaminated, toxic childhoods that all related circuits became super strong as well in their participation and involvement with “solving” the task at hand.

Maybe for us there was no other way, and today in the present when this kind of focused work is not needed and our commitments to making things work no longer serves us – we are so entrenched in our application of effort based upon what worked for us in the past that we do not know how to deviate from our tried and true methods from the past.  They are built into our brain based on our successes, or we wouldn’t be here now to debate the issue.  “Never give up!  Never surrender!” is our motto. We can keep our nose to the grindstone until we’ve worn a hole through the back of our head.

Maybe this is a sort of perseverance gene that gives everyone in my family a peculiar form of intensity.  All my siblings share it, all six of us.  All three of my children have it.  It makes sense that the human species would have evolved a particular option to persevere, to work without ceasing to solve problems, to tackle the seemingly impossible task, to apply concentrated effort toward accomplishing a goal.  This work takes intense, concentrated application of working memory.  How could it not?

It makes sense to me that the dopamine circuits, which also control both liking and wanting, would be involved in working memory and concentration of focused effort.  I suppose people without histories of early severe abuse would utilize this genetic combination differently and actually have some fun with it.  Or, if they tip over into personality disorder, this combination would keep them focused on working for what they detect they need in the environment at the cost of all others.

I am equating tenacity with focus – not at all sure this is really the same thing.

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Tan et al 2007

Abstract – MD

Dopaminergic and glutamatergic systems are critical components responsible for prefrontal signal-to-noise tuning in working memory.

Recent functional MRI (fMRI) studies of genetic variation in these systems in catechol-O-methyltransferase (COMT) and in metabotropic glutamate receptor mgluR3 (GRM3), respectively, suggest that

…….. these genes influence prefrontal physiological signal-to-noise in humans.

Here, using fMRI, we extend these individual gene findings to examine the combined effects of COMT and GRM3 on dissociable components of the frontoparietal working memory network.

We observed an apparent epistatic interaction of these two genes on the engagement of prefrontal cortex during working memory.

Specifically, the GRM3 genotype putatively associated with suboptimal glutamatergic signaling

….was significantly associated with inefficient prefrontal engagement and altered prefrontal-parietal coupling on the background of COMT Val-homozygous genotype.

Conversely, COMT Met-homozygous background mediated against the effect of GRM3 genotype.

These findings extend putative brain dopaminergic and glutamatergic relationships indexed by COMT and GRM3 to a systems-level interaction in human cortical circuits implicated in working memory dysfunction such as in schizophrenia.

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Apud et al 2007

Abstract – Genes, Cognition and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20854, USA.

Prefrontal cortical dopamine (DA)

regulates various executive cognitive functions,

including attention and working memory.

Efforts to enhance prefrontal-related cognition, which have focused on catecholaminergic stimulant drugs, have been unsatisfactory. Recently, the demonstration that

a functional polymorphism in the

catecholamine-O-methyltransferase (COMT) gene

impacts prefrontal cognition

raises the possibility of a novel pharmacological approach for the treatment of prefrontal lobe executive dysfunction.

To explore in a proof of concept study the effects of

tolcapone,

a CNS penetrant specific COMT inhibitor,

we performed a randomized, double blind, placebo controlled, and crossover design of this drug in normal subjects stratified by

COMT (val158met) genotype.

COMT enzyme activity was determined in peripheral blood. Forty-seven normal volunteers with no family history of psychiatric disorders underwent neuropsychological testing and 34 of those subjects underwent physiological measurement of prefrontal information processing assessed by blood oxygen level-dependent functional magnetic resonance imaging (fMRI).

We found significant drug effects on measures of executive function and verbal episodic memory and a significant drug by genotype interaction on the latter, such that individuals with

val/val genotypes improved,

whereas individuals with met/met genotypes

worsened on tolcapone.

fMRI revealed a significant tolcapone-induced improvement in the efficiency of information processing in prefrontal cortex during a working memory test. This study demonstrates enhancement of prefrontal cortical function in normal human subjects with a nonstimulant drug having COMT inhibitory activity. Our results are consistent with data from animal studies and from computational models of the

effects of selective enhancement of DA [dopamine] signaling in the prefrontal cortex.

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Goldberg et al 2003

Abstract – Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. goldbert@intra.nimh.nih.gov

Cognitive dysfunction in the working memory domain

seems to be under genetic control

and is a candidate intermediate phenotype in schizophrenia.

Genes that affect working memory processing may contribute to risk for schizophrenia. METHODS: Working memory and attentional processing were assessed in a large and unselected sample of schizophrenic patients, their healthy siblings, and controls (N = 250). We used the n-back task because it allows parametric analysis over increasing loads and delays and parsing of subcomponents of executive cognition and working memory, including temporal indexing and updating. Participants were genotyped for

catechol-O-methyltransferase (COMT) at the Val158Met locus,

which has been shown to

affect executive cognition and frontal lobe function, likely because of genetically determined variation in prefrontal dopamine signaling.

RESULTS: A significant COMT genotype effect was found:

Val/Val individuals had the lowest n-back performance,

and Met/Met individuals had the highest performance.

Effects were similar in the 1- and 2-back conditions and across all groups, whereas no effect on the Continuous Performance Test was seen, suggesting that genotype was not affecting working memory subprocesses related to attention, load, or delay. Siblings also performed significantly worse than controls on the 1- and 2-back conditions.

CONCLUSIONS: A prefrontal cognitive mechanism common to the 1- and 2-back conditions, probably executive processes involved in information updating and temporal indexing, is sensitive to the COMT genotype. Considering that the 3 participant groups were affected more or less linearly by the COMT genotype,

an additive genetic model

in which the effect of allele load is similar in its effects

on prefrontally based working memory

irrespective of the genetic or environmental background

in which it is expressed is suggested.

The findings also provide convergent evidence that

an intermediate phenotype

related to prefrontal cortical function

represents a viable approach to understanding

neuropsychiatric disorders with complex genetic etiologies

and individual differences in cognition.

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Northoff et al 2004

Abstract – Laboratory for Magnetic Brain Stimulation, Division of Behavioral Neurology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. Georg.Northoff@Medizin.Uni-Magdeburg.DE

Everyday and clinical experience demonstrates strong interactions between emotions and cognitions. Nevertheless the neural correlates underlying emotional-cognitive interaction remain unclear. Using event-related fMRI, we investigated BOLD-signal increases and decreases in medial and lateral prefrontal cortical regions during emotional and non-emotional judgment of photographs taken from the International Affective Picture System (IAPS). Emotional and non-emotional judgment conditions were compared to each other as well as with baseline allowing for distinction between relative signal changes (comparison between conditions) and true signal changes (referring to baseline). We have found that:

(1) both emotional and non-emotional judgment of IAPS pictures were characterized by

signal increases in ventrally and dorsally located lateral prefrontal cortical areas and

concurrent signal decreases in ventro- and dorsomedial prefrontal cortex;

(2) direct comparison between emotional and non-emotional judgment showed relative signal increases in ventro- and dorsomedial prefrontal cortex,

and in contrast, relative signal increases were detected in ventrally and dorsally located lateral prefrontal cortical areas when comparing non-emotional to emotional judgment; and

(3) as shown in separate comparisons with baseline, these relative signal changes were due to smaller signal decreases in ventro- and dorsomedial prefrontal cortex and smaller signal increases in ventrally and dorsally located lateral prefrontal cortical areas during emotional judgment.

Therefore, the emotional load of a cognitive task

lead to both less deactivation of medial prefrontal regions

and, at the same time,

less activation of lateral prefrontal regions.

Analogous patterns of reciprocal modulation and attenuation have previously been described for other cortical regions such as visual and auditory areas.

Reciprocal modulation and attenuation

in medial and lateral prefrontal cortex

might constitute the neurophysiologic basis

for emotional-cognitive interaction

as observed in both healthy and psychiatric subjects.

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Northoff et al 2000

Abstract- Department of Psychiatry, Otto-von-Guericke University of Magdeburg, Düsseldorf, Germany. Georg.Northoff@Medizin.Uni-Magdeburg.de

The orbitofrontal cortex has been cytoarchitectonically and connectionally subdivided into a medial and a lateral part which are assumed to subserve distinct functions in emotional processing.

However the exact spatiotemporal mechanisms of negative and positive emotional processing in medial and lateral orbitofrontal cortex remain unclear. We therefore investigated spatiotemporal orbitofrontal and prefrontal cortical activation patterns during emotional stimulation in a combined fMRI/MEG study. We investigated 10 healthy subjects, 5 women and 5 men. Positive and negative pictures from the International Affective Picture system (IAPS) were used for emotional stimulation, whereas neutral and gray pictures were taken as control conditions. fMRI/MEG measurements covered the whole frontal lobe and a time window between -2000 and +200 ms around motor responses (right index finger extension) associated with each picture. Positively and negatively correlated activities were determined in various prefrontal/frontal cortical regions in fMRI. Isocontour maps and single dipoles in MEG were analyzed in 50 ms time windows ranging from -2000 to +200 ms. Dipoles and fMR images were mapped on three-dimensional anatomical MRI so that anatomical localization of single dipoles and regional fMRI activity could be compared.

Both negative and positive emotional conditions

differed from non-emotional control conditions by strong orbitofrontal and lateral prefrontal activation as well as by the presence of early magnetic fields (-1700 to +1100 ms).

Negative emotional processing

was characterized by strong medial orbitofrontal activation and earlier (-1700 ms), stronger and more medially oriented orbitofrontal dipoles.

In contrast positive emotional processing

showed a rather strong activation in lateral prefrontal cortex with later (-1500 ms), weaker and more laterally oriented orbito and prefrontal dipoles.

Negative emotional processing

can be characterized by strong and early medial orbitofrontal cortical activation,

whereas positive emotional processing

showed rather later and weaker activation in lateral orbitofrontal/prefrontal cortex.

Such a functional dissociation between medial and lateral orbito-frontal/prefrontal cortex during negative and positive emotional processing lends further support to the assumption of a functional subdivision in the orbitofrontal cortex.

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Siegle et al 2007

Abstract – Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. gsiegle@pitt.edu

Major depressive disorder

is characterized by increased and sustained emotional reactivity, which has been linked to sustained amygdala activity.

It is also characterized by disruptions

in executive control,

linked to abnormal dorsolateral prefrontal cortex (DLPFC) function.

These mechanisms have been hypothesized to interact

in depression.

This study explored relationships between amygdala and DLPFC activity during emotional and cognitive information processing in unipolar depression. METHOD: Twenty-seven unmedicated patients with DSM-IV unipolar major depressive disorder and 25 never-depressed healthy control subjects completed tasks requiring executive control (digit sorting) and emotional information processing (personal relevance rating of words) during event-related functional magnetic resonance imaging (fMRI) assessment. RESULTS: Relative to control subjects,

depressed subjects displayed sustained amygdala reactivity

on the emotional tasks and

decreased DLPFC activity on the digit-sorting task.

Decreased relationships between the time-series of amygdala and DLPFC activity were observed within tasks in depression, but different depressed individuals showed each type of bias. CONCLUSIONS:

Depression is associated with increased limbic activity in response to emotional information processing and decreased DLPFC activity in response to cognitive tasks though these may reflect separate mechanisms.

Depressed individuals also display decreased relationships between amygdala and DLPFC activity,

potentially signifying decreased functional relationships

among these structures.

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Wang et al 2008

Abstract – Brain Imaging and Analysis Center, Duke University Medical Center, Durham, NC, USA.

A dysfunction in the interaction

between executive function and mood regulation

has been proposed as the pathophysiology of depression.

We must be aware that our judgment of the “dysfunctionality” of this condition reflects our cultural biases.  If, in fact, this disequilibrium is a realistic alteration in the abilities of sensitive dove types to notice details in their environment.  In support of this variation between types of people geared to operate differently in their environment BECAUSE WE ARE NOT ALL THE SAME AND HAVE DIFFERENT GIFTS, is supported by the genetic and the epigenetic overlay, or more accurately the underlay of these same brain operational factors.

However, few studies have investigated the alteration in brain systems related to executive control over emotional distraction in depression. To address this issue, 19 patients with major depressive disorder (MDD) and 20 healthy controls were scanned using functional magnetic resonance imaging. Participants performed an emotional oddball task in which infrequently presented circle targets required detection while sad and neutral pictures were irrelevant novel distractors. Hemodynamic responses were compared for targets, sad distractors, and for targets that followed sad or neutral distractors (Target-after-Sad and Target-after-Neutral).

Patients with MDD revealed attenuated activation overall to targets in executive brain regions.

Behaviorally, MDD patients were slower in response to Target-after-Sad than Target-after-Neutra stimuli. Patients also revealed a

reversed activation pattern from controls in response

to this contrast in the

left anterior cingulate,

insula,

right inferior frontal gyrus (IFG), and

bilateral middle frontal gyrus.

Those patients who engaged the right inferior frontal gyrus (IFG), more during Target-after-Neutral stimuli responded faster to targets, confirming a role of this region in coping with emotional distraction.

The results provide direct evidence of an

alteration in the neural systems that interplay cognition

with mood in MDD.

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Wang et al 2008b

Abstract – Brain Imaging and Analysis Center, Duke University Medical Center, PO Box 3918, Rm. 163, Bell Building, Durham, NC 27710, USA. wang@biac.duke.edu

Geriatric depression has been associated with a heterogeneous neuropathology. Identifying both depressive state-related and disease-related alterations in brain regions associated with emotion and cognitive function could provide useful diagnostic information in geriatric depression. METHOD: Twelve late-onset acutely depressed patients, 15 patients fully remitted from major depression, and 20 healthy comparison subjects underwent event-related functional MRI. Brain activation and deactivation associated with executive and emotional processing were investigated using an emotional oddball task in which circles were presented infrequently as attentional targets and sad and neutral pictures as novel distractors. RESULTS: Significant changes in brain activation in patients were found mainly in response to attentional targets rather than to sad distractors.

Relative to healthy comparison subjects, the

depressed patients had

attenuated activation in the regions of the executive system, including the right middle frontal gyrus, the cingulate, and inferior parietal areas.

They do not mention the medial parietal region, or precuneus

Activity in the middle frontal gyrus revealed depressive state-dependent modulation,

whereas attenuated activation in the anterior portion of the posterior cingulate and inferior parietal regions persisted in the remitted subjects, suggesting a disease-related alteration.

Enhanced deactivation was observed in the

posterior portion of the posterior cingulate,

which was also state dependent.

The remitted group did not show this deactivation.

CONCLUSIONS: Our results indicate distinct roles for the right middle frontal gyrus and the anterior and posterior portions of the posterior cingulate cortex in geriatric depression. The deactivation of the posterior portion of the posterior cingulate could be informative for differentiation of cognitive dysfunction related to depression from other conditions, such as mild cognitive impairment.

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Grimm et al 2008

Abstract – Department of Psychiatry, University of Zurich, Switzerland.

Although recent neuroimaging and therapeutic transcranial magnetic cortex stimulation (TMS) studies suggest

imbalance between left and right dorsolateral prefrontal cortex (DLPFC) in major depressive disorder (MDD)

the fundamental neuropsychological characterization of

left DLPFC hypoactivity and

right DLPFC hyperactivity in MDD

remains poorly understood. METHODS: We used event-related functional magnetic resonance imaging (fMRI) to investigate neural activity in left and right DLPFC related to unattended (unexpected) and attended (expected) judgment of emotions. Participating in the study were 20 medication-free patients with MDD and 30 healthy subjects. RESULTS: The

MDD patients showed

hypoactivity in the left DLPFC

during both unattended and attended emotional judgment and hyperactivity in the right DLPFC

during attended emotional judgment.

In contrast to healthy subjects,

left DLPFC activity during emotional judgment

was not parametrically modulated by negative emotional valence and was inversely modulated by positive emotional valence

in MDD patients.

Hyperactivity in the right DLPFC

correlated with depression severity.

CONCLUSIONS: Results demonstrate that

left DLPFC hypoactivity is associated with

negative emotional judgment

rather than with emotional perception or attention while

right DLPFC hyperactivity is linked to attentional modulation.

Left-right DLPFC imbalance

is characterized in neuropsychological regard,

which bridges the gap

from resting metabolism

and therapeutic repetitive transcranial magnetic stimulation effects

to functional neuroanatomy of

altered emotional-cognitive interaction in MDD.

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Lee et al 2008b

Abstract – Department of Psychiatry, Hangang Sacred Heart Hospital, Hallym University Medical Center, Seoul, South Korea.

Mood abnormalities related to major depressive disorder (MDD)

seem to result from disturbances in pathways

connecting the fronto-limbic and subcortical,

both regions known to be involved in the

processing of emotional information.

Using functional magnetic resonance imaging (fMRI), we measured neural responses to viewing images of sad, angry and neutral faces in 21 patients with MDD and 15 healthy controls. When shown pictures of

sad faces,

patients with MDD relative controls

showed decreased activations

bilaterally in the dorsolateral prefrontal cortex,

inferior orbitofrontal cortex (OFC),

medial OFC,

caudate, and

hippocampus.

We also found significant group differences under the

angry face condition,

bilaterally, in the inferior OFC and medial OFC areas.

Our findings indicate that

decreased activations in the fronto-limbic and subcortical regions in response to affectively negative stimuli may be associated with pathophysiology of MDD.

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Lee et al 2007

Abstract – Department of Psychiatry, Hangang Sacred Heart Hospital, Hallym University Medical Center, Seoul, South Korea.

Previous studies examining neural responses to emotional stimuli in individuals with major depressive disorder (MDD) have indicated

increased responses within the left amygdala to sad faces, and increased activity within the visual cortex and striatum

to expressions of happiness.

Using functional magnetic resonance imaging (fMRI), the current study measured neural responses to neutral, positive and negative pictures of the International Affective Picture System in 15 healthy individuals and 15 patients with MDD. Depressed individuals demonstrated

lower activity in the right hippocampus and the

right insula to negative affective pictures,

whereas they showed

lower activity in the right anterior cingulate cortex and the

left insula to positive pictures.

However, within the MDD group, the

severity of depression correlated with the activity of the

left amygdala,

bilateral inferior orbitofrontal areas, and the

left insula to negative pictures,

whereas there were no clear indications of association between specific cerebral regions and positive pictures. Our findings indicate that

preferential decreases in the left amygdala in response to negative pictures might be involved in the processing of emotional stimuli in depressed individuals.

Also, these findings suggest that the

bilateral inferior orbitofrontal cortices and left amygdala

may be preferentially recruited in MDD patients,

but not in healthy individuals.

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Jollant et al 2008

Abstract – Université Montpellier I, Institut National de la Santé et de la Recherche Médicale U 888, Centre Hospitalier Universitaire, Montpellier, France. f-jollant@chu-montpellier.fr

OBJECTIVE: The authors sought to elucidate the functional neural basis of the neurobiological abnormalities underlying the vulnerability to suicidal behavior. METHOD: Event-related functional MRI was used to measure neural activity in response to angry and happy versus neutral faces. Thirteen currently euthymic men with a history of major depressive disorder and suicidal behavior were compared with 14 currently euthymic men with a history of major depressive disorder but not of suicidal acts (affective comparison subjects) and 16 healthy male comparison subjects. RESULTS: Relative to affective comparison subjects, suicide attempters showed greater activity in the right lateral orbitofrontal cortex (Brodmann’s area 47) and decreased activity in the right superior frontal gyrus (area 6) in response to prototypical angry versus neutral faces, greater activity in the right anterior cingulate gyrus (area 32 extending to area 10) to mild happy versus neutral faces, and greater activity in the right cerebellum to mild angry versus neutral faces. However, activation in these frontal regions did not differ between healthy individuals and either patient group. That makes no sense to me! Relative to healthy comparison subjects, both patient groups showed reduced activity in the right cerebellum to neutral faces and to mild happy versus neutral faces.

CONCLUSIONS: Suicide attempters were distinguished from nonsuicidal patients by responses to angry and happy faces that may suggest increased sensitivity to others’ disapproval, higher propensity to act on negative emotions, and reduced attention to mildly positive stimuli. These patterns of neural activity and cognitive processes may represent vulnerability markers of suicidal behavior in men with a history of depression.

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Mitterschiffthaler et al 2008

Abstract – Neuroimaging Research Group, Clinical Neuroscience, Institute of Psychiatry, King’s College London, UK. m.mitterschiffthaler@iop.kcl.ac.uk

A mood-congruent sensitivity towards negative stimuli has been associated with development and maintenance of major depressive disorder (MDD). The emotional Stroop task assesses interference effects arising from the conflict of emotional expressions consistent with disorder-specific self-schemata and cognitive color-naming instructions. Functional neuroimaging studies of the emotional Stroop effect advocate a critical involvement of the anterior cingulate cortex (ACC) during these processes. METHOD: Subjects were 17 medication-free individuals with unipolar MDD in an acute depressive episode (mean age 39 years), and 17 age-, gender- and IQ-matched healthy volunteers. In an emotional Stroop task, sad and neutral words were presented in various colors, and subjects were required to name the color of words whilst undergoing functional magnetic resonance imaging (fMRI). Overt verbal responses were acquired with a clustered fMRI acquisition sequence. RESULTS:

Individuals with depression showed greater increases in response time from neutral to sad words relative to controls. fMRI data showed a

significant engagement of

left rostral ACC (BA 32) and

right precuneus

during sad words in patients relative to controls.

Additionally, rostral ACC activation was positively correlated with latencies of negative words in MDD patients. Healthy controls did not have any regions of increased activation compared to MDD patients. CONCLUSIONS: These findings provide evidence for a behavioural and neural emotional Stroop effect in MDD and highlight the

importance of the ACC during monitoring of conflicting cognitive processes and

mood-congruent processing in depression.

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Fales et al 2008

Abstract – Department of Psychology, Washington University in St. Louis, St. Louis, Missouri 63110, USA.

Major depression is characterized by a negativity bias:

an enhanced responsiveness to, and memory for, affectively negative stimuli.

Just as a dove sensitive would even under normal conditions?

However, it is not yet clear whether this bias represents 1) impaired top-down cognitive control over affective responses, potentially linked to deficits in dorsolateral prefrontal cortex function; or 2) enhanced bottom-up responses to affectively laden stimuli that dysregulate cognitive control mechanisms, potentially linked to deficits in amygdala and anterior cingulate function. METHODS: We used an attentional interference task using emotional distracters to test for top-down versus bottom-up dysfunction in the interaction of cognitive-control circuitry and emotion-processing circuitry. A total of 27 patients with major depression and 24 control participants was tested. Event-related functional magnetic resonance imaging was carried out as participants directly attended to, or attempted to ignore, fear-related stimuli. RESULTS:

Compared with control subjects, patients with depression showed an enhanced amygdala response to unattended fear-related stimuli (relative to unattended neutral). By contrast,

control participants showed increased activity in

right dorsolateral prefrontal cortex (Brodmann areas 46/9) when ignoring fear stimuli (relative to neutral), which the patients with depression did not show.

In addition, the depressed participants failed to show evidence of error-related cognitive adjustments (increased activity in bilateral dorsolateral prefrontal cortex on posterior trials), but the control group did show them. CONCLUSIONS: These results suggest

multiple sources of dysregulation

in emotional and cognitive control circuitry in depression, implicating both

top-down and

bottom-up dysfunction.

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Holmes & Pizzagalli 2008

Abstract – Department of Psychology, Harvard University, Cambridge, MA 02138, USA.

Depression is characterized by executive dysfunctions and abnormal reactions to errors; however, little is known about the brain mechanisms that underlie these deficits. OBJECTIVE: To examine whether abnormal reactions to errors in patients with major depressive disorder (MDD) are associated with exaggerated paralimbic activation and/or a failure to recruit subsequent cognitive control to account for mistakes in performance. DESIGN: Between February 15, 2005, and January 19, 2006, we recorded 128-channel event-related potentials while study participants performed a Stroop task, modified to incorporate performance feedback. SETTING: Patients with MDD and healthy comparison subjects were recruited from the general community. PARTICIPANTS: Study participants were 20 unmedicated patients with MDD and 20 demographically matched comparison subjects. MAIN OUTCOME MEASURES: The error-related negativity and error positivity were analyzed through scalp and source localization analyses. Functional connectivity analyses were conducted to investigate group differences in the spatiotemporal dynamics of brain mechanisms that underlie error processing. RESULTS: Relative to comparison subjects,

patients with MDD displayed significantly lower accuracy after incorrect responses, larger error-related negativity, and higher current density in the rostral anterior cingulate cortex (ACC) and medial prefrontal cortex (PFC) (Brodmann area 10/32) 80 milliseconds after committing an error.

Functional connectivity analyses revealed that for the comparison subjects, but not the patients with MDD, rostral ACC and medial PFC activation 80 milliseconds after committing an error predicted left dorsolateral PFC (Brodmann area 8/9) activation 472 milliseconds after committing an error.

CONCLUSIONS: Unmedicated patients with MDD showed

reduced accuracy and potentiated error-related negativity immediately after committing errors, highlighting

dysfunctions in the automatic detection

of unfavorable performance outcomes.

New analytic procedures allowed us to show that

abnormal reaction

to committing errors

was accompanied by

hyperactivation in rostral ACC

and medial PFC regions

80 milliseconds after committing errors and a

failure to recruit dorsolateral PFC-based cognitive control.

Future studies are warranted to investigate whether these dysfunctions might foster the emergence and maintenance of negative processing biases and thus increase vulnerability to depression.

Are these changes orchestrated by epigenetic control?  If so, are they compensatory response patterns related to fear conditioning and hence to memory formation and retention?   One must also consider that these responses within the brain might be possible responses that were put in place far earlier than the time when language in words became a possibility for humans.

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Holmes & Pizzagalli 2008b

Abstract – Department of Psychology, Harvard University, Cambridge, MA 02138, USA.

Individuals with major depressive disorder (MDD) often exhibit impaired executive function, particularly in experimental tasks that involve

response conflict and require

adaptive behavioral adjustments.

Prior research suggests that these deficits might be

due to dysfunction within frontocingulate pathways

implicated in response conflict monitoring

and the recruitment of cognitive control.

However, the temporal unfolding of conflict monitoring impairments in MDD remains poorly understood. To address this issue, we recorded 128-channel event-related potentials while 20 unmedicated participants with MDD and 20 demographically matched, healthy controls performed a Stroop task. Compared to healthy controls, MDD subjects showed larger Stroop interference effects and reduced N2 and N450 amplitudes. Source localization analyses at the time of maximal N450 activity revealed that

MDD subjects had significantly reduced

dorsal anterior cingulate cortex (dACC; Brodmann area 24/32) and left dorsolateral prefrontal cortex (Brodmann area 10/46) activation to incongruent relative to congruent trials.

Interesting, the introduction of this term, congruency, in the MDD brain function considerations.  When Teicher talks about the brain developed in and for a malevolent world not being able to adjust down the road to a benevolent one, he is talking about a later appearing incongruency between response ability in match to the existing current environment.  This, to me, is a time issue, a timing issue, where a rupture and repair demand resulted in a possibly even epigenetic adjustment that remains “fixed” and unable to be moderated or modulated in a plastic fashion resulting in a rigid pattern that is incongruent with later environments.

Consistent with the heterogeneous nature of depression, follow-up analyses revealed that depressed participants with the lowest level of conflict-related dACC activation 620 ms post-stimulus were characterized by the largest Stroop interference effects (relatively increased slowing and reduced accuracy for incongruent trials). Conversely, MDD participants with relatively stronger dACC recruitment did not differ from controls in terms of interference effects. These findings suggest that

for some, but not all individuals,

MDD is associated with impaired performance

in trials involving

competition among different response options,

and reduced recruitment of frontocingulate pathways implicated in conflict monitoring and cognitive control.

An interesting and very useful addition to research structure at this point would be to include measures of dissociation.  My certain guess is that those with the highest difficulties with competition among different response options would show high dissociation patterns.

Not being able to choose, or to even recognize what the different response options might even be, is, to me, a key component of dissociation!

It might be possible that “nature” increases sensitivity without at the same time increasing the cognitive abilities necessary to choose response options.  I would also guess that in these individuals an extreme sensitivity to PTSD might simultaneously and concurrently exist.

This is also where the fissure could appear that allows hopelessness and helplessness to meet confusion – powerlessness and loss of control, loss of competence in the PAST to meet demands that match, are perceived to be congruent with present demands, only in the past the person was overwhelmed – what does Schore call that?  Faced with the “unsolvable paradox,” over and over and over again.  Being sensitive enough to detect when “danger” appears, but left without adequate responses to deal with it.

This must be tied to memory, and to working memory.  If nothing is remembered but the cue, and there was no adequate coping, one will be remembered but not, obviously, the other.

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Wagner et al 2006

Abstract – Department of Psychiatry, University of Jena, Jena, Germany. wagner.gerd@uni-jena.de

The present study is aimed to examine the neuronal correlates of Stroop interference in medication-free patients with major depressive disorder. METHODS: Sixteen patients fulfilling Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for unipolar depression and 16 healthy control subjects matched for age, gender, and education were included. All subjects underwent an event-related functional magnetic resonance imaging (fMRI) design with an adapted version of the Stroop task including congruent and incongruent task conditions. The fMRI experiment was conducted on a 1.5 T magnetic resonance (MR) scanner, and item responses were given manually by the subjects. RESULTS: With regard to behavioral performance, patients revealed no differences in both reaction time and accuracy relative to control subjects.

With regard to brain activations,

direct comparison of patients with control subjects

in the interference condition revealed

hyperactivity in rostral anterior cingulate gyrus (rACG) and

left dorsolateral prefrontal cortex (DLPFC)

in depressive patients,

which correlated strongly with the Stroop interference.

CONCLUSIONS: The study provides new evidence for the

functioning and dissociation of the anterior cingulate in depressed patients.

The greater prefrontal activation may reflect a cortical inefficiency due to hyperactivity in rACG

enhancing the cognitive interferences

from the emotional state.

That would mean the inefficiency is related and connected to the emotional state, sounding here like the emotional state is CAUSING the cognitive interferences.

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Smolka et al 2007

Abstract – Germany

Emotional reactivity and regulation

…………are fundamental to human behavior.

As inter-individual behavioral variation is affected by a multitude of different genes, there is intense interest to investigate gene-gene effects. Functional sequence variation at two genes has been associated with response and resiliency to emotionally unpleasant stimuli.

These genes are the catechol-O-methyltransferase gene (COMT Val158Met) and the regulatory region (5-HTTLPR) of the serotonin transporter gene.

Recently, it has been proposed that 5-HTT expression is not only affected by the common S/L variant of 5-HTTLPR but also by an A to G substitution.

Using functional magnetic resonance imaging, we assessed the effects of COMT Val(158)Met and both 5-HTT genotypes on brain activation by standardized affective visual stimuli (unpleasant, pleasant, and neutral) in 48 healthy subjects.

Based on previous studies, the analysis of genotype effects was restricted to limbic brain areas.

…………To determine allele-dose effects, the number of COMT Met158 alleles (i.e., lower activity of COMT) and the number of 5-HTT low expressing alleles (S and G) was correlated with the blood oxygen level-dependent (BOLD) response to pleasant or unpleasant stimuli compared to neutral stimuli.

We observed an additive effect of COMT and both 5-HTT polymorphisms, accounting for 40% of the inter-individual variance in the averaged BOLD response of amygdala, hippocampal and limbic cortical regions elicited by unpleasant stimuli.

Effects of 5-HTT and COMT genotypes did not affect brain processing of pleasant stimuli.

……………..These data indicate that functional brain imaging may be used to assess the interaction of multiple genes on the function of neuronal networks.

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Bertolino et al 2005

Abstract – Psychiatric Neuroscience Group, Section on Mental Disorders, Department of Psychiatric and Neurological Sciences, University of Bari, Bari, Italy. bertolia@psichiat.uniba.it

In the brain, processing of fearful stimuli engages the amygdala, and the variability of its activity is

associated with genetic factors

as well as with emotional salience.

The objective of this study was to explore the relevance of personality style for variability of amygdala response. Now this seems like a silly “which came first, the chicken or the egg” scenario!

METHODS: We studied two groups (n=14 in each group) of healthy subjects categorized by

contrasting cognitive styles

with which they attribute salience to fearful stimuli:

so-called phobic prone subjects who exaggerate potential environmental threat

versus so-called eating disorders prone subjects

who tend to be much less centered around fear.

That’s kind of a scary comparison, in more ways than one.  Firstly, this is a value judgment that would be more accurately be measured by anxiety scales.  Secondly, eating disordered subjects sound like vampires, me having been watching perhaps too many Buffy shows!  The ones who eat big things, perhaps, closer to the hawk traits, the predators and the carnivores versus the herbivores?  Do we have genetic predispositions based on ancient genetic memory of being more one or the other, and now both?

The two groups underwent functional magnetic resonance imaging (fMRI) at 3T during performance of a perceptual task of threatening stimuli and they were also matched for the genotype of the

5′ variable number tandem repeat (VNTR) polymorphism in the serotonin transporter. RESULTS: The fMRI results indicated that

phobic prone subjects selectively recruit the amygdala to a larger extent than eating disorders prone subjects.

Activity in the amygdala was also independently predicted by personality style and genotype of the serotonin transporter.

Moreover, brain activity during a working memory task did not differentiate the two groups. CONCLUSIONS:

The results of the present study suggest that

aspects of personality style

are rooted in biological responses of the fear circuitry associated with processing of environmental information.

Well, that would certainly indicate an open spot for epigenetics to enter and adjust!  But nothing is that simple, and this has to be a polygenetic condition – not ignoring vasopressin, the operation of the cannabinoid system, etc.  The doves and hawks, the “loomers” and the “flutterers.”

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Rubino et al 2007

Abstract – Psychiatric Neuroscience Group, Section on Mental Disorders, Department of Psychiatric and Neurological Sciences, University of Bari, Bari, Italy.

Cognitive evaluation of emotional stimuli involves a network of brain regions including the medial prefrontal cortex (mPFC).

However, threatening stimuli may be perceived with differential salience in different individuals.

The goal of our study was to evaluate how different personality styles are associated with differential modulation of brain activity during explicit recognition of fearful and angry facial expressions.

Twenty-eight healthy subjects [doesn’t say here any of them had eating disorders!?] underwent fMRI. Based on a cognitivist model, subjects were categorized according to how they attribute salience to emotional stimuli and how they regulate their emotional activation. Define “how.”

We compared 14 phobic prone (PP) subjects,

whose identity is more centered on the inner experience (“inward”) and around control of environmental threat,

and 14 eating disorders prone (EDP) subjects,

whose identity is more centered on external referential contexts (“outward”) and much less around control of threatening stimuli.

During fMRI subjects either matched the identity of one of two angry and fearful faces to that of a simultaneously presented target face or identified the expression of a target face by choosing one of two simultaneously presented linguistic labels. The fMRI results indicated that PP subjects had greater mPFC activation when compared with EDP subjects during cognitive labeling of threatening stimuli.

Activity in the mPFC also correlated with personality style scores.

These results demonstrate that

PP subjects

recruit greater neuronal resources in mPFC

whose activity is associated with cognitive aspects

that are closely intertwined with emotional processing.

These findings are consistent with the contention that

cognitive evaluation and salience of emotional stimuli

are associated with different personality styles.

In the OLD ways, ancient food finding patterns perhaps – things that loom versus things that flutter.  Both having a place in the ordering of the species, and in meeting the needs of the species for diversification of abilities and needs in finding and using resources.  The allostatic load people also tie these differences into how the immune system is geared to operate differently – in interaction with how the brain is processing information.

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Harenski & Hamann 2006

Abstract – Department of Psychology, Emory University, 532 North Kilgo Circle, Atlanta, GA 30322, USA.

Previous neuroimaging studies have identified several brain regions associated with regulating emotional responses. Different kinds of emotional stimuli, however, may recruit different regulatory processes and, in turn, recruit different regions. We compared emotion regulation for two types of negative emotional stimuli: those involving moral violations (moral stimuli), and those not involving moral violations (non-moral stimuli). In addition, we investigated whether activation in medial prefrontal cortex (MPFC), a region implicated previously in specifically moral processing, may instead reflect greater social and emotional content. Ten female subjects were scanned using fMRI while they passively viewed or were instructed to decrease emotional reactions to moral and non-moral pictures closely matched on social and emotional content. Passive viewing of both picture types elicited similar activations in areas related to the processing of social and emotional content, including MPFC and amygdala. During regulation, different patterns of activation in these regions were observed for moral vs. non-moral pictures. These results suggest that the neural correlates of regulating emotional reactions are modulated by the emotional content of stimuli, such as moral violations. In addition, the current findings suggest that

some brain regions previously implicated in moral processing reflect the processing of greater social and emotional content in moral stimuli.

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Phan et al 2003

Abstract – Department of Psychiatry, University of Michigan, Ann Arbor, Michigan 48109-0118, USA.

Activation of the medial prefrontal cortex and extended amygdala by individual ratings of emotional arousal: a fMRI study.

Significant differences between individual responses to emotional stimuli can be important for the study of emotion…

medial prefrontal cortex (MPFC) and

sublenticular extended amygdala (SLEA),

areas implicated in the processing of emotional salience.

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Kerestes et al 2008

Abstract – Behavioural Neuroscience Laboratory, School of Psychology, Psychiatry and Psychological Medicine, Monash University, Melbourne, Australia, Rebecca.Kerestes@med.monash.edu.au.

Serotonergic (SSRI) and noradrenergic (NRI) antidepressants modulate biases in emotional processing

such that perceptual bias is shifted away from negative and towards positive emotional material.

Well, isn’t that convenient!  Artificial, external editorship, censoring —  well, really, the effect seems to be to augment the emotion expression decoding of happy facial expressions in healthy male subjects.  This would be helpful as per research that shows depressed mother’s do not respond to their infant’s happy expressions and therefore the happy part of the infant’s brain does not form “correctly” – hence, passing it down the generations.  It has been shown in other research that depressed people do not see others’ happy expressions.  Sort of a “tuning out” of the happy information, I guess.  This research is not about depressed people, though – supposedly these subjects were healthy and normal.

However, the effects of serotonergic and noradrenergic modulation on the temporal course (occurring in milliseconds) of emotional processing, and in particular, the rapid physiological changes associated with the different stages of emotional processing, are unknown. OBJECTIVE: The current study assessed the effects of acute serotonergic (i.e. with citalopram) and noradrenergic (i.e. with reboxetine) augmentation on event-related potential (ERP) measures associated with ‘structural encoding’ (N170) and emotion expression decoding (N250 and late positive potential [LPP]) for positive (happy) and negative (sad) facial stimuli relative to neutral facial stimuli. MATERIALS AND METHODS: This study employed a double-blind, placebo-controlled, cross-over design in which 12 healthy male participants completed a facial expression recognition task tested under three acute conditions: (a) placebo, (b) citalopram (20 mg) and (c) reboxetine (4 mg). RESULTS: Both citalopram and reboxetine had no effect on the N170 ERP component associated with structural encoding, but potentiated the N250 associated with happy (relative to neutral) emotional facial expression decoding. Both drugs had no valence effects on later ERP measures of emotion expression decoding (LPP). CONCLUSIONS: Citalopram [acute serotonergic] and reboxetine [noradrenergic augmentation] have selective effects on the temporal course of emotional processing with evidence to suggest specific effects on emotion expression decoding of positive (happy) emotional facial stimuli as evidenced by changes in the attention-modulated N250 but not structural encoding. These findings provide physiological evidence that antidepressants may shift perceptual biases in emotional processing away from negative and towards positive stimuli. Hence, we could all live in the HAPPY world, forget the “negative” no matter how important or real?  Is this related to what avoidant insecure attachment people can do?  Or, do they not see the happy either?  This research is saying nothing, of course, about what the molecular or genetic level is doing with this alteration or process.

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Blau et al 2007

Abstract – Sackler Institute for Developmental Psychobiology, Weill Medical College of Cornell University, New York, USA. v.blau@psychology.unimaas.nl

According to the traditional two-stage model of face processing, the face-specific N170 event-related potential (ERP) is linked to structural encoding of face stimuli, whereas later ERP components are thought to reflect processing of facial affect. This view has recently been challenged by reports of N170 modulations by emotional facial expression. This study examines the time-course and topography of the influence of emotional expression on the N170 response to faces. METHODS: Dense-array ERPs were recorded in response to a set (n = 16) of fear and neutral faces. Stimuli were normalized on dimensions of shape, size and luminance contrast distribution. To minimize task effects related to facial or emotional processing, facial stimuli were irrelevant to a primary task of learning associative pairings between a subsequently presented visual character and a spoken word. RESULTS:

N170 [linked to structural encoding of face stimuli – but here shown to be “more than” this only] to faces showed a strong modulation by emotional facial expression.

A split half analysis demonstrates that this effect was significant both early and late in the experiment and was therefore not associated with only the initial exposures of these stimuli, demonstrating a form of robustness against habituation.

The effect of emotional modulation of the N170 to faces did not show significant interaction with the gender of the face stimulus, or hemisphere of recording sites. Subtracting the fear versus neutral topography provided a topography that itself was highly similar to the face N170. CONCLUSION: The face N170 response can be influenced by emotional expressions contained within facial stimuli. The topography of this effect is consistent with the notion that fear stimuli exaggerates the N170 response itself.

This finding stands in contrast to previous models

suggesting that N170 processes linked to structural analysis

of faces precede analysis of emotional expression,

and instead may reflect early top-down modulation from neural systems involved in rapid emotional processing.

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Blair et al 2007

Abstract – Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-2670, USA. peschark@mail.nih.gov <peschark@mail.nih.gov>

In this study, we examined the impact of goal-directed processing on the response to emotional pictures and the impact of emotional pictures on goal-directed processing. Subjects (N=22) viewed neutral or emotional pictures in the presence or absence of a demanding cognitive task.

Goal-directed processing disrupted the BOLD response to emotional pictures. In particular, the

BOLD response within bilateral amygdala and inferior frontal gyrus decreased during concurrent task performance. Moreover, the presence of both positive and negative distractors disrupted task performance, with

reaction times increasing for emotional relative to neutral distractors. With dissociation, the reaction time can extend into infinity – when no adequate response is available – or so says the trained trauma brain

Moreover, in line with the suggestion of the importance of lateral frontal regions in emotional regulation [Ochsner, K. N., Ray, R. D., Cooper, J. C., Robertson, E. R., Chopra, S., Gabrieli, J. D., et al. (2004). For better or for worse: neural systems supporting the cognitive down-and up-regulation of negative emotion. NeuroImage, 23(2), 483-499], connectivity analysis revealed

positive connectivity between

lateral superior frontal cortex and regions of middle frontal cortex previously implicated in emotional suppression [Beauregard, M., Levesque, J., and Bourgouin, P. (2001). Neural correlates of conscious self-regulation of emotion. J. Neurosci., 21 (18), RC165.; Levesque, J., Eugene, F., Joanette, Y., Paquette, V., Mensour, B., Beaudoin, G., et al. (2003). Neural circuitry underlying voluntary suppression of sadness. Biol. Psychiatry, 53 (6), 502-510.; Ohira, H., Nomura, M., Ichikawa, N., Isowa, T., Iidaka, T., Sato, A., et al. (2006). Association of neural and physiological responses during voluntary emotion suppression. NeuroImage, 29 (3), 721-733] and negative connectivity with bilateral amygdala. These data suggest that processes involved in emotional regulation are recruited during task performance in the context of emotional distractors.

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Koch et al 2007

Abstract – Department of Psychiatry and Psychotherapy, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany.

The interaction of emotion and cognition has become a topic of major interest. However, the influence of gender on the interplay between the two processes, along with its neural correlates have not been fully analyzed so far. In this functional magnetic resonance imaging (fMRI) study we induced negative emotion using negative olfactory stimulation while male (n=21) and female (n=19) participants performed an n-back verbal working memory task. Based on findings indicating increased emotional reactivity in women, we expected the female participants to exhibit stronger activation in characteristically emotion-associated areas during the interaction of emotional and cognitive processing in comparison to the male participants. Both groups were found to be significantly impaired in their working memory performance by negative emotion induction. However, fMRI analysis revealed distinct differences in neuronal activation between groups.

In men, cognitive performance under negative emotion induction

was associated with extended activation patterns in

mainly prefrontal and superior parietal regions.

In women, the interaction between emotion and working memory yielded a significantly stronger response in the amygdala and the orbitofrontal cortex (OFC) compared to their male counterparts.

Our data suggest that in

women the interaction of verbal working memory and negative emotion is associated with relative hyperactivation in more emotion-associated areas whereas in

men regions commonly regarded as important for cognition and cognitive control are activated.

These results provide new insights in gender-specific cerebral mechanisms.

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Vuilleumier & Pourtois 2007

Abstract – Laboratory for Behavioral Neurology & Imaging of Cognition, Clinic of Neurology, University Hospital of Geneva, Geneva, Switzerland. patrik.vuilleumier@medecine.unige.ch

Brain imaging studies in humans have shown that face processing in several areas is modulated by the affective significance of faces, particularly with fearful expressions, but also with other social signals such gaze direction. Here we review haemodynamic and electrical neuroimaging results indicating that

activity in the face-selective fusiform cortex

may be enhanced by emotional (fearful) expressions,

without explicit voluntary control,

and presumably through direct feedback connections

from the amygdala.

fMRI studies show that these increased responses in fusiform cortex to fearful faces are abolished by amygdala damage in the ipsilateral hemisphere, despite preserved effects of voluntary attention on fusiform; whereas emotional increases can still arise despite deficits in attention or awareness following parietal damage, and appear relatively unaffected by pharmacological increases in cholinergic stimulation.

Fear-related modulations of face processing driven by amygdala signals may implicate not only fusiform cortex, but also earlier visual areas in occipital cortex (e.g., V1) and other distant regions involved in social, cognitive, or somatic responses (e.g., superior temporal sulcus, cingulate, or parietal areas).

In the temporal domain, evoked-potentials show a widespread time-course of emotional face perception, with some increases in the amplitude of responses recorded over both occipital and frontal regions for fearful relative to neutral faces (as well as in the amygdala and orbitofrontal cortex, when using intracranial recordings), but with different latencies post-stimulus onset.

Early emotional responses may arise around 120ms, prior to a full visual categorization stage indexed by the face-selective N170 component, possibly reflecting rapid emotion processing based on crude visual cues in faces. Other electrical components arise at later latencies and involve more sustained activities, probably generated in associative or supramodal brain areas, and resulting in part from the modulatory signals received from amygdala.

Altogether, these fMRI and ERP results demonstrate that emotion face perception is a complex process that cannot be related to a single neural event taking place in a single brain regions, but rather implicates an interactive network with distributed activity in time and space.

Moreover, although traditional models in cognitive neuropsychology have often considered that facial expression and facial identity are processed along two separate pathways, evidence from fMRI and ERPs suggests instead that

emotional processing can strongly affect brain systems responsible for face recognition and memory.

The functional implications of these interactions remain to be fully explored, but might play an important role in the normal development of face processing skills and in some neuropsychiatric disorders.

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Noesselt et al 2005

Abstract – Institute of Cognitive Neuroscience, University College London, 17 Queen Square, London WC1N 3AR, United Kingdom. toemme@neuro2.med.uni-magdeburg.de

Traditional split-field studies and patient research indicate a privileged role for the right hemisphere in emotional processing [1-7], but there has been little direct fMRI evidence for this, despite many studies on emotional-face processing [8-10](see Supplemental Background). With fMRI, we addressed differential hemispheric processing of fearful versus neutral faces by presenting subjects with faces bilaterally [11-13]and orthogonally manipulating whether each hemifield showed a fearful or neutral expression prior to presentation of a checkerboard target. Target discrimination in the left visual field was more accurate after a fearful face was presented there. Event-related fMRI showed right-lateralized brain activations for fearful minus neutral left-hemifield faces in right visual areas, as well as more activity in the right than in the left amygdala. These activations occurred regardless of the type of right-hemifield face shown concurrently, concordant with the behavioral effect. No analogous behavioral or fMRI effects were observed for fearful faces in the right visual field (left hemisphere). Right or left handed subjects?

The amygdala showed enhanced functional coupling with right-middle and anterior-fusiform areas in the context of a left-hemifield fearful face.

These data provide behavioral and fMRI evidence for right-lateralized emotional processing during bilateral stimulation involving enhanced coupling of the amygdala and right-hemispheric extrastriate cortex.

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Pourtois & Vuilleumier 2006

Abstract – Neurology & Imaging of Cognition, Clinic of Neurology, University Hospital & Department of Neurosciences, University Medical Center, University of Geneva, Switzerland. gilles.pourtois@medecine.unige.ch

An efficient detection of threat is crucial for survival and requires an appropriate allocation of attentional resources toward the location of potential danger. Recent neuroimaging studies have begun to uncover the brain machinery underlying the reflexive prioritization of spatial attention to locations of threat-related stimuli. Here, we review functional brain imaging experiments using event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI) in a dot-probe paradigm with emotional face cues, in which we investigated the spatio-temporal dynamics of attentional orienting to a visual target when the latter is preceded by either a fearful or happy face, at the same (valid) location or at a different (invalid) location in visual periphery. ERP results indicate that fearful faces can bias spatial attention toward threat-related location, and enhance the amplitude of the early exogenous visual P1 activity generated within the extrastriate cortex in response to a target following a valid rather than invalid fearful face. Furthermore, this gain control mechanism in extrastriate cortex (at 130-150 ms) is preceded by an earlier modulation of activity in posterior parietal regions (at 40-80 ms) that may provide a critical source of top-down signals on visual cortex.

Happy faces produced no modulation of ERPs in extrastriate and parietal cortex. fMRI data also show increased responses in the occipital visual cortex for valid relative to invalid targets following fearful faces, but in addition reveal significant decreases in intraparietal cortex and increases in orbitofrontal cortex when targets are preceded by an invalid fearful face,

suggesting that negative emotional stimuli

may not only draw but also hold spatial attention more strongly than neutral or positive stimuli.

These data confirm that threat may act as a powerful exogenous cue and trigger reflexive shifts in spatial attention

toward its location,

through a rapid temporal sequence of neural events

in parietal and temporo-occipital areas,

with dissociable neural substrates

for engagement benefits in attention

affecting activity in extrastriate occipital areas and increased disengagement costs affecting intraparietal cortex.

These brain-imaging results reveal how emotional signals related to threat can play an important role in modulating spatial attention to afford flexible perception and action.

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Nobre 2001

Abstract – Brain & Cognition Laboratory, University of Oxford, Department of Experimental Psychology, South Parks Road, Oxford OX1 3UD, UK. kia.nobre@psy.ox.ac.uk

Orienting attention to instants in time.

My colleagues and I have investigated whether the temporal framework can be used to guide selective attention, and have applied non-invasive methodology to reveal the brain systems and mechanisms involved. Our findings show that

we are able to orient attention selectively

to different points in time, enhancing behavioral performance.

These effects are mediated by a left-hemisphere dominant parietal-frontal system, which partially overlaps

with the networks involved in spatial orienting.

The neural system for temporal orienting also includes

brain areas associated with motor preparation and anticipation, suggesting that sensorimotor areas with different specializations can contribute to attentional orienting depending on the stimulus attributes guiding selection.

The optimization of behavior by temporal orienting

involves enhancement of the latency and amplitude

of event-related potentials that are associated with motor responses and decisions.

How could we not look here for dissociation?

The effects are distinct from those during visual spatial attention, indicating that behavioral advantages can be conferred by multiple types of neural mechanisms.

Taken together, the findings illustrate the

flexibility of attentional functions in the human brain.

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Griffin, Miniussi & Nobre 2001

Abstract – University of Oxford, Department of Experimental Psychology, South Parks Road, Oxford, OX1 3UD, UK.

Orienting attention in time.

Temporal information

is essential for effective perception and action

in the dynamic environment in which we exist.

However, our ability to use information about time intervals flexibly to direct attention to an expected point in time

has until recently been unexplored.

Here we report a series of behavioral, neuroimaging and electrophysiological experiments that investigate and define the ability to orient attention in the temporal domain. These studies reveal that

we are able to orient attention selectively

to different time intervals,

enhancing behavioral performance.

These effects are mediated by a left-hemisphere dominant frontal-parietal system, which partially overlaps with the networks involved in spatial orienting.

The optimization of behavior by temporal orienting

appears to be achieved via motor-related mechanisms,

in contrast to the typical perceptual enhancements produced by spatial attention.

From a more general perspective, these findings illustrate the flexibility of attentional functions in the human brain.

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Hopfinger, Buonocore & Mangun 2000

Abstract – Center for Neuroscience and Department of Psychology, One Shields Ave., University of California, Davis, California 95616, USA.

The neural mechanisms of top-down attentional control.

Selective visual attention involves dynamic interplay between attentional control systems and sensory brain structures. It also has to involve memory – making and remembering.  One must think about an infant’s growing brain as it interacts with its environment – what is it learning and how?  What happens that can cause dissociation in these developing circuits and their actions and interactions?

We used event-related functional magnetic resonance imaging (fMRI) during a cued spatial-attention task to

Dissociate

brain activity related to attentional control

from that related to selective processing of target stimuli.

Distinct networks were engaged by attention-directing cues versus subsequent targets.

Superior frontal,

inferior parietal and

superior temporal cortex were selectively activated by cues, indicating that these structures are part of a network for voluntary attentional control.

This control biased activity in multiple visual cortical areas, resulting in selective sensory processing of relevant visual targets.

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Hopfinger et al 2001

Abstract – Department of Psychology, CB 3270, Davie Hall, University of North Carolina at Chapel Hill, 27599-3270, USA. hopfinger@unc.edu

Dissociating top-down attentional control from selective perception and action.

Research into the neural mechanisms of attention has revealed a complex network of brain regions that are involved in the execution of attention-demanding tasks.

Recent advances in human neuroimaging now permit investigation of the elementary processes of attention being subserved by specific components of the brain’s attention system. Here we describe recent studies of spatial selective attention that made use of positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and event-related brain potentials (ERPs) to investigate the spatio-temporal dynamics of the attention-related neural activity.

We first review the results from an event-related fMRI study that examined the neural mechanisms underlying top-down attentional control versus selective sensory perception. These results

defined a fronto-temporal-parietal network

involved in the control of spatial attention.

Activity in these areas biased the neural activity

in sensory brain structures coding the spatial locations

of upcoming target stimuli,

preceding a modulation of subsequent target processing in visual cortex.

We then present preliminary evidence from a fast-rate event-related fMRI study of spatial attention that demonstrates how to disentangle the potentially overlapping hemodynamic responses elicited by temporally adjacent stimuli in studies of attentional control. Finally, we present new analyses from combined neuroimaging (PET) and event-related brain potential (ERP) studies that together reveal the

timecourse of activation of brain regions

implicated in attentional control and selective perception.

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Hahn, Ross & Stein 2006

Abstract – NIH/National Institute on Drug Abuse, Intramural Research Program, Neuroimaging Research Branch, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA. bhahn@intra.nida.nih.gov

Neuroanatomical dissociation between bottom-up and top-down processes of visuospatial selective attention.

Allocation of attentional resources to portions

of the available sensory input can be regulated

by bottom-up processes, i.e., spontaneous orientation towards an oncoming stimulus (stimulus-driven attention),

and by top-down processes, i.e., intentionally and driven by knowledge, expectation and goals.

The present study aimed at advancing the understanding of brain networks mediating bottom-up and top-down control of visuospatial attention by employing a paradigm that parametrically varied demands on these two processes. Spatial predictability of peripheral targets was parametrically varied by centrally cueing one, two, three or four of four possible locations. Reaction time decreased linearly with more precise valid cueing of the target location and increased with more precise invalid cueing. Event-related functional magnetic resonance imaging (fMRI) enabled measurement of blood oxygenation level-dependent (BOLD) responses to cues and to targets.

A mostly left-hemispheric network consisting of left intraparietal sulcus, inferior and superior parietal lobule, bilateral precuneus, middle frontal gyri including superior frontal sulci, and middle occipital gyri displayed BOLD responses to cues that increased linearly with more precise spatial cueing, indicating engagement by top-down spatial selective attention.

In contrast, bilateral temporoparietal junction, cingulate gyrus, right precentral gyrus and anterior and posterior insula, bilateral fusiform gyri, lingual gyri and cuneus displayed BOLD responses to targets that increased with their spatial unpredictability, indicating engagement by stimulus-driven orienting.

The results suggest two largely

dissociated neural networks

mediating top-down and bottom-up control of visuospatial selective attention.

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Wilson et al 2005b

Abstract – Center for Cognitive Neuroscience, Duke University, Durham, NC 27708-0999, USA. kwilson@gettysburg.edu

Control networks and hemispheric asymmetries in parietal cortex during attentional orienting in different spatial reference frames.

Neuropsychological research has consistently demonstrated that

spatial attention can be anchored in one of several

coordinate systems, including those defined with respect to an observer (viewer-centered), to the

gravitational vector (environment-centered), or to

individual objects (object-centered).

In the present study, we used hemodynamic correlates of brain function to investigate the neural systems that mediate attentional control in two competing reference frames. Healthy volunteers were cued to locations defined in either viewer-centered or object-centered space to discriminate the shape of visual targets subsequently presented at the cued locations. Brain responses to attention-directing cues were quantified using event-related functional magnetic resonance imaging.

A fronto-parietal control network was activated by attention-directing cues in both reference frames. Voluntary shifts of attention produced increased neural activity bilaterally in several cortical regions including the intraparietal sulcus, anterior cingulate cortex, and the frontal eye fields.

Of special interest was the observation of

hemispheric asymmetries in parietal cortex;

there was significantly

greater activity in left parietal cortex than in the right,

but this asymmetry was more pronounced for

object-centered shifts of attention,

relative to viewer-centered shifts of attention.

Measures of behavioral performance did not differ significantly between the two reference frames. We conclude that

a largely overlapping, bilateral, cortical network mediates our ability to orient spatial attention in multiple coordinate systems,

and that the left intraparietal sulcus plays an additional role for orienting in object-centered space.

As an infant’s brain grows, these circuits become established.  I doubt they are well defined in operation in the womb.

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Rushworth et al 1997

Abstract – Department of Experimental Psychology, University of Oxford, U.K. matthew.rushworth@psy.ox.ac.uk

The left parietal cortex and motor attention.

The posterior parietal cortex, particularly in the right hemisphere, is crucially important for covert orienting; lesions impair the ability to disengage the focus of covert orienting attention from one potential saccade target to another (Posner, M. I. et al., Journal of Neuroscience, 1984, 4, 1863-1874). We have developed a task where precues allow subjects to covertly prepare subsequent cued hand movements, as opposed to an orienting or eye movement. We refer to this process as motor attention to distinguish it from orienting attention. Nine subjects with lesions that included the left parietal cortex and nine subjects with lesions including the right parietal cortex were compared with control subjects on the task. The left hemisphere subjects showed the same ability as controls to engage attention to a movement when they were forewarned by a valid precue. The left hemisphere subjects, however, were impaired in their ability to disengage the focus of motor attention from one movement to another when the precue was incorrect. The results support the existence of two distinct attentional systems allied to the orienting and limb motor systems. Damage to either system causes analogous problems in disengaging from one orienting/movement target to another. The left parietal cortex, particularly the supramarginal gyrus, is associated with motor attention.

All the left hemisphere subjects had ideomotor apraxia and had particular problems performing sequences of movements. We suggest that the well documented left hemisphere and apraxic impairment in movement sequencing is the consequence of a difficulty in shifting the focus of motor attention from one movement in a sequence to the next.

Is this another area where dissociation can occur with a corresponding inability to shift the focus of attention?

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Rushworth, Krams & Passingham 2001

Abstract – Wellcome Institute of Cognitive Neurology, London, UK. matthew.rushworth@psy.ox.ac.uk

The attentional role of the left parietal cortex: the distinct lateralization and localization of motor attention in the human brain.

It is widely agreed that visuospatial orienting attention depends on a network of frontal and parietal areas in the right hemisphere. It is thought that the visuospatial orienting role of the right parietal lobe is related to its role in the production of overt eye movements. The experiments reported here test the possibility that other parietal regions may be important for directing attention in relation to response modalities other than eye movement. Specifically, we used positron emission tomography (PET) to test the hypothesis that a ‘left’ parietal area, the supramarginal gyrus, is important for attention in relation to limb movements (Rushworth et al., 1997; Rushworth, Ellison, & Walsh, in press). We have referred to this process as ‘motor attention’ to distinguish it from orienting attention. In one condition subjects spent most of the scanning period covertly attending to ‘left’ hand movements that they were about to make. Activity in this first condition was compared with a second condition with identical stimuli and movement responses but lacking motor attention periods.

Comparison of the conditions revealed that motor attention-related activity was almost exclusively restricted to the ‘left’ hemisphere despite the fact that subjects only ever made ipsilateral, left-hand responses. Left parietal activity was prominent in this comparison, within the parietal lobe the critical region for motor attention was the supramarginal gyrus and the adjacent anterior intraparietal sulcus (AIP), a region anterior to the posterior parietal cortex identified with orienting attention.

In a second part of the experiment we compared a condition in which subjects covertly rehearsed verbal responses with a condition in which they made verbal responses immediately without rehearsal. A comparison of the two conditions revealed verbal rehearsal-related activity in several anterior left hemisphere areas including Broca’s area. The lack of verbal rehearsal-related activity in the left supra-marginal gyrus confirms that this area plays a direct role in motor attention that cannot be attributed to any strategy of verbal mediation.

The results also provide evidence concerning the importance of ventral premotor (PMv) and Broca’s area in motor attention and language processes.

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Rushworth, Ellison & Walsh 2001

Abstract – Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford, OX1 3UD, UK. matthew.rushworth@psy.ox.ac.uk

Complementary localization and lateralization of orienting and motor attention

It is widely agreed that the right posterior parietal cortex has a preeminent role in visuospatial and orienting attention. A number of lines of evidence suggest that although orienting and the preparation of oculomotor responses are dissociable from each other, the two are intimately related. If this is true, then it should be possible to identify other attentional mechanisms tied to other response modalities. We used repetitive transcranial magnetic stimulation (rTMS) to demonstrate the

existence of a distinct anterior parietal mechanism of motor attention. The critical area for motor attention is anterior to the one concerned with orienting, and it is lateralized to the left hemisphere in humans.

Does this region’s activity change with some people’s altered brain lateralization patterns and handedness?  Could this happen during infant brain developmental stages when action and consequence are often not predictable and are in fact life threatening to the infant – when no compensatory action is possible on the part of the infant to caregiver “motor actions?”

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Rushworth et al 2003

Abstract – Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford, OX1 3UD, UK. matthew.rushworth@psy.ox.ac.uk

The left parietal and premotor cortices: motor attention and selection.

It is well established that the premotor cortex has a central role in the selection of movements. The role of parts of the parietal cortex in movement control has proved more difficult to describe but appears to be related to the preparation and the redirection of movements and movement intentions. We have referred to some of these processes as motor attention. It has been known since the time of William James that covert motor attention can be directed to an upcoming movement just as visuospatial attention can be directed to a location in space.

While some parietal regions, particularly in the right hemisphere, are concerned with covert orienting and the redirecting of covert orienting it may be useful to consider other parietal regions, in the anterior inferior parietal lobule and in the posterior superior parietal lobule, particularly in the left hemisphere, as contributing to motor attention.

Such parts of the parietal lobe are activated in neuroimaging experiments when subjects covertly prepare movements or switch intended movements. Lesions or transcranial magnetic stimulation (TMS) affect the redirecting of motor attention. The difficulties apraxic patients experience when sequencing movements may partly be due to an inability to redirect motor attention from one movement to another. The role of the premotor cortex in selecting movements is also lateralized to the left hemisphere. Damage to left hemisphere movement selection mechanisms may also contribute to apraxia [Apraxia is a neurological disorder characterized by loss of the ability to execute or carry out learned purposeful movements, despite having the desire].

If, however, it remains intact after a stroke then the premotor cortex may contribute to the recovery of arm movements. A group of patients with unilateral left hemisphere lesions and impaired movements in the contralateral right hand was studied. Functional magnetic resonance imaging showed that in some cases the premotor cortex in the intact hemisphere was more active when the stroke-affected hand was used. TMS in the same area in the same patients had the most disruptive effect on movements. In summary, patterns of motor impairment and recovery seen after strokes can partly be explained with reference to the roles of the parietal and premotor cortices in motor attention and selection.

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Halsband & Lange 2006

Abstract – Department of Psychology and Neuropsychology, University of Freiburg, Engelbergerstr 41, D-79085 Freiberg, Germany. halsband@psychologie.uni-freiburg.de

Motor learning in man: a review of functional and clinical studies.

This chapter reviews results of clinical and functional imaging studies which investigated the time-course of cortical and subcortical activation during the acquisition of motor a skill. During the early phases of learning by trial and error, activation in prefrontal areas, especially in the dorsolateral prefrontal cortex, has been reported. The role of these areas is presumably related to explicit working memory and the establishment of a novel association between visual cues and motor commands. Furthermore, motor associated areas of the right hemisphere and distributed cerebellar areas reveal strong activation during the early motor learning. Activation in superior-posterior parietal cortex presumably arises from visuospatial processes, while sensory feedback is coded in the anterior-inferior parietal cortex and the neocerebellar structures. With practice, motor associated areas of the left-hemisphere reveal increased activity. This shift to the left hemisphere has been observed regardless of the hand used during training, indicating a left-hemispheric dominance in the storage of visuomotor skills.

Concerning frontal areas, learned actions of sequential character are represented in the caudal part of the supplementary motor area (SMA proper), whereas the lateral premotor cortex appears to be responsible for the coding of the association between visuo-spatial information and motor commands.

Functional imaging studies which investigated the activation patterns of motor learning under implicit conditions identified for the first, a motor circuit which includes lateral premotor cortex and SMA proper of the left hemisphere and primary motor cortex, for the second, a cognitive loop which consists of basal ganglia structures of the right hemisphere. Finally, activity patterns of intermanual transfer are discussed.

After right-handed training, activity in motor associated areas maintains during performance of the mirror version, but is increased during the performance of the original-oriented version with the left hand. In contrary, increased activity during the mirror reversed action, but not during the original-oriented performance of the untrained right hand is observed after left-handed training. These results indicate the transfer of acquired right-handed information which reflects the mirror symmetry of the body, whereas spatial information is mainly transferred after left-handed training.

Taken together, a combined approach of clinical lesion studies and functional imaging is a promising tool for identifying the cerebral regions involved in the process of motor learning and provides insight into the mechanisms underlying the generalization of actions.

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Nobre 2001b

Abstract – University of Oxford, Department of Experimental Psychology, OX1 3UD, Oxford, UK.

The attentive homunculus: now you see it, now you don’t.

The nature of the neural system that directs our attention toward selective items in the extrapersonal world is a longstanding and interesting puzzle.

In this article, I review the contributions of brain imaging toward the characterization of attentional control in the human brain. The majority of experiments to date have investigated visual spatial orienting. A consistent pattern of brain areas has been revealed, comprising most notably the posterior parietal cortex around the intraparietal sulcus and frontal regions including the frontal eye fields.

The brain areas implicated in the control of visual spatial attention were noted to resemble those involved in the control of eye movements, and direct experimental comparisons supported a tight link between the two systems.

The findings suggested a sensible view of the attentional ‘homunculus’ as a distributed neural system related to the control of eye movements. Eye movements form perhaps the most basic orienting response, and can be shifted rapidly and efficiently based on multiple frames of reference. Some attention experiments using objects and features instead of spatial locations as the target of selection also obtained similar patterns of parietal-frontal activations, rendering further support to this view of the attentional control system. Some recent experiments, however, have cautioned against a premature conclusion regarding the ubiquity of the attentional control system revealed by studies of visual spatial attention.

Different parietal and frontal regions become engaged when attention is shifted along non-spatial dimensions, such as when attention is directed toward a particular motor act or toward a specific point in time. In these cases, the neural system resembles those involved in the control of limb movements.

The attentional homunculus thus begins to dissolve. The alternative view suggested is that attentional control may be a property of specialized parietal-frontal systems that transform perception into action.

Future studies will be needed to validate this view of attention,

or to provide a more mature understanding of its true nature.

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Coull & Nobre 1998

Abstract – Functional Imaging Laboratory, Wellcome Department of Cognitive Neurology, Institute of Neurology, London WC1N 3BG, United Kingdom.

Where and when to pay attention: the neural systems for directing attention to spatial locations and to time intervals as revealed by both PET and fMRI.

Although attention is distributed across time as well as space, do they directly consider where memory/learning comes into this interactional process? the temporal allocation of attention has been less well researched than its spatial counterpart.

A temporal analog of the covert spatial orientation task [Posner MI, Snyder CRR, Davidson BJ (1980) Attention and the detection of signals. J Exp Psychol Gen 109:160-174] was developed to compare the neural systems involved in directing attention to spatial locations versus time intervals.

We asked whether there exists a general system for allocating attentional resources, independent of stimulus dimension, or whether functionally specialized brain regions are recruited for directing attention toward spatial versus temporal aspects of the environment.

We measured brain activity in seven healthy volunteers by using positron emission tomography (PET) and in eight healthy volunteers by using functional magnetic resonance imaging (fMRI). The task manipulated cued attention to spatial locations (S) and temporal intervals (T) in a factorial design. Symbolic central cues oriented subjects toward S only (left or right), toward T only (300 msec or 1500 msec), toward both S and T simultaneously, or provided no information regarding S or T. Subjects also were scanned during a resting baseline condition.

Behavioral data showed [I don’t have the article to know what author means by the following]

benefits and costs

for performance during temporal attention

similar to those established for spatial attention.

Brain-imaging data revealed a partial overlap between neural systems involved in the performance of spatial versus temporal orientation of attention tasks.

hemispheric asymmetries revealed

preferential right parietal activation for spatial attention

and left parietal activation for temporal attention

Parietal cortex

[precuneus – medial parietal region – implicated?  If so, then has something to do with reference and involvement of the self]

was activated bilaterally by attending to both dimensions simultaneously.

This is the first direct comparison of the neural correlates of attending to spatial versus temporal cues.

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Thiel, Zilles & Fink 2004

Abstract – Institute of Medicine, Research Centre Jülich, 52425, Jülich, Germany. c.thiel@fz-juelich.de

Cerebral correlates of alerting, orienting and reorienting of visuospatial attention: an event-related fMRI study.

The identification of brain systems contributing to different aspects of visuospatial attention is of both clinical and theoretical interest. Cued target detection tasks provide a simple means to

Dissociate

attentional subcomponents, such as alerting, orienting or reorienting of attention.

Event-related functional magnetic resonance imaging (fMRI) was used to study neural correlates of these distinct attentional processes. Volunteers were scanned while performing a centrally cued target detection task. Four different types of trials (no cue, neutral cue, valid cue and invalid cue trials) with targets appearing either in the right or left hemifield were randomly intermixed. Behaviorally, the data provided evidence for alerting, spatial orienting and reorienting of attention.

Neurally, the alerting effect was seen in bilaterally increased extrastriatal blood oxygenation level-dependent (BOLD) activity in neutral as compared to no cue trials. Neural correlates of spatial orienting were seen in anterior cingulate cortex, which was more active during valid as compared to neutral cue trials.

Neural correlates of reorienting of attention, that is, higher BOLD activity to invalid as compared to validly cued trials were evident in several brain regions including left and right intraparietal sulcus, right temporo-parietal junction and middle frontal gyrus bilaterally.

The data suggest

that frontal and parietal regions

are specifically involved in reorienting rather than orienting attention to a spatial position.

Alerting effects were seen in extrastriate regions

which suggest that increased phasic alertness

results in a top-down modulation of neural activity in visual processing areas.

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Thiel, Zilles & Fink 2005

Abstract – Institute of Medicine, Research Centre Jülich, Jülich, Germany. c.thiel@fz-juelich.de

Nicotine modulates reorienting of visuospatial attention and neural activity in human parietal cortex.

Prior studies in animals and humans indicate that

reorienting of visuospatial attention

is modulated by the cholinergic agonist

nicotine.

We have previously identified

neural correlates of alerting and reorienting attention in humans and found that the parietal cortex is specifically involved in reorienting.

This study investigates whether the alerting and reorienting systems, especially in the parietal cortex, are modulated by nicotine. We used event-related functional magnetic resonance imaging (fMRI) and studied 15 nonsmoking volunteers under placebo and nicotine (NICORETTE) polacrilex gum 1 and 2 mg). Subjects performed a cued target detection task with four different types of randomly intermixed trials (no, neutral, valid, and invalid cue trials). Alerting was captured by comparing BOLD activity and reaction times (RTs) in neutrally cued trials with no cue trials. Reorienting was isolated by comparing invalidly with validly cued trials.

On the behavioral level, nicotine affected reorienting of attention

by speeding RTs in invalidly cued trials;

alerting was not affected by nicotine.

Neurally, however, nicotine modulated both attentional systems.

Pharmacologic effects on alerting-related brain activity were mainly evident as modulation of BOLD responses in the right angular gyrus and right middle frontal gyrus due to a reduction of neural activity in no cue trials.

In the reorienting system, effects of nicotine were mainly evident in the left intraparietal sulcus and

precuneus

and

due to a reduction of neural activity in invalidly cued trials.

We conclude that

nicotine enhances reorienting of attention in visuospatial tasks and that one behavioral correlate of speeded RTs

is reduced parietal activity.

So does this mean that we “give ourselves a break” here by reducing referent activation or involvement of the self?  Is this related to what I called the “sunglasses effect” of nicotine on the gating response?

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Giessing et al 2006

Abstract – Institute of Medicine, Research Centre Jülich, 52425 Jülich, Germany. c.giessing@fz-juelich.de

The modulatory effects of nicotine on parietal cortex activity in a cued target detection task depend on cue reliability.

This functional magnetic resonance imaging study investigates the effects of nicotine in a cued target detection task when changing cue reliability. Fifteen non-smoking volunteers were studied under placebo and nicotine (Nicorette polacrilex gum 1 and 2 mg).

Validly and invalidly cued trials were arranged in blocks with high, middle and low cue reliability.

Two effects of nicotine were investigated: its influence on

i) parietal cortex activity underlying the processing of invalid vs. valid trials (i.e. validity effect) and

ii) neural activity in the context of low, middle and high informative value of the cue (i.e. cue reliability effect).

Nicotine did not affect behavioral performance.

However, nicotine reduced the difference in the blood oxygenation level dependent (BOLD) signal between invalid and valid trials in the right intraparietal sulcus.

The reduction of parietal activity in invalid trials was smaller in the low cue reliability condition. The same posterior parietal region exhibited a nicotinic modulation of BOLD activity in valid trials which was dependent on cue reliability:

Nicotine specifically enhanced the neural activity

during valid trials in the context of low cue reliability,

i.e. when subjects are already in a state of low certainty.

We speculate that the right intraparietal sulcus

might be part of two networks working in parallel:

one responsible for reorienting attention and the

other for the cholinergic modulation of cue reliability.

By reducing the use of the cue,

nicotine modulates parietal activity

related to reorienting attention

in conditions with higher cue certainty.

On the other hand, nicotine increases parietal activity in states of low certainty. This enhanced activation might influence brain regions, such as the posterior cingulate, directly involved in the processing of cue reliability.

This is too complicated for me to understand at the moment – but anything that regulates reactions to cues is implicated in anxiety problems, including PTSD

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these  may be useful here, placed somewhere else, not sure where

Pourtois et al 2005

Pourtois & Vuilleumier 2006

Pourtois et al 2006

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Arrington et al 2000

Abstract – Michigan State University, USA.

Neural mechanisms of visual attention: object-based selection of a region in space.

Objects play an important role in guiding spatial attention through a cluttered visual environment.

We used event-related functional magnetic resonance imaging (ER-fMRI) to measure brain activity during cued discrimination tasks requiring subjects to orient attention either to a region bounded by an object (object-based spatial attention) or to an unbounded region of space (location-based spatial attention) in anticipation of an upcoming target. Comparison between the two tasks revealed

greater activation when attention selected a region bounded by an object. This activation was strongly lateralized to the left hemisphere and formed a widely distributed network including (a) attentional structures in parietal and temporal cortex and thalamus,

(b) ventral-stream object processing structures in occipital, inferior-temporal, and parahippocampal cortex, and

(c) control structures in medial- and dorsolateral-prefrontal cortex.

These results suggest that object-based spatial selection is achieved by imposing additional constraints over and above those processes already operating to achieve selection of an unbounded region. In addition, ER-fMRI methodology allowed a comparison of validly versus invalidly cued trials, thereby delineating brain structures involved in the reorientation of attention after its initial deployment proved incorrect.

All areas of activation that differentiated between these two trial types resulted from greater activity during the invalid trials. This outcome suggests that all brain areas involved in attentional orienting and task performance in response to valid cues are also involved on invalid trials. During invalid trials, additional brain regions are recruited when a perceiver recovers from invalid cueing and reorients attention to a target appearing at an uncued location. Activated brain areas specific to attentional reorientation were strongly right-lateralized and included posterior temporal and inferior parietal regions previously implicated in visual attention processes, as well as prefrontal regions that likely subserve control processes, particularly related to inhibition of inappropriate responding.

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Coull et al 2000

Abstract – Wellcome Department of Cognitive Neurology, Institute of Neurology, 12 Queen Square, London, UK. j.coull@fil.ion.ucl.ac.uk

Orienting attention in time: behavioural and neuroanatomical distinction between exogenous and endogenous shifts.

Temporal orienting of attention is the ability to

focus resources at a particular moment in time in order to optimize behavior,

and is associated with activation of

left parietal and premotor cortex

[Coull, J. T., Nobre, A. C. Where and when to pay attention: the neural systems for directing attention to spatial locations and to time intervals as revealed by both PET and fMRI. Journal of Neuroscience, 1998, 18, 7426-7435].

In the present experiment, we explored the behavioral and anatomical correlates of temporal orienting to novel visual stimuli, in order to eliminate any spatial attention confounds. We implemented a two-way factorial design in an event-related fMRI study to examine the factors of trial validity (predictability of target by cue), length of delay (cue-target interval), and their interaction. There were two distinct types of invalid trial: those where attention was automatically drawn to a premature target and those where attention was voluntarily shifted to a delayed time-point. Reaction times for valid trials were shorter than those for invalid trials, demonstrating appropriate allocation of attention to temporal cues. All trial-types activated a shared system, including frontoparietal areas bilaterally, showing that this network is consistently associated with attentional orienting and is not specific to spatial tasks.

Distinct brain areas were sensitive to cue-target delays and to trial validity. Long cue-target intervals activated areas involved in motor preparation: supplementary motor cortex, basal ganglia and thalamus. Invalid trials, where temporal expectancies were breached, showed enhanced activation of left parietal and frontal areas, and engagement of orbitofrontal cortex bilaterally. Finally, trial validity interacted with length of delay. Appearance of targets prematurely selectively activated visual extrastriate cortex; while postponement of target appearance selectively activated right prefrontal cortex. These findings suggest that

distinct brain areas are involved in redirecting attention based upon sensory events (bottom-up, exogenous shifts) and based upon cognitive expectations (top-down, endogenous shifts).

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Pourtois et al 2006

Abstract – Neurology and Imaging of Cognition, Clinic of Neurology, University Hospital and Department of Neurosciences, University Medical Center, Switzerland. patrik.vuilleumier@medecine.unige.ch

Attention may reflexively shift towards the location of perceived threats, but it is still unclear how these spatial biases recruit the distributed fronto-parietal cortical networks involved in other aspects of selective attention. We used event-related fMRI to determine how brain responses to a neutral visual target are influenced by the emotional expression of faces appearing at the same location during a covert orienting task. On each trial, two faces were briefly presented, one in each upper visual field (one neutral and one emotional, fearful or happy), followed by a unilateral target (a small horizontal or vertical bar) replacing one of the faces. Participants had to discriminate the target orientation, shown on the same (valid) or opposite (invalid) side as the emotional face. Trials with faces but no subsequent target (cue-only trials) were included to disentangle activation due to emotional cues from their effects on target detection.

We found increased responses in bilateral temporo-parietal areas and right occipito-parietal cortex for fearful faces relative to happy faces, unrelated to the subsequent target and cueing validity. More critically, we found a selective modulation of intraparietal and orbitofrontal cortex for targets following an invalid fearful face, as well as an increased visual response in right lateral occipital cortex for targets following a valid fearful face. No such effects were observed with happy faces. These results demonstrate that

fearful faces can act as exogenous cues by increasing sensory processing in extrastriate cortex for a subsequent target presented at the same location, but also produce a cost in disengaging towards another location by altering the response of IPS to invalidly cued targets.

Neural mechanisms responsible for orienting attention

towards emotional vs. non-emotional stimuli

are thus partly shared in parietal and visual areas,

but also partly distinct.

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Pourtois et al 2005

Abstract – Department of Neuroscience, Neurology and Imaging of Cognition, Clinic of Neurology, University Medical Centre (CMU), Bat. A, Physiology, Geneva, Switzerland. gilles.pourtois@medecine.unige.ch

Visuo-spatial attention tends to be prioritized towards emotionally negative stimuli such as fearful faces, as opposed to neutral or positive stimuli. Here is the other side of the info on changing bias through antidepressants – the visual attention, at least, certainly has a survival component

Using a covert orienting task, we previously showed that a lateral occipital P1 component, with extrastriate neural sources, was selectively enhanced to lateralized visual targets replacing a fearful face (fear-valid trial) than the same targets replacing a neutral face (fear-invalid trial), providing evidence for

exogenous spatial orienting of attention towards threat cues.

Here, we describe a new analysis of these data, using topographic evoked potentials mapping methods combined with a distributed source localization technique. We show that an early field topography (40-80 ms post-target onset) with a centro-parietal negativity and a left posterior parietal source

distinguished fear-valid from fear-invalid trials,

whereas a distinct activity with anterior cingulate sources

was selectively evoked during fear-invalid trials.

At the same latency, or later, no difference in field topography was found for valid compared to invalid trials with happy faces. The early parietal map preceded a modulation in amplitude of the field strength (approximately 130 ms), corresponding to the enhanced lateral occipital P1 during valid trials in the fear condition. Furthermore, this early topography at 40-80 ms was positively correlated with the subsequent amplitude modulation of P1 at 130-160 ms in the fear condition, suggesting a possible functional coupling between these two successive events.

These data have important implications for models of

spatial attention and interactions with emotion.

They suggest two successive stages of neural activity

during exogenous orienting of attention towards visual targets following fearful faces,

including an early posterior parietal negativity,

followed by gain control mechanisms

enhancing visual responses in

extrastriate occipital cortex.

Well, what can I say.  I have seen more separate incidents of a fearful face than most people could see in several lifetimes – or more.  What affect those encounters had on my developing brain had to include the creation of a chasm, not a track or a rut, of a different kind of orienting of attention toward visual targets following fearful faces – Schore and all describe the disorganized, disoriented insecure attachment following mothering by either a frightened or a frightening mother – and it has been very hard for me to equate these two in my thoughts – and yet here is an area where it might not matter to the brain, certainly mattering little to the developing brain – if the face is full of terror or is so terrifying itself that it creates terror in its wake – something has to, had to have happened in these brain regions that is NOT NORMAL in a secure benevolent world.

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Holmes, Richards & Green 2006

Abstract – School of Psychology, Birkbeck University of London, UK. a.holmes@roehampton.ac.uk

This paper reports three studies in which stronger orienting to perceived eye gaze direction was revealed when observers viewed faces showing fearful or angry, compared with happy or neutral, emotional expressions.

Gaze-related spatial cueing effects to

laterally presented fearful faces and

centrally presented angry faces were also

modulated by the anxiety level of participants, with high- but not low-state anxious individuals revealing enhanced shifts of attention.

In contrast, both high- and low-state anxious individuals demonstrated enhanced orienting to averted gaze when viewing laterally presented angry faces. These results provide novel evidence for

the rapid integration of facial expression and

gaze direction information, and for the

regulation of gaze-cued attention by both the emotion conveyed in the perceived face and the

degree of anxiety experienced by the observer.

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Fox, Derakshan & Shoker 2008

Abstract – Department of Psychology, University of Essex, Colchester, Essex , UK. efox@essex.ac.uk

We investigated the electrophysiological markers of attentional bias for threat in anxiety. Low-anxiety and high-anxiety individuals performed a spatial-cueing task, in which an emotional facial expression (angry or happy) was presented alongside a neutral expression. Results revealed that angry expressions elicited an enhanced N2pc component, … true only for those reporting high levels of trait anxiety. These results confirm the early capture of spatial attention by threat-related stimuli, and demonstrate that this early bias is modulated by trait anxiety.

Enhanced P1 amplitudes to targets after presentations of angry expressions were also found; however, this effect was not modulated by trait anxiety levels. Our findings indicate that

individual differences in temperament

are an important determinant

of the early neural response to threat.

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Santesso et al 2008

Abstract – Department of Psychology, Harvard University, Cambridge, MA, USA.

The goal of this study was to examine behavioral and electrophysiological correlates of involuntary orienting toward rapidly presented angry faces in non-anxious, healthy adults using a dot-probe task in conjunction with high-density event-related potentials and a distributed source localization technique. Consistent with previous studies, participants showed hypervigilance toward angry faces, as indexed by facilitated response time for validly cued probes following angry faces and an enhanced P1 component.

An opposite pattern was found for happy faces suggesting that attention was directed toward the relatively more threatening stimuli within the visual field (neutral faces). Source localization of the P1 effect for angry faces indicated increased activity within the anterior cingulate cortex, possibly reflecting conflict experienced during invalidly cued trials. No modulation of the early C1 component was found for affect or spatial attention. Furthermore, the face-sensitive N170 was not modulated by emotional expression. Results suggest that the earliest modulation of spatial attention by face stimuli is manifested in the P1 component, and provide insights about mechanisms underlying attentional orienting toward cues of threat and social disapproval.

This social disapproval and cue of threat has to be connected to dominance and domination in the social hierarchy.  This would be about, in part, oxytocin and vasopressin.

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Pourtois et al 2004

Abstract – Neurology & Imaging of Cognition, University of Geneva, Switzerland. gilles.pourtois@medecine.unige.ch

We investigated the spatio-temporal dynamic of attentional bias towards fearful faces. Twelve participants performed a covert spatial orienting task while recording visual event-related brain potentials (VEPs). Each trial consisted of a pair of faces (one emotional and one neutral) briefly presented in the upper visual field, followed by a unilateral bar presented at the location of one of the faces. Participants had to judge the orientation of the bar. Comparing VEPs to bars shown at the location of an emotional (valid) versus neutral (invalid) face revealed an early effect of spatial validity: the lateral occipital P1 component (approximately 130 ms post-stimulus) was selectively increased when a bar replaced a fearful face compared to when the same bar replaced a neutral face. This effect was not found with upright happy faces or inverted fearful faces. A similar amplification of P1 has previously been observed in electrophysiological studies of spatial attention using non-emotional cues. In a behavioural control experiment, participants were also better at discriminating the orientation of the bar when it replaced a fearful rather than a neutral face. In addition, VEPs time-locked to the face-pair onset revealed a C1 component (approximately 90 ms) that was greater for fearful than happy faces. Source localization (LORETA) confirmed an extrastriate origin of the P1 response showing a spatial validity effect, and a striate origin of the C1 response showing an emotional valence effect. These data suggest that activity in primary visual cortex might be enhanced by fear cues as early as 90 ms post-stimulus, and that such effects might result in a subsequent facilitation of sensory processing for a stimulus appearing at the same location. These results provide evidence for neural mechanisms allowing rapid, exogenous spatial orienting of attention towards fear stimuli.

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Fox et al 2007

Abstract – Department of Psychology, University of Essex, Colchester, Essex, England. efox@essex.ac.uk

This study investigated the role of neutral, happy, fearful, and angry facial expressions in enhancing orienting to the direction of eye gaze. Photographs of faces with either direct or averted gaze were presented. A target letter (T or L) appeared unpredictably to the left or the right of the face, either 300 ms or 700 ms after gaze direction changed. Response times were faster in congruent conditions (i.e., when the eyes gazed toward the target) relative to incongruent conditions (when the eyes gazed away from the target letter). Facial expression did influence reaction times, but these effects were qualified by individual differences in self-reported anxiety.

High trait-anxious participants showed an enhanced orienting

to the eye gaze of faces with fearful expressions

relative to all other expressions.

In contrast, when the eyes stared straight ahead,

trait anxiety was associated with slower responding

when the facial expressions depicted anger.

Thus, in anxiety-prone people

attention is more likely to be held by an expression of anger, whereas attention is guided more potently by fearful facial expressions.

Maybe we need to find a different word to use other than anxiety.

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Putman, Hermans & van Honk 2006

Abstract – Affective Neuroscience Section, Helmholtz Institute, Utrecht University, Utrecht, Netherlands. P.Putman@fss.uu.nl

This study investigated in 2 experiments whether reflexive cuing of attention that occurs after perception of a gaze cue is greater for fearful than for happy faces in normal participants, as hypothesized from a social neuroscience perspective. To increase neuroecological validity, dynamic stimulus presentation was used to display faces that simultaneously morphed from a neutral expression into a happy or fearful one and shifted eye gaze from the center to the periphery. Shifts of attention resulting from a natural fearful gaze were expected to be related to participants’ anxiety traits, in agreement with the often found increased selective attention to threat in anxious participants.

Both hypotheses were confirmed: Fearful faces induced stronger gaze cuing than happy faces, and the strength of this cuing effect was correlated to participants’ anxiety levels. These results

suggest a

neural network,

which integrates

the processing of gaze, expression, and emotional states

to adaptively prime vigilance under threatening circumstances.

Is that all they can do, study the perception of emotion but not the expression of emotion?

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Putman, Saevarsson & van Honk 2007

Abstract – Affective Neuroscience, Helmholtz Institute, Utrecht University, Utrecht, The Netherlands. pputman@fsw.leidenuniv.nl

Hypomania

in bipolar disorders

is characterized by disinhibited, fearless and reward-seeking behavior.

This behavioral pattern suggests that early and automatic responding

to socio-emotional cues such as facial expressions

might be aberrant in hypomania.

The present study tested the predictions that participants selected on hypomania-like trait would show hypovigilant responses to facial cues of danger and increased responses to facial cues of reward. METHODS: From a group of 513, the 16 most trait-hypomanic individuals were selected by use of a shortened version of an established self-report instrument, the General Behavior Inventory (GBI). Their spatial-attentional responses after perception of dynamic fearful and happy facial gaze cues were compared with those of 12 controls. RESULTS: The group difference for full GBI hypomania scores was reliable (p=0.000).

Individuals with elevated hypomanic traits

clearly demonstrated attentional hypovigilance

after perception of fearful, laterally gazing faces

In addition, unlike controls, they demonstrated reliable attentional responding to happy gaze cues (p=0.007). CONCLUSIONS: These data provide the first experimental evidence that

hypomania-like trait

is associated with hypovigilant, fearless responding

to the social cue of an emotionally expressive gaze.

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Brosch et al 2008

Abstract – Swiss Centre for Affective Sciences, Department of Psychology, University of Geneva, Geneva, Switzerland. tobias.brosch@pse.unige.ch

There is much empirical evidence for

modulation of attention by negative — particularly fear-relevant — emotional stimuli.

This modulation is often explained in terms of a fear module.

Appraisal theories of emotion posit a more general mechanism, predicting attention capture by stimuli that are relevant for the needs and goals of the organism, regardless of valence. To examine the brain-activation patterns underlying attentional modulation, we recorded event-related potentials from 20 subjects performing a dot-probe task in which the cues were fear-inducing and nurturance-inducing stimuli (i.e., anger faces and baby faces). Highly similar validity modulation was found for the P1 time-locked to target onset, indicating

early attentional capture by both positive and negative emotional stimuli.

Topographic segmentation analysis and source localization indicate that

the same amplification process is involved

whether attention orienting is triggered by

negative, fear-relevant stimuli

or positive, nurturance-relevant stimuli.

These results confirm that

biological relevance,

and not exclusively fear,

produces an automatic spatial orienting

toward the location of a stimulus.

This is an important finding and lets us know that expenditure of energy in the brain is equal on the attentional level for the good and for the bad – what happens next, and which brain circuits are recruited to respond determine which neural circuits get reinforced, deepened, “firmed up” in the brain – from the beginning.  Orienting in physical space includes the space within our skull.

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Pourtois et al 2006b

Abstract – Neurology & Imaging of Cognition Laboratory, Department of Neuroscience & Neurology Clinic, University Medical Centre (CMU), Geneva, Switzerland. patrick.vuilleumier@medicine.unige.ch

People often remain “blind” to visual changes occurring during a brief interruption of the display.

The processing stages responsible for such failure remain unresolved. We used event-related potentials to determine the

time course of brain activity during conscious change detection versus change blindness.

Participants saw two successive visual displays, each with two faces, and reported whether one of the faces changed between the first and second displays.

Relative to blindness, change detection was associated with a distinct pattern of neural activity at several successive processing stages, including an enhanced occipital P1 response and a sustained frontal activity (CNV-like potential) after the first display, before the change itself. The amplitude of the N170 and P3 responses after the second visual display were also modulated by awareness of the face change. Furthermore, a unique topography of event-related potential activity was observed during correct change and correct no-change reports, but not during blindness, with a recurrent time course in the stimulus sequence and simultaneous sources in the parietal and temporo-occipital cortex.

These results indicate that

awareness of visual changes may depend on the attentional state subserved by coordinated neural activity in a distributed network,

before the onset of the change itself.

Another implication for dissociation in my book – if our attention cannot shift away from what it is “fixed” on easily and flexibly, we will “stagger” if not miss entirely changes that come up in our constantly changing environment.

This is not true only of visual changes.

What about auditory perceptions?

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Kim & Hamann 2007

Abstract – Psychology Department, Emory University, Atlanta, GA 30322, USA.

The ability to cope adaptively with emotional events

by volitionally altering one’s emotional reactions

is important for psychological and physical health

as well as social interaction.

This is the action abilities damaged with early abuse during brain development.  This is also one of the modulatory requirements of the empathy experience.

Cognitive regulation of emotional responses

to aversive events

engages prefrontal regions that modulate activity

in emotion-processing regions such as the amygdala.

Here, to, implications for avoidant insecure attachment patterns.

However,

the neural correlates of the regulation of positive emotions

remain largely unexplored. We used event-related functional magnetic resonance imaging to examine the neural correlates of cognitively increasing and decreasing emotional reactions to positive and negative stimuli. Participants viewed negative, positive, and neutral pictures while attempting to increase, decrease, or not alter their emotional reactions. Subjective reactions were assessed via on-line ratings. Consistent with previous studies,

increasing negative and positive emotion engaged primarily

left-lateralized prefrontal regions,

whereas decreasing emotion activated

bilateral prefrontal regions.

Different activations unique to increasing versus decreasing emotion were observed

for positive and negative stimuli:

Unique increase-related activations were observed only for positive stimuli,

whereas unique decrease-related activations were observed only for negative stimuli.

Regulation also modulated activity in the amygdala,

a key emotion-processing region.

Regulation effects on amygdala activity were larger for positive than for negative stimuli, potentially reflecting a greater malleability of positive emotional reactions.

Increasing and decreasing positive and negative emotion

can thus increase and decrease subjective reactions

and associated amygdala activity in line with regulatory goals,

and is associated with different patterns of prefrontal activation

as a function of emotional valence and regulatory goal.

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Ochsner et al 2004

Abstract – Department of Psychology, Columbia University, 369 Schermerhorn Hall, New York, NY 10027, USA. ochsner@psych.columbia.edu

Functional neuroimaging studies examining the

neural bases of the cognitive control of emotion

have found increased prefrontal and decreased amygdala activation for the reduction or down-regulation of negative emotion. This would probably show as a turning of the head, even slightly, to the right to activate the left regions of the brain?

It is unknown, however, (1) whether the same neural systems underlie the enhancement or up-regulation of emotion, and (2) whether altering the nature of the regulatory strategy alters the neural systems mediating the regulation. To address these questions using functional magnetic resonance imaging (fMRI), participants

up- and down-regulated negative emotion

either by focusing internally

on the self-relevance of aversive scenes

or by focusing externally on alternative meanings

for pictured actions and their situational contexts.

Results indicated

(1a) that both up- and down-regulating negative emotion recruited prefrontal and anterior cingulate regions implicated in cognitive control,

(1b) that amygdala activation was modulated up or down in accord with the regulatory goal, and

(1c) that up-regulation

uniquely recruited regions of left rostromedial PFC implicated in the retrieval of emotion knowledge, yet, I bet, another region implicated in dissociation

whereas down-regulation

uniquely recruited regions of

right lateral and orbital PFC implicated in behavioral inhibition.

self-focused regulation recruited

medial prefrontal regions

implicated in internally focused processing, this possibly including the precuneus [medial parietal region?]

whereas situation-focused regulation

recruited lateral prefrontal regions implicated in

externally focused processing.

These data suggest that both common and distinct neural systems support various forms of reappraisal and that

which particular prefrontal systems modulate the amygdala

in different ways

depends on the regulatory goal and strategy employed.

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Ochsner et al 2002

Abstract – Stanford University, USA.

The ability to cognitively regulate emotional responses to aversive events is important for mental and physical health. Little is known, however, about neural bases of the cognitive control of emotion. The present study employed functional magnetic resonance imaging to examine the neural systems used to reappraise highly negative scenes in unemotional terms. Reappraisal of highly negative scenes reduced subjective experience of negative affect.

Neural correlates of reappraisal

were increased activation of the lateral and medial prefrontal regions and

decreased activation of the amygdala and medial orbito-frontal cortex.

These findings support the hypothesis that

prefrontal cortex is involved in constructing

reappraisal strategies that can modulate activity

in multiple emotion-processing systems.

This is not accounting for the fact that much of this activity occurs automatically and unconsciously.

I am extremely uncomfortable if I cannot read someone’s emotions.  It is like they

Are emotionally dead to me and I am “with” a corpse.  To feel is to live to me.  Btu, then, I am not one of the people who can easily use cognition to change or control how I feel about anything.

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Eippert et al 2007

Abstract – Institute of Medical Psychology and Behavioral Neurobiology, University of Tuebingen, Germany. f.eippert@uke.uni-hamburg.de

The capacity to voluntarily regulate emotions is critical for mental health, especially when coping with aversive events.

Several neuroimaging studies of emotion regulation found the amygdala to be a target for downregulation and

prefrontal regions to be associated with downregulation.

To characterize the role of prefrontal regions in bidirectional emotion regulation and to investigate regulatory influences on amygdala activity and peripheral physiological measures, a functional magnetic resonance imaging (fMRI) study with simultaneous recording of self-report, startle eyeblink, and skin conductance responses was carried out. Subjects viewed threat-related pictures and were asked to up- and downregulate their emotional responses using reappraisal strategies. I would think that reappraisal strategies would be laborious and very slow compared to the innate automatic responses!  The laboratory is NOT a natural environment for threat

While startle eyeblink responses (in successful regulators) what makes a person a successful regulator? and skin conductance responses were amplified during upregulation, but showed no consistent effect during downregulation,

amygdala activity was increased and decreased according to the regulation instructions. Trial-by-trial ratings of regulation success correlated positively with activity in amygdala during upregulation and orbitofrontal cortex during downregulation.

Downregulation

was characterized by left-hemispheric activation peaks

in anterior cingulate cortex,

dorsolateral prefrontal cortex, and

orbitofrontal cortex

and upregulation

was characterized by a pattern of prefrontal activation

not restricted to the left hemisphere.

Further analyses showed significant overlap of prefrontal activation across both regulation conditions, possibly reflecting cognitive processes underlying both up- and downregulation, but also showed distinct activations in each condition.

The present study demonstrates that

amygdala responses to threat-related stimuli

can be controlled through the use of cognitive strategies depending on recruitment of prefrontal areas,

thereby changing the subject’s affective state.

This study is not about REAL threat – not in a natural situation.  Is this related to the process of detachment?  Of avoidance?  Whatever it is, it beats drugs in my opinion.  And yet for people whose brains formed under extremely adverse conditions, I suspect that there are complications and additive difficulties in implementing this process.  But we can all learn?  This report does not take into consideration the social context of our species, either, and seems to suggest that it is an independent process – which it is essentially, as it is an internal one.

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Sander et al 2005

Abstract – Geneva Emotion Research Group, Department of Psychology, University of Geneva, Switzerland. david.sander@pse.unige.ch

Multiple levels of processing

are thought to be involved in the appraisal

of emotionally relevant events,

with some processes

being engaged relatively independently of attention,

whereas other processes may depend on attention and current task goals or context.

We conducted an event-related fMRI experiment to examine how processing angry voice prosody,

an affectively and socially salient signal,

is modulated by voluntary attention.

Think here about an infant, or even one still in the womb, hears and responds to the sound of rage.  The fact that we have innate reactions to this “social signal” implicates genetic involvement – and plasticity or flexibility and adaptability

In this area is especially important to consider with abused children who in the beginning have no way, except biologically, to process these rage filled experiences.

To manipulate attention orthogonally to emotional prosody, we used a dichotic listening paradigm in which meaningless utterances, pronounced with either angry or neutral prosody, were presented simultaneously to both ears on each trial. In two successive blocks, participants selectively attended to either the left or right ear and performed a gender-decision on the voice heard on the target side.

Our results revealed a functional dissociation

between different brain areas.

We need to begin to understand that so-called dissociation

Has at its source very real functional dissociational abilities

Locked into the actual physiological operational processes

Of and within the brain itself.

Dissociation is NOT a mystery.  In all my thousands of hours of study I have yet to encounter an adequate description of what dissociation might ACTUALLY be.  It no more involves defense “mechanisms” than does the processes involved in remembering our name.

Whereas the

right amygdala and bilateral superior temporal sulcus responded to anger prosody irrespective of

whether it was heard from

a to-be-attended or to-be-ignored voice,

the orbitofrontal cortex and the cuneus in medial occipital cortex showed greater activation

to the same emotional stimuli when the angry voice

was to-be-attended rather than to-be-ignored.

So if we talk about the developing brain in this regard, an infant would learn very early on that the angry voice was connected to harm, threat, pain and therefore could not be ignored.  The orbitofrontal cortex and the cuneus in medial occipital cortex would be called into play very early, far earlier than it would need to either in an infant that never heard an angry voice, or heard one that was not connected to persona harm to itself.

Would the experts call this fear conditioning?  Pretty essential and natural response, I would say.  Of course I am not enough of an expert to follow my own trains of thoughts here, but if I were an expert, this is one of the places I would look for the genesis of dissociation!  And therefore for the epigenetic contributions to how these early disasters play themselves out in a persons body, brain, and life time.

Furthermore, regression analyses revealed

a strong correlation between orbitofrontal regions

and sensitivity

on a behavioral inhibition scale measuring

proneness to anxiety reactions.

I always sense a bias here that “sensitivity” and “anxiety proneness”

Are a BAD thing, undesirable – “dysfunctional”

Is this an American bias, in a country where we are all supposed to be TOUGH?

Our results underscore the importance of emotion and attention interactions in social cognition by demonstrating that multiple levels of processing are involved in the appraisal of emotionally relevant cues in voices, and by showing a modulation of some emotional responses by both the current task-demands and individual differences.

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some internet interplay around the word “anxiety”:

  • S: (n) anxiety, anxiousness ((psychiatry) a relatively permanent state of worry and nervousness occurring in a variety of mental disorders, usually accompanied by compulsive behavior or attacks of panic)
  • S: (n) anxiety (a vague unpleasant emotion that is experienced in anticipation of some (usually ill-defined) misfortune)

Definition

Anxiety is a multisystem response to a perceived threat or danger. It reflects a combination of biochemical changes in the body, the patient’s personal history and memory, and the social situation. As far as we know, anxiety is a uniquely human experience. Other animals clearly know fear, but human anxiety involves an ability, to use memory and imagination to move backward and forward in time, that animals do not appear to have. The anxiety that occurs in post-traumatic syndromes indicates that human memory is a much more complicated mental function than animal memory. Moreover, a large portion of human anxiety is produced by anticipation of future events. Without a sense of personal continuity over time, people would not have the “raw materials” of anxiety.

It is important to distinguish between anxiety as a feeling or experience, and an anxiety disorder as a psychiatric diagnosis. A person may feel anxious without having an anxiety disorder. Also a person facing a clear and present danger or a realistic fear is not usually considered to be in a state of anxiety. In addition, anxiety frequently occurs as a symptom in other categories of psychiatric disturbance.

Who decides what a “realistic clear and present danger” is?  Especially when a person is prepared not only through their DNA to be especially sensitive, but also through horrific early experiences that formed their entire body in the first place?

I bristle at the word anxious and anxiety.

Webster places anxiety at 1525 for introduction into our language.

Main Entry:

anx·ious

Pronunciation:

\ˈaŋ(k)-shəs\

Function:

adjective

Etymology:

Latin anxius; akin to Latin angere to strangle, distress — more at anger

Date:

circa 1616

1 : characterized by extreme uneasiness of mind or brooding fear about some contingency : worried <anxious parents> 2 : characterized by, resulting from, or causing anxiety : worrying <an anxious night> 3 : ardently or earnestly wishing <anxious to learn more>

Oh, that’s interesting.  Word origin strangle, distress, anger, even this word entering the language in 1616 is a newcomer.  How did we change anger into worry in our language?  In looking at “worry” the same I find the same connotation of restriction, strangulation, choking.  Yet if one follows “choke” it leads to what matters, either abiding or not abiding – e.g. life or death.

The streams, like blood vessels shifting into capillaries, rivers into streams back up to the headwaters, to the source – the whole “image” in the word anxiety is hard to define, hard to trace, hard to pin down – yet seems to head backwards into an area that concerns an ancient pattern of power versus no power – who has the power and who does not or is not allowed to have the power or be empowered, the disempowered.  The issue underlying the anxiety spectrum is about dominance and competence in the fight to stay alive, not to succumb to what is dangerous, not to be overwhelmed and eliminated by what one must fight.

It is connected in its origins to “reckless blindness in the darkness (temerity).”  It is about what we can withstand, tolerate, stand against.  It concerns acquiescing, giving in or giving up – or not.  About being daring, bold, fool hardy.  It is connected deeply to a sense and a concern with caution.  It is connected to waiting, continuance, continuing on, the sojourn (temporary stay in a place).  Through its connection to “bide” it goes directly to belief and trust.

Now I am getting the sense of the history of the human race in our recent history, at most 70,000 years ago when we began our journey out of Africa.  We traveled and we tarried for a time in one place or another.  Some of us continued to move more than other groups did.  What concepts do we, as humans, still retain in our languages that talk of time so far back?  What did we converse about 140,00 – 200,000 years ago when our FOXP2 gene became active and we began to talk to each other?  Before the traveling began?

When we go to bearing something, withstanding something, again the concept and image go back prior to the 12th century.

Main Entry: 1wor·ry

Function: verb

Inflected Form(s): wor·ried; wor·ry·ing

Etymology: Middle English worien, from Old English wyrgan; akin to Old High German wurgen to strangle, Lithuanian veržti to constrict

Date: before 12th century

transitive verb1dialect British : choke , strangle2 a: to harass by tearing, biting, or snapping especially at the throat b: to shake or pull at with the teeth <a terrier worrying a rat> c: to touch or disturb something repeatedly d: to change the position of or adjust by repeated pushing or hauling3 a: to assail with rough or aggressive attack or treatment : torment b: to subject to persistent or nagging attention or effort4: to afflict with mental distress or agitation : make anxious intransitive verb1dialect British : strangle , choke2: to move, proceed, or progress by unceasing or difficult effort : struggle3: to feel or experience concern or anxiety : fret <worrying about his health>

wor·ried·ly \-(r)ēd-lē, -(r)əd-\ adverb

wor·ri·er \-(r)ē-ər\ noun

wor·ry·ing·ly adverb

synonyms worry , annoy , harass , harry , plague , pester , tease mean to disturb or irritate by persistent acts. worry implies an incessant goading or attacking that drives one to desperation <pursued a policy of worrying the enemy>. annoy implies disturbing one’s composure or peace of mind by intrusion, interference, or petty attacks <you’re doing that just to annoy me>. harass implies petty persecutions or burdensome demands that exhaust one’s nervous or mental power <harassed on all sides by creditors>. harry may imply heavy oppression or maltreatment <the strikers had been harried by thugs>. plague implies a painful and persistent affliction <plagued all her life by poverty>. pester stresses the repetition of petty attacks <constantly pestered with trivial complaints>. tease suggests an attempt to break down one’s resistance or rouse to wrath <children teased the dog>.

Main Entry: 1choke

Function: verb

Inflected Form(s): choked; chok·ing

Etymology: Middle English, alteration of achoken, from Old English ācēocian, from ā-, perfective prefix + cēoce, cēace jaw, cheek — more at abide, cheek

Date: 14th century

Main Entry: abide

Function: verb

Inflected Form(s): abode \-ˈbōd\ or abid·ed; abid·ing

Etymology: Middle English, from Old English ābīdan, from ā-, perfective prefix + bīdan to bide; akin to Old High German ir-, perfective prefix — more at BIDE

Date: before 12th century

transitive verb1: to wait for : await2 a: to endure without yielding : withstand b: to bear patiently : tolerate <cannot abide such bigots>3: to accept without objection <will abide your decision>intransitive verb1: to remain stable or fixed in a state2: to continue in a place : sojourn

synonyms see bear, continue

abid·er noun

abide by

1: to conform to <abide by the rules>2: to acquiesce in <will abide by your decision>

Main Entry: 1cheek

Function: noun

Etymology: Middle English cheke, from Old English cēace; akin to Middle Low German kāke jawbone

Date: before 12th century

1: the fleshy side of the face below the eye and above and to the side of the mouth ; broadly : the lateral aspect of the head2: something suggestive of the human cheek in position or form ; especially : one of two laterally paired parts3: insolent boldness and self-assurance4: buttock 1

synonyms see temerity

cheek·ful \-ˌfu̇l\ noun

Main Entry: te·mer·i·ty

Function: noun

Inflected Form(s): plural te·mer·i·ties

Etymology: Middle English temeryte, from Latin temeritas, from temere blindly, recklessly; akin to Old High German demar darkness, Latin tenebrae, Sanskrit tamas

Date: 15th century

1 : unreasonable or foolhardy contempt of danger or opposition : rashness , recklessness 2 : an act or instance of temerity

synonyms temerity , audacity , hardihood , effrontery , nerve , cheek , gall , chutzpah mean conspicuous or flagrant boldness. temerity suggests boldness arising from rashness and contempt of danger <had the temerity to refuse>. audacity implies a disregard of restraints commonly imposed by convention or prudence <an entrepreneur with audacity and vision>. hardihood suggests firmness in daring and defiance <admired for her hardihood>. effrontery implies shameless, insolent disregard of propriety or courtesy <outraged at his effrontery>. nerve , cheek , gall, and chutzpah are informal equivalents for effrontery <the nerve of that guy> <has the cheek to call herself a singer> <had the gall to demand proof> <the chutzpah needed for a career in show business>.

Main Entry: bide

Function: verb

Inflected Form(s): bode \ˈbōd\ or bid·ed; bided; bid·ing

Etymology: Middle English, from Old English bīdan; akin to Old High German bītan to wait, Latin fidere to trust, Greek peithesthai to believe

Date: before 12th century

transitive verb1past usually bided : to wait for —used chiefly in the phrase bide one’s time2archaic : withstand <two men…might bide the winter storm — W. C. Bryant>3chiefly dialect : to put up with : tolerate intransitive verb1: to continue in a state or condition2: to wait awhile : tarry3: to continue in a place : sojourn

bid·er noun

Main Entry: 2bear

Function: verb

Inflected Form(s): bore \ˈbȯr\ ; borne also born \ˈbȯrn\ ; bear·ing

Etymology: Middle English beren to carry, bring forth, from Old English beran; akin to Old High German beran to carry, Latin ferre, Greek pherein

Looking elsewhere, this is a fascinating connection: metaphor, from metapherein, to transfer : meta-, meta- + pherein, to carry.] —  “a carrying over,” from metapherein “transfer, carry over,” from meta- “over, across” (see meta- above, beyond) + pherein “to carry, bear” — “Metaphor” comes from the Greek meta, over, and pherein, to bear. The basic definition of metaphor thus has to do with movement, with a carrying over – Derived from the Greek verb meta-pherein, which means to transfer or to translate (the Latin word for metaphor being ‘translatio’)

Also: The term “pheromone” was introduced by Peter Karlson and Martin Lüscher in 1959, based on the Greek pherein (to transport) and hormon (to stimulate).  [chemical signaling, communication]

Also: EuphoriaNew Latin, from Greek, from euphoros, healthy : eu-, eu- + pherein, to bear; “bearing well,” from eu- “well” + pherein “to carry”

Also: Periphery[Greek peri- around + pherein to bear] — The word “peripheral” comes from the Greek “peripheria” (“peri-“, around or about + “pherein“, to bear, carry).

Also: ChristopherEtymology: ME Christofre < LL(Ec) Christophorus < Gr(Ec) Christophoros, lit., bearing Christ < christos (see Christ) + pherein, to bear  [word Christ is related to Greek origins in “anointed” which is related to “grime” – smearing over – anointed – ointment – back to Sanskrit “he slaves” back to Greek oil flask]

Also:  connected on the internet to “right to bear arms”; also a discussion of Aristotle and emotions, “bearing or carrying a favor to someone else”

Date:  before 12th century

transitive verb1 a: to move while holding up and supporting b: to be equipped or furnished with c: behave , conduct <bearing himself well> d: to have as a feature or characteristic <bears a likeness to her grandmother> e: to give as testimony <bear false witness> f: to have as an identification <bore the name of John> g: to hold in the mind or emotions <bear malice> h: disseminate i: lead , escort j: render , give2 a: to give birth to b: to produce as yield c (1): to permit growth of (2): contain <oil-bearing shale>3 a: to support the weight of : sustain b: to accept or allow oneself to be subjected to especially without giving way <couldn’t bear the pain> <I can’t bear seeing you cry> c: to call for as suitable or essential <it bears watching> d: to hold above, on top, or aloft e: to admit of : allow f: assume , accept4: thrust , pressintransitive verb1: to produce fruit : yield2 a: to force one’s way b: to extend in a direction indicated or implied c: to be situated : lie d: to become directed e: to go or incline in an indicated direction3: to support a weight or strain —often used with up4 a: to exert influence or force b: apply , pertain —often used with on or upon<facts bearing on the question>

bear a hand

: to join in and help out

bear arms

1: to carry or possess arms2: to serve as a soldier

bear fruit

: to come to satisfying fruition, production, or development

bear in mind

: to think of especially as a warning : remember

bear with

: to be indulgent, patient, or forbearing with

synonyms bear , suffer , endure , abide , tolerate , stand mean to put up with something trying or painful. bear usually implies the power to sustain without flinching or breaking <forced to bear a tragic loss>. suffer often suggests acceptance or passivity rather than courage or patience in bearing <suffering many insults>. endure implies continuing firm or resolute through trials and difficulties <endured years of rejection>. abide suggests acceptance without resistance or protest <cannot abide their rudeness>. tolerate suggests overcoming or successfully controlling an impulse to resist, avoid, or resent something injurious or distasteful <refused to tolerate such treatment>. stand emphasizes even more strongly the ability to bear without discomposure or flinching <unable to stand teasing>.

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Main Entry: 1an·ger

Function: verb

Inflected Form(s): an·gered; an·ger·ing \-g(ə-)riŋ\

Date: 13th century

transitive verb : to make angry <he was angered by the decision> intransitive verb : to become angry

This word, anger, still is new to our language – 14th century.  But now I think about a sort of emotional constriction even on the reality of our experience with this emotion, anger.  Looking into its relations, grief enters the picture – and narrow, strangling.  Perhaps a sort of choking or choking up over something?

The more I look into this strain of thought stemming from the word anxious, the less I like it.  I sense – being an “anxious” sensitive type – that there is a lie and a deception going on here, to disempower those of us who are “anxious trait types” and it reminds me of the witch hunts!

Main Entry: 2anger

Function: noun

Etymology: Middle English, affliction, anger, from Old Norse angr grief; akin to Old English enge narrow, Latin angere to strangle, Greek anchein

Date: 14th century

1 : a strong feeling of displeasure and usually of antagonism 2 : rage 2

an·ger·less \-ləs\ adjective

synonyms anger , ire , rage , fury , indignation , wrath mean an intense emotional state induced by displeasure. anger, the most general term, names the reaction but in itself conveys nothing about intensity or justification or manifestation of the emotional state <tried to hide his anger>. ire, more frequent in literary contexts, may suggest greater intensity than anger, often with an evident display of feeling <cheeks flushed dark with ire>. rage suggests loss of self-control from violence of emotion <screaming with rage>. fury is overmastering destructive rage that can verge on madness <in her fury she accused us all of betrayal>. indignation stresses righteous anger at what one considers unfair, mean, or shameful <a comment that caused general indignation>. wrath is likely to suggest a desire or intent to revenge or punish <rose in his wrath and struck his tormentor>.

anginas

One entry found.

Main Entry: an·gi·na

Function: noun

Etymology: Latin, throat inflammation, from Greek anchonē strangling, from anchein to strangle

Date: 1578

: a disease marked by spasmodic attacks of intense suffocative pain: as a: a severe inflammatory or ulcerated condition of the mouth or throat b: angina pectoris

— an·gi·nal \an-ˈjī-nəl, ˈan-jə-\ adjective

I’m going to look at strangle

Main Entry: stran·gle

Function: verb

Inflected Form(s): stran·gled; stran·gling \-g(ə-)liŋ\

Etymology: Middle English, from Anglo-French estrangler, from Latin strangulare, from Greek strangalan, from strangalē halter — more at strain

Date: 14th century

transitive verb1 a: to choke to death by compressing the throat with something (as a hand or rope) : throttle b: to obstruct seriously or fatally the normal breathing of c: stifle2: to suppress or hinder the rise, expression, or growth of <repression strangles free speech>intransitive verb1: to become strangled2: to die from or as if from interference with breathing

— stran·gler \-g(ə-)lər\ noun

Main Entry: 2strain

Function: verb

Etymology: Middle English, from Anglo-French estreindre, from Latin stringere to bind or draw tight, press together; akin to Greek strang-, stranx drop squeezed out, strangalē halter

Date: 14th century

transitive verb1 a: to draw tight : cause to fit firmly <strain the bandage over the wound> b: to stretch to maximum extension and tautness <strain a canvas over a frame>2 a: to exert (as oneself) to the utmost b: to injure by overuse, misuse, or excessive pressure <strained his back> c: to cause a change of form or size in (a body) by application of external force3: to squeeze or clasp tightly: as a: hug b: to compress painfully : constrict 4 a: to cause to pass through a strainer : filter b: to remove by straining <strain lumps out of the gravy>5: to stretch beyond a proper limit <that story strains my credulity>6obsolete : to squeeze out : extortintransitive verb1 a: to make violent efforts : strive <has to strain to reach the high notes> b: to pull against resistance <a dog straining at its leash> c: to contract the muscles forcefully in attempting to defecate —often used in the phrase strain at stool2: to pass through or as if through a strainer <the liquid strains readily>3: to make great difficulty or resistance : balk

strain a point

: to go beyond a usual, accepted, or proper limit or rule

Main Entry: 1hal·ter

Function: noun

Etymology: Middle English, from Old English hælftre; akin to Old High German halftra halter, Old English hielfe helve

Date: before 12th century

1 a: a rope or strap for leading or tying an animal b: a headstall usually with noseband and throatlatch to which a lead may be attached2: a rope for hanging criminals : noose ; also : death by hanging3: a woman’s blouse or top that leaves the back, arms, and midriff bare and that is typically held in place by straps around the neck and across the back

Main Entry: strive

Function: intransitive verb

Inflected Form(s): strove \ˈstrōv\ also strived \ˈstrīvd\ ; striv·en \ˈstri-vən\ or strived; striv·ing \ˈstrī-viŋ\

Etymology: Middle English, to quarrel, contend, fight, endeavor, from Anglo-French estriver to quarrel, from estri, estrif strife — more at strife

Date: 13th century

1 : to devote serious effort or energy : endeavor <strive to finish a project> 2 : to struggle in opposition : contend

synonyms see attempt

striv·er \ˈstrī-vər\ noun

Main Entry: strife

Function: noun

Etymology: Middle English strif, from Anglo-French estrif, estri, of Germanic origin; akin to Middle Dutch striden to fight, Old High German strītan to quarrel — more at stride

Date: 13th century

1 a: bitter sometimes violent conflict or dissension <political strife> b: an act of contention : fight , struggle2: exertion or contention for superiority3archaic : earnest endeavor

synonyms see discord

strife·less \ˈstrī-fləs\ adjective

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Mitchell 2006

abstract – School of Psychology and Clinical Language Sciences, University of Reading, Whiteknights Road, Reading, Berkshire RG6 6AL, UK. r.l.c.mitchell@rdg.ac.uk

We frequently encounter conflicting emotion cues. This study examined how the neural response to emotional prosody differed in the presence of congruent and incongruent lexico-semantic cues. Two hypotheses were assessed:

(i) decoding emotional prosody with conflicting lexico-semantic cues would activate

brain regions associated with

cognitive conflict

(anterior cingulate and dorsolateral prefrontal cortex)

or (ii) the increased attentional load of incongruent cues would modulate the activity of

regions that decode emotional prosody

(right lateral temporal cortex).

While the participants indicated the emotion conveyed by prosody, functional magnetic resonance imaging data were acquired on a 3T scanner using blood oxygenation level-dependent contrast. Using SPM5, the response to congruent cues was contrasted with that to emotional prosody alone, as was the response to incongruent lexico-semantic cues (for the ‘cognitive conflict’ hypothesis). The right lateral temporal lobe region of interest analyses examined modulation of activity in this brain region between these two contrasts (for the ‘prosody cortex’ hypothesis). Dorsolateral prefrontal and anterior cingulate cortex activity was not observed, and neither was attentional modulation of activity in right lateral temporal cortex activity. However,

decoding emotional prosody with incongruent lexico-semantic cues was strongly associated with

left inferior frontal gyrus activity.

This specialist form of conflict

is therefore not processed by the brain using the same neural resources as non-affective cognitive conflict

and neither can it be handled by associated sensory cortex alone.

The recruitment of inferior frontal cortex may indicate increased semantic processing demands but other contributory functions of this region should be explored

How does an infant’s developing brain learn about “matching” the look on its mother’s face with the sound of her words, and then as it progresses, determine the “matching” or congruency between her actual words and the sound of the words?

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Pourtois et al 2005b

Abstract – Donders Laboratory for Cognitive and Affective Neuroscience, University of Tilburg, Tilburg, The Netherlands. gilles.pourtois@medecine.unige.ch

Using positron emission tomography we explored brain regions activated during the perception of face expressions, emotional voices and combined audio-visual pairs.

A convergence region

situated in the left lateral temporal cortex

was more activated by bimodal stimuli

than by either visual only or auditory only stimuli.

Separate analyses for the emotions happiness and fear

revealed supplementary convergence areas

situated mainly

anteriorly in the left hemisphere for happy pairings

and in the right hemisphere for fear pairings

indicating

different neuro-anatomical substrates for multisensory integration of positive versus negative emotions.

Activation in the right extended amygdala

was obtained for fearful faces and fearful audio-visual pairs

but not for fearful voices only.

That’s interesting!  The visual information has to be put together with the audio part to trigger an amygdala involvement.  Does seeing a rageful face trigger this area even if the voice-only does not?

But what about fear contextual learning as the infant brain develops?  It had to happen quickly that I was terrified by the SOUND of my mother’s rageful voice, even if I could not see her.

These results suggest that

during the multisensory perception of emotion,

affective information from face and voice converge

in heteromodal regions of the human brain.

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O’Neill et al 2008

Abstract – Biological Psychiatry Research Unit, Brain Sciences Institute, Swinburne University of Technology, Melbourne, Australia. boneill@groupwise.swin.edu.au

BACKGROUND: The loudness dependence of the auditory evoked potential (LDAEP) has been suggested as a possible in vivo measure of central serotonin function. However, more recent studies suggest that the LDAEP may be modulated by multiple neuromodulatory systems in addition to the serotonergic system. Accordingly we further examined the effects of selective serotonin, dopamine and simultaneous serotonin and dopamine depletion on the LDAEP in healthy subjects. METHODS: The study employed a placebo-controlled, double-blind, cross over design. Fourteen subjects were tested under four acute treatment conditions: placebo (balanced amino acid drink), tryptophan (serotonin) depletion (ATD), tyrosine/phenylalanine (dopamine) depletion (ATPD) and combined tryptophan/tyrosine/phenylalanine (serotonin and dopamine) depletion (CMD). Testing was conducted 5.5 h post-depletion and changes in the amplitude of the N1/P2 at varying intensities (60, 70, 80, 90, 100 dB) were examined at C(Z). RESULTS: Greater than 80% plasma precursor depletion was achieved across all conditions. Despite significant depletion of monoamine precursors, ATD, (p = 0.318), ATPD (p = 0.061) and CMD (p = 0.104) had no effects on the LDAEP (60-100 dB). CONCLUSION:

Acute serotonin and dopamine depletion

did not modulate the loudness dependence of the auditory evoked potential (LDAEP).

This finding adds support to growing evidence that the loudness dependence of the auditory evoked potential (LDAEP) is insensitive to acute changes in serotonin and dopamine neurotransmission.

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Mann et al 2008

Abstract – Behavioural Neuroscience Laboratory, School of Psychology, Psychiatry and Psychological Medicine, Monash University, Melbourne, VIC, Australia.

Schizophrenia is associated with

impairments of sensorimotor [PPI] and sensory gating [P50]

as measured by

prepulse inhibition (PPI) of the acoustic startle response and

P50 suppression of the auditory event-related potential respectively.

While serotonin and dopamine play an important role in the pathophysiology and treatment of schizophrenia, their role in modulating PPI and P50 suppression in humans is yet to be fully clarified. To further explore the role of serotonin and dopamine in PPI and P50 suppression, we examined the effects of acute tryptophan depletion (to decrease serotonin) and acute tyrosine/phenylalanine depletion (to decrease dopamine) on PPI and P50 suppression in healthy human participants. In addition, we also examined for the first time, the effects of simultaneous serotonin and dopamine depletion (ie combined monoamine depletion) on PPI and P50 suppression. The study was a double-blind, placebo-controlled cross-over design in which 16 healthy male participants completed the PPI and P50 paradigms under four acute treatment conditions: (a) balanced/placebo control, (b) acute tryptophan depletion, (c) acute tyrosine/phenylalanine depletion, and (d) acute tyrosine/phenylalanine/tryptophan depletion (combined monoamine depletion). Selective depletion of dopamine had no significant effect on either PPI or P50 suppression, whereas selective serotonin depletion significantly disrupted PPI, but not P50 suppression. Finally, the simultaneous depletion of both serotonin and dopamine resulted in significant reduction of both PPI and P50 suppression.

We suggest these results can be explained by theories relating to optimal levels of monoaminergic neurotransmission and synergistic interactions between serotonergic and dopaminergic systems for normal ‘gating’ function.

These findings suggest that a dysfunction in both serotonin and dopamine neurotransmission may, in part, be responsible for the gating deficits observed in schizophrenia, and their normalization following administration of atypical antipsychotic drugs.

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Rose et al 2008

Abstract – Institut für Anatomie, Medizinische Fakultät, Otto-von-Guericke Universität, Magdeburg, Germany.

In the present study, reciprocal embryo transfers were conducted to examine genetic and maternal effects on the baseline and fear-sensitized acoustic startle response (ASR) in the two inbred strains C3H/HeN and DBA/2JHd and the outbred strain NMRI. The largest differences in the ASR were found in untreated strains (effect size 0.6). The transfer procedure per se had a significant effect on the behavior of NMRI mice resulting in a reduction in the baseline, and an increase in the fear-sensitized ASR. In contrast, there were no significant effects of the transfer procedure in the two inbred strains. Autosomal genetic effects had a stronger impact on the amplitude of the ASR (effect sizes 0.5) than sex (effect sizes 0.06) as revealed by reciprocal embryo transfer. Nevertheless, the genetic effects on the fear-sensitized ASR were somewhat more variable and strain-dependent (effect sizes 0.1-0.2). Global maternal effects were detected after embryo transfer into NMRI mothers resulting in a larger reduction of the ASR in the offspring of DBA and NMRI donors than C3H donors (effect sizes 0.1-0.2). An additional fostering procedure was introduced to dissect uterine and postnatal maternal effects in NMRI offspring. Uterine factors changed the baseline ASR of the offspring in direction of the recipient mother strain.

Surprisingly, postnatal maternal effects on the ASR were contrary to the behavior of the rearing mother. In conclusion,

both genetic and prenatal/postnatal maternal factors

persistently influenced the ASR of the offspring,

whereas the fear-sensitized ASR was mainly influenced by genetic factors.

Our study shows that uterine and postnatal maternal influences deserve more attention when determining the phenotype of genetically engineered mice at least in the first generation following embryo transfer.

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Bitsios & Giakoumaki 2005

Abstract – Department of Psychiatry and Behavioural Sciences, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece. pbitsios@med.uoc.gr

Relationship of prepulse inhibition of the startle reflex to attentional and executive mechanisms in man.

Prepulse inhibition (PPI) of the startle reflex

at short lead intervals is thought to reflect the operation

of a preattentive “sensorimotor gating” mechanism,

which suggests that processing of the prepulse stimulus

should not be modulated prior to its inhibitory effects on startle.

To test this hypothesis, we examined whether PPI is affected following habituation to the prepulse. PPI was measured in two sessions associated with either the presence (habituation condition) or the absence (control condition) of prepulse repetition. There was a trend for prepulse repetition to reduce the effectiveness of that prepulse in inhibiting the startle response. We also explored the relationship of PPI to scores in tests of selective and sustained attention and planning ability. Overall PPI performance was correlated to performance indices of planning ability and there was a trend level correlation with scores in selective but not sustained attention tests. These preliminary results merit further investigation.

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Ludewig et al 2002

Abstract – Psychiatric University Hospital Zurich, Department of Clinical Research, Zurich, Switzerland.

Prepulse inhibition (PPI) is an operational measure

of sensorimotor gating that is reduced in several neuropsychiatric disorders that are characterized by deficits in inhibition or gating of intrusive or irrelevant stimuli [might be related to latent inhibition?  Might be related to intrusions in PTSD, etc?]

Clinically, panic disorder (PD) patients have been described as having difficulties in inhibition of responding to sensory and cognitive events.

Because such difficulties may be due to failures in early stages of information processing, we examined PPI in patients with PD. Acoustic startle reactivity, habituation, and PPI (30-, 60-, 120-, 240-, and 2,000-ms interstimulus intervals) were assessed in patients with panic disorder (m/f = 10, 10) and age- and gender-matched healthy controls (m/f = 11, 10). PD patients were assessed with structured clinical interview for DSM-IV criteria with benzodiazepine treatment as an exclusion criterion.

Panic disorder patients exhibited normal startle reactivity, reduced habituation, and significantly reduced PPI in the 30-, 60-, and 240-ms prepulse conditions.

Within the PD group, the patients with high trait and state anxiety exhibited less PPI than patients with low trait and state anxiety.

Furthermore, in PD patients, decreased PPI correlated significantly with high trait but not state anxiety.

These data indicate that

early stages of sensory information processing

are abnormal in patients with PD.

These observed deficits in PPI could reflect

a more generalized difficulty in suppressing or gating information in panic disorder.

How is this related to difficulties with affect regulation overall?

The correlation between high trait anxiety and deficient PPI supports the hypothesis that sensorimotor gating abnormalities are an enduring feature of subjects with PD.

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Ludewig et al 2005

Abstract – Department of Research, Psychiatric Services of Aargau Canton, Brugg, Switzerland.

The plasticity of the startle reflex, including prepulse inhibition (PPI) and habituation, provides operational measures of information processing that are abnormal in several neuropsychiatric disorders characterized by deficits in suppression or inhibition of intrusive or irrelevant stimuli.

Clinically, patients with panic disorder (PD) have been described as having difficulties in the inhibition of their response to sensory and cognitive events.

Because such difficulties may be the result of failures in early stages of information processing, we hypothesized that startle reactivity, PPI and habituation are deficient in unmedicated patients with PD. Moreover, we tested whether there was a relation between startle reflex measures and dysfunctional cognition. METHODS: Fourteen unmedicated patients with PD (7 men, 7 women) and 28 healthy comparison subjects (14 men, 14 women) were recruited. Acoustic startle reactivity, habituation and PPI (30-ms, 60-ms, 120-ms, 240-ms and 2000-ms interstimulus intervals) were assessed in the patients with PD and the age-matched and sex-matched healthy controls. These data for unmedicated patients with PD were compared with those for 24 medicated patients with PD. Moreover, dysfunctional cognition in patients with PD was measured using the Body Sensations Questionnaire. RESULTS: Unmedicated patients with PD exhibited increased startle reactivity, reduced habituation and significantly reduced PPI in the 30-ms, 60-ms, 120-ms and 240-ms prepulse conditions.

Furthermore, in unmedicated patients with PD,

increased startle response and decreased habituation

were correlated significantly with higher cognitive dysfunction scores, but this was not the case for PPI.

CONCLUSIONS: These data indicate that the early stages of sensory information processing are abnormal in patients with PD in the absence of medication.

The observed deficits in PPI and habituation could reflect a more generalized difficulty in suppressing or gating information in PD.

The correlation between cognitive symptoms

and higher startle response and deficient habituation

supports the hypothesis that subjects with PD

have abnormalities in the early stages of information processing that lead to a cascade of downstream effects on cognition.

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Duley et al 2007

Abstract – University of Central Florida, Institute for Simulation and Training, Orlando, FL 32826, USA. aaronduley@gmail.com

This investigation examined whether gating related deficits among individuals with high trait anxiety could be moderated by an acute bout of exercise.

Low (LA) and high (HA) trait anxious participants engaged in either a quiet rest or an exercise session on separate occasions. Replicating previous findings, HA participants exhibited significantly reduced PPI at lead intervals of 30 and 60 ms relative to LA controls.

HA and LA participants were also found to occasion similar PPI following exercise relative to quiet rest.

This finding was found to be independent of the order in which quiet rest or exercise occurred, and was not a function of differences in raw startle blink amplitude between sessions.

The current results highlight the potential for PPI to index the potential anxiolytic effects of an acute exercise bout.

Exercise – modulating anxiety reaction as measured by PPI

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Varty et al 2006

Abstract – Department of Neurobiology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.

Male 129T2 and C57BL/6J mice were housed either in groups of three (socials) or singly (isolates) at weaning. Six and seven weeks later, prepulse inhibition (PPI), startle reactivity, and locomotor activity (LMA) were measured.

Isolation-reared mice of both strains exhibited PPI deficits compared to socially reared controls in at least one of the two PPI test sessions.

Isolation rearing had no effect on startle reactivity or habituation and only 129T2 isolates exhibited increased LMA.

Isolation rearing induced locomotor hyperactivity and PPI deficits in mice and may be an effective developmental manipulation to use in combination with studies of genetically altered mice.

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Powell et al 2002

Abstract – Department of Psychiatry, University of California San Diego, 9500 Gilman Drive -0804, La Jolla, CA 92093, USA.

Prepulse inhibition (PPI) of the acoustic startle reflex is an operational measure of sensorimotor gating and is reduced in neuropsychiatric disorders such as schizophrenia.

Isolation rearing of rats

is a developmentally specific, nonpharmacological manipulation that leads to deficits in sensorimotor gating

that mimic those observed in schizophrenia patients.

This study examined the effects of an added stressor (water deprivation) on the magnitude of the isolation rearing effect on PPI and locomotor activity. At the time of weaning, male (n = 80) and female (n = 80) rats were assigned to either social housing or isolation housing and were subsequently assigned to the water-deprived or non-water-deprived groups. Rats were tested for acoustic startle and PPI at 3, 5 and 7 weeks postweaning. Isolated rats showed a significant decrease in PPI that was apparent at all 3 weeks. Water deprivation did not significantly affect PPI, nor was there a significant interaction between housing and water treatment or between sex and housing. When tested in the Behavior Pattern Monitor to assess locomotor activity, isolated rats displayed decreased habituation across the 1-h test session. Water deprivation did not affect locomotor activity in any significant, independent manner, nor did it potentiate the effects of isolation rearing on locomotor habituation. In these studies,

both male and female Long-Evans rats

were sensitive to the PPI-disruptive and

locomotor-activating effects

of social isolation.

Isolation rearing significantly disrupts PPI

and locomotor habituation

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Bakshi & Geyer 1999

Abstract – Department of Psychiatry, University of Wisconsin at Madison, 53719, USA.

Presentation of a weak stimulus immediately before a startling stimulus decreases the magnitude of the resultant startle response.

This phenomenon, termed prepulse inhibition (PPI),

provides an operational measure of sensorimotor gating,

and is deficient in schizophrenia patients.

Clinically observed PPI deficits can be modeled in rodents by housing rats individually from weaning until adulthood.

The developmental time course of isolation rearing-induced PPI deficits, however, is unknown. The present studies characterized the ontogeny of isolation-induced PPI deficits and hyperactivity. Separate groups of Sprague-Dawley and Lister hooded rats were either singly housed (ISO) or socially housed (SOC, groups of two to three per cage) upon weaning and then maintained in these housing conditions for different periods of time until assessment of PPI and locomotor activity; animals were tested at time points that roughly corresponded to before puberty (2 weeks postweaning), during puberty (4 weeks postweaning), or after puberty (6-7 weeks post weaning).

PPI deficits were seen in Sprague-Dawley ISO rats at either the 4- or 6-, but not the 2-week time points. In contrast, hyperactivity was noted in these animals starting at the 2-week time point.

Lister rats showed the same general pattern of ISO-induced effects, with ISO-induced hyperactivity (observed 4 weeks postweaning) preceding ISO-induced PPI deficits (observed 7 weeks postweaning).

Therefore,

ISO produces

dissociable

effects on PPI and locomotor activity,

with PPI deficits emerging only during or after puberty.

ISO might thus provide a useful noninvasive tool with which to study the neural substrates of delayed-onset sensorimotor gating abnormalities.

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Krebs-Thomson et al 2001

Abstract – Department of Psychiatry, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, USA.

Isolation rearing is a developmentally specific non-pharmacological manipulation in rats that produces a deficit in sensorimotor gating, as measured by prepulse inhibition (PPI) of the startle reflex.

Previous research has demonstrated that the isolation rearing effect on PPI is sensitive to several factors, including the time of testing with respect to length of isolation, prepulse intensities used, strain of rats, and type of housing environment. This study tested whether handling is another factor that interacts with the isolation-rearing paradigm in PPI. Rats were housed either in the social (three rats per cage) or isolate (one rat per cage) conditions and were handled either 1-2 times per week (minimal handling) or on a daily basis (daily handling). All rats were then tested at 8 and 10 weeks post-weaning.

There was an interaction between housing and handling. In the minimal handling condition, isolation rearing produced a deficit in PPI. This effect was absent, however, in the daily handling condition. What, exactly, does handling change?  Stimulation?  “Bonding?” Thus, regular handling of rats may interfere with the observation of the isolation rearing effect on PPI and should be carefully controlled in studies using this animal model of PPI deficits.

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Cilia et al 2005

Abstract – Psychiatry CEDD, GlaxoSmithKline plc, New Frontiers Science Park, Third Avenue, Harlow, Essex, UK CM19 5AW. Jackie.2.Cilia@GSK.com

RATIONALE: Rats reared in social isolation from weaning show prepulse inhibition (PPI) deficits which are thought to model the sensorimotor gating deficits seen in schizophrenia and other psychiatric disorders. We have previously reported that ten cohorts of Lister Hooded rats reared in isolation showed robust and reliable PPI deficits. OBJECTIVE: Our methodology differed from those used by others (Weiss and Feldon in Psychopharmacology 156(2-3):305-326, 2001), most notably in the weaning of pups at postnatal day (PND) 28 compared with PND20-22. Since our initial report, we have studied 18 more cohorts weaned at PND28 and one cohort weaned at PND21. METHOD: At weaning, male Lister Hooded pups were singly (isolates) or group (n=5) housed (grouped). Eight weeks later, startle and PPI responses of isolates and grouped rats were investigated using conditions of fixed inter-stimulus interval (ISI) (pulse=110 dB/50 ms; prepulse (PP)=75-80 dB/30 ms; ISI=100 ms). RESULTS: Isolates from 14 of the subsequent 18 cohorts demonstrated PPI deficits, giving an overall success rate of 86% for all 28 cohorts. %PPI ranged from 12 to 26% in the isolates and from 26 to 47% in the grouped for the successful cohorts, compared to 16-30% (isolates) and 19-35% (grouped) for those that failed. Only five out of the 19 subsequent cohorts demonstrated startle hyperreactivity, which was unrelated to PPI response. The isolates from the cohort weaned at PND21 did not show a significant deficit in PPI, suggesting, in our hands at least, a requirement for weaning at PND28. CONCLUSION: The data presented here reinforce our original findings that isolation-rearing of Lister Hooded rats provides a viable, non-pharmacological model of impaired PPI.

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Perry et al 2007

Abstract – Department of Psychiatry, University of California, San Diego, California, USA. wperry@ucsd.edu

Prepulse inhibition (PPI) is an operational measure of sensorimotor gating and is impaired in a family of neuropsychiatric disorders

characterized by abnormalities of inhibitory function.

Adults with autistic disorder (AD) exhibit clinical features of inhibitory deficits, such as restrictive and repetitive behaviors, that may be explained by deficits in sensorimotor gating.

Adults with AD have sensorimotor gating deficits similar to other neurodevelopmental disorders, implicating a failure of normal inhibitory regulation of sensory, motor, and attentional mechanisms. Thus, PPI deficits may be indirectly linked to one of the hallmark features of AD.

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Babiloni et al 2005b

Abstract – Dipartimento di Fisiologia Umana e Farmacologia, Sezione di EEG ad Alta Risoluzione, Università degli Studi di Roma La Sapienza, Piazzale Aldo Moro 5, 00185 Rome, Italy. Claudio.Babiloni@uniroma1.it

It is well known that synchronization of cortical neurons

is modulated (“gating“) by the chronological interaction

between somatosensory and sensorimotor events.

I suspect this process is ripe for dissociation, particularly because it involves a chronological interaction which implicates time and timing, both distorted and affected by histories of inadequate and abusive early caregiving during brain formative time lines.

Information on gating and anticipation are both connected to the pain anticipation process, and anticipation and coping with incoming stimuli information.

This study tested the hypothesis that the

anticipatory processes for this interaction

increase the synchronization of cortical neurons

as revealed by negative event-related potentials (contingent negative variation, CNV). High-resolution electroencephalographic data (128 electrodes) were recorded in 14 subjects. In the “sensorimotor interaction” condition, the subjects were waiting for a galvanic somatosensory stimulation at the left hand concomitant with a Go or NoGo stimulus (50% of Go trials triggering right hand movements). In the control condition, the Go/NoGo stimulus followed the somatosensory stimulation of 1.5s. The electroencephalographic data were spatially enhanced by surface Laplacian estimation.

In the control condition, the CNV was observed only in the foreperiod between the somatosensory stimulation and Go/NoGo task (i.e. no CNV before the somatosensory stimuli). It was spatially localized in the primary sensorimotor area contralateral to the possible motor response.

In the “sensorimotor interaction” condition, the CNV preceded the concomitant somatosensory stimulation and Go/NoGo task and was distributed to the frontocentral midline other than the contralateral sensorimotor area.

These results suggest that the

anticipatory processes for sensorimotor interactions

increase the

synchronization of cortical neurons

in the frontocentral midline,

possibly due to mechanisms sub-serving

top-down attentional processes.

When the brain forms under conditions of no cause and effect, no accurate predictions, violence and chaos

How does one anticipate anything, let alone anticipate a “come back” or protective response to an impossible, overwhelming situation?

To what Schore refers to as the “unsolvable paradox?”

Authors are describing something that is supposed to happen at the frontocentral midline – an area NOT working right after severe child abuse – doesn’t even develop normally – maybe because it never got to “do its job”

Front, center, in the middle – what could we pay attention to?

What could we synchronize to?

How could we respond in an impossible situation?

What could we learn, practice, remember?  What could we trust?

What could we reliably pass back and forth between our hemispheres that could help us?

Danger.  Threat to existence.

The gating information leads directly to the expectation and anticipation of pain – in the pain section

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Babiloni et al 2005c

Abstract – Dipartimento di Fisiologia Umana e Farmacologia, Università degli Studi di Roma La Sapienza, Rome, Italy. claudio.babiloni@uniroma1.it

This high-resolution electroencephalographic (EEG) study on alpha event-related desynchronization (ERD) evaluated whether anticipatory activity precedes a sensorimotor interaction induced by concomitant painful stimuli and sensorimotor demand. An omitted-stimulus paradigm induced the expectancy of the painful stimulation at the left hand. In the experimental condition, the painful stimulation was associated with a visual go/no-go task triggering right-hand movements. Two control conditions manipulated the painful sensorimotor interaction variable.

Compared with the control conditions, the expectancy of the painful sensorimotor interaction increased the high-band alpha EEG oscillations over the right primary sensorimotor cortex contralateral to the nociceptive stimuli and, to a lesser extent, over the centroparietal midline. These findings suggest that concomitant painful stimuli and simple sensorimotor go/no-go demands affect anticipatory activity as revealed by alpha ERD

Thinking about the anticipation a severely abused child feels – all the time.  Where will the blows fall, when will they fall, there is no escape, no prediction, no avoiding the violence.  It has to play havoc with the developing brain one neural interaction after another – with consequences in the “finished” evolutionarily altered brain.

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Swerdlow et al 2006

Abstract – Department of Psychiatry, UCSD School of Medicine, La Jolla, CA 92093-0804, USA. nswerdlow@ucsd.edu

Prepulse inhibition of startle (‘PPI’), a cross-species measure of sensorimotor gating, is impaired in schizophrenia patients. Suppression of P50 event-related potentials (ERPs) in response to the second of two clicks (‘P50 gating’) is also impaired in schizophrenia. Suppression of N40 ERPs to the second of two clicks (‘N40 gating’) is thought by some to be a rat homolog of human P50 gating. Emerging evidence suggests differences in the neurobiology of deficits detected by PPI vs P50 (or N40) gating. We recorded PPI and N40 gating contemporaneously in rats, to assess convergence and divergence in the neurochemical regulation of these measures. Dose-response studies examined the effects of apomorphine (APO), phencyclidine (PCP) or the 5HT2A agonist DOI on PPI, and on motor responses to stimuli (S1 and S2) that elicit N40 gating. Effects of optimal drug doses on PPI and N40 gating were then assessed in other rats with implanted cortical surface electrodes. APO, PCP and DOI caused dose-dependent disruptions of both PPI and gating of motor responses to N40 stimuli. Reduced PPI reflected diminished prepulse effectiveness, demonstrated by increased startle levels on prepulse + pulse trials. In contrast, reduced gating of motor responses to N40 stimuli reflected a reduced motor response to S1. In separate rats, robust PPI, N40 potentials and N40 gating could be detected within one test. PPI and N40 gating were disrupted by APO, PCP, and DOI. Again, drug effects on PPI reflected increased startle on prepulse + pulse trials, while those on N40 gating reflected reduced ERP responses to S1. In conclusion, when PPI and N40 gating were studied concurrently in rats, drug effects on PPI reflected reduced inhibition of startle by the prepulse, while diminished N40 gating reflected S1 response suppression. Despite similarities in drug sensitivity, these results suggest that distinct neurobiological mechanisms underlie drug-induced deficits in PPI and N40 gating.

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Hazlett et al 2008

Abstract – Department of Psychiatry, Box 1505, Mount Sinai School of Medicine, New York, NY 10029, USA. erin.hazlett@mssm.edu

Prepulse inhibition (PPI)

refers to a reduction in the amplitude of

the startle eyeblink reflex

to a strong sensory stimulus, the pulse,

when it is preceded shortly by a weak stimulus, the prepulse.

PPI is a measure of sensorimotor gating

which serves to prevent the interruption

of early attentional processing

and it is impaired in schizophrenia-spectrum patients.

In healthy individuals, PPI is more robust

when attending to than ignoring a prepulse.

Animal and human work demonstrates that

frontal-striatal-thalamic (FST) circuitry

modulates PPI.

This study used functional magnetic resonance imaging (fMRI) to investigate FST circuitry during an attention-to-prepulse paradigm in 26 unmedicated schizophrenia-spectrum patients (13 schizotypal personality disorder (SPD), 13 schizophrenia) and 13 healthy controls. During 3T-fMRI acquisition and separately measured psychophysiological assessment of PPI, participants heard an intermixed series of high- and low-pitched tones serving as prepulses to an acoustic-startle stimulus. Event-related BOLD response amplitude curves in FST regions traced on co-registered anatomical MRI were examined.

Controls showed greater activation during attended

than ignored PPI conditions in all FST regions-

dorsolateral prefrontal cortex (Brodmann areas 46, 9), [9 is the precuneus?]

striatum (caudate, putamen), and the

thalamic mediodorsal nucleus.

In contrast, schizophrenia patients failed to show differential BOLD responses in frontal-striatal-thalamic (FST) circuitry

during attended and ignored prepulses, whereas SPD patients showed greater-than-normal activation during ignored prepulses.

Among the three diagnostic groups, lower left caudate BOLD activation during the attended PPI condition was associated with more deficient sensorimotor gating as measured by PPI.

Schizophrenia-spectrum patients exhibit inefficient utilization of FST circuitry during attentional modulation of PPI.

Schizophrenia patients have reduced recruitment of FST circuitry during task-relevant stimuli, whereas

SPD patients allocate excessive resources during task-irrelevant stimuli.

Dysfunctional

frontal-striatal-thalamic (FST)

activation, particularly in the caudate may underlie PPI abnormalities in schizophrenia-spectrum patients.

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Campbell et al 2007

Abstract – Schizophrenia Research Institute, Sydney, Australia.

Feedforward inhibition

deficits have been consistently demonstrated in a range of neuropsychiatric conditions using prepulse inhibition (PPI) of the acoustic startle eye-blink reflex when assessing sensorimotor gating.

While PPI can be recorded in acutely decerebrated rats, behavioral, pharmacological and psychophysiological studies

suggest the involvement of a complex neural network

extending from brainstem nuclei to higher order cortical areas.

The current functional magnetic resonance imaging study investigated the neural network underlying PPI and its association with electromyographically (EMG) recorded PPI of the acoustic startle eye-blink reflex in 16 healthy volunteers. A sparse imaging design was employed to model signal changes in blood oxygenation level-dependent (BOLD) responses to acoustic startle probes that were preceded by a prepulse at 120 ms or 480 ms stimulus onset asynchrony or without prepulse. Sensorimotor gating was EMG confirmed for the 120-ms prepulse condition, while startle responses in the 480-ms prepulse condition did not differ from startle alone. Multiple regression analysis of BOLD contrasts

identified activation in

pons, thalamus, caudate nuclei, left angular gyrus and

bilaterally in anterior cingulate,

associated with EMG-recorded sensorimotor gating.

Planned contrasts confirmed increased pons activation for startle alone vs 120-ms prepulse condition, while increased anterior superior frontal gyrus activation was confirmed for the reverse contrast. Our findings are consistent with a

primary pontine circuitry of sensorimotor gating

that interconnects

with inferior parietal, superior temporal, frontal and prefrontal cortices via thalamus and striatum.

PPI processes in the prefrontal, frontal and superior temporal cortex

were functionally distinct

from sensorimotor gating.

So they are saying that the gating itself is separate from the startle response based on a prepulse “warning” – as title of the article states – primary and secondary neural networks of auditory prepulse inhibition

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Quednow et al 2008b

Abstract – University Hospital of Psychiatry, Experimental Psychopathology and Brain Imaging, University of Zurich, Switzerland. quednow@bli.uzh.ch

Prepulse inhibition (PPI) of the acoustic startle response (ASR) has been established as an operational measure of sensorimotor gating.

Animal and human studies have shown that PPI can be modulated by dopaminergic, serotonergic, and glutamatergic drugs

and consequently it was proposed that impaired sensorimotor gating in schizophrenia parallels a central abnormality within the corresponding neurotransmitter systems.

Recent animal studies suggest that

the opioid system may also play a role

in the modulation of sensorimotor gating.

Thus, the present study investigated the influence of the mu-opioid receptor agonist morphine on PPI in healthy human volunteers. Eighteen male, non-smoking healthy volunteers each received placebo or 10 mg morphine sulphate (p.o.) at a 2-wk interval in a double-blind, randomized, and counterbalanced order. PPI was measured 75 min after drug/placebo intake. The effects of morphine on mood were measured by the Adjective Mood Rating Scale and side-effects were assessed by the List of Complaints. Additionally, we administered a comprehensive neuropsychological test battery consisting of tests of the Cambridge Neuropsychological Test Automated Battery and the Rey Auditory Verbal Learning Test. Morphine significantly increased PPI without affecting startle reactivity or habituation.

Furthermore, morphine selectively improved the error rate in an attentional set-shifting task but did not influence vigilance, memory, or executive functions.

These results imply that

the opioid system is involved in the modulation of PPI and attentional set-shifting in humans

and they raise the question whether the opioid system plays a crucial role also in the regulation of PPI and attentional set-shifting in schizophrenia.

Enter connections with brain formation and setting the operations for life regarding the fundamental circuitry underlying our responses within and to our environment on the most fundamental level.

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Swerdlow et al 2004

Abstract – Department of Psychiatry, UCSD School of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, USA. nswerdlow@ucsd.edu

RATIONALE AND OBJECTIVES: The disruption of prepulse inhibition (PPI) of startle in rats by dopamine agonists has been used in a predictive model for antipsychotics, and more recently, to study the neural basis of strain differences in dopaminergic function. We have previously reported that Sprague-Dawley (SDH) and Long Evans (LEH) rats differed in their sensitivity to the PPI-disruptive effects of the D(1)/D(2) agonist apomorphine (APO) in two distinct ways: 1) compared to LEH rats, SDH rats were more sensitive to the ability of APO to disrupt PPI with relatively long prepulse intervals (60-120 ms), and 2) APO enhanced PPI in LEH rats with 10-30 ms prepulse intervals, but this effect was limited to 10 ms prepulse intervals in SDH rats. METHODS: In the present study, we replicated this temporal profile in SDH versus LEH rats, assessed the role of D(1) versus D(2) substrates in the two components of this strain difference, and assessed the heritability of these temporally distinct processes. RESULTS: Pharmacologic studies revealed that: 1) D(2) blockade prevented the long interval PPI-disruptive effects of APO in both strains, and extended the temporal range of the PPI-enhancing effects of APO from 10 to 30 ms in SDH rats, and 2) D(1) blockade increased PPI and blocked the PPI-enhancing effects of APO at short intervals in both strains. Generational studies in adult F0 (SDH and LEH), F1 (SDHxLEH) and N2 (SDHxF1) rats demonstrated that sensitivity to APO of both short and long interval PPI were inherited in a manner suggestive of relatively simple additive effects of multiple genes. CONCLUSIONS: The present findings demonstrate that inherited differences in the dopaminergic regulation of sensorimotor gating are manifested not only in quantitative shifts (more versus less), but also in qualitative shifts in the temporal properties of sensorimotor gating that appear to be under separate control of D(1) and D(2) substrates.

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Csomor et al 2008

Abstract – 2University Hospital of Psychiatry Zurich, PO Box 1931, CH-8032 Zurich, Switzerland.

Deficient sensorimotor gating as indexed by prepulse inhibition (PPI) of the startle response has been reported repeatedly in patients suffering from schizophrenia.

According to the widely accepted “protective hypothesis,” PPI reflects the protection of ongoing information processing against interference by other stimuli.

Alternatively, it has been proposed that PPI might be regulated by startle reflex circuit excitability. In the present study, we evaluated these 2 conceptually divergent approaches underlying the regulation of PPI. To this end, we assessed sensorimotor gating as indexed by PPI, the reactivity to the prepulse-alone stimulus indexed as prepulse-elicited reactivity (PPER), and acoustic blink reflex excitability in terms of paired pulse suppression (PPS) within a single recording session in 13 unmedicated and 24 medicated (11 first break) schizophrenia patients in comparison to 43 healthy control subjects.

The results showed that PPI was significantly reduced in unmedicated, but not in medicated schizophrenia patients. Furthermore, unmedicated patients could be distinguished from the medicated patients and control subjects in terms of PPER. In contrast to PPI, PPS did not differ between patients and control subjects.

These findings are in line with the “protective hypothesis” of PPI and indicate that reduced sensorimotor gating in schizophrenia patients might be based on a reduced perception and/or processing of the prepulse stimulus.

The extent to which PPER may or may not be causally associated with sensorimotor gating in schizophrenia has to be further investigated in human and animal studies.

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Quednow et al 2008

Abstract – 2Department of Psychiatry, University of Bonn, Bonn, Germany.

It has been recently shown that

Catechol O-methyltransferase (COMT) Val(158)Met polymorphism

strongly influences prepulse inhibition (PPI)

of the acoustic startle response (ASR) in healthy human volunteers.

Given that schizophrenia patients exhibit impairment in PPI and that COMT is a putative susceptibility gene for schizophrenia, we investigated the impact of the COMT Val(158)Met polymorphisms on PPI in schizophrenic inpatients. We analyzed COMT Val(158)Met polymorphisms and assessed startle reactivity, habituation, and PPI of ASR in 68 Caucasian schizophrenia inpatients. Clinical symptoms were measured with the Positive and Negative Syndrome Scale (PANSS). Patients carrying the Val(158)Met Met/Met allele showed elevated PPI levels whereas startle reactivity and habituation did not differ from the other two genotypes.

These preliminary results imply that PPI is influenced by COMT Val(158)Met genotype in schizophrenia as well. In concert with other findings, our data suggest that

PPI is a polygenic trait.

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Roussos et al 2008

Abstract – Department of Psychiatry and Behavioural Sciences, University of Crete, Heraklion, Greece.

BACKGROUND: Recent evidence suggests that dopamine (DA) agonist-induced disruption of prepulse inhibition (PPI) depends on basal PPI values, in a manner that suggests an inverted U-shaped relationship between PPI and prefrontal DA levels. This is the first study to examine possible genetic determinants of PPI and the

catechol O-methyltransferase (COMT) Val158Met polymorphism,

the main catabolic pathway of released DA in the prefrontal cortex (PFC)

.Method PPI was measured in 93 healthy males presented with 75-dB and 85-dB prepulses at 60-ms and 120-ms prepulse-pulse intervals. Subjects were grouped according to their COMT status into a Val/Val, a Val/Met and a Met/Met group. RESULTS: ANOVAs showed that at all prepulse and interval conditions,

Val/Val individuals had the lowest PPI,

Met/Met the highest, and

Val/Met were intermediate.

CONCLUSIONS: These results suggest that PPI is regulated by DA neurotransmission in the PFC and its levels depend on the COMT Val158Met gene polymorphism. These findings enhance the value of the PPI paradigm in examining

individual variability

of early information processing in healthy subjects

and psychiatric disorders associated with changes in PFC DA activity and attentional deficits such as schizophrenia.

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Roussos, Giakoumaki & Bitsios 2008

Abstract – Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Greece.

DOPAMINE

BACKGROUND: The dopamine D(3) receptor (DRD(3)) is suspected to modulate prepulse inhibition (PPI) in animals and humans, but definite conclusions cannot be drawn due to lack of selective DRD(3) ligands.

The Ser9Gly polymorphism is a common variant of the DRD(3) gene and determines the gain of function of the D(3) receptor. This is the first study to examine the influence of the DRD(3) Ser9Gly polymorphism on human PPI. METHODS: Prepulse inhibition was measured in 101 healthy male subjects presented with 75-dB and 85-dB prepulses at 30-, 60-, and 120-msec prepulse-pulse intervals. Subjects were grouped according to their DRD(3) status into a Gly/Gly, a Ser/Gly, and a Ser/Ser group. RESULTS: Analyses of variance showed that

at all prepulse and interval conditions,

Gly/Gly individuals had the lowest PPI and the greatest onset latency facilitation and

Ser/Ser individuals had the highest PPI and the lowest onset latency facilitation, while

Ser/Gly individuals were intermediate.

CONCLUSIONS: These results suggest that PPI

is modulated by the D(3) receptor

and its levels depend on the Ser9Gly polymorphism.

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Postma et al 2006

Abstract – Department of Psychology, P078, Institute of Psychiatry, King’s College London, De Crespigny Park, London SE5 8AF, UK.

RATIONALE: Schizophrenia patients display an excessive rate of smoking compared to the general population.

Nicotine increases acoustic prepulse inhibition (PPI)

in animals as well as healthy humans,

suggesting that smoking may provide a way

of restoring deficient sensorimotor gating in schizophrenia.

So it helps protect against incoming stimuli, a sort of increase in screening or filtering of input, a down regulator of stimulation from external environment

No previous study has examined the neural mechanisms of the effect of nicotine on PPI in humans. OBJECTIVES: To investigate whether nicotine enhances tactile PPI in healthy subjects and patients with schizophrenia employing a double-blind, placebo-controlled, cross-over design and, if so, what are the neural correlates of nicotine-induced modulation of PPI. MATERIALS AND METHODS: In experiment 1, 12 healthy smokers, 12 healthy non-smokers and nine smoking schizophrenia patients underwent testing for tactile PPI on two occasions, 14 days apart, once after receiving (subcutaneously) 12 microg/kg body weight of nicotine and once after receiving saline (placebo). In experiment 2, six healthy subjects and five schizophrenia patients of the original sample (all male smokers) underwent functional magnetic resonance imaging (fMRI) under the same drug conditions and the same tactile PPI paradigm as in experiment 1. RESULTS:

Nicotine enhanced PPI in both groups.

A comparison of patterns of brain activation on nicotine vs placebo conditions showed increased activation of limbic regions and striatum

in both groups after nicotine administration. Subsequent correlational analyses demonstrated that

the PPI-enhancing effect of nicotine was related to

increased hippocampal activity in both groups.

CONCLUSIONS: Nicotine enhances tactile PPI in both healthy and schizophrenia groups. Our preliminary fMRI findings reveal that this effect is modulated by increased limbic activity.

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Hong et al 2008

Abstract – Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228, USA. ehong@mprc.umaryland.edu

Acoustic prepulse inhibition (PPI) is considered an important biomarker in animal studies of psychosis and a number of psychiatric conditions. Nicotine has been shown to improve acoustic PPI in some animal strains and in humans. However, there is little data on effects of nicotine on acoustic PPI in schizophrenia patients using a double-blind, placebo-controlled study design. The primary aim of the current study was to test the effect of nicotine nasal spray on acoustic PPI in schizophrenia patients. The secondary aim was to test nicotine effect on prepulse facilitation (PPF). The study included 18 schizophrenia patient smokers and 12 healthy control smokers, tested in a double-blind, placebo-controlled, crossover, randomized design immediately after nicotine or saline placebo nasal sprays. PPI was tested using 120 ms prepulse-pulse interval. PPF was tested using 4500 ms prepulse-pulse interval. The results showed a significant main effect of drug on PPI in that nicotine improved PPI compared to placebo (p=0.008) with no drug by diagnosis interaction (p=0.90).  True effect for both healthy and diagnosed

Improvement in PPI in response to nicotine was significantly correlated with the baseline severity of clinical symptoms (r=0.59, p=0.02) in patients. There was no significant drug or drug by diagnosis interaction for the 4500 ms prepulse-pulse interval condition. However, nicotine improved inhibition in a subgroup of subjects exhibiting PPF (p=0.002). In conclusion, the findings confirmed that nicotine transiently improves acoustic PPI in schizophrenia patients. Additionally, schizophrenia patients with more clinical symptoms may have benefited more from nicotinic effect on PPI.

So this is kind of like putting on sunglasses to cut glare and screen out UV rays – screening what we cannot process – preventing overload – used as a protection.  Does it have any similar effect against internal overload – or work in tandem with other internal gating operations?

This would suggest that those of us who have had too much stimulation from childhood, already having experienced overload, and those of us who are genetically geared to be super sensitive to our environments, and those who are working hard NOT to feel or react – are at high risk once we discover the gating effects of nicotine.

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Kumari et al 1997

Abstract – Department of Psychology, University of London, UK. v.kumari@iop.bpmf.ac.uk

In a double-blind placebo-controlled trial, the effects of two doses (6 micrograms/kg, 12 micrograms/kg) of acute SC nicotine were investigated on prepulse inhibition (PPI) of the acoustic startle reflex in healthy non-smoker male volunteers. Each subject received three injections [placebo (saline), 6 micrograms/kg nicotine, 12 micrograms/kg nicotine] on separate occasions, 2 weeks apart. No influence of either 6 micrograms/kg or 12 micrograms/kg nicotine was observed for the amplitude and habituation of the startle response over pulse-alone stimuli, relative to the saline-treated condition. Percent of PPI (expressed as percent reduction of non-prepulse trials) was significantly greater, but PPI as measured by absolute difference scores was not significantly different, when subjects were given the 12 micrograms/kg dose of nicotine than saline. There was an increase in percent of PPI from saline through low to high doses of nicotine, but PPI observed under the low dose did not differ significantly from either the high dose or placebo.

These results provide some support for previous findings showing an enhancement in PPI by cigarette smoking in overnight smoking-deprived smokers and by acutely administered nicotine in experimental animals. The findings indicate that

previously observed effects of smoking on percent of PPI

in smoking-deprived subjects were not attributable to the restoration of a deficit induced by smoking withdrawal,

but represent a direct pharmacological action of nicotine.

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Smolka et al 2006

Abstract – Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, Mannheim, Germany. smilka@zi-mannheim.de

RATIONALE: In nicotine-dependent subjects, cues related to smoking elicit activity in brain regions linked to attention, memory, emotion and motivation.

Cue-induced brain activation is associated with self-reported craving but further correlates are widely unknown. OBJECTIVES: This study was conducted to investigate whether brain activity elicited by smoking cues increases with severity of nicotine dependence and intensity of cue-elicited craving. METHODS: Ten healthy male smokers whose degree of nicotine dependence ranged from absent to severe were investigated. Visual smoking cues and neutral stimuli were presented in a block design during functional magnetic resonance imaging (fMRI). Using multiple linear regression analysis, the blood oxygen level dependent (BOLD) response to smoking cues was correlated with severity of nicotine dependence assessed with the Fagerström Test of Nicotine Dependence (FTND) and with cue-induced craving. RESULTS: Significant positive correlations between the BOLD activity and FTND scores were found in

brain areas related to

visuospatial attention (anterior cingulate cortex, parietal cortex, parahippocampal gyrus and cuneus)

and in regions involved in motor preparation and imagery (primary and premotor cortex, supplementary motor area).

Intensity of cue-induced craving was significantly associated with greater BOLD activation

in mesocorticolimbic areas engaged in incentive motivation

and in brain regions related to episodic memory.

Mirror neurons no doubt also come into play when exposed to people who are still smoking

The parietal cortex is associated with imagery, and with self reference – interesting, “I am a smoker” implications with self image

CONCLUSIONS: Our study suggests that

severity of nicotine dependence and intensity of craving

are independently associated with cue-induced brain activation in separate neuronal networks.

The observed association between severity of dependence and brain activity in regions involved in allocation of attention, motor preparation and imagery might reflect preparation of automated drug taking behavior thereby facilitating cue-induced relapse.

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McClernon, Kozink & Rose 2008

Abstract – Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27708, USA. mccle011@mc.duke.edu

Exposure to smoking cues increases craving for cigarettes and can precipitate relapse. Whereas brain imaging studies have identified a distinct network of brain regions subserving the processing of smoking cues, little is known about the influence of individual difference factors and withdrawal symptoms on brain cue reactivity. Multiple regression analysis was used to evaluate relations between individual difference factors and withdrawal symptoms and event-related blood oxygen level-dependent responses to visual smoking cues in a sample of 30 smokers. Predictors were self-report nicotine dependence (Fagerström test of nicotine dependence, FTND), prescan withdrawal symptoms (craving and negative affect), and sex. The unique variance of each predictor was examined after controlling for each of the others.

Positive associations were observed between FTND and reactivity to cues in right anterior cingulate and orbitofrontal cortex (OFC)

whereas negative associations were observed between prescan craving and reactivity in ventral striatum.

Higher negative affect or being male was associated with greater reactivity in left hippocampus and left OFC.

Women exhibited greater cue reactivity than men in regions including the cuneus and left superior temporal gyrus.

Individual difference factors and withdrawal symptoms were uniquely associated with brain reactivity to smoking cues in regions subserving reward, affect, attention, motivation, and memory. These findings provide further evidence that

In other words, pervasive.  Wondering about implications with cannabinoid system here

reactivity to conditioned drug cues is multiply determined and suggest that smoking cessation treatments designed to reduce cue reactivity focus on each of these variables.

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Quadflieg et al 2008

Abstract – Department of Biological and Clinical Psychology, Friedrich-Schiller-University, Am Steiger 3//1, D-07743 Jena, Germany. s.quadflieg@abdn.ac.uk

Individuals with social phobia [very new in our language, 1786; phobic, 1897] display neural hyperactivation towards angry facial expressions.

However, it is uncertain whether they also show abnormal brain responses when processing angry voices. Well, that’s what I mean, “abnormal.”  How do we know that these reactions are not perfectly normal??

In an event-related functional magnetic resonance imaging study, we investigated brain responses to neutral and angry voices in 12 healthy control participants and 12 individuals with social phobia when emotional prosody was either task-relevant or task-irrelevant.

Regardless of task, both phobic and non-phobic participants recruited a network comprising

frontotemporal regions,

the amygdala,

the insula, and

the striatum,

when listening to angry compared to neutral prosody.

Across participants, increased activation in orbitofrontal cortex during task-relevant as compared to task-irrelevant emotional prosody processing was found. Compared to healthy controls,

individuals with social phobia

displayed significantly stronger orbitofrontal activation

in response to angry versus neutral voices

under both task conditions.

These results suggest a disorder-associated increased involvement of the orbitofrontal cortex in response to threatening voices in social phobia.

This makes me “defensive” and angry.  Disorder-associated?  Why?  Because we sense different things differently and process this information differently?  WE ARE NOT ALL THE SAME!

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The following information is in my hardcopy dictionary, but I could not access it online.  In my opinion, it is near ludicrous, and “mentally ill” of any professional who would blanket a fear, flight and flight reaction as indicated in the roots of this concept as wrong or sick.  There is a reason why the fear reaction exists, even if it seem “pathological” and creates difficulties in a person’s life.  Dishonoring the process is, to me, as faulty as dishonoring the person whose genes have prepared them to react in such a manner to a perception of threat.

Note in the origins of the word fear reference to sudden danger, ambush, peril – and attempt.

-phobia: a combined form [NL, fr. LL, fr. Gk, fr. –phobos fearing, fr. Phobos fear, flight, fr. Phebesthai to flee; akin to Lith begt to flee, OCS bezati]

1:  exaggerated fear of

2:  intolerance or aversion for

Main Entry: 2fear

Function: noun

Etymology: Middle English fer, from Old English fǣr sudden danger; akin to Old High German fāra ambush and perhaps to Latin periculum attempt, peril, Greek peiran to attempt

Date: 12th century

Look, see, hear, feel the images in the word, ambush.  Ancient awarenesses and sensitivities here.  Danger hiding and lurking in the dead wood!  Things lying in wait to do us harm, things we cannot see, and don’t know if we are prepared to attempt to conquer.

Main Entry: 1am·bush

Function: verb

Etymology: Middle English embushen, from Anglo-French embuscher, from en in (from Latin in) + busche log, firewood

Date: 14th century

1 a: an unpleasant often strong emotion caused by anticipation or awareness of danger b (1): an instance of this emotion (2): a state marked by this emotion2: anxious concern : solicitude3: profound reverence and awe especially toward God4: reason for alarm : danger

synonyms fear , dread , fright , alarm , panic , terror , trepidation

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Ethofer et al 2006

Abstract – Section of Experimental MR of the CNS, Department of Neuroradiology, University of Tuebingen, Tuebingen, Germany. Thomas.Ethofer@med.uni-tuebingen.de

Emotional information can be conveyed by various means of communication, such as propositional content, speech intonation, facial expression, and gestures. Prior studies have demonstrated that inputs from one modality can alter perception in another modality. To evaluate the impact of emotional intonation on ratings of emotional faces, a behavioral study first was carried out. Second, functional magnetic resonance (fMRI) was used to identify brain regions that mediate crossmodal effects of emotional prosody on judgments of facial expressions. In the behavioral study, subjects rated fearful and neutral facial expressions as being more fearful when accompanied by a fearful voice as compared to the same facial expressions without concomitant auditory stimulus, whereas no such influence on rating of faces was found for happy voices. In the fMRI experiment, this shift in rating of facial expressions in presence of a fearfully spoken sentence was correlated with the hemodynamic response in the left amygdala extending into the periamygdaloid cortex, which suggests that crossmodal effects on cognitive judgments of emotional information are mediated via these neuronal structures. Furthermore, significantly stronger activations were found in the mid-portion of the right fusiform gyrus during judgment of facial expressions in presence of fearful as compared to happy intonations, indicating that enhanced processing of faces within this region can be induced by the presence of threat-related information perceived via the auditory modality. Presumably, these

increased extrastriate activations

[mid-portion of the right fusiform gyrus]

correspond to enhanced alertness,

whereas responses within the left amygdala

modulate cognitive evaluation

of emotional facial expressions.

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Kreifelts et al 2007

Abstract – Department of Psychiatry and Psychotherapy, University of Tuebingen, Osianderstrasse 24, 72076 Tuebingen, Germany. benjamin.kreifelts@med.uni-tuebingen.de

In a natural environment, non-verbal emotional communication is multimodal (i.e. speech melody, facial expression) and multifaceted concerning the variety of expressed emotions.

Understanding these communicative signals and integrating them into a common percept is paramount to successful social behavior.

While many previous studies have focused on the neurobiology of emotional communication in the auditory or visual modality alone, far less is known about multimodal integration of auditory and visual non-verbal emotional information. The present study investigated this process using event-related fMRI. Behavioural data revealed that

audiovisual presentation of non-verbal emotional information

resulted in a significant increase in correctly classified stimuli

when compared with visual and auditory stimulation.

This behavioral gain was paralleled by enhanced activation in

bilateral posterior superior temporal gyrus (pSTG)

and right thalamus,

when contrasting audiovisual to auditory and visual conditions

Further, a characteristic of these brain regions,

substantiating their role in

the emotional integration process,

is a linear relationship between the gain in classification accuracy and the strength of the BOLD response during the bimodal condition.

enhanced effective connectivity

Yet another area I would investigate for dissociation from when things went wrong during brain formation stages.  I don’t think my “associative auditory and visual cortices” are integrated the way they are supposed to be.  This is an area where I have difficulty in hearing a person’s words because on one level I am dissociated from WHAT they are saying and sensing what their intention is behind the words – what their emotional message is – what the message is behind the words – attempting to detect threat of harm, the ambush, to determine what is hiding and lying in wait in the woods.

My brain had to detect threat way before I knew words, or even knew visually what things were specifically – other than my crazy caregiver.

between audiovisual integration areas

and associative auditory and visual cortices

was observed during audiovisual stimulation,

offering further insight into the

neural process

accomplishing multimodal integration.

Finally, we were able to document an enhanced sensitivity of the putative integration sites to stimuli with emotional non-verbal content as compared to neutral stimuli.

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Wildgruber et al 2006

Abstract – Department of Psychiatry, University of Tübingen, Osianderstr. 24, 72076 Tübingen, Germany. dirk.wildgruber@med.uni-tuebingen.de

During acoustic communication in humans, information about a speaker’s emotional state is predominantly conveyed by modulation of the tone of voice (emotional or affective prosody). Based on lesion data,

a right hemisphere superiority for cerebral processing of emotional prosody has been assumed.

However, the available clinical studies do not yet provide a coherent picture with respect to interhemispheric lateralization effects of prosody recognition and intrahemispheric localization of the respective brain regions. To further delineate the cerebral network engaged in the perception of emotional tone, a series of experiments was carried out based upon functional magnetic resonance imaging (fMRI).

The findings obtained from these investigations allow for the separation of three successive processing stages during recognition of emotional prosody:

(1) extraction of suprasegmental acoustic information predominantly subserved by right-sided primary and higher order acoustic regions;

(2) representation of meaningful suprasegmental acoustic sequences within posterior aspects of the right superior temporal sulcus;

(3) explicit evaluation of emotional prosody at the level of the bilateral inferior frontal cortex.

Moreover, implicit processing of affective intonation seems to be bound to subcortical regions mediating automatic induction of specific emotional reactions such as activation of the amygdala in response to fearful stimuli.

As concerns lower level processing of the underlying suprasegmental acoustic cues, linguistic and emotional prosody seem to share the same right hemisphere neural resources.

Explicit judgment

of linguistic aspects of speech prosody

appears to be linked to left-sided language areas

bilateral orbitofrontal cortex has been found involved in

explicit evaluation

of emotional prosody.

These differences in hemispheric lateralization effects might explain that specific impairments in nonverbal emotional communication subsequent to focal brain lesions are relatively rare clinical observations as compared to the more frequent aphasic disorders.

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Ethofer et al 2008

Abstract – 1University of Tübingen, Tübingen, Germany, 2University Medical Center of Geneva, Geneva, Switzerland.

We investigated the functional characteristics of

brain regions implicated in processing of speech melody

by presenting words spoken in either neutral or angry prosody during a functional magnetic resonance imaging experiment using a factorial habituation design. Subjects judged either affective prosody or word class for these vocal stimuli, which could be heard for either the first, second, or third time.

Voice-sensitive temporal cortices,

as well as the amygdala, insula, and mediodorsal thalami, reacted stronger to angry than to neutral prosody.

These stimulus-driven effects were not influenced by the task, suggesting that these brain structures are

automatically engaged during processing of emotional information in the voice and operate relatively

independent of cognitive demands.

By contrast, the right middle temporal gyrus

and the bilateral orbito-frontal cortices (OFC)

responded stronger during emotion than word classification,

but were also sensitive to anger expressed by the voices, suggesting that

some perceptual aspects of prosody

are also encoded within these regions

subserving explicit processing of vocal emotion.

The bilateral OFC showed a selective modulation by emotion and repetition, with particularly pronounced responses to angry prosody during the first presentation only, indicating a

critical role of the orbito-frontal cortices (OFC)in detection of vocal information

that is both novel and behaviorally relevant.

These results converge with previous findings obtained for angry faces and suggest a

general involvement of the orbito-frontal cortices (OFC)

for recognition of anger

irrespective of the sensory modality.

Taken together, our study reveals that different aspects of voice stimuli and perceptual demands modulate distinct areas involved in the processing of emotional prosody.

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Bach et al 2008

Abstract – University Hospital of Psychiatry, University of Bern, Switzerland. d.bach@fil.ion.ucl.ac.uk

In visual perception of emotional stimuli,

low- and high-level appraisal processes

have been found to engage different neural structures.

Beyond emotional facial expression,

emotional prosody is an important auditory cue for social interaction.

Neuroimaging studies have proposed a network for emotional prosody processing that involves a right temporal input region and explicit evaluation in bilateral prefrontal areas.

However, the comparison of different appraisal levels has so far relied upon using linguistic instructions during low-level processing, which might confound effects of processing level and linguistic task. In order to circumvent this problem, we examined processing of emotional prosody in meaningless speech during

gender labeling

(implicit, — low-level appraisal) and

emotion labeling

(explicit, — high-level appraisal).

While bilateral amygdala,

left superior temporal sulcus and

right parietal areas [implicating the precuneus?]

showed stronger blood oxygen level-dependent (BOLD) responses during implicit processing,

areas with stronger BOLD responses during explicit processing included the left inferior frontal gyrus,

bilateral parietal,

anterior cingulate and

supplemental motor cortex.

Emotional versus neutral prosody

evoked BOLD responses in

right superior temporal gyrus,

bilateral anterior cingulate,

left inferior frontal gyrus,

insula and

bilateral putamen.

Basal ganglia and

right anterior cingulate responses to emotional versus neutral prosody were particularly pronounced during

explicit processing.

These results are in line with an

amygdala-prefrontal-cingulate network

controlling different appraisal levels,

and suggest a specific role of the left inferior frontal gyrus in explicit evaluation of emotional prosody.

In addition to brain areas commonly related to prosody processing, our results suggest specific functions of

anterior cingulate and basal ganglia

in detecting emotional prosody, particularly when explicit identification is necessary.

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Rymarczyk & Grabowska 2007

Abstract – Department of Neurophysiology, Nencki Institute of Experimental Biology, Pasteur 3, 02-093 Warsaw, Poland. k.rymarczyk@nencki.gov.pl

Affective (emotional) prosody is a neuropsychological function that encompasses non-verbal aspects of language that are necessary for recognizing and conveying emotions in communication,

whereas non-affective (linguistic) prosody indicates whether the sentence is a question, an order or a statement.

Considerable evidence points to a dominant role for the right hemisphere in both aspects of prosodic function. However, it has yet to be established whether separate parts of the right hemisphere are involved in processing different kinds of emotional intonation.

The aim of this study was to answer this question. In addition, the issue of sex differences in the ability to understand prosody was considered. Fifty-two patients with damage to frontal, temporo-parietal or subcortical (basal) parts of the right hemisphere and 26 controls were tested for their ability to assess prosody information in normal (well-formed) sentences and in pseudo-sentences. General impairment of prosody processing was seen in all patient groups but the effect of damage was more apparent for emotional rather than linguistic prosody. Interestingly, appreciation of emotional prosody appeared to depend on the type of emotional expression and the location of the brain lesion.

The patients with frontal damage were mostly impaired in comprehension of happy intonations;

those with temporo-parietal damage in assessment of sad intonations,

while subcortical lesions mostly affected comprehension of angry intonations.

Differential effects of lesion location on the performance of men and women were also observed.

Frontal lesions were more detrimental to women,

whereas subcortical lesions led to stronger impairment in men. This suggests sex differences in brain organization of prosodic functions.

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Wildgruber et al 2004

Abstract – Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany. dirk.wildgruber@med.uni-tuebingen.de

In addition to the propositional content of verbal utterances, significant linguistic and emotional information is conveyed by the tone of speech. To differentiate brain regions subserving processing of linguistic and affective aspects of intonation, discrimination of sentences differing in linguistic accentuation and emotional expressiveness was evaluated by functional magnetic resonance imaging. Both tasks yielded rightward lateralization of hemodynamic responses at the level of the dorsolateral frontal cortex as well as bilateral thalamic and temporal activation. Processing of linguistic and affective intonation, thus, seems to be supported by overlapping neural networks comprising partially right-sided brain regions.

Comparison of hemodynamic activation during the two different tasks, however, revealed bilateral orbito-frontal responses restricted to the affective condition

as opposed to activation of the left lateral inferior frontal gyrus confined to evaluation of linguistic intonation. These findings indicate that

distinct frontal regions contribute to higher level processing of intonational information depending on its communicational function.

In line with other components of language processing,

discrimination of linguistic accentuation

seems to be lateralized to the left inferior-lateral frontal region whereas bilateral orbito-frontal areas subserve

evaluation of emotional expressiveness.

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Nakashima et al 2008

Abstract – Department of Clinical Neurophysiology, Neurological Institute, Faculty of Medicine Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Japan Society for the Promotion of Science (JSPS), Tokyo, Japan.

It is generally accepted that the N170 component of an event-related potential (ERP) reflects the structural encoding of faces and is specialized for face processing. Recent neuroimaging and ERP studies have demonstrated that spatial frequency is a crucial factor for face recognition. To clarify which early ERP components reflect either coarse (low spatial frequency, LSF) or fine (high spatial frequency, HSF) processing of faces, we recorded ERPs induced by manipulated face stimuli. By filtering the original grayscale faces (broadband spatial frequency) spatially, we created LSF and HSF face stimuli. Next, we created physically equiluminant (PEL) face stimuli to eliminate the effects of lower order information, such as luminance and contrast. The P1 amplitude at the occipital region was augmented by LSF faces, while the N170 amplitude increased for HSF faces. The occipital P1 amplitude for PEL faces was relatively unaffected compared with that for PEL houses. In addition, the occipital N2 for PEL faces was spatiotemporally separable from N170 in a time-window between P1 and N170. These results indicate that P1 reflects coarse processing of faces, and that the face robustness further assures face-specific processing in the early component. Moreover, N2 reflects the early contrast processing of faces whereas N170 analyzes the fine facial features. Our findings suggest the presence of spatial frequency-and-contrast detectors for face processingNot sure what this means, maybe only shop talk for those in the know who perform these tests

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Malhi et al 2007

Abstract – CADE Clinic, Royal North Shore Hospital, University of Sydney, Australia. gmalhi@med.usyd.edu.au

To determine the neural responses invoked in the recognition of facial fear and disgust in euthymic [Word origin: Greek “eu” (good, well) + Greek “thumos” (spirit, soul)] bipolar patients as compared with healthy subjects.

METHODS: This study examined 10 female euthymic bipolar patients, and 10 suitably matched healthy subjects using functional magnetic resonance imaging (fMRI) while subjects were engaged in an explicit facial emotion recognition task involving fear, disgust and neutral expressions. The activation paradigm involved nominating the facial expression using specified response keys. Behavioural data were collected and analyzed and both within-group (Fear versus Neutral; Disgust versus Neutral) and random-effects between-group analyses were performed on fMRI data using BrainVoyager (Brain Innovations, Maastricht, the Netherlands). RESULTS: Patients were equally accurate in identifying facial expressions as healthy subjects but were slower to respond, especially with respect to fear and disgust.

Responses to fear and disgust (within-group analyses) resulted in activation of anticipated brain regions such as amygdala and insula, respectively.

However, between-group random effects analysis revealed differential responses to both disgust and fear in both healthy subjects and euthymic bipolar patients such that euthymic bipolar patients responded largely to fear and healthy subjects responded more so to disgust.

This partitioning of responsiveness was reflected by differential activation involving the hippocampus and amygdala.

CONCLUSIONS: Greater responsiveness to fear with hippocampal activation in patients perhaps reflects recollection of traumatic events associated with past experiences of illness or simply the use of a more

mnemonic (hippocampal)

as opposed to affective (amygdala) approach

when performing the task.

It is possible that in bipolar disorder, prefrontal-subcortical network dysfunction that relegates neural processing to limbic regions is impaired and that clinically

euthymic bipolar patients,

although able to accurately and effectively identify emotions such as fear and disgust,

are limited in their ability to interpret their salience.

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Lemche et al 2007

Abstract – Section of Neuroscience and Emotion, Brain Image Analysis Unit, Neuroimaging Research Group, Centre for Neuroimaging Sciences, Institute of Psychiatry, London, UK. e.lemche@iop.kcl.ac.uk

Depersonalization disorder,

characterized by emotional detachment,

has been associated with

increased prefrontal cortical and

decreased autonomic activity

to emotional stimuli.

Event-related fMRI with simultaneous measurements of skin conductance levels occurred in nine depersonalization disorder patients and 12 normal controls to neutral, mild and intense happy and sad facial expressions. Patients, but not controls, showed

This is perhaps the opposite of what I experience with my heightened perception, threat detection radar – how is this effect they are presenting different from avoidant detachment?  How is it different from the “healthy” detachment from emotions?  Perhaps because the choice is not consciously controlled, rather the automatic response is to shut it all down?

decreases in subcortical limbic activity to increasingly intense happy and sad facial expressions, respectively.

For both happy and sad expressions, negative correlations between skin conductance measures in bilateral dorsal prefrontal cortices occurred only in

depersonalization disorder patients.

Abnormal decreases

in limbic activity to increasingly intense emotional expressions,

and increases in dorsal prefrontal cortical activity to emotionally arousing stimuli

may underlie the emotional detachment of depersonalization disorder.

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Lemche et al 2008

Abstract – Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK. e.lemche@iop.kcl.ac.uk

Depersonalization disorder is

characterized by emotion suppression,

but the cerebral mechanisms of this symptom are not yet fully understood. AIMS: To compare brain activation and autonomic responses of individuals with the disorder and healthy controls. METHOD: Happy and sad emotion expressions in increasing intensities (neutral to intense) were presented in an implicit event-related functional magnetic resonance imaging (fMRI) design with simultaneous measurement of autonomic responses. RESULTS:

Participants with depersonalization disorder

showed fMRI signal decreases,

whereas the control group showed signal increases

in response to emotion intensity increases

in both happy and sad expressions.

The analysis of evoked haemodynamic responses from

regions exhibiting functional connectivity between central and autonomic nervous systems indicated that

in depersonalization disorder

initial modulations of haemodynamic response occurred significantly earlier (2 s post-stimulus) than in the control group (4-6 s post-stimulus).

Wee are supposed to be able, except in extreme situations and under dangerous conditions, be able to consciously modulate our emotions BY CHOICE.  When there is a “too much” condition of being under unconscious control, or not being able at all to consciously control our emotions, there is trouble.

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Herba et al 2008

Abstract – Department of Psychological Medicine, Institute of Psychiatry, KCL, London, UK. c.herba@erasmusmc.nl

The impact of personal familiarity upon children’s developing emotion-processing has been largely ignored in previous research, yet may prove particularly important given the emotional salience of such stimuli and children’s greater exposure to familiar others compared to strangers. We examined the impact of personal familiarity upon developing facial expression recognition (FER). METHODS: Participants included 153 children, 4-15 years old. We employed dynamic expressions of

five emotions (happy, sad, anger, fear, disgust),

posed by familiar (parents, teachers) and unfamiliar identities.

RESULTS: Accuracy improved with age for recognizing sad and fear expressions, but not anger.

Children tended to correctly recognize happiness and fear at lower intensities.

The impact of familiarity on FER depended on emotion-category.

Familiarity did not affect recognition of sad expressions,

but children were less accurate at recognizing anger, fear, and disgust in familiar individuals compared to strangers.

CONCLUSION: Personal familiarity may exert a distracting effect on children’s performance. Findings highlight the importance of incorporating different emotion-categories and familiarity when examining the development of FER. Does this vary with attachment – secure4 versus insecure?

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Herba et al 2006

Abstract – Department of Psychological Medicine, Institute of Psychiatry, KCL, UK. c.herba@erasmusmc.nl

This study examined the effects of age and two novel factors (intensity and emotion category) on healthy children’s developing emotion-processing from 4 to 15 years using two matching paradigms. METHODS: An explicit emotion-matching task was employed in which children matched the emotion of a target individual, and an implicit task whereby participants ignored the emotive facial stimulus and matched identity. Four intensities (25%, 50%, 75%, and 100%) for each of five emotion categories (sad, anger, happy, fear, and disgust) were included and provided a novel avenue of emotion-processing exploration. RESULTS: Increasing age significantly improved children’s performance on both tasks, particularly for fear and disgust.

Age was not associated with more subtle processing (i.e., lower intensity of expression).

When explicitly matching emotion expressions, increasing intensity was associated with improved performance. When matching identities (implicit emotion-matching), emotion category and intensity influenced task performance. Sex effects were minimal. CONCLUSIONS: In children, age, facial expression intensity and emotion category are important for predicting accuracy on emotion-processing tasks. Emotion category and expression intensity differentially affect performance on explicit and implicit emotion-processing tasks.

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Richards et al 2007

Abstract – School of Psychology, Birkbeck College, University of London, London, UK. a.richards@bbk.ac.uk

The relationship between children’s anxiety and cognitive biases was examined in two tasks. A group of 50 children aged 10 to 11 years (mean = 11 years, SD = 3.71 months) was given two tasks. The first tested children’s selective attention (SA) to threat in an emotional Stroop task. The second explored facial processing biases using morphed angry-neutral and happy-neutral emotional expressions that varied in intensity. Faces with varying levels of emotion (25% emotion-75% neutral, 50% emotion-50% neutral, 100% emotion-0% neutral [prototype] and 150% emotion-0% neutral [caricature]) were judged as being angry or happy. Results support previous work highlighting a link between anxiety and selective attention (SA) to threat In addition,

increased anxiety in late childhood

is associated with

decreased ability to discriminate facial expression.

One would think the increased anxiety would be designed by nature to facilitate an increased rather than a decreased ability to detect – accurately – facial expressions as an indicator of safety or threat.

Is this same effect found in adulthood?

Is this a form of “dissociation” where there is a split of some kind resulting from the fear that interferes with the discrimination?

lack of discrimination in the emotional expression task

was related to lack of inhibition to threat in the Stroop task.

Is this effect from higher anxiety creating a lack of competence in reaction to the perception or reality of threat in the environment, then?  Is this a consequence of being overwhelmed, of having been pushed past a sensitivity threshold?

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Masten et al 2008

Abstract – Department of Psychology, University of California, 1285 Franz Hall, Box 951563, Los Angeles, CA 90095, USA.

The purpose of this study is to examine processing of facial emotions in a sample of maltreated children showing high rates of post-traumatic stress disorder (PTSD).

Maltreatment during childhood

has been associated independently with both

atypical processing of emotion

and the development of PTSD.

However, research has provided little evidence indicating how high rates of PTSD might relate to maltreated children’s processing of emotions. METHOD: Participants’ reaction time and labeling of emotions were measured using a morphed facial emotion identification task. Participants included a diverse sample of maltreated children with and without PTSD and controls ranging in age from 8 to 15 years. Maltreated children had been removed from their homes and placed in state custody following experiences of maltreatment. Diagnoses of PTSD and other disorders were determined through combination of parent, child, and teacher reports. RESULTS:

Maltreated children

displayed faster reaction times than controls

when labeling emotional facial expressions,

and this result was most pronounced for

fearful faces.

Relative to children who were not maltreated, maltreated children both with and without PTSD showed enhanced response times when identifying fearful faces.

There was no group difference in labeling of emotions when identifying different facial emotions. CONCLUSIONS:

Maltreated children show heightened ability

to identify fearful faces,

evidenced by faster reaction times relative to controls.

This association

between maltreatment and atypical processing of emotion

is independent of PTSD diagnosis

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Famularo, Fenton & Kinscherff 1993

Abstract – Boston Juvenile Court Clinic, Massachusetts Department of Mental Health, Boston, MA 02108.

The purpose of this study was to compare the relative effects of various forms of maltreatment on the development of posttraumatic stress disorder (PTSD) in children. DESIGN–Children were randomly selected from a population of court-involved maltreated children. The children were then assigned to a PTSD group and a non-PTSD group on the basis of their responses to a structured interview. SETTING–A juvenile/family court in a large urban area. PARTICIPANTS–This study examined 101 children who were before a juvenile/family court because of severe child maltreatment. All children had been removed from parental custody as a result of the maltreatment. INTERVENTIONS–None. MEASUREMENTS AND RESULTS–Structured clinical psychiatric interviews were administered to each child and each parent, and all court records were reviewed. The major analyses assessed the extent to which the presence and duration of the most common types of severe maltreatment were associated with a diagnosis of PTSD. Thirty-nine children met criteria for PTSD.

Those who were sexually maltreated and those who witnessed family violence had a much greater likelihood of developing PTSD than did those whose histories of maltreatment did not include these types of events.

The duration of emotional abuse (psychological terror)

also proved to be a significant factor in discriminating children diagnosed as having PTSD from other severely maltreated children.

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Famularo et al 1996

Abstract – Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.

One-hundred and fifty-six children were randomly evaluated at an inner-city juvenile/family court. These children were removed from their parent’s custody subsequent to a finding of severe child maltreatment. From our original sample of 156 children, 62 met strict criteria for Post Traumatic Stress Disorder (PTSD). Fifty-two of these 62 were successfully recruited and participated in the 2 year re-examination. Each PTSD diagnosis was conferred by the Diagnostic Interview for Children and Adolescents (DICA). From our sample of 52 PTSD children re-examined after 2 years, 17 (32.7%) retained the full PTSD diagnosis, while 67.3% did not meet criteria.

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Famularo & Fenton 1994

Abstract – Boston Juvenile Court, Massachusetts Department of Mental Health.

OBJECTIVE: To determine which factors from the early developmental histories of maltreated children are associated with the risk of developing posttraumatic stress disorder (PTSD). DESIGN: Retrospective cohort analytic study. SETTING: A county juvenile/family court (not a criminal court). SAMPLE: The sample consisted of 117 severely maltreated children, aged 5 to 12 years, whose maltreatment was so severe that they were removed from parental custody. Forty-one (35%) of these children met criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, for PTSD. MAIN OUTCOME MEASURES: Individual developmental and temperament-independent variables were used to compare children with PTSD and the maltreated children who did not reach PTSD inclusion criteria. The child’s PTSD status was the primary dependent variable.

RESULTS: Variables representing the three factors from the early developmental history, along with markers for sex and race (black vs other), were entered into a logistic regression, with PTSD status as the outcome variable. Indicators of five different types of child maltreatment were also entered as predictors, to control for previously discovered effects associated with the type of trauma suffered by the children. This analysis disclosed that, while we controlled for the other predictors, one of the developmental factors remained statistically significant, one was marginally significant (P = .07), and one made no contribution toward predicting the probability of PTSD. Sex did not make a significant contribution to the logistic model, but

being black

continued to be associated with a lower probability of developing PTSD.

CONCLUSIONS: We conclude that PTSD may be caused by factors

[that’s a stupid statement – not caused by these!  These are very likely not a cause, but a correlational effect, though abuse and early life trauma CAN cause these difficulties]

discernible in the first year of life that leave a maltreated child vulnerable to this disorder. These include birth weight less than 2.25 kg, jaundice, vomiting, diarrhea, infections, sleep problems, frequent crying, poor weight gain, fussiness, jumpiness, and distress when moved.

How would researchers know this info without getting it from the same family that caused the abuse in the first place?  How accurate would those parental reports be on ANYTHING, in my book.

The seemingly protective effect of being black was an unexpected, although provocative, finding whose interpretation will require further investigation.  One thing to look for is adequate social support as a mediating and moderating factor

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Famularo et al 1996b

Abstract – Boston Juvenile Court, Massachusetts Department of Mental Health, USA.

OBJECTIVE: The purpose of this study was to examine the psychiatric comorbidity between children presenting with Post Traumatic Stress Disorder (PTSD) and traumatized children not developing this disorder. DESIGN: One-hundred and seventeen severely maltreated children were examined for evidence of PTSD. Analyses probed for diagnostic relationship, between PTSD and other formal diagnoses on The Diagnostic Interview for Children and Adolescents, Revised Version (DICA-CR). PARTICIPANTS: All children presented before a juvenile/family court due to severe child maltreatment and psychological trauma. These children had been ordered removed from parental custody due to the trauma suffered by the child. For the purposes of analyses, this entire group of maltreated and traumatized children were dichotomized into a PTSD group and a non-PTSD group. Thirty-five percent (41 of 117) of the children met strict DICA criteria for PTSD. MEASUREMENTS: The children were examined by means of a structured clinical interview. The Diagnostic Interview for Children and Adolescents, revised version (DICA-Child-R), along with a more general psychiatric interview. The DICA-Child-R responses provided the only determination of whether the children met formal PTSD criteria. Data gathering on the sample also included a comprehensive review of risk factors for the development of PTSD, including demographics, and type(s) of trauma suffered. RESULTS: Findings revealed that the

PTSD diagnosis was significantly correlated with:

1. Attention Deficit Hyperactivity Disorder (ADHD)

2. Other anxiety disorders

3. Brief Psychotic Disorder or Psychotic Disorder NOS

4. The presence of suicidal ideation

5. A trend toward mood disorders.

There were no differences between the two samples on measures of age, race, and family income. CONCLUSIONS:

Pediatric PTSD is a severe psychiatric disorder. In this study, PTSD was statistically related to other formal psychiatric diagnoses. The investigators attended to the issues relating to true comorbidity versus inaccurate diagnosis secondary to symptom overlap between different conditions. Applying strict criteria, the results suggest that

the presence of PTSD in children confers a substantial likelihood of other formal diagnosis. Moreover, the symptom of suicidal ideation was overrepresented among PTSD subjects. Given these additional conditions, more extensive evaluation and specialized, multi-modal treatment should be considered in children presenting with PTSD.

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Famularo et al 1994

Abstract – Boston Juvenile Court Clinic, MA 02108.

The purpose of this study was to examine the rates of posttraumatic stress disorder (PTSD) among a sample of severely maltreated children and their mothers, and to investigate the age of onset of documented maltreatment in these children. The sample consisted of 109 pairs of women and their children who were before a juvenile/family court due to maltreatment of sufficient severity to warrant removal of the child from parental custody. Children were examined using the PTSD Section of the Diagnostic Interview for Children and Adolescents, Revised 6th Version (DICA-6-R). The PTSD Module of the Structured Clinical Interview for DSM-III-R (SCID) was administered to all mothers. Clinical psychiatric interviews were also administered to all children and mothers. From the sample of 109 cases, 15.6% of the mothers met SCID criteria for a current presentation of PTSD, while 36.7% had a past history of PTSD.

Of the 109 evaluated children, 35.8% met current DICA criteria for PTSD.

Posttraumatic stress disorder is significantly overrepresented in the children of mothers diagnosed with PTSD (p = .001).

The average age of maltreatment onset was 46.4 months among the children diagnosed as PTSD, and was 61.3 months in the group of seriously maltreated children who did not develop PTSD (p = .038).

The onset of maltreatment is significantly earlier among children whose mothers meet PTSD criteria than among other maltreated children (p = .025).

Intergenerational transmission of violence and developmental effects of traumatic experiences upon the young child are discussed.

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Shaffer, Huston & Egeland 2008

Abstract – Institute of Child Development, University of Minnesota, 51 East River Road, Minneapolis, MN 55455, USA.

One of the greatest methodological problems in the study of childhood maltreatment is the discrepancy in methods by which cases of child maltreatment are identified. The current study compared incidents of maltreatment identified prospectively, retrospectively, or through a combination of both methods. METHOD: Within a cohort of 170 participants followed from birth to age 19, incidents of maltreatment which occurred prior to age 17.5 were identified via prospective case review and interviewer ratings of retrospective self-reports. Multi-informant measures of behavior problems were obtained at age 16, and diagnostic assessments of psychopathology were completed at age 17.5. RESULTS: While the maximal number of maltreatment cases was identified by using a combination of all available identification methods, the prospective method was the single most comprehensive method for identifying the most cases of childhood physical abuse, sexual abuse, and neglect.

Those who were identified as maltreated by a combination of both prospective and self-report methods experienced the greatest number of incidences of maltreatment (i.e., 49% of this group experienced more than one type of maltreatment) and displayed the most emotional and behavioral problems in late adolescence (i.e., 74% met diagnostic criteria for a clinical disorder). CONCLUSIONS: This study emphasizes the variability in the incidence rates of maltreatment and the psychological outcomes that result from utilizing different methods of identification. The most severe cases of maltreatment are likely to be identified by both prospective and retrospective methods; however, cases that are identified solely through retrospective self-report may have unique relations to psychopathology in late adolescence. PRACTICE IMPLICATIONS: Reliance on a single method to identify childhood maltreatment incidents often overlooks many cases. Comparing both prospective case reviews and retrospective self-reports in late adolescence, the most severe cases of multiple incidents of abuse were most likely to be identified by both methodologies. The less severe maltreatment incidents were more likely to be missed, either by prospective methods or, more frequently, by self-report methods. Practitioners must be continually sensitive to possible abuse histories among their clients, seeking out information from multiple sources whenever feasible. Additionally, the potential effects of abuse disclosure on pre-existing or developing psychopathology should be considered.

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Cohen, Brown & Smaile 2001

Abstract – New York State Psychiatric Institute, New York 10032, USA.

Child abuse and neglect have repeatedly been shown to be risks for psychiatric and personality disorders. However, much of this evidence is based on retrospective reports of adults. In addition, little is known about the developmental course of psychopathology among those exposed to child maltreatment. In this study, we report mental disorders assessed from early childhood to adulthood in those later identified as victims of abuse or neglect by official or self-report.

Findings show elevated rates of mental disorders and symptoms in each of four groups relative to the normative sample. Groups included those who had been victims of physical abuse or neglect according to official report and those who had been victims of physical or sexual abuse by self-report.

As expected, the maltreated groups were quite different demographically from the community comparison sample, especially those with official reports.

The group with retrospective self-reports of physical abuse differed only modestly from the comparison group on the symptom and disorder measures, while the sexually abused group showed the most consistently elevated patterns, even after controls for demographic differences were taken into account. The disorder and symptom patterns differed both by group and by age: neglect cases showed a partial remission in adulthood, while

official physical abuse cases showed an increasingly consolidated pattern of antisocial and impulsive behavior.

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Johnson et al 1999

Abstract – Columbia University, New York, USA.

BACKGROUND: Data from a community-based longitudinal study were used to investigate whether childhood abuse and neglect increases risk for personality disorders (PDs) during early adulthood. METHODS: Psychosocial and psychiatric interviews were administered to a representative community sample of 639 youths and their mothers from 2 counties in the state of New York in 1975, 1983, 1985 to 1986, and 1991 to 1993. Evidence of childhood physical abuse, sexual abuse, and neglect was obtained from New York State records and from offspring self-reports in 1991 to 1993 when they were young adults. Offspring PDs were assessed in 1991 to 1993. RESULTS:

Persons with documented childhood abuse or neglect were more than 4 times as likely as those who were not abused or neglected to be diagnosed with PDs during early adulthood after age, parental education, and parental psychiatric disorders were controlled statistically.

Childhood physical abuse, sexual abuse, and neglect were each associated with elevated PD symptom levels during early adulthood after other types of childhood maltreatment were controlled statistically.

Of the 12 categories of DSM-IV PD symptoms, 10 were associated with childhood abuse or neglect. Different types of childhood maltreatment were associated with symptoms of specific PDs during early adulthood. Would need article to know which ones, is a 1999 article, probably won’t call it in

CONCLUSIONS: Persons in the community who have experienced childhood abuse or neglect are considerably more likely than those who were not abused or neglected to have PDs and elevated PD symptom levels during early adulthood. Childhood abuse and neglect may contribute to the onset of some PDs.  How vague is this?

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Johnson et al 2001

Abstract – Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, NY 10032, USA.

Data from a community-based longitudinal study were used to investigate whether childhood verbal abuse increases risk for personality disorders (PDs) during adolescence and early adulthood. Psychiatric and psychosocial interviews were administered to a representative community sample of 793 mothers and their offspring from two New York State counties in 1975, 1983, 1985 to 1986, and 1991 to 1993, when the mean ages of the offspring were 5, 14, 16, and 22 years, respectively. Data regarding childhood abuse and neglect were obtained from the psychosocial interviews and from official New York State records.

Offspring who experienced maternal verbal abuse

during childhood were more than three times as likely

as those who did not experience verbal abuse

to have borderline, narcissistic, obsessive-compulsive, and paranoid PDs during adolescence or early adulthood.

This is correlational and does not prove cause and effect.  The same difficulties and factors that made the children sick may have made the mothers mean.

These associations remained significant after offspring temperament, childhood physical abuse, sexual abuse, neglect, physical punishment during childhood, parental education, parental psychopathology, and co-occurring psychiatric disorders were controlled statistically.

In addition, youths who experienced childhood verbal abuse had elevated borderline, narcissistic, paranoid, schizoid, and schizotypal PD symptom levels during adolescence and early adulthood after the covariates were accounted for.

These findings suggest that childhood verbal abuse may contribute to the development of some types of PDs, independent of offspring temperament, childhood physical abuse, sexual abuse, neglect, physical punishment during childhood, parental education, parental psychopathology, and co-occurring psychiatric disorders.

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Johnson et al 2006

Abstract – Department of Psychiatry, Columbia University and the New York State Psychiatric Institute, New York 10032, USA. jjohnso@pi.cpmc.columbia.edu

CONTEXT: Research has suggested that some types of parental child-rearing behavior may be associated with risk for offspring personality disorder (PD), but the association of parenting with offspring PD has not been investigated comprehensively with prospective longitudinal data. OBJECTIVE: To investigate the association of parental child-rearing behavior with risk for offspring PD during adulthood. DESIGN: The Children in the Community study, a prospective longitudinal investigation. SETTING AND PARTICIPANTS: A community-based sample of 593 families interviewed during childhood (mean age, 6 years), adolescence (mean ages, 14 and 16 years), emerging adulthood (mean age, 22 years), and adulthood (mean age, 33 years) of the offspring. MAIN OUTCOME MEASURE: The Structured Clinical Interview for DSM-IV Personality Disorders. RESULTS: Ten types of parenting behavior that were evident during the child-rearing years were associated with elevated offspring risk for PD during adulthood when childhood behavioral or emotional problems and parental psychiatric disorders were controlled statistically.

Parental behavior in the home during the child-rearing years was associated with elevated risk for offspring PD at mean ages of 22 and 33 years. Risk for offspring PD at both assessments increased steadily as a function of the number of problematic parenting behaviors that were evident.

Low parental affection or nurturing was associated with elevated risk for offspring antisocial (P = .003), avoidant (P = .01), borderline (P = .002), depressive (P = .02), paranoid (P = .002), schizoid (P = .046), and schizotypal (P<.001) PDs.

Aversive parental behavior (eg, harsh punishment) was associated with elevated risk for offspring borderline (P = .001), paranoid (P = .004), passive-aggressive (P = .046), and schizotypal (P = .02) PDs.

CONCLUSIONS: Parental behavior during the child-rearing years may be associated with risk for offspring PD that endures into adulthood. This risk may not be attributable to offspring behavioral and emotional problems or parental psychiatric disorder, and it may not diminish over time. Low parental nurturing and aversive parental behavior during child rearing may both be associated with elevated risk for offspring PDs.

I need to call this article in to find out what the 10 parental behaviors are

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Pine et al 2005

Abstract – Section on Development and Affective Neuroscience, National Institute of Mental Health Intramurral Research Program, Bethesda, MD 20817-2670, USA. daniel.pine@nih.gov

OBJECTIVE: Previous research in adults implicates attention bias in posttraumatic stress disorder (PTSD). To study attention bias in children, the authors used picture-based versions of the visual-probe attention bias task previously used with adults. They tested the hypothesis that attention bias to threatening facial photographs is associated with maltreatment and PTSD. METHOD: A visual-probe task that manipulated threat levels was used to test 34 children who had been maltreated and 21 children who had not been maltreated. The visual-probe task involved showing photographs of actors with faces depicting neutral, angry/threatening, or happy expressions for 500 msec each. RESULTS:

Attention bias away from threat

was associated with severity of physical abuse

and diagnosis of PTSD.

This association reflected the tendency for high levels of abuse or PTSD to predict attention avoidance of threatening faces.

CONCLUSIONS: Previous studies examined the engagement of specific brain regions associated with attention orientation to angry/threatening faces. The current study used similar methods to document associations between attention bias and maltreatment in children. This sets the stage for studies examining relationships in children among perturbed brain function, psychopathology, attention bias, and maltreatment.

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Monk et al 2006

Abstract – Department of Psychology, University of Michigan, 2000 East Hall, 530 Church St., Ann Arbor, MI 48109, USA. csmonk@umich.edu

OBJECTIVE: While adolescent anxiety disorders represent prevalent, debilitating conditions, few studies have explored their brain physiology. Using event-related functional magnetic resonance imaging (fMRI) and a behavioral measure of attention to angry faces, the authors evaluated differences in response between healthy adolescents and adolescents with generalized anxiety disorder. METHOD: In the primary trials of interest, 18 adolescents with generalized anxiety disorder and 15 comparison subjects of equivalent age/gender/IQ viewed angry/neutral face pairs during fMRI acquisition. Following the presentation of each face pair, subjects pressed a button to indicate whether a subsequent asterisk appeared on the same (congruent) or opposite (incongruent) side as the angry face. Reaction time differences between congruent and incongruent face trials provided a measure of attention bias to angry faces. RESULTS: Relative to the comparison subjects, patients with generalized anxiety disorder manifested greater right ventrolateral prefrontal cortex activation to trials containing angry faces.

Patients with generalized anxiety disorder also showed greater attention bias away from angry faces.

Ventrolateral prefrontal cortex activation differences remained evident when differences in attention bias were covaried. Finally, in an examination among patients of the association between degree of anxiety and brain activation, the authors found that

as ventrolateral prefrontal cortex activation increased,

severity of anxiety symptoms diminished.

CONCLUSIONS: Adolescents with generalized anxiety disorder show greater right ventrolateral prefrontal cortex activation and attentional bias away from angry faces than healthy adolescents. Among patients, increased ventrolateral prefrontal cortex activation is associated with less severe anxiety, suggesting that this activation may serve as a compensatory response.

Avoidance or detachment?

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Famularo, Kinscherff & Fenton 1992

Abstract – Boston Juvenile Court Clinic, Massachusetts 02108.

The Structured Clinical Interview for DSM-III-R diagnoses of 54 mothers who had maltreated their children were compared with those of 37 controls. The maltreatment group showed a significantly greater incidence of both current and past diagnoses. Maltreating mothers exhibited a significantly greater incidence of current mood disorder, alcohol abuse, and personality disorder than did controls. The results indicate that past abuse of cocaine, alcohol, other substances and past mood disorders were significantly more prevalent among the maltreatment sample than among controls.

Mothers who had maltreated their children were significantly more likely to have histories of posttraumatic stress disorder than were controls.

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Johnson et al 2000

Abstract – Columbia University, New York, NY, USA.

Data from a community-based longitudinal study were used to investigate the association between childhood neglect and personality disorder (PD) symptom levels during adolescence and early adulthood. Psychosocial and psychiatric interviews were administered to a representative sample of 738 youths and their mothers from upstate New York in 1975, 1983, 1985-1986, and 1991-1993. Evidence of childhood cognitive, emotional, physical, and supervision neglect was obtained from the maternal interviews that were conducted in 1975, 1983, and 1985-1986, and from New York State records. PDs were assessed among the youths in 1985-1986, when they were adolescents, and in 1991-1993, when they were young adults.

Findings indicated that childhood emotional, physical, and supervision neglect were associated with increased risk for PDs and with elevated PD symptom levels during adolescence and early adulthood, after age, sex, childhood physical or sexual abuse, other types of childhood neglect, and cooccurring PD symptoms were controlled statistically.

Childhood emotional neglect was associated with increased risk for avoidant PD and with paranoid and Cluster A PD symptom levels during adolescence and early adulthood.

Childhood physical neglect was associated with increased risk for schizotypal PD and with Cluster A PD symptom levels during adolescence and early adulthood.

Childhood supervision neglect was associated with increased risk for passive-aggressive and Cluster B PDs and with borderline, paranoid, and passive-aggressive PD symptom levels during adolescence and early adulthood.

The present findings suggest that childhood emotional, physical, and supervision neglect may play a role in the etiology of some PDs.

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Guyer et al 2006

Abstract – Mood and Anxiety Program, National Institute of Mental Health, Bethesda, MD 20892-2670, USA. amandaguyer@mail.nih.gov

OBJECTIVE: To examine in children the influence of maltreatment and associated psychiatric sequelae on behavioral responses to reward stimuli. METHOD: A computerized two-choice decision-making task involving probabilistic monetary gains was used to probe elemental processes of goal-directed actions. Using different risk contingencies, the authors examined decision-making, expectations of outcomes, and affective responses to rewards in 38 maltreated children and 21 demographically matched controls (8-14 years old). RESULTS:

Maltreated children selected risk options faster than controls; however, whereas controls responded more quickly as the chance of winning increased, maltreated children did not vary in response speed as a function of the likelihood of winning.

When choosing between high- and low-risk options,

maltreated children with depressive disorders

more frequently selected safe over risky choices

than did controls.

No group differences emerged in self-report ratings of positive or negative reactions to winning or not winning, respectively. CONCLUSIONS: This initial experimental study of responses to reward lays the groundwork for subsequent research on neurodevelopmental aspects of reward processes in relationship to maltreatment and psychopathology. Clinical applications of these data may be relevant for developing treatment plans for maltreated children, particularly those with depression.

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Monk et al 2008b

Abstract – Department of Psychology, University of Michigan, Ann Arbor, MI 48109, USA. csmonk@umich.edu

OBJECTIVE: Offspring of parents with major depressive disorder face a threefold higher risk for major depression than offspring without such family histories.

Although major depression is a significant cause of morbidity and mortality, neural correlates of risk for major depression remain poorly understood. This study compares amygdala and nucleus accumbens activation in children and adolescents at high and low risk for major depression under varying attentional and emotional conditions. METHOD: Thirty-nine juveniles, 17 offspring of parents with major depression (high-risk group) and 22 offspring of parents without histories of major depression, anxiety, or psychotic disorders (low-risk group) completed a functional magnetic resonance imaging study. During imaging, subjects viewed faces that varied in intensity of emotional expressions across blocks of trials while attention was unconstrained (passive viewing) and constrained (rate nose width on face, rate subjective fear while viewing face).

RESULTS: When attention was unconstrained, high-risk subjects showed greater amygdala and nucleus accumbens activation to fearful faces and lower nucleus accumbens activation to happy faces (small volume corrected for the amygdala and nucleus accumbens).

No group differences emerged in amygdala or nucleus accumbens activation during constrained attention. Exploratory analysis showed that constraining attention was associated with greater medial prefrontal cortex activation in the high-risk than in the low-risk group.

CONCLUSIONS:

Amygdala and nucleus accumbens responses to affective stimuli may reflect vulnerability for major depression.

Constraining attention may normalize emotion-related neural function

possibly by engagement of the medial prefrontal cortex;

face-viewing with unconstrained attention may engage aberrant processes associated with risk for major depression.

This is an example of how unconscious influence can change how some humans process incoming information.  If conscious choice and decision is the ideal, then this unconscious alteration is not the ideal, and therefore leads to consequences that distinguish the people who utilize this “defense” automatically from those who do not.  This process is evidently NOT what experts refer to as detachment, which is under conscious control.

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Wildgruber et al 2005

Abstract – Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany. dirk.wildgruber@med.uni-tuebingen.de

During acoustic communication among human beings, emotional information can be expressed both by the propositional content of verbal utterances and by the modulation of speech melody (affective prosody). It is well established that linguistic processing is bound predominantly to the left hemisphere of the brain. By contrast, the encoding of emotional intonation has been assumed to depend specifically upon right-sided cerebral structures. However, prior clinical and functional imaging studies yielded discrepant data with respect to interhemispheric lateralization and intrahemispheric localization of brain regions contributing to processing of affective prosody. In order to delineate the cerebral network engaged in the perception of emotional tone, functional magnetic resonance imaging (fMRI) was performed during recognition of prosodic expressions of five different basic emotions (happy, sad, angry, fearful, and disgusted) and during phonetic monitoring of the same stimuli. As compared to baseline at rest, both tasks yielded

widespread bilateral hemodynamic responses within frontal, temporal, and parietal areas,

the thalamus, and the cerebellum.

A comparison of the respective activation maps, however, revealed

comprehension of affective prosody to be bound to a distinct right-hemisphere pattern of activation, encompassing posterior superior temporal sulcus (Brodmann Area [BA] 22), dorsolateral (BA 44/45), and orbitobasal (BA 47) frontal areas.

Activation within left-sided speech areas, in contrast, was observed during the phonetic task. These findings indicate that

partially distinct cerebral networks

subserve processing of phonetic and intonational information during speech perception.

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Lemche et al 2004

Abstract – Department of Psychotherapy and Psychosomatic Medicine, Dresden University of Technology, Dresden, Germany. erwin.lemche@mailbox.tu-dresden.de

The construct of alexithymia

implies a deficit in symbolization for

emotional, somatic, and mental states.

However, the etiologic factors for alexithymia have not yet been fully elucidated. The present study investigated the use of mentalizing language, i.e. the utterance of internal states, from a developmental perspective according to attachment organization and disorganization. METHODS: A longitudinal design across 4 time points was applied to a volunteer We must understand that a truly dangerous parent will not volunteer for this kind of research or for any other research – so the worst attachment scenarios will NOT be represented!!

sample of 42 children. At 12 months, children were tested with the strange situation procedure, the standard measure of attachment at the optimal age, and attachment classifications were taken of videotapes. At ages 17, 23, 30 and 36 months, mother and child were observed in simplified separation episodes of 30 min duration. Transcripts of the sessions were subject to coding of internal state words. RESULTS: During the investigated span,

securely attached children

rapidly acquired emotion, physiology, cognition and emotion-regulatory language, whereas

insecurely attached and disorganized children either completely lacked internal state language or displayed a considerable time lag in the use of emotion and cognition vocabulary.

CONCLUSION: The results raise the possibility that alexithymia might be a consequence of deficits in the development of internal state language in the context of insecure or disorganized childhood attachment relationships.

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Levenson & Sweatt 2005

Abstract – Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, S607, Houston, Texas 77030, USA.

Discoveries concerning the molecular mechanisms of cell differentiation and development have dictated the definition of a new sub-discipline of genetics known as epigenetics.

Epigenetics refers to a set of

self-perpetuating, God making God!?

post-translational modifications of DNA and nuclear proteins that produce lasting alterations in chromatin structure

as a direct consequence,

and lasting alterations in patterns of gene expression

as an indirect consequence.

The area of epigenetics is a burgeoning subfield of genetics in which there is considerable enthusiasm driving new discoveries. Neurobiologists have only recently begun to investigate the possible roles of epigenetic mechanisms in behavior, physiology and neuropathology.

Strikingly, the relevant data from the few extant

neurobiology-related studies have already indicated a theme – epigenetic mechanisms probably have an important role

in synaptic plasticity and memory formation.

It seems a sort of divine synchronicity that I would encounter epigenetics tied specifically to memory. But, of course, epigenetics is about memory – as DNA is itself.  I found one of the doorways into the study of epigenetics – interesting that memory is it.  Tying epigenetics, memory, traumatic stress and the HPA axis together will be challenging – along with connection to the sex hormones – because of course it is all finally about survival to reproduce, anyway.  Nature will forgo the finer trappings of a happy life if it needs to.

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Allen 2008

Abstract – School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, UK. allennd@cf.ac.uk

The anticipated therapeutic uses of neural stem cells depend on their ability to retain a certain level of developmental plasticity.

In particular, cells must respond to developmental manipulations designed to specify precise neural fates.

Studies in vivo and in vitro have shown that the developmental potential of neural progenitor cells changes and becomes progressively restricted with time. For in vitro cultured neural progenitors, it is those derived from embryonic stem cells that exhibit the greatest developmental potential.

It is clear that both extrinsic and intrinsic mechanisms

determine the developmental potential of neural progenitors

and that

epigenetic, or chromatin

structural, changes

regulate and coordinate hierarchical changes

in fate-determining gene expression.

Here, we review the temporal changes in developmental plasticity of neural progenitor cells and discuss the epigenetic mechanisms that underpin these changes.

We propose that understanding the processes of epigenetic programming within the neural lineage is likely to lead to the development of more rationale strategies for cell reprogramming that may be used to expand the developmental potential of otherwise restricted progenitor populations.

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Kuwabara et al 2004

Abstract – Laboratory of Genetics, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.

Discovering the molecular mechanisms that regulate neuron-specific gene expression remains a central challenge for CNS research. Here, we report that

small, [define small!] noncoding double-stranded (ds) RNAs

play a critical role in mediating neuronal differentiation.

The sequence defined by this dsRNA is NRSE/RE1,

which is recognized by NRSF/REST,

known primarily as a negative transcriptional regulator

that restricts neuronal gene expression

to neurons.

The NRSE dsRNA can trigger gene expression of neuron-specific genes through interaction with NRSF/REST transcriptional machinery, resulting in the

Transition

from neural stem cells with neuron-specific genes silenced by NRSF/REST

into cells with neuronal identity

that can express neuronal genes.

The mechanism of action appears to be mediated through a dsRNA/protein interaction, rather than through siRNA or miRNA. The

discovery of small modulatory dsRNAs (smRNAs)

extends the important contribution of noncoding RNAs

as key regulators of cell behavior at both

transcriptional and posttranscriptional levels.

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Watanabe et al 2004

Abstract – Department of Molecular Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA

Repressor element 1 (RE1)-silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF)

can repress several terminal neuronal differentiation genes

by binding to a specific DNA sequence (

RE1/neuron-restrictive silencer element [NRSE])

present in their regulatory regions.

REST-VP16 binds to the same RE1/NRSE, but activates these REST/NRSF target genes. However, it is unclear whether REST-VP16 expression is sufficient to cause formation of functional neurons either from neural stem cells or from heterologous stem cells. Here we show that the

expression of REST-VP16 in myoblasts

grown under muscle differentiation conditions

blocked entry into the muscle differentiation pathway,

countered endogenous REST/NRSF-dependent repression, activated the REST/NRSF target genes, and, surprisingly,

activated other neuronal differentiation genes

and converted the myoblasts to a physiologically active neuronal phenotype.

Furthermore, in vitro differentiated neurons

produced by REST-VP16-expressing myoblasts,

when injected into mouse brain,

survived,

incorporated into the normal brain,

and did not form tumors.

This is the first instance in which myoblasts

were converted to a neuronal phenotype.

Our results suggest that direct activation of REST/NRSF target genes with a single transgene, REST-VP16,

is sufficient to activate other

terminal neuronal differentiation genes

and to override the muscle differentiation pathways,

and they suggest that this approach provides an efficient way of triggering neuronal differentiation in myoblasts and possibly other stem cells.

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Ballas & Mandel 2005

Abstract – ward Hughes Medical Institute, Department of Neurobiology and Behavior, State University of New York, Stony Brook, NY 11794, USA.

Nervous system development relies on a complex signaling network to engineer the orderly transitions that lead to the acquisition of a neural cell fate.

Progression from the non-neuronal pluripotent stem cell

to a restricted neural lineage is characterized by distinct patterns of gene expression,

particularly the restriction of neuronal gene expression to neurons.

Concurrently, cells outside the nervous system acquire and maintain a non-neuronal fate that permanently excludes expression of neuronal genes.

See Watanabe et al 2004

Studies of the transcriptional repressor REST, which regulates a large network of neuronal genes, provide

a paradigm for elucidating the link between epigenetic mechanisms and neurogenesis.

REST orchestrates a set of epigenetic modifications

that are distinct between non-neuronal cells

that give rise to neurons

and those that are destined to remain

as nervous system outsiders.

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Ballas et al 2005

Abstract – Howard Hughes Medical Institute, Dept. of Neurology and Behavior, The State University of New York at Stony Brook, Stony Brook, NY 11794, USA. nballas@notes.cc.sunysb.edu

Regulation of neuronal gene expression is critical to central nervous system development. Here, we show that

REST regulates the transitions from pluripotent

to neural stem/progenitor cell

and from progenitor to mature neuron.

In the transition to progenitor cell,

REST is degraded to levels just sufficient to maintain

neuronal gene chromatin in an inactive state

that is nonetheless poised for expression.

As progenitors differentiate into neurons,

REST and its co-repressors dissociate from the RE1 site,

triggering activation of neuronal genes.

In some genes, the level of expression is adjusted further in neurons by CoREST/MeCP2 repressor complexes that remain bound to a site of methylated DNA distinct from the RE1 site. Expression profiling based on this mechanism indicates that

REST defines a gene set subject to plasticity in mature neurons. Thus, a multistage repressor mechanism

controls the orderly expression of genes

during development

while still permitting fine tuning in response to specific stimuli.

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Lunyak & Rosenfeld 2005

Abstract – comment on Cell. 2005 May 20;121(4):645-57.

Epigenetic strategies control the orderly acquisition and maintenance of neuronal traits. Phenotypes

A complex network of transcriptional repressors and co-repressors mediates gene specificity for these strategies. In this issue of Cell, a study by Ballas and coworkers (Ballas et al., 2005) provides insight into the early lineage commitment events during neurogenesis. This study demonstrates that regulation of the REST/NRSF transcriptional repressor plays a fundamental role in the progression of pluripotent cells to lineage-restricted neural progenitors.

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Hamby, Coskun & Sun 2008

Abstract – Mental Retardation Research Center, David Geffen School of Medicine, University of California Los Angeles, USA.

The transcriptional programs of neural progenitor cells change dynamically during neurogenesis, a process regulated by both intrinsic and extrinsic factors.

Although many of the transcription factors required for neuronal differentiation have long been identified, we are only at the brink of understanding how epigenetic mechanisms influence transcriptional activity and the accessibility of transcription factors to bind consensus cis-elements.

Herein, we delineate the chief epigenetic modifications and the machinery responsible for these alterations. Further, we review the epigenetic modifications presently known to participate in the maintenance of the neural progenitor cell state and in the regulation of neuronal differentiation.

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Hsieh & Gage 2005

Abstract – Department of Molecular Biology and Cecil H and Ida Green Center for Reproductive Biology Sciences, UT Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390, USA. Jenny.Hsieh@UTSouthwestern.edu

Neural stem cells generate distinct cell types

for tissue formation and cell replacement

during development and throughout adulthood.

Neural development and plasticity are determined by both extrinsic and intrinsic factors that interface to regulate gene programs for controlling neuronal cell fate and function.

Recent reports have shown that chromatin remodeling

and epigenetic gene regulation

play an important role in such diverse areas as neural cell fate specification and synaptic development and function.

These epigenetic mechanisms include

cell-type-specific transcriptional regulators,

histone modifications and

chromatin remodeling enzymes, and the

activity of retrotransposons.

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Miller, Campbell & Sweatt 2008

Abstract – Department of Neurobiology, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, 1074 Shelby Building, 1825 University Boulevard, Birmingham, AL, USA. cmiller@nrc.uab.edu

A clear understanding is developing concerning the

importance of epigenetic-related molecular mechanisms

in transcription-dependent long-term memory formation.

My guess is that most mental health problems are connected HERE – including incoherent insecure attachment life histories

And dissociation

Chromatin modification,

in particular histone acetylation,

is associated with transcriptional activation,

and acetylation of histone 3 (H3) occurs in Area CA1 of the hippocampus following contextual fear conditioning training.

Conversely, DNA methylation is associated with transcriptional repression, but is also dynamically regulated in Area CA1 following training. We recently reported that inhibition of the enzyme responsible for DNA methylation,

DNA methyltransferase (DNMT),

in the adult rat hippocampus blocks behavioral memory formation.

Here, we report that DNMT inhibition also blocks the concomitant memory-associated H3 acetylation, without affecting phosphorylation of its upstream regulator, extracellular signal-regulated kinase (ERK).

Interestingly, the DNMT inhibitor-induced deficit in memory consolidation, along with deficits in long-term potentiation, can be rescued by pharmacologically increasing levels of histone acetylation prior to DNMT inhibition.

These observations suggest that DNMT activity is not only necessary for memory and plasticity, but that DNA methylation may work in concert with histone modifications to regulate plasticity and memory formation in the adult rat hippocampus.

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If epigenetic mechanisms can enable bodies to communicate through the generations that there “used to be” a famine, or that there “used to be fungicides” in the environment, why couldn’t it communicate transgenerationally that there is risk to attachment, which is the social foundation of our species?  Broken attachment systems HURT.  I think this pain is permanently hardwired into us – yet in the cases of my and my siblings’ children, I think we provided strong enough “earned secure” attachment in the here and now to avert the carry over of the pain to our offspring.

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Seckl & Meaney 2006

Abstract – Endocrinology Unit, Centre for Cardiovascular Science, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. J.Seckl@ed.ac.uk

Epidemiological data have linked an adverse fetal environment with increased risks of cardiovascular, metabolic, neuroendocrine, and psychiatric disorders in adulthood.

Prenatal stress and/or glucocorticoid excess might underlie this link. In animal models, prenatal stress, glucocorticoid exposure or inhibition/knockout of 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD-2), the feto-placental barrier to maternal glucocorticoids, reduces birth weight and causes permanent hypertension, hyperglycemia, increased hypothalamic-pituitary-adrenal (HPA) axis activity and behavior resembling of anxiety. In humans, 11 beta-HSD-2 gene mutations cause low birth weight and placental 11 beta-HSD-2 activity correlates directly with birth weight and inversely with infant blood pressure. Low birth weight babies have higher plasma cortisol levels throughout adult life, indicating HPA programming.

In human pregnancy, severe maternal stress affects the offspring HPA axis and associates with neuropsychiatric disorders. Posttraumatic stress disorder (PTSD) appears to be a variable in the effects.

Intriguingly, some of these effects appear to be ‘inherited’ into a further generation, itself unexposed to exogenous glucocorticoids at any point in the lifespan from fertilization, implying epigenetic marks persist into subsequent generation(s).

Overall, the data suggest that prenatal exposure to excess glucocorticoids programs peripheral and CNS functions in adult life, predisposing to some pathologies, perhaps protecting from others, and these may be transmitted perhaps to one or two subsequent generations.

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Seckl & Meaney 2004

Abstract – Endocrinology Unit, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Edinburgh, EH4 2XU, UK. J.Seckl@ed.ac.uk

Epidemiological evidence suggests that an adverse fetal environment permanently programs physiology, leading to increased risks of cardiovascular, metabolic, and neuroendocrine disorders in adulthood. Prenatal glucocorticoid excess or stress might link fetal maturation and adult pathophysiology. In a variety of animal models, prenatal glucocorticoid exposure or inhibition of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the fetoplacental “barrier” to maternal glucocorticoids, reduces birth weight and causes permanent hypertension, hyperglycemia, and increased hypothalamic-pituitary-adrenal axis (HPA) activity and behavior resembling anxiety. In humans, 11beta-HSD2 gene mutations cause low birth weight and reduced placental 11beta-HSD2 activity associated with intrauterine growth retardation. Low birth weight babies have higher plasma cortisol levels throughout adult life, indicating HPA programming. The molecular mechanisms may reflect permanent changes in the expression of specific transcription factors; key is the glucocorticoid receptor itself. Differential programming of the glucocorticoid receptor in different tissues reflects effects upon one or more of the multiple tissue-specific alternate first exons/promoters of the glucocorticoid receptor gene. Overall, the data suggest that either pharmacological or physiological exposure to excess glucocorticoids prenatally programs pathologies in adult life.

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Seckl 2001

Abstract – Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. j.seckl@ed.ac.uk

It has been long recognized that the glucocorticoid administration to pregnant mammals (including humans) reduces offspring birth weight. Epidemiologically, low weight or thinness at birth is associated with an increased risk of cardiovascular and metabolic disorders in adult life. So, does fetal exposure to glucocorticoids produce such ‘programming’ of adult disorders? Here data are reviewed which show, in rodents and other model species, that antenatal exposure to glucocorticoids reduces offspring birth weight and produces permanent hypertension, hyperglycaemia, hyperinsulinaemia, altered behavior and neuroendocrine responses throughout the lifespan.

This occurs with exogenous (dexamethasone) or endogenous glucocorticoids, the latter achieved by inhibiting 11 beta-hydroxysteroid dehydrogenase type 2, the feto-placental enzymic barrier to maternal glucocorticoids.

Processes underlying fetal programming

include determination of the

‘set point’

of the hypothalamic-pituitary-adrenal axis

and of tissue glucocorticoid receptor expression.

Detailed molecular mechanisms are being dissected. Analogous stress axis hyperreactivity occurs in lower birth weight humans and may be an early manifestation and indicate approaches to

manipulation or prevention of the phenotype.

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Seckl 2004

Abstract – Endocrinology Unit, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK. J.Seckl@ed.ac.uk

Epidemiological evidence suggests that low birth weight is associated with an increased risk of cardiovascular, metabolic and neuroendocrine disorders in adult life. Glucocorticoid administration during pregnancy reduces offspring birth weight and alters the maturation of the lung and other organs. We hypothesized that prenatal exposure to excess glucocorticoids or stress might represent a mechanism linking foetal growth with adult pathophysiology. In rats, birth weight is reduced following prenatal exposure to the synthetic steroid dexamethasone, which readily crosses the placenta, or to carbenoxolone, which inhibits 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), the physiological feto-placental ‘barrier’ to maternal glucocorticoids. As adults, the offspring exhibit permanent hypertension, hyperglycaemic, increased hypothalamic-pituitary-adrenal (HPA) axis activity and behavior reminiscent of anxiety. Physiological variations in placental 11beta-HSD2 activity correlate directly with foetal weight. In humans, 11beta-HSD2 gene mutations cause low birth weight. Moreover, low-birth-weight babies have higher plasma cortisol levels throughout adult life, indicating HPA axis programming. The molecular mechanisms may reflect permanent changes in the expression of specific transcription factors, key among which is the glucocorticoid receptor (GR) itself.

The differential programming of the GR in different tissues reflects effects upon one or more of the multiple tissue-specific alternate first exons/promoters of the GR gene. Overall, the data suggest that both pharmacological and physiological exposure prenatally to excess glucocorticoids programs cardiovascular, metabolic and neuroendocrine disorders in adult life.

I need the link for this with early postnatal stress causing similar changes.

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Seckl & Homes 2007

Abstract – College of Medicine and Veterinary Medicine, University of Edinburgh, UK.

Epidemiological evidence suggests that an adverse prenatal environment permanently ‘programs’ physiology and increases the risk of cardiovascular, metabolic, neuroendocrine and psychiatric disorders in adulthood.

Prenatal stress or exposure to excess glucocorticoids might provide the link between fetal maturation and adult pathophysiology. In a variety of animal models, prenatal stress, glucocorticoid exposure and inhibition (or knockout of) 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2)–the fetoplacental barrier to maternal glucocorticoids–reduce birth weight and cause increases in adult blood pressure, glucose levels, hypothalamic-pituitary-adrenal (HPA) axis activity and anxiety-related behaviors. In humans, mutations in the gene that encodes 11beta- hydroxysteroid dehydrogenase type 2 are associated with low birth weight. Babies with low birth weight have higher plasma cortisol levels throughout life, which indicates HPA-axis programming.

In human pregnancy, severe maternal stress affects the offspring’s HPA axis and is associated with neuropsychiatric disorders; moreover, maternal glucocorticoid therapy alters offspring brain function.

The molecular mechanisms that underlie prenatal programming might reflect permanent changes in the expression of specific transcription factors, including the glucocorticoid receptor; tissue specific effects reflect modification of one or more of the multiple alternative first exons or promoters of the glucocorticoid receptor gene. Intriguingly,

some of these effects seem to be inherited by subsequent generations that are unexposed to exogenous glucocorticoids at any point in their lifespan from fertilization, which implies that these epigenetic effects persist.

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O’Reagan et al 2001

Abstract – Endocrinology Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.

Increasing epidemiological evidence supports the notion that adverse events in fetal life permanently alter the structure and physiology of the adult offspring, a phenomenon dubbed ‘fetal programming’.

In particular, low weight or thinness at birth in humans is associated with an increased risk of cardiovascular and metabolic disorders as well as neuroendocrine dysfunction in adult life.

Glucocorticoid administration during pregnancy is well-documented to both reduce offspring birth weight and alter the maturation of organs (hence their use to accelerate fetal lung maturation in premature labor). Here data are reviewed which show, in rodents and other models, that antenatal exposure to endogenous or exogenous glucocorticoids reduces offspring birth weight and produces permanent hypertension, hyperglycaemia, hyperinsulinaemia, altered behavior and neuroendocrine responses throughout the lifespan.

Processes underlying fetal programming include determination of the ‘set point’ of the hypothalamic-pituitary-adrenal (HPA) axis and of tissue glucocorticoid receptor (GR) expression. Similar HPA axis hyperreactivity occurs in lower birth weight humans and may be an early manifestation of the ‘low birth weight’ phenotype.

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Wells 2007

Abstract – Childhood Nutrition Research Centre, Institute of Child Health, 30 Guilford Street, London WC1N 1EH. J.Wells@ich.ucl.ac.uk

Human diseases in adulthood are increasingly associated with growth patterns in early life, implicating early-life nutrition as the underlying mechanism. Cannot ignore effects of epigenetics

The thrifty phenotype hypothesis

proposed that early-life metabolic adaptations

promote survival, with the developing organism responding to cues of environmental quality by selecting an appropriate trajectory of growth.

Reminds me of Teicher’s evolutionarily altered brain – early stress does effect metabolism, and how nutrition is handled in the brain.  In a wholeness scenario, metabolism, immune system, brain all being affected with adjustments toward thrift

Recently, some authors have proposed that the thrifty phenotype is also adaptive in the longer-term, by preparing the organism for its likely adult environment. However,

windows of plasticity close early during human development,

and subsequent environmental changes

may result in the selected trajectory becoming inappropriate, leading to adverse effects on health.

This paradox generates uncertainty as to whether the thrifty phenotype is indeed adaptive for the offspring in humans. The

thrifty phenotype should not be considered a dichotomous concept, rather it refers to the capacity of all offspring to respond to environmental information during early ontogenetic development.

This article argues that the thrifty phenotype is the consequence of three different adaptive processes – niche construction, maternal effects, and developmental plasticity – all of which in humans are influenced by our large brains. While developmental plasticity represents an adaptation by the offspring, both niche construction and parental effects are subject to selection on parental rather than offspring fitness.

The three processes also operate at different paces.

Human offspring do not become net calories-producers until around 18 years of age, such that the high energy costs of the human brain are paid primarily by the mother, even after weaning.

………The evolutionary expansion of human brain volume occurred in environments characterized by high volatility, inducing strong selective pressure on maternal capacity to provision multiple offspring simultaneously.

………The thrifty phenotype is therefore best considered as a manipulation of offspring phenotype for the benefit of maternal fitness.

The information that enters offspring phenotype

during early development

does not predict the likely future environment of the offspring, but rather reflects the mother’s own developmental experience and the quality of the environment

during her own maturation.

This is fascinating – implications for child abuse such as mine

Offspring growth trajectory thus becomes aligned with long-term maternal capacity to provision.

……..In contemporary populations, the sensitivity of offspring development to maternal phenotype exposes the offspring to adverse effects, through four distinct pathways.

………The offspring may be exposed to

(1) poor maternal metabolic control (e.g. gestational diabetes), (

2) maternally derived toxins (e.g. maternal smoking), or

(3) low maternal social status (e.g. small size). Adverse consequences of these effects may then be exacerbated by

(4) exposure either to the “toxic” western environment in postnatal life, in which diet and physical activity levels are mismatched with metabolic experience in utero, or at the other extreme to famine. Even emotionally

The rapid emergence of the epidemic of the metabolic syndrome in the 20th Century reflects the rapid acceleration in the pace of niche construction relative to the slower physiological combination of developmental plasticity and parental effects

This fits in with what I have been thinking for some time, that once the evolutionary scenario is implemented in early development that the world is a malevolent place, all the adaptations that occur during development are designed to operate in adulthood for survival in the same kind of world.  In the end, when things go far off kilter, mother’s kill their offspring, males mate more, kill more enemies, find more food – all fitting in the “thrifty phenotype” model.

Early social interventions that change the developing phenotype and moderate its understanding of the famine world would logically change the resulting phenotype – as they are finding with genes for depression being modulated in childhood by adequate social support interventions.  Quite clear and simple.  As Schore notes, early stress changes the nutritional environment in the brain and changes how it develops.  Stress equals famine from the brain’s point of view.

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Wells 2003

Abstract – MRC Childhood Nutrition Research Centre, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. j.well@ich.ucl.ac.uk

Medical research is increasingly focusing on the contribution of nutritional programming to disease in later life.

Programming is a process whereby a stimulus during a critical window of time permanently affects subsequent structure, function or developmental schedule of the organism.

The thrifty phenotype hypothesis is widely used to interpret such studies, with

early growth restriction seen as

adaptation to environmental deprivation.

However, such permanent adjustment is less beneficial

than maintaining flexibility

so as to recover

from early growth deficits if the environment improves.

Thus, the existing thrifty phenotype hypothesis fails to explain why plasticity is lost so early in development in species with extended growth. Extremes of deprivation in the environment, I would think, signal special circumstances – really bad ones where the body has to take over – doomsday world

One explanation is that the developing organism

simply cannot maintain phenotypic plasticity

throughout the period of organ growth.

This article adds a life history perspective, arguing that programming of the offspring may in some species benefit maternal fitness more than it does that of individual offspring. Perfect place to include the concept that the intergenerational transmission of “unresolved trauma” comes down through the mother to the offspring – communication through her about the condition of the present, but more importantly, about the FUTURE of the world the offspring are growing into.  Epigenetic factors can include not only emotional but also toxic environment poisons – the body does not care about “psychological.”  The body will take over and the luxury of having a self or a “psychology” can be eliminated – ontogeny recapitulates phylogeny

Closing the critical window early in development

allows the preservation of maternal strategy in offspring phenotype, which in humans benefits the mother by constraining offspring demand after weaning.

The offspring gains by being buffered against environmental fluctuations during the most sensitive period of development,

allowing coherent adaptation of organ growth including brain and nervous system

to the state of the environment.

The critical window is predicted to close when offspring physiology becomes independent of maternal physiology, the timing of which depends on offspring trait.

Because placental nutrition and lactation buffer against short-term environmental fluctuations, maternal strategy is predicted to derive from long-term experience, encapsulated in maternal size and nutritional status. Including in humans the stress-response pattern

Such an approach implies that public health programs for improving birth weight may be more effective if they target maternal development rather than nutrition during pregnancy. Equally, aggressive nutritional management of infants born small or pre-term may induce the very environmental fluctuations that are naturally softened by maternal nutrition.

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Gluckman et al 2005

Abstract – Liggins Institute, University of Auckland and National Research Centre for Growth and Development, 2-6 Park Avenue, Grafton, Private Bag 92019, Auckland, New Zealand.

Early experience has a particularly great effect on most organisms. Normal development may be disrupted by early environmental influences; individuals that survive have to cope with the damaging consequences. Additionally, the responses required to cope with environmental challenges in early life may have long-term effects on the adult organism.

A further set of processes,

those of developmental plasticity,

may induce a phenotype that is adapted to the adult environment predicted by the conditions of early life.

I think all the rest of the “issues” fit under this umbrella

A mismatch between prediction and subsequent reality

can cause severe health problems in those human societies where economic circumstances and nutrition are rapidly improving. Don’t just think food – neurotransmission is a feeding on the cellular levels – and operates within these same parameters

Understanding the underlying mechanisms of plasticity is, therefore, clinically important.

However, to conduct research in this area,

developmental plasticity

must be disentangled from

disruption and the

adverse long-term effects of coping.

The paper reviews these concepts and explores ways in which such distinctions may be made in practice.

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Kuzawa 2005

Abstract – Department of Anthropology, Northwestern University, Evanston, Illinois 60208, USA. kuzawa@northwestern.edu

Evidence that fetal nutrition triggers permanent adjustments in a wide range of systems and health outcomes is stimulating interest in the evolutionary significance of these responses. This review evaluates the

postnatal adaptive significance of fetal developmental plasticity from the perspective of life history theory

and evolutionary models of energy partitioning.

Birthweight is positively related to multiple metabolically costly postnatal functions, suggesting that the

fetus has the capacity to distribute the burden of energy insufficiency

when faced with a nutritionally challenging environment.

As Schore says, stress in the developing brain changes the nutritional environment and affects genetic factors

Lowering total requirements

may reduce the risk of negative energy balance,

which disproportionately impacts functions

that are not essential for survival

but that are crucial for reproductive success.

Having a self is not essential for anything from an evolutionary standard.  It is a luxury that results from an adequate or a usually-predictable excess of basic survival essentials.  Nutrition availability to the developing brain cues it for its eventual life circumstances

The long-term benefit of these metabolic adjustments is contingent upon the fetus having access to a cue that is predictive of its future nutritional environment, a problem complicated in a long-lived species by short-term ecologic fluctuations like seasonality.   How does the body know what to predict in a life as long as ours has become?  How can it know all the changes that are possible?  Best educated guess from early signals and cues – cutting the line through the middle of up and down variations, even in the middle ground of essential balance between MR and GR activation in the HPA axis

Evidence is reviewed suggesting that the

flow of nutrients reaching the fetus [and the postnatal brain] provides an integrated signal of nutrition as experienced by recent matrilineal ancestors, which effectively limits the responsiveness to short-term ecologic fluctuations during any given pregnancy.

This capacity for fetal nutrition to minimize the growth response to transient ecologic fluctuations is defined here as intergenerational “phenotypic inertia,” and is hypothesized

to allow the fetus [and young neonate]

to cut through the “noise” of seasonal

or other stochastic influences to

read the “signal” of longer-term ecologic trends. Cut through the temporary like finding the best middle ground, and aiming a trajectory toward that end – what it responds to and how

As a mode of adaptation, phenotypic inertia may

help the organism cope with ecologic trends

too gradual to be tracked by conventional developmental plasticity,

but too rapid to be tracked by natural selection.

Sounds like epigenetics could fit here

From an applied perspective, if a trait like fetal growth is designed to minimize the effects of short-term fluctuations by integrating information across generations,

public health interventions may be most effective if focused not on the individual but on the

matriline.

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Horton 2005

Abstract – Department of Neurobiology and Physiology and the Centers for Reproductive Science, Northwestern University, Evanston, Illinois 60208, USA. thorton@northwestern.edu

The interaction of the genetic program with the environment shapes the development of an individual.

Accumulating data from animal models indicate that prenatal and early-postnatal events (collectively called “early-life events”) can

initiate long-term changes in the expression of the genetic program which persist, or may only become apparent, much later in the individual’s life.

Researchers working with humans or animal models of human diseases often view the effects of early-life events through the lens of pathology, with a focus on whether the events increase the risk for a particular disease. Alternatively, comparative biologists often view the effects of early-life events through the lens of evolution and adaptation by natural selection; they investigate the

processes by which environmental conditions

present early in life may prompt the adoption of different developmental pathways

leading to alternative life histories.

Examples of both approaches are presented in this article. This article reviews the concepts of phenotypic plasticity, natural selection, and evidence from animal models that early-life events can program the activity of the neuroendocrine system, at times altering life history patterns in an adaptive manner. Adaptive to the “best guess” during critical windows of development, with corresponding lack of flexibility to adapt, during a long life, to changes for the extreme better or worse that might be encountered.

Data from seasonally breeding rodents are used to illustrate the use of maternally derived information to alter the life history of young. In several species, the maternal system transfers photoperiodic information to the young in utero. And very early on during nervous system and brain development of the neonate

This maternally derived information

alters the response of young to photoperiods

encountered later and life, producing

seasonally distinct life histories.

Now that’s an interesting concept – seasonally distinct life histories. Perhaps it is here that we could look biologically to the human characteristic of both dissociation and incoherent life stories – as if each segment (see working memory) of life that represents a “shock” or extreme contrast having to do with biological availability on the continuum of “famine” or “toxic” results in an inability to link these extremes of “seasonally distinct life histories” together.  A season of safety, a season of danger, a season of scarcity, a season of plenty – If we stick to what the body knows, this makes perfect sense!

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Worthman & Kuzara 2005

Abstract – Department of Anthropology, Emory University, Atlanta, Georgia 30322, USA. worthman@emory.edu

Current epidemiologic models concerning the fetal [and neonate] origins of later health risk are evaluated from the perspectives of evolutionary and developmental biology. Claims of adaptive value for and biological status of fetal programming are critically examined.

Life history theory is applied to identify

key trade-offs in adaptive strategies

that constrain developmental design

to use information from the environment

to guide ontogeny and establish cost-benefit trade-offs

that weigh early survival advantage

against remote or unlikely future costs.

Or remote and unlikely changes in the “known environmental factors” even if they should be less costly, more beneficial – there are limitations in what the organism can grow up expecting from in the womb. And limitations to the developmental possibilities it can accomplish!

Expectable environments of evolutionary adaptedness, please don’t limit it here – neonate experiences are crucial, also, in this process – particularly of gestation, are characterized and their impact on human adaptive design discussed.

The roles of neuroendocrine mechanisms in scaffolding life course development, negotiating ongoing cost-benefit trade-offs, and mediating their long-term impacts on function and health are reviewed in detail.

Overviews of gestational biology and the postnatal physiologic, cognitive-affective, and behavioral effects of gestational stress identify a

shared central role for the hypothalamic-pituitary-adrenal (HPA) axis.

Rather than merely mediating stress responses,

the axis emerges an agent of resource allocation

that draws a common thread among conditions of gestation, postnatal environments, and functional and health-related outcomes.

The preponderance of evolutionary and developmental analysis identifies environments as agents on both sides

of the health risk equation, by influencing vulnerabilities

and capacities established in early and later life course development, and determining exposures and demands encountered over the life course.

These people have it right!  All the other strategies of research focus on what’s already wrong with the systems, and only begin to look down into the origins of how this all happened in the first place.  Just throw a drug at the problem – never mind how things got to be this way.  I believe that the light of understanding, education and insight allow people to focus some healing energy into themselves, transgenerationally – and that this light of understanding can help, partly because it can enlighten us on the flexibility and adativeness of human life – and what we evolved to include over the wide array of possibilities in our environments – with the best case, optimal being development under conditions of plenty, of play, of joy.

We can also learn to see the bigger picture which includes information on what heals us – including language, social contact, dance, music – and we can quit blaming the victim.  We are talking evolutionary capacities – the life history of our species, not only our own personal life histories.  We can learn the language to talk about what we can learn to understand – the big and the tiny picture of adaptation in interaction with our environment

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Crespi & Denver 2005

Abstract – Department of Molecular, Cellular and Developmental Biology, The University of Michigan, Ann Arbor, Michigan 48109, USA.

Animals have the ability to alter development, physiology, growth, and behavior in response to different environmental conditions.

These responses represent critical assessments of both external and internal factors. For example, the timing of metamorphosis, hatching, or birth depends on the trade-offs between growth opportunity and mortality risk in the developmental habitat. Physiological sensors compute these trade-offs as a function of energy balance and environmental stress, and effectors initiate physiological, developmental, and behavioral responses to these determinations.

The neuroendocrine stress axis

provides a means for animals to integrate information from multiple sources and to respond accordingly.

Considerable evidence now supports the view that the

secretion of hormones critical to development

(corticosteroid and thyroid hormones)

is controlled by a common neuroendocrine stress pathway involving corticotropin-releasing factor (CRF)

and related peptides.

CRF produced in the hypothalamus

stimulates the biosynthesis and secretion of both

thyroid and corticosteroid hormones,

leading to accelerated tadpole metamorphosis. Similarly, in mammals CRF of fetal and placental origin has been shown to influence the timing of birth. Studies in several experimental animal models and in humans show that early life experience can have long-term phenotypic consequences. No may about it – early life experience makes us, no matter what the details of the experience are – for good or for ill or for middle of the road it shapes all of us

Furthermore, there is evidence that

phenotypic expression

is strongly influenced by the actions of

stress hormones produced during development.

The integrated neuroendocrine response to stress,

and its role in timing critical life history transitions

and establishing long-term phenotypic expression,

arose early in the evolution of vertebrates.

Now I would go one step further and look for the link between this process and the immune response.  Once we have even one cell, our immune system response goes into operation – that it could influence development might be hard for people to think about, because it would be saying the truth, that development requires a best guess projection into the future in order to guide development for better survival odds once we get there.  This connection between immune system response and guided organism development requires future-think – remembering the future – evolution can do that, or we would not be here, plain and simple.

We need to work together as a whole, which means we need to consider all the individual areas of human concern that are being researched, and look for how the research links together.  We need to stop wasting time, energy and resources.  We need not wonder like children would about how some people end up depressed, or bipolar, or borderline, or with PTSD, or without a “conscience” or low on empathy or anxious or not anxious, etc.  Nature is logical.  There are projections that are resulting consequences of incoming information about the environment with resulting best guess adaptations.  All of this happens in interaction with gene manifestation and plasticity.  Risk and protective factors.

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Jones 2005

Abstract – Department of Anthropological Sciences, Stanford University, Stanford, California, USA. jhj1@stanford.edu

Fetal [and neonate] programming is an ontogenetic phenomenon of increasing interest to human biologists. Because the downstream consequences of fetal programming have clear impacts on specific life-history traits (e.g., age at first reproduction and the general age-pattern of reproductive investments), a number of authors have raised the question of the adaptive significance of fetal programming.

In this paper, I review in some detail several classical models in life-history theory and discuss their relative merits and weaknesses for human biology. I suggest that

an adequate model of human life-history evolution must account for the highly structured nature of the human life cycle, with its late age at first reproduction, large degree of iteroparity, highly overlapping generations, and extensive, post-weaning parental investment.

I further suggest that an understanding of stochastic demography is essential for answering the question of the adaptive significance of fetal programming, and specifically the finding of low birth weight on smaller adult body size and earlier age at first reproduction. Using a stage-structured stochastic population model, I show that the downstream consequences of early deprivation may be “making the best of a bad start” rather than an adaptation per se.

When a high-investment strategy entails survival costs,

the alternate strategy of early reproduction with relatively low investment

may have higher fitness than trying to play the high-investment strategy

and failing.

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Ellison 2005

Abstract – Department of Anthropology, Harvard University, Cambridge, Massachusetts 02138, USA. AJHB@fas.harvard.edu

The fetal origins hypothesis, or Barker hypothesis, is both stimulating and challenging for evolutionary human biologists. While evidence of a correlation between conditions around the time of birth and later health outcomes has been presented before, the more recent evidence of a connection between fetal growth and chronic disease risk later in life Including mental health disease has attracted considerable attention among epidemiologists and human biologists. Several themes that are fundamental to human biology emerge from an engagement with the fetal origins hypothesis.

Among them are the tension between concepts of pathology, constraint, and adaptation; the importance of a life history perspective that embraces the notion of trade-offs; the question of environmental predictability; and the mechanisms of energy mobilization and allocation.

Bringing the insights of evolutionary biology to bear on the fetal origins hypothesis illustrates the value of the field now known as evolutionary medicine.

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van Goozen & Fairchild 2008

abstract – School of Psychology, Cardiff University, Cardiff, UK. vangoozens@cardiff.ac.uk

Children with severe antisocial behavior have an increased risk of showing violently aggressive and other forms of problem behavior in adolescence and adulthood. It is well established that both biological and social factors are involved in the development of antisocial behavior. The primary aim of this paper is to discuss the evidence that specific neurobiological systems are involved in the etiology of childhood-onset antisocial behavior. These factors are responsible for the severity of the behavioral problems observed in antisocial children, but they also play a role in their persistence, because they influence children’s interactions with their environment. We will discuss the possible causes of disruptions in neurobiological systems in childhood antisocial behavior and point out the implications of these findings for theory and clinical practice.

We will argue that

familial factors

(e.g., genetic influences, early childhood adversity)

are linked to negative behavioral outcomes

(e.g., antisocial behavior problems)

through the mediating and transactional interplay

with neurobiological deficits.

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see this in mutant genes

Stein, Schork & Gelernter 2008

Abstract – Anxiety and Traumatic Stress Disorders Program, Departments of Psychiatry and Family & Preventive Medicine, University of California San Diego, La Jolla, CA 92093-0855, USA. mstein@ucsd.edu

Stein MB, Schork NJ, Gelernter J.

Gene-by-environment (serotonin transporter and childhood maltreatment) interaction for anxiety sensitivity, an intermediate phenotype for anxiety disorders.

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de Kloet et al 2005b – call in this article

abstract – Department of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research and Leiden University Medical Center, P.O. Box 9502, 2300 RA Leiden, The Netherlands. e.kloet@lacdr.leidenuniv.nl

Adverse conditions during early life

are a risk factor for stress-related diseases

such as depression and post-traumatic stress disorder (PTSD).

How this long-term effect of early adversity occurs is not known, although evidence accumulates that the action of stress hormones is an important determinant.

In rodents after a variety of experiences, even minor ones, during postnatal life permanent changes in emotional and neuroendocrine reactivity have been observed.

Also stressful events occurring prenatally and even the pre-implantation hormonal conditions can have permanent consequences.

Here we will focus on evidence obtained from

(i) the blastocyst implantation during conditions of ovarian hyperstimulation, which is commonly used in the generation of transgenic mice;

(ii) the stress system activity in the newborn under various conditions of maternal care;

(iii) the long-term consequences of maternal separation procedures.

The results clearly demonstrate that

early experiences trigger immediate changes

in the stress system that may

permanently alter brain and behavior.

These changes happen within the context of the early attachment experience – maternal separation for rodents creates irreversible stress responses

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Fone & Porkess 2008 – call in this article

Abstract – Institute of Neuroscience, School of Biomedical Sciences, Medical School, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. kevin.fone@nottingham.ac.uk

Exposing mammals to early-life adverse events,

including maternal separation or social isolation,

profoundly affects brain development

and adult behavior and may contribute to the occurrence of psychiatric disorders, such as depression and schizophrenia in genetically predisposed humans.

I don’t buy this.  If the isolation and adverse experiences are severe enough, NOBODY is going to escape unscathed.  It is not humanly possible to adapt and adjust to overwhelming malevolent experiences, especially while the brain is growing in early infanthood, without alterations occurring.

If such an individual’s genetic code and processes do not include enough plasticity in one way or another, they will not survive.  At the very least they will develop an insecure attachment system, and that by itself is a pathological condition.  The only salvation is adequate social support during these crucial developmental stages that can moderate the effects of the maltreatment.

There is no magic here.  Alterations will occur.  There is no other way.  Nobody possesses immunity from the requirement of adaptation and adjustment to adverse early experiences.  If someone appears to have made it through unscathed, then we must look for the external supportive mechanisms that were available to the infant from the beginning, and that allowed the infant to utilize these external resources in order to mitigate the damage caused by severe early abuse, maltreatment and neglect.  Nobody is supposed to come into this world to be alone.  This degree of trauma and its resulting forced adjustments do not create what we fondly enjoy referring to as “abandonment issues” or “problems with intimacy.”  This degree of maltreatment creates alterations in the BODY of the organism on all levels – nervous system including the brain, operation of the hormones and neurotransmitters, alterations in the immune system.  And these changes happen on the molecular level.

The molecular mechanisms

underlying these environmentally induced

developmental adaptations

are unclear and best evaluated in animal paradigms with translational salience.

Rearing rat pups from weaning in isolation,

to prevent social contact with conspecifics,

produces reproducible, long-term changes including; neophobia [tendency to avoid the new] , impaired sensorimotor gating, aggression, cognitive rigidity, reduced prefrontal cortical volume and decreased cortical and hippocampal synaptic plasticity.

These alterations are associated with

hyperfunction of mesolimbic dopaminergic systems,

enhanced presynaptic dopamine (DA)

and serotonergic (5-HT) function

in the nucleus accumbens (NAcc),

hypofunction of mesocortical DA and

attenuated 5-HT function in the

prefrontal cortex and hippocampus.

These behavioral, morphological and neurochemical abnormalities, as reviewed herein, strongly resemble core features of schizophrenia.

Therefore unraveling the mechanisms that trigger these sequelae will improve our knowledge of the aetiology of neurodevelopmental psychiatric disorders, enable identification of longitudinal biomarkers of dysfunction and permit predictive screening for novel compounds with potential antipsychotic efficacy.

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Lapiz et al 2001

Abstract – School of Biomedical Sciences, University of Nottingham Medical School, Queen’s Medical Centre, Nottingham NG7 2UN, United Kingdom.

There is substantial evidence that

early life events influence brain development

and subsequent adult behavior and play an important role

in the causation of certain psychiatric disorders including schizophrenia and depression.

The underlying mechanism of the effects of these early environmental factors is still not understood. It is a challenge to attempt to model early environmental factors in animals to gain understanding of the basic mechanisms that underlie the long-term effects. This paper reviews the effects of rearing rats from weaning in social isolation and reports some recent results indicating

hippocampal dysfunction.

Isolation rearing in rats from weaning Infant abuse by mother often begins long before weaning.  In such descriptions of damage as this one, I am finding myself represented.  Finally.  No wonder nobody ever told me what happened to me.  Few but experts in the field of molecular bioscience could ever understand this.  All those of us who had this type of damage done to us are allowed to know is that we are different, our feelings are different, our behaviors, our reactions, our thoughts and brain and how we process life..

produces a range of persistent behavioural changes in the young adult, including hyperactivity in response to novelty and amphetamine and altered responses to conditioning.

These are associated with

alterations in the central aminergic neurotransmitter functions

in the mesolimbic areas and other brain regions.

Isolation-reared rats have

enhanced presynaptic dopamine (DA) and 5-HT function

in the nucleus accumbens (NAC) associated with

decreased presynaptic 5-HT function in the frontal cortex and hippocampus.

Isolation-reared rats have

reduced presynaptic noradrenergic function in the hippocampus,

but have enhanced presynaptic DA function in the amygdala.

These neurochemical imbalances

may contribute to the

exaggerated response of the isolated rat to a novel stimulus or to stimuli predictive of danger,

Our bodies had to adjust this way to our malevolent environments.  Are we now only left with drugs to “change us back” into a creature that is better adjusted to live in a supposedly malevolent world?

Or can we learn what happened to us, how our bodies adapted, and who we are now and learn to live with ourselves?

and isolation-induced behavioural changes.

These changes have neuroanatomical correlates;

changes which seem to parallel to a certain degree

those seen in human schizophrenia.

A greater understanding of the processes that underlie these changes should improve our knowledge of how environmental events may alter brain development and function, and play a role in the development of neuropsychiatric disorders.

Ok, see here that what might appear as a disorder to someone in the benevolent world is perfectly understandable to those made in, by and for a malevolent world.  The disorder lies in whatever “toxicity” existed in the first place that allowed us to have to experience and endure the horrors that we did.

Place the blame and criticism, if you have it, directly where it belongs – and that is NOT ON US, the survivors.

Teach us what these changes mean in terms of how we experience the world and how we react to it.

And understand that we do NOT need to be FIXED.  We are not broken.  We are different.  We were made differently.  If you want to “change us back” then at least be very clear about what you are attempting to do, what you are suggesting we change into and why.

If you see us as unproductive members of society because we have difficulty walking the narrow line of benevolent normalcy, then say that and say it clearly.  And in the future, prevent it.

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Jay et al 2004

Abstract – INSERM E 0117, Physiopathologie des Maladies Psychiatriques, Centre Paul Broca, 2ter rue d’Alésia, 75014 Paris, France. jay@broca.inserm.fr

The direct hippocampal to prefrontal cortex pathway

and its changes in synaptic plasticity

is a useful framework for investigating the functional operations of hippocampal-prefrontal cortex communication

in cognitive functions.

Synapses on this pathway are modifiable and synaptic strength can be turned up or down depending on specific patterns of activity in the pathway.

The objective of this review will be to summarize the different studies carried out on this topic including very recent data and to underline the importance of animal models for the development of new and effective medications in psychiatric diseases. We have shown that

long-term potentiation (LTP) of hippocampal-prefrontal synapses is driven by the level of mesocortical dopaminergic (DA) activity

and more recently that

stress is also an environmental determinant of LTP

at these cortical synapses.

Stimulation of the ventral tegmental area at a frequency known to evoke DA overflow in the prefrontal cortex produces a long-lasting enhancement of the magnitude of hippocampal-prefrontal cortex LTP whereas a depletion of cortical DA levels generates a dramatic decrease in this LTP.

Moreover, hippocampal stimulation induces a transient

but significant increase in DA release in the prefrontal cortex and an optimal level of D1 receptor activation is essential for LTP expression.

We recently investigated the

impact of stress on hippocampal-prefrontal LTP and demonstrated that exposure to an acute stress causes a

remarkable

and long-lasting inhibition of LTP.

Furthermore, we demonstrated that tianeptine, an antidepressant which has a unique mode of action, and clozapine an atypical antipsychotic when administered at doses normally used in human testing are able to reverse the impairment in LTP.

Stressful life events have a substantial causal association

with psychiatric disorders like schizophrenia and depression

and recent imaging studies have shown

an important role of the limbic-cortical circuit

in the pathophysiology of these illnesses.

Therefore, we proposed that agents capable of

reversing the impairment of plasticity at hippocampal

to prefrontal cortex synapses

have the potential of becoming new therapeutic classes of antidepressant or antipsychotic drugs.

Again I ask, is there no other way other than drugs to repair and heal these problems once they are caused?  Don’t pretend that drugs will make us “normal.”  Teach us, and let us change ourselves.

What if we don’t want our brain flooded with drugs?

That changes us, and is too high a price to pay for something that we did not do to ourselves.

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Dupin et al 2006

Abstract – INSERM, U796, Pathophysiology of Psychiatric Disorders, University Paris Descartes, Faculty of Medecine Paris Descartes, Paris F-75014, France.

We recently investigated the

effects of stress on synaptic plasticity in the prefrontal cortex, namely the prelimbic area

or the apparent homologue of the primate subgenual prefrontal cortex in humans where most of the hippocampal terminal fields are localized.

Exposure to an acute stress

causes a remarkable and long-lasting inhibition

of long term potentiation (LTP) in the frontal cortex

evoked by stimulation of hippocampal outflow

and this impairment is prevented by the glucocorticoid receptor antagonist mifepristone.

Thus, the frontal cortex

is also a target

for glucocorticoids involved in the

stress response.

Current data show that antidepressants of various types, i.e., tianeptine and fluoxetine, at doses normally used in antidepressant testing, restore LTP impaired by prior acute stress. Interestingly, clozapine administered in a similar way after stress rapidly reverses the stress-induced impairment of LTP at doses which do not affect LTP alone.

This stress paradigm highlights comorbidity for both etiology and treatment of psychiatric disorders like depression and schizophrenia.

Restoring appropriate cognitive functions in circuits associated with dysfunctions in coping with stress

may be proposed as a new systems-level approach to drug discovery and development. We are presently investigating the

involvement of signaling molecules in producing these plastic changes.

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Qi et al 2008

Abstract – Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, 171 77 Stockholm, Sweden.

Exposure to stress

causes dysfunctions in circuits

connecting hippocampus and prefrontal cortex (H-PFC).

Long term potentiation (LTP)

induced in vivo in rats at H-PFC synapses is impaired by acute elevated platform stress in a manner that can be restored by treatment with certain antidepressants.

To identify biochemical pathways in rat frontal cortex underlying this stress-mediated impairment of synaptic plasticity, we examined the phosphorylation state of receptors, signaling proteins and transcription factors implicated in neuronal plasticity.

So what we are losing in part is the plasticity of our brain

Transient changes in the phosphorylation states of Ser(217/221)-MEK, Thr(183)/Tyr(185)-p42MAPK, Thr(202)/Tyr(204)-p44MAPK, Thr(180)/Tyr(182)-p38MAPK, Thr(218)/Tyr(220)-ERK5, Thr(308)-Akt, Ser(63)-ATF-1, Ser(1303)-GluN2B, Tyr(490/515)-TrkA/B were found.

BDNF was down-regulated after elevated platform stress suggesting that it could regulate the

MEK/MAPK signaling cascade.

Acute treatment with the antidepressants tianeptine and imipramine reversed the stress-induced down-regulation of P-Ser(217/221)-MEK. However, stress-induced impairment of H-PFC LTP was only restored by acute treatment with tianeptine and not by imipramine. Tianeptine, but not imipramine, increased the phosphorylation of Ser(831)-GluA1.

Altogether, these results indicate that acute elevated platform stress down-regulates a putative BDNF/MEK/MAPK signaling cascade in the frontal cortex

in a manner that is reversible by the antidepressants tianeptine and imipramine.

Moreover, changes in LTP may be associated with phosphorylation of AMPA receptors and with some specificity for certain antidepressants. Indeed, stress-induced impairment of H-PFC LTP was only restored by acute treatment with tianeptine and not by imipramine. Tianeptine, but not imipramine, increased the phosphorylation of Ser(831)-GluA1, indicating a

potential effect on AMPA receptor phosphorylation being involved in the reversal of LTP.

How about somebody telling me what these brain changes are designed by nature to accomplish due to stress exposure?  Again, what do they FEEL like to us?  Can they be restored in any other way other than by the use of drugs?  Does stress cause these changes in everyone’s brain to happen?

It is interesting to read this information on a level other than being about the HPA axis changes.

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Shakesby, Anwyl & Rowan 2002

Abstract – Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland.

Acute inescapable stress

dramatically affects the inducibility of plasticity

at glutamatergic synapses in the intact hippocampus.

In other research recorded here the differences are indicated in how rats already prior exposed to isolation at weaning do not have the same responses to this stress as do animals who have not previously ALREADY been changed.  This stress reaction builds itself right into the developing brain from the beginning.

If a stress is truly inescapable, what is to be learned from the experience?  What learning could prevent this from happening again?

The present study examined the involvement of serotonergic mechanisms in mediating and modulating the block of long-term potentiation (LTP) in the CA1 area of anesthetized rats after exposure to an elevated platform stress.

Fluoxetine and fenfluramine, agents that

raise hippocampal

extracellular 5-HT concentration,

blocked the induction of LTP in nonstressed animals,

thus mimicking the effect of stress.

In contrast, (+/-)-tianeptine, a drug that decreases 5-HT levels, had no effect on LTP induction in nonstressed animals.

Remarkably, (+/-) administration of tianeptine after the stress rapidly overcame the block of LTP induction without affecting baseline excitatory transmission. Consistent with a reduction of 5-HT levels being responsible for this effect of tianeptine, the (-) enantiomer, which is associated with the 5-HT uptake enhancing action of (+/-)-tianeptine, also caused a recovery of the induction of LTP in previously stressed animals, whereas the relatively inactive (+) enantiomer had no effect. Furthermore, fluoxetine prevented the effect of tianeptine in stressed animals. These findings show that

Antidepressants

have rapid and powerful interactions

with the mechanisms

controlling the persistence of the

block of LTP by inescapable stress.

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Rocher et al 2004

Abstract – NAMC, CNRS UMR 8620, Bat. 446, Université Paris-Sud, 91405 Orsay, France.

Acute stress inhibits long-term potentiation (LTP)

at synapses from the hippocampus to prefrontal cortex

in the rat, a model of the dysfunction

in the anterior cingulate/orbitofrontal cortices

which has been observed in human depression.

We demonstrate that the antidepressants tianeptine and, to a lesser extent, fluoxetine, are able to

reverse the impairment in LTP,

a measure of frontal synaptic plasticity,

caused by stress on an elevated platform.

LTP was induced by stimulation of hippocampal outflow.

Beneficial effects on neuronal plasticity, defined as a reversal of the effects of stress in this paradigm,

can be considered as a new animal model for the impact of stress on hippocampal/frontal circuits,

a key target in psychiatric diseases.

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Gurden, Takita & Jay 2000

Abstract – Neurobiologie de l’Apprentissage, de la Mémoire et de la Communication, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8620, 91405 Orsay, France.

An intact mesocortical dopaminergic

(DA) input

to the prefrontal cortex (PFC) has been reported to be necessary for long-term potentiation (LTP) to occur

at hippocampal-prefrontal cortex synapses.

Here, we investigated the role

of D1 and D2 receptors in this

NMDA receptor-dependent LTP.

Local infusion of the D1 agonist SKF81297 at an optimal dose induced a sustained enhancement of hippocampal-PFC LTP, whereas the D1 antagonist SCH23390 caused a dose-related impairment of its induction. The D1 agonist effect was mimicked by infusion of a low dose of the adenylyl cyclase activator forskolin, whereas LTP was severely attenuated with a protein kinase A inhibitor, Rp-cAMPS. To further assess the complex interplay between DA and NMDA receptors, changes in extracellular DA levels in the PFC were estimated during LTP, and a significant increase was observed immediately after tetanus. Taken together, these data suggest that

D1 but not D2 receptors

are crucial for the DA control of the NMDA receptor-mediated synaptic response on a specific excitatory input to the PFC.

The interactions of these receptors may play a crucial role in the storage and transfer of hippocampal information in the PFC.

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Chen et al 2007

Abstract – National Standard Lab of Pharmacology for Chinese Materia Medica, Research Center of Acupuncture and Pharmacology, Nanjing University of Traditional Chinese Medicine, Nanjing, China.

Prefrontal cortex (PFC) dopamine D1/5 receptors

modulate long- and short-term neuronal plasticity

that may contribute to cognitive functions.

Synergistic to synaptic strength modulation,

direct postsynaptic D1/5 receptor activation also modulates

voltage-dependent ionic currents that regulate spike firing,

thus altering the neuronal input-output relationships in a process called long-term potentiation of intrinsic excitability (LTP-IE).

Here, the intracellular signals that mediate this D1/5 receptor-dependent LTP-IE were determined using whole cell current-clamp recordings in layer V/VI rat pyramidal neurons from PFC slices. After blockade of all major amino acid receptors (V(hold) = -65 mV) brief tetanic stimulation (20 Hz) of local afferents or application of the D1 agonist SKF81297 (0.2-50 microM) induced LTP-IE, as shown by a prolonged (>40 min) increase in depolarizing pulse-evoked spike firing. Pretreatment with the D1/5 antagonist SCH23390 (1 microM) blocked both the tetani- and D1/5 agonist-induced LTP-IE, suggesting a D1/5 receptor-mediated mechanism. The SKF81297-induced LTP-IE was significantly attenuated by Cd(2+), [Ca(2+)](i) chelation, by inhibition of phospholipase C, protein kinase-C, and Ca(2+)/calmodulin kinase-II, but not by inhibition of adenylate cyclase, protein kinase-A, MAP kinase, or L-type Ca(2+) channels.

Thus this form of D1/5 receptor-mediated LTP-IE relied on Ca(2+) influx via non-L-type Ca(2+) channels, activation of PLC, intracellular Ca(2+) elevation, activation of Ca(2+)-dependent CaMKII, and PKC to mediate modulation of voltage-dependent ion channel(s).

This D1/5 receptor-mediated modulation by PKC [?]

coexists with the previously described PKA-dependent modulation of K(+) and Ca(2+) currents

to dynamically regulate overall excitability of PFC neurons.

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Tseng & O’Donnell 2004

Abstract – Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York 12208, USA. tsengky@mail.amc.edu

Although the importance of dopamine (DA) for prefrontal cortical (PFC) cognitive functions is widely recognized, the nature of DA actions in the PFC remains controversial.

A critical component in DA actions

is its modulation of glutamate transmission,

which can be different when specific receptors are activated.

To obtain a clear picture of cellular mechanisms involved in these interactions, we studied the effects of DA-glutamate coactivation on pyramidal cell excitability in brain slices obtained from developmentally mature rats using whole-cell patch-clamp recordings. Bath application of NMDA, AMPA, and the D1 agonist SKF38393 induced concentration-dependent excitability increases, whereas bath application of the D2 receptor agonist quinpirole induced a concentration-dependent excitability decrease. The NMDA-mediated response was potentiated by SKF38393. This NMDA-D1 synergism required postsynaptic intracellular Ca2+ and protein kinase A (PKA) and was independent of membrane depolarization. On the other hand, the excitatory effects of both NMDA and AMPA were attenuated by a D2 agonist. Surprisingly, the D2-NMDA interaction was also blocked by the GABA(A) antagonists bicuculline and picrotoxin, suggesting that

the inhibitory action of D2 receptors

on NMDA-induced responses in the PFC

may be mediated by GABAergic interneurons.

In contrast, the D2-AMPA interaction involves inhibition of PKA and activation of phospholipase lipase C-IP3 and intracellular Ca2+ at a postsynaptic level.

Thus, the modulatory actions of D1 and D2 receptors

on PFC pyramidal cell excitability

are mediated by multiple intracellular mechanisms

and by activation of GABA(A) receptors,

depending on the glutamate receptor subtypes involved.

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Wang et al 2003

Abstract – Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214, USA.

Increasing evidence has suggested that the

interaction between dopaminergic and glutamatergic systems

in prefrontal cortex (PFC)

plays an important role in normal mental functions

and neuropsychiatric disorders.

In this study, we examined the

regulation of NMDA-type glutamate receptors

by the PFC dopamine D4 receptor

(one of the principal targets of antipsychotic drugs).

Application of the D4 receptor agonist PD168077 caused a reversible decrease of the NMDA receptor (NMDAR)-mediated current in acutely isolated and cultured PFC pyramidal neurons, an effect that was blocked by selective D4 receptor antagonists. Furthermore, application of PD168077 produced a potent reduction of the amplitude (but not paired-pulse ratio) of evoked NMDAR EPSCs in PFC slices. The D4 modulation of NMDA receptors in PFC involved the inhibition of protein kinase A, activation of protein phosphatase 1 and the ensuing inhibition of active Ca2+-calmodulin-dependent kinase II (CaMKII). Moreover, PD168077 reduced the surface expression of NMDARs and triggered the internalization of NMDARs in a manner dependent on CaMKII activity.

These results identify

a mechanistic link between D4 and NMDA receptors in PFC pyramidal neurons,

suggesting that D4 receptors may play an important role

in modulating synaptic plasticity

and thus cognitive and emotional processes in PFC circuits.

T this point I would wonder about epigenetic factors and mechanisms that modify these receptors and their actions – including wondering about the genes modulating the D4 receptors

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Mailliet et al 2008

Abstract – INSERM, Physiopathologie des Maladies Psychiatriques, U894-7, Paris, France.

Protection of stress-induced impairment of hippocampal/prefrontal LTP through blockade of glucocorticoid receptors: implication of MEK signaling.

We previously reported that

exposure to acute and chronic stress impairs

long-term potentiation (LTP) in the hippocampal-prefrontal cortex pathway and showed evidence for

a fundamental role of the prefrontal cortex

in maladaptive responses to stress.

Here again I am not willing to say that this is a “maladaptive response to stress.”  There is some kind of evolutionarily prepared body wisdom operating here.

It makes me think of the African research where terrible trauma and stress occurrences for two different groups in two different cities did not have the same effect or outcome.

There are other factors in operation here – and until we know what they are and how they operate, we cannot definitively state what is being stated by these – and most researchers.

If there is a social and cultural interference with “bad” outcomes of stress, we need to know what this is about.  I know in my gut it’s about learning and adaptation – either possible or not.  But the determining factors are interactional with the individual and its social environment.  These researches are still not taking these factors into account, and are carrying over the archaic thought forms related to Freud that all the problems are within the single individual.  Not so.

There are other effects that can block this overdose of steroids in many cases – what are they?

The goal of the current studies was to examine whether

blockade of glucocorticosteroid receptors (GR),

by mifepristone (a Type II glucocorticoid receptor antagonist),

just after exposure to acute stress could prevent stress-induced

impairment of prefrontal LTP.

We further examine the effects of mifepristone on mitogen-activated protein/ERK kinase (MEK) signaling pathway in the prefrontal cortex.

The data show that an acute injection of mifepristone after stress restored the stress-induced blockade of prefrontal LTP

and reduction of phospho-Ser217/221-MEK.

These findings have significance for the

treatment of memory

deficits in

hypercortisolemic states,

such as stress and depression.

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Huang et al 2004

Abstract – Center for Neurobiology and Behavior, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

To address the role of D1 receptors in the medial prefrontal cortex, we combined pharmacological and genetic manipulations to examine long-term synaptic potentiation (LTP)/long-term synaptic depression (LTD) in brain slices of rats and mice.

We found that the D1 antagonist SCH23390 selectively blocked the maintenance but not the induction of LTP in the prefrontal cortex.

Conversely, activation of D1 receptors facilitated the maintenance of LTP, and this effect is impaired in heterozygous D1 receptor knockout mice. Low-frequency stimulation induced a transient depression in the medial prefrontal cortex. This depression could be transformed into LTD by coapplication of dopamine. Coapplication of dopamine, however, shows no facilitating effect on LTD in heterozygous D1 receptor knockout mice.

These results provide pharmacological and genetic evidence for a

role of D1 receptors in the bidirectional modulation

of synaptic plasticity

in the medial prefrontal cortex.

The absence of this modulation in heterozygous knockout mice shows that

a dysregulation of dopamine receptor expression levels

can have dramatic effects on synaptic plasticity

in the prefrontal cortex.

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Matsuda, Marzo & Otani 2006

Abstract – Laboratory of Neuromodulation, Neuronal Plasticity and Cognition, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 7102 Neurobiologie des Processus Adaptatifs, Université Paris VI Pierre et Marie Curie, 75005 Paris, France.

Executive functions of the brain

are believed to require tonic dopamine inputs

to the prefrontal cortex (PFC).

It is unclear, however, how this background dopamine activity controls synaptic plasticity in the PFC, a possible underlying mechanism of executive functions.

Using PFC slices, we show that pairing of dopamine with weak tetanic stimulation, a maneuver that otherwise induces NMDA receptor-independent long-term depression (LTD), induces long-term potentiation (LTP) when “primed” with dopamine. This priming” occurs through the combined activation of D1 and D2 receptors and requires 12-40 min to develop.

Moreover, concurrent synaptic activation of NMDA receptors during priming is necessary for this novel form of LTP.

We suggest that a role of background dopamine signals

in the PFC is to prevent high-frequency synaptic inputs

from abnormally inducing LTD

and to secure the induction of LTP.

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Laroche, Davis & Jay 2000

Abstract – Laboratoire de Neurobiologie de l’Apprentissage, de la Mémoire et de la Communication, CNRS UMR 8620, Université Paris-Sud, Orsay, France. serge.laroche@ibaic.u-psud.fr

The involvement of the hippocampus and the prefrontal cortex in cognitive processes and particularly in learning and memory has been known for a long time.

However, the specific role of the projection which connects these two structures has remained elusive.

The existence of a direct monosynaptic pathway from the ventral CA1 region of the hippocampus and subiculum to specific areas of the prefrontal cortex provides a useful model for conceptualizing the functional operations of hippocampal-prefrontal cortex communication in learning and memory.

It is known now that hippocampal to prefrontal cortex synapses are modifiable synapses and can express different forms of plasticity, including long-term potentiation, long-term depression, and depotentiation.

Here we review these findings and focus on recent studies that start to relate synaptic plasticity in the hippocampo-prefrontal cortex pathway to two specific aspects of learning and memory, i.e., the consolidation of information and working memory.

The available evidence suggests that

functional interactions between the hippocampus and prefrontal cortex in cognition and memory are more complex than previously anticipated, with the

possibility for bidirectional regulation of synaptic strength

as a function of the specific demands of tasks.

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Kawashima et al 2006

Abstract – Human Science and Biomedical Engineering, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan.

The hippocampal-medial prefrontal cortex (mPFC) pathway provides highly convergent input to the mPFC in rats and shows two types of short-term plasticity in terms of paired-pulse facilitation (PPF) of the field potential under urethane anesthesia.

We now report that stimulating either the dorsal or ventral subregions of the posterior hippocampus elicited PPF (by about 335 and 120%, respectively) of field potentials recorded in the mPFC at 100 ms interpulse interval. This PPF-like interaction occurred when projections were stimulated in the ventral-dorsal order (by about 200% of the single-pulsed response), but not vice versa.

When weak long-term potentiation (LTP) of the dorsal projection was evoked simultaneously with strong LTP of the ventral projection, an associative effect was revealed (about +55%), although the magnitudes of LTP in each projection were not correlated.

Even when the impermutable PPF-like facilitation was further enhanced (by about +120%), the enhancement was not correlated with either form of LTP, but exhibited the interaction of changes in the dorsal PPF, rather than in the heterotopic priming effect through the ventral projection. Moreover, this change was correlated with the associated LTP ratio of dorsal to ventral projection LTP (i.e., LTP associativity). Larger increases in LTP associativity correlated with greater impermutable PPF-like facilitation; in addition, there was hardly attenuation of the response to the dorsal projection by subsequent electrolytic lesions of the ventral subregion. These results indicate that

the mPFC functionally integrates discrete sources

of hippocampal information

via cooperativity

between short- and long-term plasticity.

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Beazely et al 2006

Abstract – Department of Physiology, University of Toronto, Toronto, Ontario, Canada.

NMDA receptor function

is modulated by both G-protein-coupled receptors and receptor tyrosine kinases.

Implications for cannabinoid system, modulated by same

In acutely isolated rat hippocampal neurons, direct activation of the

platelet-derived growth factor (PDGF) receptor

or transactivation of the PDGF receptor

by D4 dopamine receptors inhibits NMDA-evoked currents

in a phospholipase C (PLC)-dependent manner.

We have investigated further the ability of D2-class dopamine receptors to modulate NMDA-evoked currents in isolated rat prefrontal cortex (PFC). We have demonstrated that, similar to isolated hippocampal neurons, the application of PDGF-BB or quinpirole to isolated PFC neurons induces a slow-onset and long-lasting inhibition of NMDA-evoked currents.

However, in contrast to hippocampal neurons, the inhibition of NMDA-evoked currents by quinpirole in PFC neurons is dependent upon D2/3, rather than D4, dopamine receptors. In PFC slices, application of both PDGF-BB and quinpirole induced a phosphorylation of the PDGF receptor at the PLCgamma binding and activation site, Tyr1021. The PDGF receptor kinase inhibitor, tyrphostin A9, and the D2/3 dopamine receptor antagonist, raclopride, inhibited quinpirole-induced Tyr1021 phosphorylation. These finding suggest that quinpirole treatment inhibits NMDAR signaling via PDGF receptor transactivation in both the hippocampus and the PFC, and that the effects of quinpirole in these regions are mediated by D4 and D2/3 dopamine receptors, respectively.

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Maroun & Richter-Levin 2003

Abstract – The Brain and Behavior Center, Faculty of Science and Science Education, University of Haifa, Haifa, 31905, Israel. mmaroun@psy.haifa.ac.il

In recent years, attention has been given to the

interaction between the emotional state of the animal

and its ability to learn and remember.

Studies into the neural mechanisms underlying these interactions have focused on stress-induced synaptic plasticity impairments

in the hippocampus. However, other brain areas,

including the amygdala and the prefrontal cortex (PFC),

have been implicated in relation to

stress-mediated effects on memory.

The present study examined whether

stress, which impairs hippocampal long-term potentiation (LTP), also affects LTP of the basolateral amygdala (BLA)-PFC pathway in vivo. We first confirmed that the stress protocol we used, i.e., the elevated platform stress, was effective in blocking LTP in the CA1 area of the hippocampus. We then characterized activity and established the ability to induce LTP at the BLA-PFC pathway. Finally, we examined the effects of an exposure to the elevated platform stress on the ability to induce LTP in this pathway. The results indicate that, at the same time when LTP is blocked in the hippocampus, it is also inhibited in the BLA-medial PFC pathway.

These results call for a shift from a focused attention

on the effects of stress on plasticity in the hippocampus

to a system level approach that emphasizes the possible

modification of interactions between relevant brain areas after an exposure to a stressful experience.

I was right.  The effects are far more widespread than the hippocampus.  And I was also correct that learning is a central and key issue related to both the purpose and the long term consequence of an animal’s exposure to stress.

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Muchimapura et al 2002

Abstract – School of Biomedical Sciences, University of Nottingham Medical School, Queen’s Medical Centre, UK.

Both human schizophrenia and the effects of isolation rearing in rats produce deficits in hippocampal and cortical functioning.

This study was concerned with identifying changes associated with altered neuronal function in the rat hippocampus following isolation rearing. Rats were isolated from weaning at 21 days postnatal for 6 weeks and the hippocampal sensitivity to isolation rearing and stress were studied using c-fos immunohistochemistry and in vivo microdialysis.

Isolation rearing altered neuronal activity measured by Fos-like immunoreactivity in the specific brain areas as measured by either increased or reduced expression. Basal neuronal activity in the ventral CA1 hippocampus in isolation-reared rats was notably higher compared to group-reared rats but markedly lower Fos-like immunoreactivity was found in the central and basolateral nuclei of the amygdala.

Exposure to stress produced differential effects on neuronal activity in isolation-reared rats between the dorsal and ventral hippocampus, with increased Fos-like immunoreactivity in the dorsal hippocampus but lower Fos-like immunoreactivity in the ventral hippocampus compared to group-reared rats.

These results indicate that

isolation rearing may alter the relationship

between hippocampal neuronal function

in the dorsal and ventral hippocampus.

An in vivo microdialysis study showed that systemically administered parachloroamphetamine (2.5 mg/kg, i.p.) enhanced extracellular 5-hydroxytryptamine (5-HT) in the dorsal hippocampus in group-reared but not in isolation-reared rats.

Restraint stress had no effect on hippocampal extracellular 5-HT in group-reared rats but

reduced levels in isolation-reared rats during the period of restraint.

Inescapable mild footshock produced a marked increase in extracellular hippocampal 5-HT in group-reared

but not isolation-reared rats.

These are reversed reactions, but I don’t understand the difference in the types of stress created by these two experiences, restraint and footshock.

Overall the results provide extensive evidence that

isolation rearing alters presynaptic 5-HT hippocampal function and that the

neuronal response to stress

is altered by isolation.

Isolation rearing in the rat alters hippocampal function, including the serotonergic system,

leading to changes in neurotransmitter systems

in other brain areas.

These changes may model aspects of human neurodevelopmental disorders such as schizophrenia.

What does this FEEL like to those of us who are not schizophrenic?

Because I literally suffered terrible, ongoing episodes of literal isolation all through my childhood from infancy, the effects of literal isolation must be something I experience continually.  What adaptive function do these alterations provide?  How are epigenetic forces operating?

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Fulford & Marsden 2007

Abstract – Department of Anatomy, University of Bristol, Southwell Street, Bristol BS2 8EJ, UK. A.J.Fulford@bris.ac.uk

We investigated the effect of the tyrosine hydroxylase inhibitor, alpha-methyl-para-tyrosine (AMPT) on extracellular dopamine and 5-HT levels in the nucleus accumbens of group- and isolation-reared rats. Microdialysis with high-performance liquid chromatography-electrochemical detection was used to quantify dopamine and 5-HT efflux in the nucleus accumbens following foot shock and in association with a conditioned emotional response (CER). Isolation- and group-reared rats received i.p. injections of either saline (0.9%) or AMPT (200 mg/kg) 15 h and 2 h prior to sampling. There was no significant difference between saline-treated isolation- or group-reared rats for basal efflux of dopamine or 5-HT, however as expected, AMPT-treatment significantly reduced dopamine efflux in both groups to an equivalent level (50-55% saline-treated controls). Exposure to mild foot shock stimulated basal dopamine efflux in saline-treated groups only, although the effect was significantly greater in isolation-reared rats. In AMPT-treated rats, foot shock did not affect basal dopamine efflux in either rearing group. Foot shock evoked a prolonged increase in 5-HT efflux in both isolation- and group-reared saline-treated rats but had no effect on 5-HT efflux in AMPT-treated rats. In response to CER, isolation-rearing was associated with significantly greater efflux of both dopamine and 5-HT in saline-treated rats, compared to saline-treated, group-reared controls. However in AMPT-treated rats, efflux of dopamine or 5-HT did not change in response to CER. These data suggest that unconditioned or conditioned stress-induced changes in 5-HT release of the nucleus accumbens are dependent upon intact catecholaminergic neurotransmission. Furthermore, as the contribution of noradrenaline to catecholamine efflux in the nucleus accumbens is relatively minor compared to dopamine, our findings suggest that dopamine efflux in the nucleus accumbens is important for the local regulation of 5-HT release in this region. Finally, these findings implicate the

isolation-enhanced presynaptic dopamine function

in the accumbens with the

augmented ventral striatal 5-HT neurotransmission

characterized by isolation-reared rats.

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Fusa et al 2005

Abstract – Department of Dental Anesthesiology, Nihon University School of Dentistry, 1-8-13, Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan.

The activation of the delta-opioid receptors in the nucleus accumbens is known to induce a large and rapid increase of accumbal dopamine efflux. (+/-)-TAN-67 (2-methyl-4a(alpha)-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a(alpha)-octahydro-quinolino[2,3,3,-g]isoquinoline) is a centrally acting non-peptidic delta opioid receptor agent which has recently become available. Interestingly, the (+) enantiomer of TAN-67 induces hyperalgesia in contrast to the (-) enantiomer of TAN-67 that produces profound antinociceptive effects in mice; the latter effects are mediated through delta-1 receptor stimulation. Using the microdialysis technique, the ability of the enantiomers of TAN-67 to alter the release of accumbal dopamine in vivo was analyzed. Like the 25-min infusion of the selective delta-1 opioid receptor agonist (D-[Pen2,5]-enkephalin) DPDPE (50 nM) and the delta-2 opioid receptor agonist deltorphin II (50 nM), the 25-min infusion of both (-)-TAN-67 (25 and 50 nM) and (+)-TAN-67 (25 and 50 nM) into the nucleus accumbens produced a similar transient dose-dependent increase in the accumbal extracellular dopamine level. Naloxone (1 mg/kg i.p., given 25 min prior to the drugs), namely a treatment that is known to inhibit the increase of dopamine induced by DPDPE and deltorphin II, did not affect the transient increase in the accumbal dopamine level produced by infusion of the enantiomers of TAN-67. The DPDPE and deltorphin II-induced increase in accumbal dopamine level, but not that of (-)-TAN-67 and (+)-TAN-67, was eliminated by subsequently perfused tetrodotoxin (2 microM) into the nucleus accumbens. The increase in accumbal dopamine level produced by an infusion of (-)-TAN-67 and (+)-TAN-67 was not altered by a Ca2+-free Ringer’s solution. The (-)-TAN-67 and (+)-TAN-67-induced accumbal dopamine efflux was strongly prevented by reserpine (5 mg/kg i.p., given 24 h earlier) or alpha-methyl-para-tyrosine (250 mg/kg i.p., given 2 h earlier). The effects of the enantiomers of TAN-67 on the accumbal dopamine were nullified by combined treatment with reserpine and alpha-methyl-para-tyrosine. The (-)-TAN-induced dopamine efflux was significantly reduced by the N-methyl-D-aspartate (NMDA) receptor antagonists ifenprodil (20 mg/kg i.p., 20 min before) and MK-801 (0.5 mg/kg i.p., 20 min before), respectively. The effects of (-)-TAN-67 on the dopamine efflux were also inhibited by the free radical scavenger N-2-mercaptopropionyl glycine (100 mg/kg i.p., 20 min before). These results show that both enantiomers of TAN-67 enhance the release of reserpine sensitive, vesicular dopamine and alpha-methyl-p-tyrosine sensitive, cytosolic dopamine from dopaminergic nerve terminals in the nucleus accumbens in a way that is independent of neural activity; activation of delta opioid receptors plays no role in these events. All together, the results suggest that (-)-TAN-67 can generate a burst of free radicals that in turn trigger a release of glutamate that ultimately via activation of NMDA receptors enhances the release of dopamine from dopaminergic nerve terminals in the nucleus accumbens.

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Hirose et al 2005

Abstract – Department of Dental Anaesthesiology, Nihon University School of Dentistry, 1-8-13, Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan.

[LINK BETWEEN OPIOID SYSTEM AND DOPAMINE RELEASE ]

The effect of interactions among mu- and delta-opioid receptors, especially the putative delta(1)- and delta(2)-opioid receptors, in the nucleus accumbens on accumbal dopamine release was investigated in awake rats by in vivo brain microdialysis. In agreement with previous studies, perfusion of the nucleus accumbens with the mu-, delta(1)- and delta(2)-opioid receptor agonists [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO), [D-Pen(2,5)]-enkephalin (DPDPE) and [D-Ser(2)]Leu-enkephalin-Thr(6), respectively, significantly enhanced the extracellular amount of accumbal dopamine in a dose-related manner (5.0 nmol and 50.0 nmol). However, the highest concentration tested (50.0 nmol) of DAMGO induced a biphasic effect, i.e. a rapid onset increase lasting for 75 min followed by a slower onset gradual and prolonged increase. The mu-opioid receptor antagonist D-Phe-Cys-Tyr-d-Trp-Orn-Thr-Phe-Thr-NH(2) (0.15 nmol) primarily reduced the DAMGO-induced second component. The delta(1)-opioid receptor antagonist (E)-7-benzylidenenaltrexone (0.15 nmol) significantly reduced the first component and abolished the second component induced by DAMGO, while the delta(2)-opioid receptor antagonist naltriben (1.5 nmol) significantly reduced only the first component. The DPDPE (50.0 nmol)-induced dopamine increase was almost completely abolished by (E)-7-benzylidenenaltrexone, but only partially reduced by D-Phe-Cys-Tyr-d-Trp-Orn-Thr-Phe-Thr-NH(2) and naltriben. The [D-Ser(2)]Leu-enkephalin-Thr(6) (50.0 nmol)-induced dopamine increase was almost completely abolished by naltriben, but not at all by D-Phe-Cys-Tyr-d-Trp-Orn-Thr-Phe-Thr-NH(2) and (E)-7-benzylidenenaltrexone. The non-selective opioid receptor antagonist naloxone (0.75 and 1.5 nmol) dose-dependently reduced the effects of DAMGO, DPDPE and [D-Ser(2)]Leu-enkephalin-Thr(6) but only to about 10-25% of the control values. Moreover, perfusion with the sodium channel blocker tetrodotoxin (0.1 nmol) reduced the DAMGO-induced dopamine increase by 75%, while it almost completely abolished the increase induced by DPDPE or [D-Ser(2)]Leu-enkephalin-Thr(6). The results show that stimulation of mu-opioid receptors or, to a lesser degree, delta(1)-opioid receptors results in a large naloxone-sensitive increase and a small naloxone-insensitive increase of extracellular dopamine. It is suggested that the naloxone-insensitive component is also tetrodotoxin-insensitive. Furthermore, it is hypothesized that stimulation of mu-opioid receptors activates delta(1)-receptors, which in turn activate delta(2)-opioid receptors, thereby giving rise to a rapid onset increase of extracellular dopamine. In addition, it is hypothesized that stimulation of another group of mu-opioid receptors activates a second group of delta(1)-opioid receptors that is not coupled to delta(2)-opioid receptors and mediates a slow onset increase of extracellular dopamine. Finally, it is suggested that stimulation of delta(1)- or delta(2)-opioid receptors inhibits mu-opioid receptors involved in the slow onset increase in extracellular dopamine, whereas stimulation of delta(1)-, but not delta(2)-, opioid receptors is suggested to activate mu-opioid receptors involved in the rapid increase in extracellular dopamine.

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Noble & Cox 1996

Abstract – Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799, USA.

1. Morphine produces a plethora of pharmacological effects and its chronic administration induces several side-effects. The cellular mechanisms by which opiates induce these side-effects are not fully understood. Several studies suggest that regulation of adenylyl cyclase activity by opioids and other transmitters plays an important role in the control of neural function. 2. The aim of this study was to evaluate desensitization of mu- and delta- opioid receptors, defined as a reduced ability of opioid agonists to inhibit adenylyl cyclase activity, in four different brain structures known to be involved in opiate drug actions: caudate putamen, nucleus accumbens, thalamus and periaqueductal gray (PAG). Opiate regulation of adenylyl cyclase in these regions has been studied in control and morphine-dependent rats. 3. The chronic morphine treatment used in the present study (subcutaneous administration of 15.4 mg morphine/rat/day for 6 days via osmotic pump) induced significant physical dependence as indicated by naloxone-precipitated withdrawal symptoms. 4. Basal adenylyl cyclase in the four brain regions was not modified by this chronic morphine treatment. In the PAG and the thalamus, a desensitization of mu- and delta-opioid receptors was observed, characterized by a reduced ability of Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (DAMGO; mu), Tyr-D-Pen-Gly-Phe-D-Pen (DPDPE; delta) and [D-Ala2]-deltorphin-II (DT-II; delta) to inhibit adenylyl cyclase, activity following chronic morphine treatment. 5. The opioid receptor desensitization in PAG and thalamus appeared to be heterologous since the metabotropic glutamate receptor agonists, L-AP4 and glutamate, and the 5-hydroxytryptamine (5-HT)1A receptor agonist, R(+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), also showed reduced inhibition of adenylyl cyclase activity following chronic morphine treatment. 6. In the nucleus accumbens and the caudate putamen, desensitization of delta-opioid receptor-mediated inhibition without modification of mu-opioid receptor-mediated inhibition was observed. An indirect mechanism probably involving dopaminergic systems is proposed to explain the desensitization of delta-mediated responses and the lack of mu-opioid receptor desensitization after chronic morphine treatment in caudate putamen and nucleus accumbens. 7. These results suggest that adaptive responses occurring during chronic morphine administration are not identical in all opiate-sensitive neural populations.

How these same brain regions are connected to attachment system operation I cannot say, but I know they are.  The interaction of extreme isolation stress on infant brain development must effect dopamine action in many brain regions –

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Muchimapura, Mason & Marsden 2003

Abstract – School of Biomedical Sciences, University of Nottingham Medical School, Queen’s Medical Centre, Nottingham, NG7 2UH, England.

Several behavioral, neurochemical, and structural alterations found in isolation-reared rats are similar to those in human schizophrenia. This study investigated changes in cholinergic and serotonergic function in the hippocampus following isolation rearing. Rats were reared in social isolation from weaning for 6 weeks before study and compared to group-reared rats. An in vitro electrophysiological study investigated the effect of isolation rearing on postsynaptic 5-HT(1A) function on CA1 hippocampal neurones activated with the muscarinic agonist carbachol and found no change in the sensitivity of these postsynaptic receptors between the groups.

However, a change in presynaptic function was identified,

as there was a significant reduction in the time taken

for neuronal firing to recover to 50% of the original rate following 5-HT (10 microM) application,

in isolation compared to group-reared rats.

These data suggest

a possible change in reuptake following isolation.

Uptake studies using (3)[H]5-HT, however, found no change in the inhibition of uptake produced by either fluoxetine or paroxetine in isolation compared to group-reared rats. The selective 5-HT(1B) antagonist CP-294253 (1 microM), increased endogenous 5-HT release from hippocampal slices in vitro and this effect was greater (P < 0.001) in group compared to isolation-reared rats.

These results indicate that

the change in presynaptic 5-HT neuronal function

was due to impaired autoreceptor responsiveness.

Carbachol (1 microM) increased the firing rate of all neurones recorded but only a proportion of these showed a concentration-related increase.

Isolation rearing increased the sensitivity of neurones,

showing a concentration-related increase in firing in response to carbachol, but had no effect on the other neurones.

In summary, the present study showed that

isolation rearing alters presynaptic 5-HT(1B) but not postsynaptic 5-HT(1A) receptor activity in the hippocampus.

Isolation rearing in the rat

results in hippocampal dysfunction,

including reduced serotonergic and enhanced muscarinic activity of some neurones.

These effects may in part underlie the behavioural consequences of isolation relevant to human developmental disorders.

I can’t, of course, tell whether or not these changes COULD occur in PTSD following trauma exposure, even if no early maltreatment was present.  When undergoing a severe trauma, if one is effectively in isolation and alone, I would think such alterations contributing to PTSD are possible – hence the known modulating effect on trauma stress recovery of adequate social support.

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El-Khodor & Boksa 1997

Abstract – Department of Psychiatry, McGill University, Douglas Hospital Research Centre, Montreal, Quebec, Canada.

Epidemiological evidence indicates a higher incidence of pregnancy and birth complications among individuals who later develop schizophrenia, a disorder linked to alterations in mesolimbic dopamine (DA) function. Two birth complications usually included in these epidemiological studies, and still frequently encountered in the general population, are birth by Caesarean section (C-section) and fetal asphyxia. To test the hypothesis that birth complications can produce long-lasting changes in DA systems, the present study examined the effects of Caesarean birth, with or without an added period of anoxia, on steady state monoamine levels and metabolism in various brain regions in a rat model. Pups born vaginally served as controls.

At 2 months of age, in animals born by rapid C-section, steady state levels of DA were decreased by 53% in the prefrontal cortex and increased by 40% in both the nucleus accumbens and striatum, in comparison to the vaginally born group.

DA turnover increased in the prefrontal cortex, decreased in the nucleus accumbens, and showed no significant change in the striatum, in the C-section group.

Thus, birth by a Caesarean

procedure produces long-term reciprocal changes in DA levels and metabolism in the nucleus accumbens and prefrontal cortex.

This is consistent with the

known inhibitory effect of increased prefrontal cortex DA activity on DA release in the nucleus accumbens.

By contrast to birth by rapid C-section alone, young adult animals, that had been born by C-section with 15 min of added anoxia [lack of oxygen – could not have been complete!], showed no change in steady state DA levels in the prefrontal cortex, nucleus accumbens, or striatum and a significant decrease in DA turnover only in the nucleus accumbens, in comparison to the vaginally born group.

Levels of norepinephrine, serotonin, and its metabolite, 5-hydroxyindole acetic acid, were unchanged in all groups, indicating relatively specific effects on DA systems.

Although appearing robust at birth on gross observation, more subtle measurements revealed that rat pups born by C-section show altered respiratory rates and activity levels and increased levels of whole brain lactate, suggestive of low grade brain hypoxia, during the first 24 h of life, in comparison to vaginally born controls. Pups born by C-section with 15 min of added acute anoxia were pale, hypotonic, and inactive at birth and showed reduced respiration and high brain lactate levels.

However, these alterations resolved by 1-5 h after birth and, with few exceptions, animals in the anoxic group remained normal with respect to these parameters during the remainder of the first 24 h of life.

Immediately after birth, levels of plasma epinephrine, a hormone known to play a role in neonatal adaptation to extrauterine life and protection against hypoxia, were decreased in pups born by C-section but increased in pups born by C-section with 15 min added anoxia, in comparison to levels measured in vaginally born controls.

These early developmental alterations could contribute to long-term alterations in dopaminergic parameters observed in rats born by C-section, with or without added anoxia.

It is concluded that C-section birth

is sufficient perturbation to produce long-lasting effects

on DA levels and metabolism in the central nervous system

of the rat.

These findings highlight the

sensitivity of DA pathways to variations in birth procedure

and support the notion

that birth complications might contribute to the pathophysiology of disorders involving central dopaminergic neurons, such as schizophrenia.

This is the first closest reference I have found in relation to my breach birth complications even though I was not taken C-section – though now I hear all breach babies are delivered that way.

I am wondering about the drugs used during these deliveries – did they drug the rat mothers?

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Susman 2006

Abstract – Biobehavioral Transitions Laboratory, Department of Biobehavioral Health, The Pennsylvania State University, E.108 Health & Human Developement Building, University Park, PA 16802, USA. ejs5@psu.edu

Stress experienced during the sensitive prenatal, postnatal and early childhood periods of brain development can have damaging consequences for developing biological systems.

Stressors imposed by early physical vulnerabilities and an adverse care giving environment is proposed to set in motion early precursors of later persistent antisocial behavior. The purpose of this report is to present an integrated theoretical perspective of potential mechanisms involved in the development of persistent antisocial behavior with an emphasis on early stressors and the neuroendocrinology of stress.

The attenuation of endocrine physiology of the stress system is considered a key mechanism involved in persistent antisocial behavior.

The amygdala is considered a structure/process linking subjective experiences,

emotional learning,

brain development and

stress physiology.

Attenuated cortisol level

subsequent to early vulnerabilities is considered a

risk marker for

persistent antisocial behavior.

Interesting – lowered cortisol, not raised, for antisocial

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van Goozen et al 2007

abstract – School of Psychology, Cardiff University, Cardiff, UK. vangoozens@cardiff.ac.uk

Children with persistent antisocial and aggressive behavior are diagnosed as having disruptive behavior disorder. The authors review evidence that antisocial children, and especially those who persist with this behavior as they grow older, have a range of neurobiological characteristics.

It is argued that serotonergic functioning and stress-regulating mechanisms are important in explaining individual differences in antisocial behavior. Moreover, low fear of punishment and physiological underactivity may predispose antisocial individuals to seek out stimulation or take risks and may help to explain poor conditioning and socialization. The authors propose a theoretical model highlighting the interplay between neurobiological deficits and cognitive and emotional functioning as mediators of the link between early adversity and antisocial behavior problems in childhood.

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van Goozen & Fairchild 2006

abstract – School of Psychology, Cardiff University, PO Box 901, Cardiff CF10 3AT, UK. VangoozenS@cardiff.ac.uk

When antisocial behavior becomes a persistent pattern that affects diverse domains of children’s functioning, psychiatrists refer to oppositional defiant disorder (ODD) or conduct disorder (CD). The term disruptive behavior disorder (DBD) covers both ODD and CD. Research shows that in the absence of effective interventions, the prognosis for DBD children is relatively unfavorable: their disorder can extend into adolescence, manifest itself in delinquency, and convert into other psychiatric symptoms, such as addiction or personality disorders. Although environmental factors have traditionally attracted most attention in explaining the origin and persistence of DBDs, it is important not to overlook the vulnerability of the child in the development of antisocial behavior. Risk in the environment is a vulnerability factor – interactions

Relatively few studies have been conducted on the neurobiological factors involved in the development of DBDs in children. In this paper, we explain how problems in hypothalamic-pituitary-adrenal (HPA) axis and serotonergic system functioning could be important factors in the behavioral problems of DBD children. Low fear of punishment and physiological underactivity may predispose antisocial individuals to seek out stimulation or take risks and may explain poor (social) conditioning and socialization. Findings consistent with this hypothesis are presented. Finally, we explain how stress in general, and adverse early life experiences in particular, could have an impact on the development of the HPA and serotonergic systems. An investigation of the neurobiological factors involved in antisocial behavior disorder might ultimately guide the development of new forms of intervention.

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Connor & Zhang 2006

Abstract – Anxiety and Traumatic Stress Program, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA.

In human terms, resilience is an ability to cope with stress and varies with context, time, age, gender, and cultural origin.

Resilience shifts the focus of psychological investigation onto increasing the positive rather than reducing the negative. We have to realize that this factor influences our genes and cannot be separated from it – positive or negative

Inquiry into resilience has evolved from

descriptions of resilient qualities,

to discovery of the process to attain resilience,

to uncovering the motivation to reintegrate in a resilient manner.

Much of the research on resilience has focused on children in settings such as family violence, extreme poverty, war, and natural disasters. A coherent pattern of characteristics associated with successful adaptation has emerged.

Salient characteristics include

commitment,

dynamism,

humor in the face of adversity,

patience,

optimism,

faith, and

altruism.

We have to be very careful not to “blame the victim” in the considerations of resiliency.  There is a point where situations are so overwhelming – and this is also in interaction with genetics – that nobody can come out and win – no matter how optimistic they are – literally, for crying out loud!

As such, resilience may represent an important target of treatment in anxiety, depression, and stress reactions. Resilience can be quantified, but available measures need to be validated transculturally. There exist many possible determinants of resilience, including neurobiologic,

genetic, temperament, and environmental influences. These are so closely intertwined and connected they cannot be separated

Resilience is modifiable on individual and cultural levels. Posttraumatic stress disorder is an example of a serious disorder associated with impaired stress coping that can improve with treatment.

This sounds like a pretty simplistic article, but I don’t have the whole thing to read it, so can’t judge

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Betancourt & Khan 2008 – called for this article

Abstract – Harvard School of Public Health, Cambridge, MA 02115, USA. Theresa_Betancourt@Harvard.edu

This paper examines the concept of resilience in the context of children affected by armed conflict. Resilience has been frequently viewed as a unique quality of certain ‘invulnerable’ children. In contrast, this paper argues that a number of protective processes contribute to resilient mental health outcomes in children when considered through the lens of the

child’s social ecology.

While available research has made important contributions to understanding risk factors for negative mental health consequences of war-related violence and loss, the focus on trauma alone has resulted in inadequate attention to factors associated with resilient mental health outcomes. This paper presents key studies in the literature that address the

interplay between risk and protective processes

in the mental health of war-affected children from an ecological, developmental perspective. It suggests that further

research on war-affected children should pay particular attention to

coping and

meaning making at the individual level; the

role of attachment relationships,

caregiver health,

resources and connection in the family, and

social support available in peer and extended social networks.

Cultural and community influences such as attitudes towards mental health and healing as well as the meaning given to the experience of war itself are also important aspects of the larger social ecology.

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McAllister 2000

Article – U of C, Davis

synaptogenesis and dendritic growth

“Nervous system development comprises several stages.  First, neurons are born and migrate to their final positions in the nervous system.  Subsequently, neurons elaborate their axons and dendrites in patterns characteristic for each cell type.  Finally, highly specific connections between neurons – synapses – are formed.  In many cases, these early synaptic connections are sculpted and remodeled by neuronal activity to achieve the mature pattern of connectivity in the brain….Such precise interconnections between neurons suggest a high degree of cellular and molecular regulation during development.”  McAllister 2000, – 963

“…evidence is rapidly accumulating that dendrites are remarkably responsive to environmental signals….growth of dendrites is highly dynamic, rather than passive.  Moreover, dendritic growth is locally regulated by synaptic activity and other molecular signals from neighboring cells.  Activity-dependent structural changes in postsynaptic cells act together with changes in presynaptic axonal arbors to shape specific patterns of connectivity in the nervous system.  Thus, the growth of dendrites is a dynamic process influenced by, and integral to, the formation of connections in the nervous system.”  McAllister 2000, – 963

“Dendritic arbors develop in a highly choreographed manner…..First, primary basal dendrites extend directly from the cell body; higher order dendrites appear by branching from the primary dendrites.  For most neuronal types, dendritic growth is slow at first but then dramatically increases with a transient overproduction of dendrites to achieve the mature dendritic arborization.”  McAllister 2000, – 963

Recent “…technical advances in our ability to label and image living neurons in real-time has dramatically changed the pervading view of how dendrites grow…Rather than the steady growth implied from studies of fixed tissue, real-time imaging has demonstrated that dendritic elaboration occurs through a net growth of highly dynamic filopodia that each extend and (p 963) retract many times a minute….dendritic filopodia rapidly extend toward nearby axonal growth cones to form synaptic connections, implying that dendrites may be a much more active force in synapse formation than previously imagined….As the neurons mature, these filopodia become much less dynamic and eventually retract into dendritic shaft just before dendritic spines are formed….Thus, dendritic filopodia may serve to increase the likelihood of synapse formation and to physically pull axons toward the dendrite…..Although these spines have classically been considered stable structures, recent imaging experiments clearly demonstrate that spines undergo rapid structural alterations in response to synaptic activity…..”  McAllister 2000, – 964

The final form and extent of dendritic arbors result from interactions between intrinsic developmental programs and local environmental cues, including levels and patterns of activity….all neurons have an intrinsic ability to produce branched dendrites….environmental signals work with intrinsic mechanisms to regulate proper dendritic arborization.  In fact, evidence for a potent role for environmental signals, including neuronal activity, in regulating dendritic growth is overwhelming.”  McAllister 2000, – 964

“Electrical activity of neurons shapes patterns of synaptic connectivity during early development of the nervous system….Although most studies have focused on the role of activity in sculpting axonal arbors, there is increasing evidence that neuronal activity also fine-tunes dendritic growth and branching.  Dendritic differentiation occurs concurrently with synapse formation, suggesting that afferent [carrying toward] axon terminals might stimulate dendritic growth.  In general, most neurons must receive a particular level and/or pattern of afferent activity for characteristic adult patterns of dendrites to develop.”  McAllister 2000, – 964

“…dendritic structure is rapidly responsive to changes in afferent activity.”  McAllister 2000, – 964

“Increasing afferent activity by raising either young or adult rats in enriched environments also has potent effects on dendritic arbors.  In many cortical areas, exposure to an enriched environment can increase dendritic branching of pyramidal neurons….These results are intriguing and have been used to support the hypothesis that experience alters dendritic form dynamically in both the developing and the mature animal as it interacts with its environment.  However, raising animals in enriched environments is likely to have complex effects on the nervous system, including nutritional and hormonal changes.”  McAllister 2000, – 964

each protein has   “…distinct effects on dendritic growth and branching.”  McAllister 2000, – 969

.mediate rapid effects of synaptic activity to alter dendritic morphology

“The protein synthesis and post-translational modification of proteins required from the growth of dendrites may be facilitated by polyribosomes located at the base of dendritic spines….Polyribosome clusters are sites of protein synthesis.  The location of polyribosomes at the base of dendritic spines may enable protein synthesis to be regulated by activity at individual synapses….As protein synthesis may be required for long-term synaptic changes…dendritic mRNA and local protein synthesis at spines could facilitate local production of proteins necessary for activity-dependent synaptic strengthening and spine formation.”  McAllister 2000, – 969

“Immediate early genes (IEGs) are also likely to be involved in the fast, activity-dependent  dendritic dynamics described above.  These genes are rapidly and transiently expressed in response to synaptic activity and growth factors [e.g. Arc – activity regulated cytoskeleton-associated protein, implicated in activity- and growth-factor-dependent dendritic plasticity, isolated in 1995; Narp – neuronal activity-regulated pentraxin, stimulates dendritic growth, “…may be one of the molecular signals that regulates concurrent dendritic growth and synapse formation.”]  McAllister 2000, – 969

“…overwhelming evidence that afferent innervation is necessary for proper formation of dendrites….”  McAllister 2000, – 969

“Activity-dependent dendritic growth implies that dendritic arborization is not only determined by the intra-cellular components of the dendrite but is also influenced by (969) both the molecular components of the synapse and the axon, and by the signals that influence synaptic stability.  This large number of molecular players acting in concert may enable dendrites to be exquisitely responsive to changes in local signals from connected neurons – a capability necessary for activity-dependent development and also perhaps for adult plasticity.”  McAllister 2000, – 970

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McAllister 2002

Abstract – Davis

The mammalian cerebral cortex requires the proper formation of exquisitely precise circuits to function correctly. These neuronal circuits are assembled during development by the formation of synaptic connections between hundreds of thousands of differentiating neurons. Although the development of the cerebral cortex has been well described anatomically, the cellular and molecular mechanisms that guide neuronal differentiation and formation of connections are just beginning to be understood. Moreover, despite evidence that coordinated patterns of activity underlie reorganization of brain circuits during critical periods of development, the molecular signals that translate activity into structural and functional changes in connections remain unknown.

Recently, the neurotrophins have emerged as attractive candidates not only for regulating neuronal differentiation in the developing brain, but also for mediating activity-dependent synaptic plasticity.

The neurotrophins meet many of the criteria required for molecular signals involved in neuronal differentiation and plasticity.

…………They are present in the cerebral cortex during development and

……….. their expression is regulated by synaptic activity.

….. In turn, the neurotrophins themselves strongly influence both short-term synaptic plasticity and long-term potentiation and depression.

In addition to their functional effects, the neurotrophins also

….profoundly regulate the structural changes that underlie axonal and dendritic differentiation.

…..Finally, the neurotrophins have been implicated in mediating synaptic competition required for activity-dependent plasticity during the critical period. …………This chapter presents and discusses the rapidly accumulating evidence that the neurotrophins are critical for neuronal differentiation and that they may be involved in activity-dependent synaptic refinement in the developing cerebral cortex.

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Cirulli et al 2008

Abstract – Italy

Early adverse events can enhance stress responsiveness and lead to greater susceptibility for psychopathology at adulthood.

The epigenetic factors involved in transducing specific features of the rearing environment into stable changes in brain and behavioural plasticity have only begun to be elucidated.

Neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are affected by stress and play a major role in brain development and in the trophism [acting on something specified] of specific neuronal networks involved in cognitive function and in mood disorders.

In addition to the central nervous system, these effectors are produced by peripheral tissues, thus being in a position to integrate the response to external challenges. In this paper we will review data, obtained from animal models, indicating that early maternal deprivation stress can affect neurotrophin levels, suggesting that they might be involved in the mechanisms underlying the mother-infant relationship. Maladaptive or repeated activation of NGF and BDNF, early during postnatal life, may influence stress sensitivity at adulthood and increase vulnerability for stress-related psychopathology.

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Alleva  & Santucci  2001

Abstract – Italy

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are well-studied polypeptide growth factors involved in the development and maintenance of specific peripheral and central populations of neuronal cells.

In addition to its role as a neurotrophic agent, NGF controls very complex functions in vertebrate physiology.

…………A variety of cells outside the nervous system are in fact able to synthesize NGF including epithelial cells, fibroblasts, lymphocytes, and macrophages. Implicating immune system here

NGF target cells have been identified in the nervous, immune, and endocrine systems, suggesting that NGF

……..may operate through multiple paths to ultimately regulate physiological homeostasis and behavioral coping.

We used a mouse model of social stress to demonstrate that NGF levels increase both in plasma and in the hypothalamus following intermale aggressive interactions. In both the aggressor and the subordinate?

The investigation has been extended to other species, including humans, to show that

………..labour, lactation,

………and the anticipation of the first jump with a parachute also result in increased NGF plasma levels and in changes in the distribution of NGF receptors on lymphocytes.

BDNF activation is caused by both physical and social stress events. The aim of this review is to

(1) outline the current understanding of the roles of NGF and BDNF in stress-related physiological changes in vertebrates, in particular for physical vs. psychological stressors, which may activate both similar and different neurobiological pathways, and

(2) summarize recent efforts to derive pharmacological strategies from the increasing body of BDNF and NGF neurobehavioral data.

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Branchi, Francia & Alleva 2004

Abstract – Italy

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are two neurotrophins involved in the differentiation, growth and maintenance of selected peripheral and central populations of neuronal cells, during development and at adulthood.

Furthermore, neuronal activity enhances expression and action of these neurotrophins, modifying synaptic transmission and connectivity. Neurotrophin production has been shown to be experience-dependent. In particular, during early developmental phases, experiences such as maternal deprivation or exposure to an enriched environment markedly affect NGF and BDNF levels.

At adulthood, psychosocial stress has been shown to markedly alter NGF and BDNF levels, both in plasma and selected brain areas, including the hypothalamus and hippocampus.

………….. These results have been extended to humans, showing that NGF levels are enhanced by emotional stress induced by parachute jumping. Overall, these findings suggest a role of neurotrophins as factors mediating both short- and long-term effects of experience on brain structure and function.

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Mendell, Albers & Davis 1999

Abstract – NY

Neurotrophins and pain

It is now well established that neurotrophins play a crucial role in the development of the nervous system.

……….However, there is increasing evidence that the function of neurotrophins persists throughout adulthood.

………The broad scope of neurotrophin action is well documented in the case of nerve growth factor (NGF) and its effect on nociceptors and nociception. …………Here, we review the evidence for these multiple roles for NGF. Two manipulations influencing NGF levels are discussed in detail. The first involves the use of transgenic mice that overexpress or underexpress neurotrophins. ……….A second strategy involves administration of NGF or its antibody in vivo to increase or decrease its level.

During prenatal development, NGF is required for survival of nociceptors. In the early postnatal period, NGF is required for expression of the appropriate nociceptor phenotype.

This must be tied to the opioid system, and probably to the immune system

In adults, NGF acts as an important intermediate in inflammatory pain, contributing to both peripheral and central sensitization

…… The sensitization of peripheral nociceptors can be very rapid and can involve non-neural cells such as mast cells, neutrophils, fibroblasts, and macrophages.

……….Recent evidence indicates that other neurotrophins also play key supporting roles in the development of nociceptors (e.g., NT-3) and in inflammatory pain (e.g., BDNF, NT-4/5).

……….Furthermore, molecules from other superfamilies (e.g., GDNF) also are required to assure survival of certain classes of nociceptors.

……….The diverse effects of neurotrophins on nociceptive processing emphasize their broad importance in the development and function of the nervous system.

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Cirulli, Berry & Alleva 2003

Abstract – Italy

Early environmental manipulations can impact on the developing nervous system, contributing to shape individual differences in physiological and behavioral responses to environmental challenges.

………In particular, it has been shown that disruptions in the mother-infant relationship result in neuroendocrine, neurochemical and behavioural changes in the adult organism, although the basic mechanisms underlying such changes have not been completely elucidated.

……….Recent data suggest that neurotrophins might be among the mediators capable of transducing the effects of external manipulations on brain development.

…………Nerve growth factor and brain-derived neurotrophic factor are known to play a major role during brain development,

……..while in the adult animal they are mainly responsible for the maintenance of neuronal function and structural integrity.

Changes in the levels of neurotrophic factors during critical developmental stages might result in long-term changes in neuronal plasticity and lead to increased vulnerability to aging and to psychopathology.

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Macrì  & Würbel 2006

Abstract – Italy

Developmental plasticity of HPA and fear responses in rats has been proposed to be mediated by environment-dependent variation in active maternal care.

Here, we review this maternal mediation hypothesis based on the postnatal manipulation literature and on our own recent research in rats. We show that developmental plasticity of HPA and fear responses in rats cannot be explained by a linear single-factor model based on environment-dependent variation in active maternal care.

……… However, by adding environmental stress as a second factor to the model, we were able to explain the variation in HPA and fear responses induced by postnatal manipulations.

In this two-factor model, active maternal care and environmental stress (as induced, e.g., by long maternal separations or maternal food restriction) exert independent, yet opposing, effects on HPA reactivity and fearfulness in the offspring.

………This accounts well for the finding that

…………completely safe and stable,

………..as well as, highly stressful maternal environments

………..result in high HPA reactivity and fearfulness

………..compared to moderately challenging maternal environments.

First that I’ve seen reference to this!  Makes sense, though…

Furthermore, it suggests that the downregulation of the HPA system in response to stressful maternal environments could reflect adaptive developmental plasticity based on the increasing costs of high stress reactivity with increasingly stressful conditions.

By contrast, high levels of environmental stress induced by environmental adversity might constrain such adaptive plasticity, resulting in non-adaptive or even pathological outcomes.

Alternatively, however, developmental plasticity of HPA and fear responses in rats might be a function of maternal HPA activation (e.g., levels of circulating maternal glucocorticoid hormones).

….. Thus, implying a U-shaped relationship

….between maternal HPA activation

……and HPA reactivity and fearfulness

………in the offspring,

increasing maternal HPA activation with increasing environmental adversity would explain the effects of postnatal manipulations equally well.

This raises the possibility that variation in active maternal care is an epiphenomenon [A secondary phenomenon that results from and accompanies another]:, rather than a causal factor in developmental plasticity of HPA and fear responses in rats.

Developmental plasticity of HPA and fear responses in rats and other animals has important implications for the design of animal experiments and for the well-being of experimental animals, both of which depend on the exact underlying mechanism(s).

Importantly, however, more naturalistic approaches are needed to elucidate the adaptive significance of environment-dependent variation of HPA reactivity and fearfulness in view of discriminating between effects reflecting adaptive plasticity, phenotypic mismatch and pathological outcomes, respectively.

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Macrì, Mason & Wurbel 2004

Abstract – Switzerland

The development of the hypothalamic-pituitary-adrenal (HPA) response to stress is influenced by the early mother-infant relationship. In rats, early handling (brief daily mother-offspring separations) attenuates the adult offspring’s HPA and fear responses compared to both nonhandling (no separations) and maternal separation (prolonged daily separations).

It has been proposed that variation in the amount of maternal care mediates these effects of neonatal manipulations on the adult offspring’s stress and fear responses. Here we tested this hypothesis by assessing maternal care and the adult offspring’s HPA and fear responses in Lister hooded rats which were subjected to either early handling (EH) or maternal separation (MS) from postnatal day 1-13, or were left completely undisturbed (nonhandled, NH) throughout this period.

………. Both EH and MS induced a more active nursing style and elevated levels of maternal care compared to NH.

………….Total levels of maternal care were indistinguishable between EH and MS, but diurnal distribution differed.

……….MS dams showed elevated levels of maternal care following the 4-h separation period, thereby fully compensating for the amount of maternal care provided by EH dams during the time MS dams were separated from their pups

. ………..However, while EH resulted in reduced HPA and fear responses in the adult offspring compared to NH, MS and NH offspring did not differ.

………Our findings therefore demonstrate dissociation in the effects of EH and MS on maternal care and on the stress and fear responses in the offspring.

This indicates that maternal care cannot be the sole mediator of these effects.

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Macrì, Chiarotti & Würbel 2008

Abstract – Switzerland

Postnatal manipulations such as brief (early handling, EH) and long, daily mother-offspring separations (maternal separation, MS) in rats are used to study the mechanisms underlying developmental plasticity of stress and fear responses, and to model stress-related disorders in humans and in non-human animals.

Current evidence suggests that, compared to non-handled rats, EH reduces hypothalamic-pituitary-adrenal (HPA) reactivity in the adult offspring through stimulating increased levels of active maternal care.

……….In contrast, despite a similar increase in active maternal care, MS does not reduce HPA reactivity, thus suggesting that long mother-offspring separations may counteract the effects of increased active maternal care.

………..We therefore attempted to selectively manipulate levels of active maternal care and durations of mother-offspring separations in neonate rats. Rat pups were exposed to different combinations of EH and MS from postnatal day (PND) 2 to 10 using a split-litter design. Maternal behaviour was recorded from PND 2 to 8 and behavioural and endocrine responses to stress were studied in adult male offspring.

Low levels of maternal care combined with long mother-offspring separations increased HPA-reactivity

……..compared to both high maternal care combined with long mother-offspring separations

……and low maternal care combined with brief separations.

…………These findings further support the hypothesis that active maternal care and long mother-offspring separation act independently,

………..and exert opposing effects, on adult offspring’s HPA responses,

………. but that increased maternal care may buffer the adverse consequences of long separations.

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Moles, Rizzi & D’Amato 2004

Abstract – Italy

Short- and long-term effects of brief maternal separation, maternal exposure to novel male odor, and standard rearing were compared in NMRI mice. The first condition consisted of 15 min of daily exposure of pups to clean bedding (CB), and the second condition consisted of 15 min of mothers’ exposure to the odor of strange males (SM), for 14 days after birth starting from postnatal Day 1. Thus, both conditions entailed the same period of maternal separation. A control mother-offspring group was left undisturbed (nonhandled, N-H). Corticosterone levels of mothers and pups were measured at the end of the last manipulation session.

…..Corticosterone levels were higher in SM mothers, differing from both those of CB and of control dams;

….CB pups showed the highest corticosterone levels in comparison with the pups belonging to the other groups.

Maternal behavior observed as furthest as possible from the daily separation session did not differ among the three groups. The behavioral response to 0.5 mg/kg of apomorphine in 15-day-old pups was enhanced in both CB and SM animals, which suggests an alteration of dopaminergic functioning.

Finally, adult CB and SM male mice showed an increase in the percentage of time and entries into the open arms of the plus-maze in comparison to nonhandled males.

………..This study indicates that exposure to ecologically relevant stimuli elicited a stress response in lactating dams.

…………This “social stress” brings about short- and long-term effects in the offspring, even in the absence of any direct manipulation of the pups.

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Moles et al 2008

Abstract – Italy

BACKGROUND: Early adverse experiences are preeminent factors for the development of affective disorders.

In the present study, we analyzed the effects of different postnatal manipulations applied either on the mother or on the offspring in mice. Maternal behavior and adrenocortical activity of both mothers and offspring at the end of postnatal stress and at adulthood were considered. METHODS: From postnatal day (PND) 1 to 14 mice underwent 15min of: (a) brief (15min) pups’ exposure to clean bedding (CB: clean bedding), (b) mothers’ exposure to the odor of a novel male (SM: stressed mother) or (c) mothers’ exposure to a clean cage (CSM: control stressed mother), and (d) standard rearing (N-H: non-handled). The behavior of mouse dams during and after stress sessions was analyzed. Serum corticosterone of mothers and pups at the end of the stress session and 30min after reunion was assessed on PND 14. Moreover, anxiety levels and HPA-axis inhibitory feedback in response to dexamethasone administration were evaluated in adult male offspring. RESULTS: Overall, during the 14 days of treatment CB mothers when reunited with their pups showed higher maternal behavior than other dams. After the last stress (PND 14) SM and CSM maternal corticosterone levels increased as well as those of CB pups. While 30min of mother-infant interaction restored baseline corticosterone levels in SM and CSM mothers and in CB pups,

…………SM and CSM offspring showed a decrease of corticosterone under baseline levels. Like a pre-PTSD condition?

At adulthood, SM and CSM males did not show the suppressive hormonal response to dexamethasone treatment.

……….Moreover, adult CB and SM male mice displayed decreased anxiety in the open field.

CONCLUSIONS: Maternal psychosocial stress during lactation seems to permanently affect the offspring’s HPA functioning.

These effects may be dissociated from the behavioral response

……….as suggested by the decrease of anxiety in SM and CB adult mice.

I don’t understand the implications of this without the article

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Vanbesien-Mailliot et al 2007

Abstract – France

PRENATAL STRESS – PRO-INFLAMMATORY CHANGES IN IMMUNE SYSTEM IN PUPS

The in utero environment is critical for initiating the ontogeny of several physiological systems, including the immune surveillance. Yet, little is known about adverse early experiences on the offspring’s immunity and vulnerability to disease. The present work aimed at investigating the impact of restraint prenatal stress (PS) on the development and responsiveness of in vitro and in vivo cellular and humoral immunity of male progeny aged 7 weeks and 6 months. In adult 6-month-old rats, we detected increased circulating CD8(+)-expressing and NK cells in PS rats as compared to controls, associated with higher mRNA expression of IFN-gamma.

……….In addition, in vitro stimulation with phytohemagglutinin-A induced an increase in both the proliferation of T lymphocytes and the secretion of IFN-gamma in PS rats. Interestingly, these alterations were undetectable in younger PS rats (7-week old), except for a slight increase in the mRNA expression of several pro-inflammatory cytokines in peripheral blood mononuclear cells. Moreover, in vivo neutralization of IFN-gamma in young rats had no effects in PS group. In conclusion, we report for the first time long-lasting pro-inflammatory [capable of promoting inflammation. For example, air pollution may have proinflammatory effects] consequences of PS in rats.

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Kraszpulski, Dickerson & Salm 2006

Abstract – Poland

PRENATAL STRESS – CHANGES AMYGDALA

The amygdala plays a critical role in generating the emotion of fear, and alterations in amygdala fear processing are thought to underlie the acquisition and maintenance of anxiety disorders.

The prenatally stressed (PS) rat displays hormonal, behavioral and brain anatomical similarities to anxious humans and is useful to study the neurobiological underpinnings of pathological anxiety. We studied PS and control male rats at postnatal days 7 (P7), P25, P45 and P60. Using unbiased stereological analyses we examined the volumes, anterior-posterior lengths and total numbers of neurons and glia of the basolateral (BL), central (Ce) and lateral (La) amygdalar nuclei.

We found prenatal stress-associated differences in the developmental trajectories of each nucleus. These were apparent in some measures as early as P7, most extensive at P25 and resolved by P45, at least as seen by Nissl staining. These changes were not a result of differential brain growth.

This early divergence in developmental trajectories seen here may be the harbinger of PS rat amygdalas that ultimately function very differently in adulthood.

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Dickerson et al 2005

Abstract – WV

We have been studying the mildly prenatally stressed (PS) rat as a potentially useful animal model of anxiety disorders.

Previously we have demonstrated that there are anatomical and biochemical alterations in the amygdalas of adult PS offspring and that these offspring show increased fearful behaviors.

………However, human data indicate that anxiety disorders often present first in early childhood and then persist throughout adolescence and adulthood.

To determine if PS rats also model this characteristic of human anxiety disorders, here we asked whether behavioral indices of increased fear would be detectable at an early age. We tested the hypotheses that young PS rats would show increased behavioral fearfulness in response to an acute stressor and that this would increase with age. A mild prenatal stressor, consisting of removal of the dam from the home cage and administration of a subcutaneous injection of 0.1 ml of 0.9% saline daily, was administered during the last week of pregnancy. Offspring were tested in the defensive-withdrawal apparatus before and after exposure to restraint stress at 25, 45 and 60 days of age.

……… PS animals showed increased defensive-withdrawal behavior following the stressor and were more fearful following restraint when compared to controls (CON). This was significant at P45 and increased to P60. ………Hence, fearful behaviors in PS rats emerge prior to sexual maturation and increase in magnitude thereafter, further validating our model as a means to investigate the underpinnings of anxiety disorders.

Too bad they didn’t measure vasopressin in these studies – were these rats high or low anxiety trait rats to start with before the prenatal stress?

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Van der Hove et al 2005

Abstract – The Netherlands

Chronic or repeated stress during critical periods of human fetal brain development has been associated with various learning, behavioral and/or mood disorders in later life.

In this investigation, pregnant Fischer 344 rats was individually restrained three times a day for 45 min during the last week of gestation in transparent plastic cylinders while at the same time being exposed to bright light. Control pregnant females were left undisturbed in their home cages. Anxiety and depressive-like behavior was measured in the offspring at an age of 6 months using the open field test, the home cage emergence test and the forced swim test.

Prenatally stressed rats spent more time in the corners and less time along the walls of an open field, while no difference in total distance moved was observed.

…….. In addition, prenatally stressed rats took more time to leave their home cage in the home cage emergence test.

……..On the other hand, no differences in immobility were observed in the forced swim test.

……Moreover, prenatally stressed rats showed lower stress-induced plasma corticosterone levels compared with control rats.

……Prenatal stress (PS) had no effect on the number of 5-bromo-2-deoxyuridine-positive cells – used as a measure for cell proliferation – in the dentate gyrus of these rats.

……..These data further support the idea that

……..PS may perturb normal anxiety-related development.

………… However, the present data also suggest that an adaptive or protective effect of PS should not be ignored.

………..Genetic factors are likely to play a role in this respect.

To be useful, they need to see what these rats are like when they are older!

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Pallares et al 2007

Abstract – Argentina

Stressor presence during the last weeks of gestation has been associated with behavioral disorders in later life. In this study we support further research on the long term effects of prenatal stress on Swiss mice descendant’s behavior. Prenatal stress procedure consisted on restraining the dams under bright light for 45 min, three times per day from the 15th day of pregnancy, until birth. After weaning, offspring’s motor performance and spontaneous exploratory behavior were measured by the tight-rope and T-maze tests, respectively. We also evaluated anxiety behavior using elevated plus maze test.

We found that maternal stress improves the performance of the animals in the tight rope test and that this effect was sex and age dependent: prenatal stressed males obtained the best scores during the first month of life, while in females the same was achieved at the second month.

Spontaneous exploratory behavior analysis revealed that it was elevated in prenatal stressed males and that this effect persisted on time.

…………However, we did not find significant differences on this behavioral response among both females groups.

Finally, differences on anxiety behavior were found only in females: prenatally stressed animals showed a higher proportion of entries into the open arms of a plus maze (reduced anxiety) compared to the control group.

Our results show that prenatal stress modifies the normal behavior of the progeny: prenatal stressed animals have a better performance in the carried out test. These notably results suggest the existence of an adaptive response to prenatal stress

Again, they need to follow to adulthood to see the long-term effects

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Estanislau & Morato 2005

Abstract – Brazil

anxiogenic effects

Prenatal stress and maternal separation are used in a large number of studies on early adversity consequences and present some similarities in their effects. The present work investigates the behavioral effects of these two procedures on two models of anxiety: the elevated plus-maze and the elevated T-maze. During pregnancy, female rats were submitted to uncontrollable electric foot shock sessions every other day or kept undisturbed. After delivery, litters from undisturbed dams were submitted to either 180-min daily periods of maternal separations from the 3-14th postnatal days or maintained with the dams all the time. Litters from the stressed dams were left undisturbed from the 3-14th postnatal days. Only males were tested. In adulthood, rats were tested in the elevated T-maze or in the elevated plus-maze. In the latter procedure half the subjects were submitted to a 60-min period of restraint immediately before being tested. The following measures were taken in the elevated plus-maze: frequency and time spent in entries into the arms, stretching, rearing, grooming and head dipping. In the T-maze measures of avoidance and escape latencies were used.

Our data indicated that prenatal stress had more pronounced anxiogenic effects than maternal separation, as judged by reduced exploration of the open arms of the elevated plus-maze, but mainly after the restraint stress, and increase in avoidance latencies in the elevated T-maze. The other measures not directly involved in the elevated plus-maze arm exploration yielded similar results. Our data indicate that prenatal stress causes more anxiogenic effects in adulthood than maternal separation but, in the elevated plus-maze, these anxiogenic effects are better seen immediately after an acute stress.

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Estanislau & Morato 2006

Abstract – Brazil

anxiogenic effects

Prenatal stress is a putative model for studying some psychopathological disorders. Indeed, submitting pregnant animals to stress leads to enhanced anxiety in the adult offspring. Conflictual study results

However, little is known about how prenatal stress effects interact with anxiety throughout development. To study this issue, prenatally stressed rats were tested in the elevated plus-maze at different ages. During pregnancy female rats were submitted to uncontrollable electric foot shock sessions every other day or kept undisturbed (controls). After delivery, litters from control and stressed dams were left undisturbed from the 3rd to the 14th postnatal days. Male and female rats were tested in the elevated plus-maze at the ages of 30, 45 or 60 days. The following measures were taken in the elevated plus-maze: number of entries and time spent in the arms (or their extremities) and frequency and time spent in naturalistic behaviors (stretching, rearing, end exploring, grooming and head dipping). Decreases in the percentage of entries into and in the time spent (only females) in the open arms were shown by 60-day-old prenatally stressed rats, but not by 30- and 45-day old. Increased open arm ends exploration was shown by 45-day-old prenatally stressed males. Rearing behavior was found to increase with age, a phenomenon more pronounced in females. Additionally, at the younger ages prenatally stressed rats were heavier than controls, an effect which disappeared at young adulthood. In conclusion, anxiogenic prenatal stress effects in the elevated plus-maze could only be detected at early adulthood, not before. Nonetheless, at late adolescence (45 days of age)

prenatal stress leaded to an anxiolytic-like effect which can be interpreted as increased risk-taking behaviorAnxiolytic [any substance taken to reduce anxiety]

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Ward et al 2000

Abstract – WV

increased activity of CRFergic systems in the amygdala.

Exposure of pregnant rats to stress results in offspring that exhibit abnormally fearful behavior and have elevated neuroendocrine responses to novelty and aversive stimuli.

…………..This study examined the effects of prenatal stress on plasma corticosterone, adrenal weight, defensive withdrawal behavior, and the density of receptors for corticotropin releasing factor (CRF) in the amygdala.

Pregnant Sprague-Dawley rats were stressed by daily handling and saline injection (s.c., 0.9%, 0.1 mL) during the last week of gestation. Male offspring were studied at adulthood (60-120 days of age). Adrenal hypertrophy and increased plasma corticosterone were observed in the prenatally stressed offspring.

………. Defensive withdrawal, an ethological measure of the conflict between exploratory behavior and retreat, was quantified in naive offspring, and in offspring exposed to restraint stress (2 h).

……….. Restraint stress increased defensive withdrawal in both control and prenatally stressed offspring. Both naive and restraint-stressed prenatally stressed offspring exhibited increased defensive withdrawal compared to control offspring.

………..There was a significant interaction between prenatal stress and restraint stress, suggesting increased vulnerability of prenatally stressed offspring.

The effects of restraint in the defensive withdrawal test were reduced by intracerebroventricular administration of the CRF antagonists, alpha-helical CRF9-41 (20 microg every hour) or D-phe(12), Nle(21, 38), C(alpha)-MeLeu(37)]-CRF((12-41)) (5 microg every hour) during the restraint period. The difference between control and prenatally stressed offspring was abolished by the CRF antagonists,

suggesting that increased activation of CRF receptors may be a factor in the behavioral abnormalities of prenatally stressed rats.

Measurement of CRF receptors in amygdala revealed a 2.5-fold increase in binding in prenatally stressed offspring.

……….In light of previous work from this laboratory demonstrating increased content and release of CRF in amygdala from prenatally stressed offspring, the present study suggests that

the increased fearfulness of prenatally stressed rats may be a consequence of increased activity of CRFergic systems in the amygdala.

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Viltart  & Vanbesien-Mailliot 2007b

Abstract – France

Since life emerged on the Earth, the development of efficient strategies to cope with sudden and/or permanent changes of the environment has been virtually the unique goal pursued by every organism in order to ensure its survival and thus perpetuate the species. In this view, evolution has selected tightly regulated processes aimed at maintaining stability among internal parameters despite external changes, a process termed homeostasis.

……Such an internal equilibrium relies quite heavily on three interrelated physiological systems:

…the nervous,

…immune, and

….endocrine systems,

….which function as a permanently activated watching network, communicating by the mean of specialized molecules: neurotransmitters, cytokines, and hormones or neurohormones.

……..Potential threats to homeostasis might occur as early as during in utero life, potentially leaving a lasting mark on the developing organism. ………..Indeed, environmental factors exert early-life influences on the structural and functional development of individuals, giving rise to changes that can persist throughout life. This organizational phenomenon, encompassing prenatal environmental events, altered fetal growth, and development of long-term pathophysiology, has been named early-life programming.

Over the past decade, increased scientific activities have been devoted to deciphering the obvious link between states of maternal stress and the behavioral, cognitive, emotional, and physiological reactivity of the progeny.

………This growing interest has been driven by the discovery of a tight relationship between prenatal stress and development of short- and long-term health disorders.

……….Among factors susceptible of contributing to such a deleterious programming, nutrients and hormones, especially steroid hormones, are considered as powerful mediators of the fetal organization since they readily cross the placental barrier.

In particular, variations in circulating maternal glucocorticoids are known to impact this programming strongly, notably when hormonal surges occur during sensitive periods of development, so-called developmental windows of vulnerability.

………….Stressful events occurring during the perinatal period may impinge on various aspects of the neuroendocrine programming, subsequently amending the offspring’s growth, metabolism, sexual maturation, stress responses, and immune system.

……..Such prenatal stress-induced modifications of the phenotypic plasticity of the progeny might ultimately result in the development of long-term diseases, from metabolic syndromes to psychiatric disorders.

………Yet, we would like to consider the outcome of this neuroendocrine programming from an evolutionary perspective.

………Early stressful events during gestation might indeed shape internal parameters of the developing organisms in order to adapt the progeny to its everyday environment and thus contribute to an increased reproductive success, or fitness, of the species.

…………..Moreover, parental care, adoption, or enriched environments after birth have been shown to reverse negative long-term consequences of a disturbed gestational environment.

In this view, considering the higher potential for neonatal plasticity within the brain in human beings as compared to other species, long-term consequences of prenatal stress might not be as inexorable as suggested in animal-based studies published to date.

This idea is mirrored in the vasopressin research in attachment chapter about the low and high anxiety pups exposed to stress in utero – each come up or down a few notches on the anxiety spectrum as a result

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Hodyl et al 2007

Abstract – Australia

Growing evidence suggests that maternal health during the prenatal period is a critical determinant of adult immuno-competence. This study aimed to characterise the innate immune response to bacterial exposure in rat offspring following maternal exposure to a pro-inflammatory stimulus. The offspring’s innate immune responses were investigated at four developmental timepoints in the rat by determination of immune cell subtypes and TNF-alpha and IL-1beta response to in-vivo LPS exposure.

…….The pre-weaned offspring of exposed dams demonstrated no immune response to the LPS challenge, whereas control offspring responded with a typical elevation in cytokine levels.

….. In pubescence no differences were observed between the responses of the control and exposed offspring.

…….In adulthood and senescence, offspring of endotoxin treated dams had significantly less monocytes in circulation than control offspring and differential sex effects were only evident in these older animals.

………The developmental profile of immune functioning following prenatal immune activation has not previously been demonstrated. This study highlights the prenatal period as one of importance in determining later immune function.

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Ashdown et al 2006

Abstract – Quebec

Maternal infections with bacterial or viral agents during pregnancy are associated with an increased incidence of schizophrenia in the offspring at adulthood

,,,,,,,,,although little is known about the mechanism by which maternal infection might affect fetal neurodevelopment.

Exposure of pregnant rodents to the bacterial endotoxin, lipopolysaccharide (LPS), results in behavioral deficits in the adult offspring that are relevant to schizophrenia.

……… It is however unknown whether these effects are due to the direct action of the inflammatory stimulus on the developing fetus,

………or due to secondary immune mediators (cytokines) activated at maternal/fetal sites.

In this study we sought to elucidate the site of action of LPS, following a single intraperitoneal (i.p.) injection, in pregnant rats at gestation day 18. Animals received 5 muCi of iodinated LPS ((125)I-LPS) and its distribution was assessed in maternal/fetal tissues (1-8 h). In addition, induction of the inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, was measured in maternal/fetal tissues following maternal LPS challenge (0.05 mg/kg, i.p.) (2-8 h). (125)I-LPS was detected in maternal tissues and placenta, but not the fetus. This distribution was accompanied by significant increases in TNF-alpha, IL-1beta and IL-6 in maternal plasma and placenta, but not in fetal liver or brain. A significant increase in IL-1beta was however detected in fetal plasma, possibly due to transfer from the maternal circulation or placenta.

Collectively, these data suggest that effects of maternal LPS exposure on the developing fetal brain are not mediated by the direct action of LPS, but via indirect actions at the level of the maternal circulation or placenta.

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Shen et al 2008

Abstract – China

Exposure to prenatal undernutrition or malnutrition increases the risk of schizophrenia, although little is known about the mechanism.

Pro-inflammatory factors are critical in brain development, and are believed to play an important role in neurodevelopmental disorders associated with prenatal exposure to infection, including schizophrenia.

However it is not known whether pro-inflammatory factors also mediate the effects on the fetus of prenatal malnutrition or undernutrition. In this study, we established a new prenatal undernourished rat model induced by maternal exposure to a diet restricted to 50% of the low (6%) protein diet (RLP50). We observed the disappearance of maternal nest-building behavior in the RLP50 dams, increased levels of TNFA and IL6 in the placentas (P<0.001; P=0.879, respectively) and fetal livers (P<0.001; P<0.05, respectively), and a decrease in the fetal brains (P<0.05; P<0.01, respectively).

Our results are similar to previous studies of maternal infection, which implies that

….a common pathway mediated by pro-inflammatory factors may contribute to the brain development,

…….consequently increasing the risk of schizophrenia and other psychiatric diseases

…..programmed by varied maternal adversities.

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Ngom et al 2004

Abstract – UK – Gambian research

BACKGROUND: In rural Gambians, the season of birth strongly predicts adult mortality. Those born during the harvest season have longer life spans than do those born during the hungry season, and the deaths associated with infectious diseases suggest permanent early-life influences on immunity. Thymic measurements showed significantly smaller thymuses in infants born during the hungry season than in those born during the harvest season. The differences were greatest at 8 wk of age, a time when all infants were exclusively breastfed, which suggests the involvement of breast milk factors. OBJECTIVE: This study tested whether thymic size differences reflect thymic output and ascertained whether thymic output is associated with breast milk interleukin 7 (IL-7) concentrations. DESIGN: We studied thymic size and output in a prospective cohort of 138 Gambian infants born in either the hungry or the harvest season by measuring signal-joint T cell receptor-rearrangement excision circles (sjTRECs) at birth and at 8 wk of age. IL-7 concentrations in breast milk were measured by using an enzyme-linked immunosorbent assay. RESULTS: By age 8 wk, those born in the hungry season had significantly lower sjTREC counts than did those born in the harvest season (0.97 and 2.12 sjTRECs/100 T cells, respectively; P = 0.006). At 1 wk postpartum, the breast milk of mothers of infants born in the hungry season had significantly lower IL-7 than did that of mothers of infants born in the harvest season (79 and 100 pg/mL, respectively; P = 0.02). The findings were similar at 8 wk postpartum. CONCLUSION: These data show a plausible pathway linking external seasonal insults to mothers with thymic development in their infants, which suggests possible implications for long-term programming of immunity.

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Moore et al 2004

Abstract – UK – Bangladesh research

BACKGROUND: Analysis of data from rural Gambia has previously shown that being born during the annual hungry season strongly influences susceptibility to mortality from infectious disease in young adulthood, possibly through an influence on immune function. In rural Bangladesh pregnancies are exposed to similar seasonality. The current paper uses data from a large demographic survey in the Matlab region of Bangladesh to retest the Gambian-derived hypothesis that early life exposures correlated with season of birth predict later patterns of mortality. METHODS: Since 1966, a continuous demographic surveillance system has been in operation in the rural Matlab region of Bangladesh. The current analysis is based on 172 228 births and 24 697 deaths between 1974 and 2000. Season of birth was defined as ‘harvest’ (January-June) and ‘hungry’ (July-December), based on monthly variations in rates of conception and neonatal mortality within the same dataset. RESULTS: Birth during the hungry season resulted in excess mortality during the first year of life. However, for adult mortality (deaths >15 years), there was no excess in individuals born during the annual hungry season: ratio of hazard July-December versus January-June = 1.12; 95% CI: 0.87, 1.45. CONCLUSIONS: The current study found no excess mortality in young adults born during the ‘hungry’ season in rural Bangladesh. This differing pattern in survival when compared with