*Allostasis and Allostatic Load

April 12, 2009

This page contains my own working notes written while studying the research of the authors noted below.  Please go to my section https://stopthestorm.wordpress.com/references/ to locate the citation for their work.  Be patient, the reference page is a bit slow to load because it contains about 200 text pages of reference material.

– risk – Allostatic Load

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September 2, 2008

I believe the concept of allostasis and allostatic load provide the foundational platform from which to consider not only PTSD, but all imbalances within the body, including the brain, that lead to any and all manners of lack of well-being, including mental illness, aging and factors leading to death.

This leaves me with the new problem of educating myself as to the ramifications of allostasis and allostatic load.  It is beginning to look to me as if these concepts, or this continuum is really like the mortar that sticks and holds all other considerations of trauma and its stresses and adaptations as a result of these stressors together.  It then becomes the overarching principle and the underlying phenomena as well as the “stuff” that fills all the cracks in between.

Yet I feel overwhelmed, as if I am indeed just starting at the beginning, or just starting over – I guess because I cannot anticipate how I can tie all my thoughts and concerns together using allostasis and allostatic load as the “kingpin” thought to which all other thoughts have an established relationship.

I see this just now as I encounter McEwen’s concept of allostatic overload – which he ties to the costs and benefits of belonging to a social species at the point now where his ideas tie into attachment research – as he introduces the fact of competition within our social species.

With this introduction of the complexities of this new concept to be intermixed with the work I have already been doing – I want to give up!  I want to give up and go play, to distract myself, to go be “normal,” whatever that might be – and do “normal” things.

Somehow this is requiring a “paradigm shift” in my thinking and writing, in my organization of thoughts and topics.  It is interesting that this is hitting me at the same time I hit his thoughts about overload.  I feel overloaded!  Part of the difficulty is that I cannot access the entire articles, only the abstracts, that I need to consider this topic!  The very topic I need to understand so that it can “fill in the holes” is, itself, due to my limited access abilities, full of holes itself!

The problem, then, is not “the intergenerational transmission of unresolved traumas.”

The problem is that we pass on allostatic load or overload, and/or patterns of attempting to achieve allostasis.  This transmission includes epigenetic factors….

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Carlson & Chamberlain 2005

Abstract – TX

“Eliminating racial and ethnic health disparities requires restructuring the biomedical models that have focused on the individual as the level of analysis and emphasized the parts rather than the whole.  A recently developed understanding of human physiology and adaptive regulation, constructs of allostasis and allostatic load, provides a theoretical orientation that needs to be explored.”

This relates to the article on well-being –

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McEwen 2000

February – Abstract – Rockfeller U, NY

“The primary hormonal mediators of the stress response, glucocorticoids and catecholamines, have both protective and damaging effects on the body.”

“In the short run, they are essential for adaptation, maintenance of homeostasis, and survival (allostasis).”

………………..”Yet, over longer time intervals, they exact a cost (allostatic load) that can accelerate disease processes.”

……………..”The concepts of allostasis and allostatic load center around the brain as interpreter and responder to environmental challenges and as a target of those challenges.”

………”In anxiety disorders, depressive illness, hostile and aggressive states, substance abuse, and post-traumatic stress disorder (PTSD), allostatic load takes the form of chemical imbalances as well as perturbations in the diurnal rhythm, and, in some cases, atrophy of brain structures.”

“In addition, growing evidence indicates that depressive illness and hostility are both associated with cardiovascular disease (CVD) and other systemic disorders.”

“A major risk factor for these conditions is early childhood experiences of abuse and neglect that increase allostatic load later in life and lead individuals into social isolation, hostility, depression, and conditions like extreme obesity and CVD.”

……………..”Animal models support the notion of lifelong influences of early experience on stress hormone reactivity.”

……….”Whereas, depression and childhood abuse and neglect tend to be more prevalent in individuals at the lower end of the socioeconomic ladder, cardiovascular and other diseases follow a gradient across the full range of socioeconomic status (SES).”

………………..”An SES gradient is also evident for measures of allostatic load.  Wide-ranging SES gradients have also been described for substance abuse and affective and anxiety disorders as a function of education.”

Emerging public health issues where the brain plays a role

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McEwen 2000

October – Abstract – Rockfeller U, NY ——-need to get this one

“The adaptive responses of the body to challenges, often known as “stressors”, consists of active responses that maintain homeostasis.  This process of adaptation is known as “allostasis”, meaning “achieving stability through change”.”

“Many systems of the body show allostasis, including the autonomic nervous system and hypothalamo-pituitary-adrenal (HPA) axis and they help to reestablish or maintain homeostasis through adaptation.”

“The brain also shows allostasis, involving activation of nerve cell activity and the release of neurotransmitters.”

“When the individual is challenged repeatedly or when the allostatic systems remain turned on when no longer needed, the mediators of allostasis can produce a wear and tear on the body that has been termed “Allostatic load”.”

……………….”Examples of allostatic load include the accumulation of abdominal fat, the loss of bone minerals and the atrophy of nerve cells in the hippocampus.”

Circulating stress hormones play a key role, and, in the hippocampus, excitatory amino acids and NMDA receptors are important mediators of neuronal atrophy.”

……………….”The aging brain seems to be more vulnerable to such effects, although there are considerable individual differences in vulnerability that can be developmentally determined.  Yet, at the same time, excitatory amino acids and NMDA receptors mediate important types of plasticity in the hippocampus.”

…………..”Moreover, the brain retains considerable resilience in the face of stress, and estrogens appear to play a role in this resilience.”

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Karlamangla et al 2002

Abstract – UCLA school of medicine

“Allostatic load has been proposed as a cumulative measure of dysregulation across multiple physiological systems….”

….postulated to impact health risks

“In the allostatic load model, increased risk is hypothesized to result not only from large and clinically significant dysregulation in individual systems, but also from more modest dysregulation, if present in multiple systems.”

Study analyzed data from 7-year longitudinal study – community based – age at baseline between 70 & 79 – studied association of 10 biological measurements representing allostatic load

CONCLUSIONS:

“…a summary measure of physiologic dysregulation, such as allostatic load, is an independent predictor of functional decline in elderly men and women.”

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McEwen 2001

Abstract

HIPPOCAMPUS

“The hippocampus is an important structure for declarative, spatial, and contextual memory and is implicated in the perception of chronic pain.”

…vulnerable to damage from seizures, ischemia, head trauma

…….particularly sensitive to effects of adrenal glucocorticoids secreted during the diurnal rhythm and chronic stress

“Adrenal steroids typically have adaptive effects in the short run, but promote pathophysiology when there is either repeated stress or dysregulation of the HPA axis.”

“The damaging actions of glucocorticoids under such conditions have been termed “allostatic load”, referring to the cost to the body of adaptation to adverse conditions.”

“Adrenal steroids display both protective and damaging effects in the hippocampus.  They biphasically modulate excitability of hippocampal neurons, and high glucocorticoid levels and severe acute stress impair declarative memory in a reversible manner.”

……… “The hippocampus also displays structural plasticity, involving ongoing neurogenesis of the dentate gyrus, synaptogenesis under control of estrogens in the CA1 region, and dendritic remodeling caused by repeated stress or elevated levels of exogenous glucocorticoids in the CA3 region.”

……… “In all three forms of structural plasticity, excitatory amino acids participate along with circulating steroid hormones.”

…….. “Glucocorticoids and stressors suppress neurogenesis in the dentate gyrus.”

……… “They also potentiate the damage produced by ischemia and seizures.”

…. “…the aging rat hippocampus displays elevated and prolonged levels of excitatory amino acids released during acute stress.”

“Our working hypothesis is that structural plasticity in response to repeated stress starts out as an adaptive and protective response, but ends up as damage if the imbalance in the regulation of the key mediators is not resolved.”

………… “It is likely that morphological rearrangements in the hippocampus brought on by various types of allostatic load alter the manner in which the hippocampus participates in memory functions and it is conceivable that these may also have a role in chronic pain perception.”

I need to look into the connection between trauma as chronic physical pain as well as emotional pain – sharing the same neural connections – and being tied into the operation of the resting default brain mode – connected finally to the precuneus and operational SELF

It is significant that many abused children have smaller hippocampal volumes, as do chronic alcoholics – but this correspondence with PTSD is inconsistently shown and not a predictable correlate with adult PTSD.  I also consider the hippocampus in regard to the ability to learn…or not to learn….from the experiences of severe trauma.  I would suspect that the brain is preparing itself to learn something useful toward continued survival and adaptation from acute trauma, but with repeated or chronic trauma – what is the brain supposed to make of that for future adaptation?  (spinning wheelies in the dust)  This has to also connect to the literature I haven’t studied yet on control and lack of controllability –  In the worst of challenges a person is better off if there is something they are empowered to competently DO in the face of trauma or after it is over – I suspect that is the way we are built

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McEwen 2002a

Abstract ————– I need to call this article in

Allostasis:  “…adaptive responses of the body that maintain homeostasis in response to stressors…”

…. “…meaning “achieving stability through change.””

……”Mediators produced by the immune system, autonomic nervous system (ANS) and hypothalamo-pituitary-adrenal (HPA) axis produce allostasis.”

…….”The brain also shows allostasis, involving the activation of nerve cell activity and the release of neurotransmitters.”

……”When the individual is challenged repeatedly or when the allostatic systems remain turned on when no longer needed, the mediators of allostasis can produce a wear and tear on the body and brain that has been termed “allostatic load”.”

…. “Examples of allostatic load include the accumulation of abdominal fat, the loss of bone minerals and the atrophy of nerve cells in the hippocampus.”

……………….. “Studies of the hippocampus as a target of stress and sex hormones have revealed a considerable degree of structural plasticity and remodeling in the adult brain that differs between the sexes.”

……. “Three forms of hippocampal structural plasticity are affected by circulating hormones:  (1) repeated stress causes remodeling of dendrites in the CA3 region; (2) different modalities of stress suppress neurogenesis of dentate gyrus granule neurons; (3) ovarian steroids regulate synapse formation during the estrous cycle of female rats.”

…….. “All here forms of structural remodeling of the hippocampus are mediated by hormones working in concert with excitatory amino acids (EAA) and NMDA receptors.  EAA and NMDA receptors are also involved in neuronal death that is caused in pyramidal neurons by seizures, by ischemia and by severe and prolonged psychosocial stress.”

………. “The aging brain seems to be more vulnerable to such effects although there are considerable individual differences in vulnerability that can be developmentally determined.”

Including the long-term and lifelong effects and consequences of infant and child abuse and childhood traumas, I would say

……. “Moreover, the brain retains considerable resilience.

” “Resilience is an example of successful allostasis in which wear and tear is minimized, and estrogens exemplify the type of agent that works against the allostatic load associated with aging.”  This review discusses the current status of work on underlying mechanisms for protection and damage.”

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McEwen 2002b

Abstract

Stress is a condition of the mind and a factoring the expression of disease that differs among individuals.

In…PTSD, traumatic events can create a long-lasting state of psychologic reactivity that amplifies and exacerbates the effects of daily life events.

The elevated activities of physiologic systems lead to wear and tear, called “allostatic load.”

It reflects not only the impact of life experiences but also of genes, individual life-style habits (e.g. diet, exercise, and substance abuse), and developmental experiences that set life-long patterns of behavior [I would add built into the brain itself] and physiologic reactivity.

Hormones associated with stress and allostatic load protect the body in the short run and promote adaptation, but in the long run allostatic load causes changes in the body that lead to disease.”

That’s pretty clear!  One must realize that this is all tied in to how the immune perception is viewing itself in relationship to its environment – that it has perceived an attack against its life and integrity, and evidently cannot tell when that threat is over – if ever it truly is over.  I suppose it is because we differ from the animals that we have stress “as a condition of the mind.”  Stress, however, seems to me to be a real function of pressure put on organisms during the course of their existence that forces them into a position of having to take some kind of protective action on their own behalf

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McEwen & Wingfield 2003

Abstract – am calling in this article

“Living organisms have regular patterns and routines that involve obtaining food and carrying out life history stages such as breeding, migrating, molting, and hibernating.”

…… “The acquisition, utilization, and storage of energy reserves (and other resources) are critical to lifetime reproductive success.”

This is economics – and also connects to entropy and negentropy, or positive entropy.  Life demands continual “inhalation” of resources to counterbalance natural entropy or movement toward “bankruptcy” and death.

“There are also responses to predictable changes, e.g., seasonal,

and unpredictable challenges, i.e., storms and natural disasters.”

“Social organization in many populations provides advantages through cooperation in providing basic necessities and beneficial social support.”

.. “But there are disadvantages owing to conflict in social hierarchies and competition for resources.”

I would think that hierarchies are ultimately concerned with reproductive fitness

allostasis

………. “…maintaining stability through change, as a fundamental process through which organisms actively adjust to both predictable and unpredictable events.”

Allostatic load

… “…refers to the cumulative cost to the body of allostasis…”

allostatic overload

……. “…being a state in which serious pathophysiology can occur.”

Type 1 allostatic overload

….. “…occurs when energy demand exceeds supply, resulting in activation of the emergency life history stage.  This serves to direct the animal away from normal life history stages into a survival mode that decreases allostatic load and regains positive energy balance.  The normal life cycle can be resumed when the perturbation passes.”

Type 2 allostatic overload

…… “…does not trigger an escape response, and can only be counteracted through learning and changes in the social structure.”

…… “…begins when there is sufficient or even excess energy consumption accompanied by social conflict and other types of social dysfunction.”

……….. “The latter is the case in human society and certain situations affecting animals in captivity.”

……….. “In all cases, secretion of glucocorticosteroids and activity of other mediators of allostasis such as the autonomic nervous system, CNS neurotransmitters, and inflammatory cytokines wax and wane with allostatic load.  If allostatic load is chronically high, then pathologies develop.”

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Korte et al 2005

Abstract – the Netherlands – I am calling in this article

HAWKS AND DOVES – differing patterns of maintaining allostasis

“It has become clear that natural selection maintains a balance of different traits preserving genes for high aggression (Hawks) and low aggression (Doves) within a population.”

………… “The existence of these personality types (Hawks-Doves) is widespread in the animal kingdom, not only between males and females but also within the same gender across species.”

There are causes for the different response patterns to stress

…….. “Hawks and Doves differ in underlying physiology and these differences are associated with their respective behavioral strategies; for example, bold Hawks preferentially adopt the fight-flight response when establishing a new territory or defending an existing territory,

………..while cautious Doves show the freeze-hide response to adapt to threats in their environment.”

Based on mother’s reaction to my attempts to stand up for myself at age 2, as I pounded my fists down the hallway walls when she sent me to my bedroom when grandmother was visiting – she extinguished my Hawk abilities to respond to stress very early – being chronically bullied perhaps does that (note school shooters, reversal)!  How can they know that naturally in humans we would show both sides of the coin in responses if allowed?  Adopting them flexibly according to situation would seem more likely?  Or are they simply suggesting that one response pattern would be dominant?

………..”Thus, adaptive processes that actively maintain stability through change (allostasis) depend on the personality type and the associated stress responses.”

…… “…expression of the various stress responses can result in specific benefits to the organism.”

This article discusses “…how the benefits of allostasis and the costs of adaptation (allostatic load) lead to different trade-offs in health and disease, thereby reinforcing a Darwinian concept of stress.  Collectively, this provides some explanation of why individuals may differ in their vulnerability to different stress-related diseases and how this relates to the range of personality types, especially aggressive Hawks and  non-aggressive Doves in a population.”

……….. “…Hawks, due to inefficient management of mediators of allostasis, are more likely to be violent, to develop impulse control disorders, hypertension, cardiac arrhythmias, sudden death, atypical depression, chronic fatigue states and inflammation.”

….. “In contrast, Doves, due to the greater release of mediators of allostasis (surplus), are more susceptible to anxiety disorders, metabolic syndromes, melancholic depression, psychotic states and infection.”

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Goldstein & McEwen 2002

Abstract – Bethesda, MD

New formulation of homeostasis that uses concepts of allostasis and homeostats

………… “The new formulation moves beyond Cannon’s concept of “homeostasis,” which posits an ideal set of conditions for maintenance of the internal environment.”

Walter Bradford Cannon, 1932- “homeostasis”

“The notion of allostasis recognizes that there is no single ideal set of steady-state conditions in life, and different stressors elicit different patterns of activation of the sympathetic nervous and adrenomedullary hormonal systems.

Allostasis reflects active, adaptive processes that maintain apparent steady states, via multiple, interacting effectors regulated by homeostatic comparators – “homeostats.”

Allostatic load

“…refers to the consequences of sustained or repeated activation of mediators of allostasis.”

From the analogy of a home temperature control system, the temperature can be maintained at any of a variety of levels (allostatic states) by multiple means (effectors), regulated by the thermostat (homeostat).”

“Allostatic load and risks of system breakdown increase when, for example, the front door is left open in the winter.”

“Applying these notions can aid in understanding how acute and chronic stress can exert adverse health consequences via allostatic load.”

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Day 2005

Abstract – Australia

ANTI ALLOSTASIS AND ALLOSTATIC LOAD

Need for close attention to conceptual frameworks used to describe stress – researchers mapping bran’s stress control pathways – Day feels the frameworks being used are poorly developed –

“…it is notable that in recent years it has been argued that the concept of homeostasis should be supplemented by the concepts of allostasis (literally ‘stability through change’) and allostatic load (in effect, the cost of allostasis).”

……. “One of the purported benefits of this change has been that it will clarify the concept of stress.  A close review of the arguments leads us to conclude that the introduction of the concept of allostasis largely occurred as a result of misunderstandings and misapprehensions concerning the concept of homeostasis.”

“In terms of understanding how the organism operates, it is not clear that the concepts of ‘allostasis’ or ‘allostatic load’ offer us anything that was not already apparent, or at least readily derivable, from an accurate reading of the original concept of homeostasis.”

“Not surprisingly then, these more recently proposed concepts also offer little help in clarifying our understanding of stress.  Indeed, rather than clarifying the concept of stress, the primary effort appears to be directed at subsuming the concept of stress within the concept of allostasis, which has the inadvertent effect of collapsing the study of homeostatic responses and stress responses together.”

“This seems to be out of step with the fact that there is now considerable evidence that the brain does indeed possess certain pathways that merit the title of ‘stress neurocircuitry’.”

…… “The attempt to subsume the concept of stress within the concept of allostasis is also counter-productive in that it distracts stress researchers from the important task of developing conceptual frameworks that allow us to tackle fundamental issues such as how the organism differentiates stressful from non-stressful challenges.”

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Kinnunen, Kaprio & Pulkkinen 2005

Article – Finland

Method developed for measuring allostatic load is known as the high-risk quartile method

…… “Participants are classified into quartiles of … parameters reflecting physiological activity across various regulatory and metabolic systems of the body, and allostatic load is the sum of the parameters for which the participant falls into the high-risk quartile ….allostatic load as a summary index has predicted health better than any primary mediator or secondary outcome component alone…”  Kinnunen, Kaprio & Pulkkinen 2005, p 20

consequences of allostatic overload — the tertiary outcomes

.hard to study because only long-term processes lead to allostatic load

……”No sex differences have been found in the pathways from stressors to allostatic load or from elevated allostatic load to tertiary outcomes.”  Kinnunen, Kaprio & Pulkkinen 2005, p21

STUDY

Part of a longitudinal study of 369 randomly selected 8-yr-old children in Finland in 1968, followed up at ages 9,14,20,27,30,36,42

…………present study focused on ages 36 and 42 – mean age 41, representative of national cohort born in 1959

“Allostatic load in this study comprised two primary mediators and six secondary outcomes that were determined to be congruent with the study of Seeman et al. (1997).

One of the primary mediators included an adrenal androgen dehydroepiandrosterone-sulfate (DHEA-S) as a neuroprotective agent (Hyppert & Van Niekerd, 2001) and a functional antagonist of actions of glucocorticoids (McEwen, 2003);

……………another primary mediator was overnight 12-h urinary norepinephrine, and index of sympathetic nervous system activity….”  Kinnunen, Kaprio & Pulkkinen 2005, p22

Secondary outcomes were high-density lipoprotein (HDL)

..cholesterol and triglycerides (TG) as indexes of long-term risks for atherosclerosis, ..glycosylated hemoglobin (GHb) as an index of short-term glucose metabolism,

..systolic (SBP) and diastolic (DBP) blood pressure as indexes of cardiovascular activity,

.and

waist-to-hip (WHR) as an index of long-term metabolism and adipose tissue distribution

thought to be influenced by elevated cortisol activity

….WHR was chosen instead of body mass index, because central obesity may occur even in normal weight individuals, and secondly, obesity may occur without risky metabolic manifestations.”  Kinnunen, Kaprio & Pulkkinen 2005, p22

RESULTS

…unstable career affects health – acts as a stressor affecting the body’s physiological regulation systems in the long-term – participants with unstable careers between ages 27 and 36 had an elevated risk for high allostatic load at age 42 compared to participants with a stable career history

….study did not use primary mediators of cortisol and epinephrine

men tended to fall into the high-risk quartiles of the secondary outcome parameters and women into those of the primary mediators

Only men fell into the high-risk quartile for WHR

For both sexes, one-third (33%) of participants had an elevated allostatic load.

Typically men (64.5%; 12.7% of women) fell into at least one of the secondary outcome risk quartiles without falling into any of the primary mediators, whereas women (30.9%; 0.5% of men) tended to fall only into the risk quartiles of primary mediators.”  Kinnunen, Kaprio & Pulkkinen 2005, p24

In most cases (73.7% allostatic load involved both primary mediators and secondary outcome parameters and in some cases (26.3%) only secondary outcome parameters  – Kinnunen, Kaprio & Pulkkinen 2005, p25

Occupational status or smoking did not elevate the risk of having high allostatic load – but were associated with higher levels of psychosomatic symptoms [headaches, etc] – Kinnunen, Kaprio & Pulkkinen 2005, p26

Participants with high allostatic load reported more psychosomatic symptoms than those with low allostatic load – Kinnunen, Kaprio & Pulkkinen 2005, p26

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These are evidently markers that they are able to use to determine how the body is responding to stress.  I don’t understand why there isn’t a concerted effort to develop a way to assess people using these markers so people would have a concrete sampling of their allostatic load – with tailor made adaptations or changes they can make to improve themselves!  But what do I know?  I didn’t even know that menopause was a health risk factor!

Identifying and treating individual physical symptoms without assessing the entire stress load on the body is like identifying the individual bubbles that float to the surface from a person drowning down below.

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from http://www.healthcalculators.org/calculators/waist_hip.asp

to determine if you have a healthy waist to hip ratio measure waist a bit above the naval and hips at widest part – divide waist measurement by hip measurement to get the ratio

…this site has an automatic calculator

they say that an apple shaped body with more weight around the waist is greater health risk -pear shaped with more weight around the hips is less of a risk

http://www.bmi-calculator.net/waist-to-hip-ratio-calculator/waist-to-hip-ratio-chart.php

health risk based solely on WHR

low risk:  male 0.95 or below, female 0.80 or below

moderate risk:  male 0.96 to 1.0, female 0.81 to 0.85

high risk: male 1.0+, female 0.85+

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Seeman et al 2001

Article

Need for an “…early warning system of biomarkers that can signal early signs of dysregulation across multiple physiological systems.”  Seeman et al 2001, 4770

…….need to include in assessments parameters of dysregulation in all important regulatory systems, e.g. measures of hemostatic or immune/inflammatory processes, would improve prediction

“AL has been conceptualized as a marker of cumulative biological dysregulation across all major regulatory systems; contributing factors include dysregulation in both system state 9or usual) levels of activity and in system dynamics.  Although our measure of AL included information on metabolism, cardiovascular activity and both HPS and sympathetic nervous system activity, it does not include information on such things as inflammatory markers clotting factors, or immune function.  Component measures are also snapshots of levels of activity; there is no information on system dynamics.”  Seeman et al 2001, 4774

………..cumulative biological burden – range of scores on AL associated with differences of risk for major health outcomes – “cumulative risks to health from biological dysregulation across multiple regulatory systems.” Seeman et al 2001, 4775

“…there is a cascade of events through which [allostatic load AL develops, with chemical messengers such as cortisol ( C) epinephrine (EPI), and norepinephrine (NE) playing the role of primary mediators [non-X risk factors]….Previous studies give no indication of the potential predictive value of such primary mediators, nor do they clarify how they contribute to a summary measure of AL beyond the syndrome X components.”  Seeman et al 2001, 4770 -no measure of parasympathetic system

standard indictors of syndrome X are used to indicate risk for cardiovascular disease (CVD):  levels of seated systolic blood pressure (SPB) and diastolic blood pressure (DBP), high density lipoproteins (HDL), and total cholesterol, glycosylated hemoglobin, and abdominal obesity [i.e., high waist-hip ration (WHR)].

Increased risk of mortality with higher AL scores, greater average decline, & cognitive decline

…………….only those at the highest levels of AL experienced significantly greater declines in functioning

………….same pattern of risk factors that predicted CVD after 7 years predicted cognitive decline

………….mortality and physical decline were better predicted with the non-X risk factors

“…the concept of AL postulates that a more comprehensive, cumulative measure of biological wear and tear will provide a better index of health risk over the life course, better that is, in comparison to more traditional approaches that assess biological risks in terms of individual parameters.  Further development of this concept, however, requires clearer delineation of the cascade of events (both within and across systems) through which AL develops, including specification of the relationships among regulatory systems and the pattern of cumulating dysregulation (e.g., what are most frequently the initial markers of dysregulation and how does this ripple outward to other systems and parameters?).”  Seeman et al 2001, 4775

and infant and child abuse sets these risk factors in motion way, way too early!

FOR THE FUTURE!?

“Along these lines, a reformulation of AL that more explicitly addresses the cascade of events by delineating three levels of events that are seen as contributing to AL…has been developed.  At the first level are primary mediators, e.g., chemical messengers such as C, NE, and EPI.

“A second level of events is represented by what we refer to as primary effects, e.g., cellular events, like enzymes, receptors, ion channels, or structural proteins induced genomically or phosphorylated via second messenger systems, that are regulated as part of allostasis by the primary mediators.”

“A third level is represented by secondary mediators, e.g., more integrated processes such as blood pressure, heart rate, and metabolic profiles that are the outcome of effects of one or more primary mediators.  The final outcome of this cascade of effects would be the actual disease outcomes.”  Seeman et al 2001, 4775

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McEwen 2000c

Abstract

Helpful and adaptive hormones and other physiological agents released in response to acute stress are meant for the short run

…….. ‘…and yet can accelerate pathophysiology when they are over-produced or mismanaged.  Here we consider the protective and damaging effects of these mediators as they relate to the immune system and brain.  Stress is a principle focus, but this term is rather imprecise.  Therefore, the article begins by noting two new terms, allostasis and allostatic load that are intended to supplement and clarify the meanings of ‘stress’ and  ‘homeostasis‘.”

“For the immune system, acute stress enhances immune function whereas chronic stress suppresses it.”

……… “These effects can be beneficial for some types of immune responses and deleterious for others.”

. “A key mechanism involves the stress-hormone dependent translocation of immune cells in the blood to tissues and organs where an immune defense is needed.”

… “For the brain, acute stress enhances the memory of events that are potentially threatening to the organism.”

I suspect what is more important for the brain to process and remember under such circumstances is not the memory of the trauma specifically as separate from the way it was successfully dealt with!  That is the learning I refer to.  If this process is not completed so that the trauma and the successful handling of the trauma are remembered together, I don’t believe the cycle is ever completed.  Perhaps when Scaer and Levine  refer to the uncompleted trauma cycle, including the shaking part of it, they are in fact referring to the completion of a learning cycle.  If the learning has not been completed, then the memory of this pairing of success with challenge met is not accomplished either – one cannot remember what one has not experienced – and perhaps it is especially with trauma that an IMMEDIATE learning process is required because the trauma is close to death, too close to threat of extinction, too close to annihilation itself for it to be otherwise. It is this coupling of trauma with mastery that is the most important learning possible for a body under threat – and something evolution can prepare us to do in the short run through its past adaptations that allowed us the ability for flexible response to novel situations in the short run.

NOT LEARNING from immediate response to threat of destruction HURTS if not kills.  If we survive it, and were not killed, then we better LEARN and REMEMBER whatever it was that we did that assisted us to be successful.  I bet a brain on an unfulfilled crisis learning task will burn itself out before it will let go of the task!

….”Chronic stress, on the other hand, causes adaptive plasticity in the brain, in which local neurotransmitters as well as systemic hormones interact to produce structural as well as functional changes, involving the suppression of ongoing neurogenesis in the dentate gyrus and remodeling of dendrites in the Ammon’s horn.”

…… “Under extreme conditions only does permanent damage ensue.”  And there are plenty of these to go around!

… “Adrenal steroids tell only part of the story as far as how the brain adapts, or shows damage, and local tissue modulators – cytokines for the immune response and excitatory amino acid neurotransmitters for the hippocampus.”  [unfinished sentence?]

… “Moreover, comparison of the effects of experimenter-applied stressors and psychosocial stressors show that what animals do to each other is often more potent than what experimenters do to them.  And yet, even then, the brain is resilient and capable of adaptive plasticity.”

“Stress-induced structural changes in brain regions such as the hippocampus have clinical ramifications for disorders such as depression, post-traumatic stress disorder and individual differences in the aging process.”

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Seeman et al 1997

Abstract – U of Southern California

Allostatic load – “the cumulative physiologic toll exacted on the body over time by efforts to adapt to life experiences.”

RESULTS of longitudinal study

“Higher allostatic load scores were associated with poorer cognitive and physical functioning and predicted larger decrements in cognitive and physical functioning as well as being associated with an increased risk for the incidence of cardiovascular disease, independent of sociodemographic and health status risk factors.”

CONCLUSIONS:

“Findings are consistent with the conceptualization of allostatic load as an index of wear and tear on the body, with elevations in allostatic load predicting an increased risk for a decline in cognitive and physical functioning as well as cardiovascular disease in a cohort of older men and women.  From a clinical perspective, the concept of allostatic load may provide the basis for a more comprehensive assessment of major risks in the aging process.”

I don’t understand the “chicken or the egg first” implications of this research.  Is it the “poorer cognitive and physical functioning” that causes the increase in allostatic load over time in the first place, or is it the other way around?

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McEwen 2003

Abstract – I need to get this article called in

“Individual differences in the aging process can be conceptualized as an accumulation of wear and tear [entropy] of daily experiences and major life stressors that interact with the genetic constitution and predisposing early life experiences.”  Realizing that epigenetic forces are in continual interaction with the genetic DNA structure

…neuroendocrine system, autonomic nervous system, immune system are mediators of adaptation to challenges of daily life [and super stressors] of daily life, referred to as allostasis, meaning “maintaining stability through change.”

“Physiological mediators such as adrenalin from the adrenal medulla, glucocorticoids from the adrenal cortex, and cytokines from cells of the immune system act upon receptors in various tissues and organs to produce effects that are adaptive in the shor run but can be damaging if the mediators are not shut off when no longer needed.”

.. “When release of the mediators is not efficiently terminated, their effects on target cells are prolonged, leading to other consequences that may include receptor desensitization and tissue damage.”

… “This process has been named “allostatic load,” and it refers to the price the tissue or organ pays for an overactive or inefficiently managed allostatic response.”

.. “Therefore, allostatic load refers to the “cost” of adaptation.”  If everything isn’t working properly!  And then, like with depression and PTSD, there is the cost of adapting to the cost that led to the stress conditions in the first place – as in cases like mine, where the severe abuse from birth changed my brain in the first place, leading to all kinds of difficulties accomplishing marriage, job choice, utilization of assets and resources, dealing with the dissociation – the costs get added onto costs – problems multiply

“This article discusses the mediators of allostasis and their contributions to allostatic load as well as their role in resilience of the aging organism to stressful experiences.”

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McEwen 2007

Abstract

“The brain is the key organ of the response to stress because it determines what is threatening and, therefore, potentially stressful, as well as the physiological and behavioral responses which can be either adaptive or damaging.”

I would think that the body itself has a wisdom about trauma – and therefore of a level of stress that is life threatening – that allows the body to react faster than the brain could process the information – but I suppose such thinking is silly because without a working brain we are dead anyway – so I suppose it depends on which level of brain operation is doing the reacting?  The older regions or the newer ones?

“Stress involves two-way communication between the brain and the cardiovascular, immune, and other systems via neural and endocrine mechanisms.  Beyond the “flight-or-flight” response to acute stress, there are events in daily life that produce a type of chronic stress and lead over time to wear and tear on the body (“allostatic load”).  Yet, hormones associated with stress protect the body in short-run and promote adaptation (“allostasis”).”

“The brain is a target of stress, and the hippocampus was the first brain region, besides the hypothalamus, to be recognized as a target of glucocorticoids.  Stress and stress hormones produce both adaptive and maladaptive effects on this brain region throughout the life course.”

Early life events influence life-long patterns of emotionality and stress responsiveness and alter the rate of brain and body aging.”

“The hippocampus, amygdala, and prefrontal cortex undergo stress-induced structural remodeling, which alters behavioral and physiological responses.”

“As an adjunct to pharmaceutical therapy, social and behavioral interventions such as regular physical activity and social support reduce the chronic stress burden and benefit brain and body health and resilience.”

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Bremner 1999

Abstract – Yale

PTSD patients and childhood abuse – deficits on neuropsychological measures – validated as probes of hippocampal function – MRI showed volume reduction in both PTSD Vietnam vets and victims of child abuse [conflictual finding on adults I note] –

“In combat veterans, hippocampal volume reduction was correlated with deficits in verbal memory on neuropsychological testing….experiences in the form of traumatic stressors can have long-term effects on the structure and function of the brain.”

Glucocorticoids, serotonin acting through excitatory amino acids to mediate hippocampal atrophy

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Vermetten & Bremner 2002

Abstract

“Preclinical studies of stress provide a comprehensive model for understanding neurobiological alterations in posttraumatic stress disorder (PTSD).  The pathophysiology of stress reflects long-standing changes in biological stress response systems and in systems involved in stress responsivity, learning, and memory.  The neural circuitry involved includes systems mediating hypothalamic-pituitary-adrenal (HPA) axis, norepinephrine (locus coeruleus), and benzodiazepine, serotonergic, dopaminergic, neuropeptide, and central amino acid systems.”

“These systems interact with brain structures involved in memory, including hippocampus, amygdala, and prefrontal cortex.”

Stress responses are of vital importance in living organisms; however excessive and/or repeated stress can lead to long-lasting alterations in these circuits and systems involved in stress responsiveness.”

Intensity and duration of the stressor, and timing of the stressor in life, have strong impact in this respect.”

It is crucial to note that evidently these traumatic stress brain changes can occur in previously healthy brains in adulthood.

They also happen in childhood, though it is unclear to me what happens next when these people whose brains  were damaged in childhood again, as adults, are exposed to further trauma.

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Mello et al 2003

Abstract – Brown med school

Early life stress – important risk factor for HPA axis dysregulation – prominence of HPA hyperactivity in adults with depressive and anxiety disorders – may be link between occurrence of adversity in childhood and development of adult psychopathology

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McEwen & Seeman 1999

Abstract

Stress, condition of life, factor in expression of disease

..”A broader view of stress is that it is not just the dramatic stressful events that exact their toll but rather the many events of daily life that elevate activities of physiological systems to cause some measure of wear and tear.  We call this wear and tear “allostatic load,” and it reflects not only the impact of life experiences but also of genetic load; individual habits reflecting items such as diet, exercise, and substance abuse; and developmental experiences that set life-long patterns of behavior and physiological reactivity….”

“Hormones associated with stress and allostatic load protect the body in the short run and promote adaptation, but in the long run allostatic load causes changes in the body that lead to disease.”

…….in body and brain

“Among the most potent of stressors are those arising from competitive interactions between animals of the same species, leading to the formation of dominance hierarchies.”

“Psychosocial stress of this type not only impairs cognitive function of lower ranking animals, but it can also promote disease (e.g. atherosclerosis) among those vying for the dominant position.  Social ordering in human society is also associated with gradients of disease, with an increasing frequency of mortality and morbidity as one descends the scale of socioeconomic status that reflects bot income and education.”

“Although the causes of these gradients of health are very complex, they are likely to reflect, with increasing frequency at the lower end of the scale, the cumulative burden of coping with limited resources and negative life events and the allostatic load that this burden places on the physiological systems involved in coping and adaptation.”

We must realize that abuse, trauma, neglect from birth and in childhood – from whatever the source – if not balanced out will create changes in the brain, mind and body of these people in such a way that their likelihood of successful social competition is impaired – they are among the have nots, even in a culture like America.

Add onto this load the load of social pressure from poverty, single parenting, prejudice, etc – costs mount – amplify – external pressures from the environment surrounding an infant, even in the womb, become internalized within the brain and body – people in “recovery” fields like to talk about boundaries – when other people’s (our parent’s) problems get built right into our growing brains, and those pressures then impact the development of all the operational systems in our bodies – then we DO have our parents problems right inside of us – no wonder it becomes hard for us to know who we are as separate people-selves – and from then on our boundaries will not be clear because they were never clear in the first place.  This is not an allostatic load that people born into secure environments will ever have to carry – and those of us who carry these loads carry them right along with the “regular” loads that others carry – in addition and from extremely young ages.

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Singer & Ryff 1999

Abstract – Princeton

Inverse associations between socioeconomic standing and incidents of chronic disease and mortality

…..”Empirical identification of pathways, or histories, requires measures that assess cumulative wear and tear on physiological systems following from psychosocial adversity and genetic predispositions.”

…………..”Such an assessment, allostatic load, has been shown to predict later life mortality, incident cardiovascular disease, and decline in physical and cognitive functioning.”

………cumulative adversity relative to advantage [or disadvantage] over a life course

[secure attachment – which is related to the secure attachment advantage history of one’s family, especially the mother – is the most essential and basic advantage one can have]

We operationalized these histories via unfolding economic circumstances and social relationship experiences (e.g., parent-child interactions, quality of spousal ties).  Findings reveal a strong direct association between the extent of adversity relative to advantage in an ordering of these histories and likelihood of high allostatic load.”

“Importantly, resilient individuals with economic disadvantage, but compensating positive social relationship histories also show low prevalence of high allostatic load.”

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CANCER

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Harding 2008

Yahoo news article

Breast cancer risk – Israel

“Young women who experience more than one stressful life event are at greater risk of developing breast cancer, but a general feeling of happiness and optimism may help guard against the disease, Israeli researchers report.”

And where do we get this ability to feel optimistic and happy?  I would say from a secure attachment history.  Finding in the study that women with a “general feeling of happiness and optimism” had a 25 percent lower risk of having been diagnosed with breast cancer has NOTHING to do – as the popular press in response to this study has stated – that women who have sunnier dispositions don’t get as much cancer.

If a person has suffered less severe traumas, and certainly NOT suffered them in early childhood, they have totally different risks for all kinds of problems – not only breast cancer – which connects to differences in allostatic load

Study also found that women who had experienced 2 or more severe or mild-to-moderate life events were 62% more likely to have breast cancer —being provided with the opportunity to be enabled or allowed to have happiness is a gift in the first place!

Ronit Peled of Ben-Gurion University of the Negev in Beer Sheva – investigated role of several severe life events such as – losing parent before age 20

……breast cancer rate in Israeli women is among highest in the world

.study:….

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Breast cancer risk – Israel

Peled et al 2008 in press

Israel – British journal

Study 622 women under 45 years old, 255 diagnosed for breast cancer between 1998-2002, 367 healthy [free of cancer – but recruited during visit to outpatient med clinic] -mean time between diagnosis and interview was one year – low response rate to solicitation for participation, only 25%, not a random sample

Cancer cases presented significantly higher scores of depression and significantly lower scores of happiness and optimism than controls – duh!

Exposure to more than one life event puts at risk, optimism and happiness has protective effect – young women exposed to number of negative life events should be considered at risk for BC

In US, 1 of 3 cancer diagnosis is breast, Israel BC among highest in world – ages 25-49 was 159.63 in 2002 and for 65+ was 350.13 per 1000,000 women

American reports every 3rd cancer is breast, in 2002 124.9 diagnosed, 25.5 died of 100,000 women – in Europe 2006 429,900 new cases (13.5% of all cancers)

…………psychological factors associated with immune dysfunctions and development of malignant cells

………..type and severity of event, effect of accumulated events, burden of psychological distress developed by the event –

RESULTS:

…….Differences in marital status between groups was significant

……..only in “loss of relative” was mean age of life event significant

…..[interesting] both groups – though mostly BC – found to have higher scores of depression and anxiety compared to Israeli standards

..significant difference found comparing groups according to cumulative number – 2 or more – of life events

DISCUSSION:

“The main results of our study suggest a negative association between happiness, optimism and BC and a positive association between depression, life events and the disease….We could not demonstrate a positive association with each separate life event.  Yet, exposure to a cumulative number of events (more than one) was positively associated with the disease.  In other words, we can carefully say, that experiencing more than one meaningful life event (severe and/or mild to moderate) is a risk factor for breast cancer among young women.”

……..interviewed after diagnosis but asked to report about before diagnosis but diagnosis might still have influenced reports

“A series of experimental studies provide some evidence of the process through which psychological stress could contribute to the increase of the risk of cancer, by modifying cell responses to environmental factors…..the mechanism  in which the central nerve, endocrine and immune systems interact and how behavior, and or external events modulate these three complex systems…not fully understood.”

“…we suggest that young women who suffered a loss in their early childhood, especially those exposed to a number of life events, should be considered as a risk group and be treated accordingly.”

Had I ever heard that exposure to multiple negative life events, especially related to child abuse, put me at high risk for breast cancer I would have paid more serious attention to the need for mammograms!

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Glaser 2005

Abstract – Ohio State U – dept of molecular virology, immunology and medical genetics, comprehensive cancer center

… probable that personality characteristics, personal resources, coping skills, social support playing important role in these associations… interaction of endocrine system, psychological distress and etiology of disease

field of psychoneuroimmunology (PNI) – field of research dealing with “…complex interactions between the central nervous system, endocrine and immune systems, and how behavior/stress can modify these interactions.”

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Glaser & Kiecolt-Glaser 2005

Abstract – Ohio state

Ways in which key mechanisms – stressors interact, with negative emotions that they generate, translated into physiological changes

How the immune system communicates bidirectionally with central nervous and endocrine systems, impact on health

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Weiner 2002

psychoneuroimmunology (PNI) – study of mind/body interaction traced to early Greek physicians – Hippocrates and Galen of ancient Greece – emotions significant role in progression and maintenance of disease – Weiner 2002, p 807

PNI – interactive – bidirectional communication between central nervous system (CNS), neuro-endocrine system, and immune system

………complex interrelationship between psychological, emotional facts, the brain, hormones and immunity and disease

……..pathways considered —- biological immune responses (cortisol levels, cytokines levels, natural killer-cell levels, etc) affected by environmental and internally mediated stress

……… “…if we accept that stressors experienced through conscious awareness and judgment impact the immune system, what can be done to reduce those stressors?”  Weiner 2002, p 807

“Stress, via bidirectional interactions between the central nervous system, endocrine system, and immune system, impacts the hypothalamic, pituitary, adrenal (HPA), and the sympathetic adrenal medullary (SAM) axes, can induce modulation of the immune system and, thereby, defense against infectious agents and health (Yang & Glaser, 2000).”  Weiner 2002, p 807

stress and depression depress immunity, stress reduction enhances immunity

…………stress reduction shown to improve survival rate of BC patients

…Hickie, Bennet, Lloyd, Heath, and Martin 1999 found positive genetic relationship between psychological distress and immunity, concluded that genotype may play significant role in reactivity of immune system to stress  Weiner 2002, p 808

…..Garssen and Goodkin 1999 evidence found low level of social support and tendency toward helplessness and repression of negative emotions promote cancer progression but not cancer initiation —- same factors also symptoms of depression  Weiner 2002, p 808

.

Christiansen, Edwards, Wiebe, Bonotsch, McKelvey, Andrews, and Lubaroff 1996 found immunosuppression (NKC activity) could be positively impacted by self-disclosure of traumatic or stressful experiences  Weiner 2002, p 808

…elevation of underlying disease processes to a level above threshold [symptom expression]   Weiner 2002, p 808

In extreme situations where physical trauma and pain are severe, the body releases endogenous opioids which reduce the perception of pain and have pain-relieving actions.  However, as a result, the immune activity of natural killer cells and lymphocytes is reduced.”  Weiner 2002, p 808

“This raises the issues of placebos and other treatments that work by altering the individual’s perception of pain without actually providing an external source of analgesia.  If, in fact, they operate as some believe by triggering pain-relieving opioids, do they then represent a two-edge sword which offers pain relief, thus, diminishing the immuno-suppressant levels of IL-6 and cortisol while possibly decreasing tumor suppression by lowering NKC and certain lymphocyte activities?”  Weiner 2002, p 808

Page and Ben-Eliyahu 1997 “…suggest that sufficient evidence exists to view pain as a pathogen in and of itself that is capable of facilitating the progression of metastatic disease via immunosuppression.”  Weiner 2002, p 808

………pain relief improves immune status and health outcomes

……..controllability of pain and level of optimism play role in impact that pain has on immune functioning

…………..demoralization, low self-esteem, perceptions of helplessness and hopelessness decreases immune functioning  Weiner 2002, p 808

interrelationship among psychological factors, immunologic activation and disease activity

…pain in the body affects depression, depression affects perception of pain  Weiner 2002, p 809

issue of impact of acute stressors on people who experience chronic life stressors

……Pike, Smith, Hauger, Nicassio, Patterson, McClintock, Costlow, and Irwin 1997 “…found that individuals experiencing chronic life stress demonstrated greater subjective stress, higher peak levels of epinephrine, lower peak levels of beta endorphin and of NK cell lysis and NK cell distribution to a mild acute stressor than did controls.  These changes persisted beyond termination of the stressor and sympathomedulary recovery.  It reinforces the concept that those already suffering, often the casein chronic illness or injury patients, are most vulnerable to further immunosuppression from acute stressors [like traumatic injury].”  Weiner 2002, p 809

… “…state of significantly decreased immunity needs to be addressed from a psychological, controlled coping skill, and pain management approach.”  Weiner 2002, p 809

Interestingly, research suggests when the stress is consistent with the stressor (perhaps demonstrating better coping skills by the individual [and I would say absence of PTSD]), immunological changes are less severe than when the stress experienced is greater than expected from the trauma.”  Weiner 2002, p 809

acute realistic response to trauma creates less disruption to aspects of immunity compared to those with more severe reactions or who repress their stress reactions

Weiner 2002, p 809 —adaptations to stress

Which those abused from birth at extremely high risk due to internal dysregulation, inability to self soothe, inability to assess threat, etc

(chronic pain syndrome)

“…clinicians must be aware of the patient’s mental state and take into account immunological susceptibilities in those patients who present with significant levels of emotional demoralization (chronic pain syndrome) when invasive potentially immunosuppressant interventions are considered.”  Weiner 2002, p 809

optimistic attitudes protect immune functioning

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IMMUNE SYSTEM REACTION – IMMUNE PHENOTYPE

Wilson et al 1999 – is with mutant genetics

Abstract – Harvard School of Medicine

……. “The ratio of CD45RO-positive to CD45RA-positive lymphocytes (CD45RO/CD45RA), an index of lymphocyte activation, was [significantly] higher…in the PTSD subjects than in the normal subjects.

These findings suggest the presence of increased lymphocyte activation in the PBL of patients with PTSD.”

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Yang & Glaser 2002

Abstract

Complex bi-directional interactions among the central nervous system (CNS), the endocrine system, and the immune system

….stress, through the HPA and sympathetic-adrenalmedullary (SAM) axes, can result in dysregulation of immune system

………review here discusses human studies and animal models, focuses on psychological stress emphasizing implications of these effects on wound healing and infectious diseases

I suspect PTSD is related to non-wound healing

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lack of social support is risk factor for depression –

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Segerstrom & Miller 2004

Article – meta-analysis of 30 years, 300 studies

“Stress-induced changes in the immune system that could accelerate wound repair and help prevent infections from taking hold would therefore be adaptive and selected along with other physiological changes that increased evolutionary fitness….human physiological response continues to reflect the demands of earlier environments.  Threats that do not require a physical response (e.g., academic exams) may therefore have physical consequences, including changes in the immune system.”  Segerstrom & Miller, 2004 p 601

CONCEPTUALIZING STRESS

….Stressors distinguished on 2 dimensions:  duration and course – discrete vs continuous

5 categories of stressors

+ 1) acute time-limited stressors –

+ 2) brief naturalistic stressors – person confronts real-life short-term challenge -+ 3) stressful event sequences – focal event such as loss of loved one or natural disaster creates series of related challenges – end not always clearly cut, but person knows they will end [predicts with confidence]

+ 4) chronic stressors – stable – person does not know if challenges will end or not, or when – usually invades/pervades person’s life and forces restructuring of identity or social roles (traumatic injury, caring for sick, refugee, etc)

+ 5) distant stressors – “…traumatic experiences [that would meet DSM-IV criterion for PTSD] that occurred in the distant past yet have the potential to continue modifying immune system function because of their long-lasting cognitive and emotional sequelae (Baum, Cohen, & Hall, 1993).”  Segerstrom & Miller, 2004 p 603

distant stressors can influence epigenetics – can be passed down as child abuse, also

OVERVIEW OF IMMUNE SYSTEM

To understand “the relationship of psychosocial stressors to the immune system, it is useful to distinguish between natural and specific immunity.

NATURAL IMMUNITY

“Natural immunity is an immune response that is characteristic not only of mammals but also lower order organisms such as sponges.  Cells involved in natural immunity do not provide defense against any particular pathogen; rather, they are all-purpose cells that can attack a number of pathogens and do so in a relatively short time frame (minutes to hurs) when challenged.”  Segerstrom & Miller, 2004 p 602

……..largest group of natural immunity cells is granulocytes

……group includes phagocytic cells that eat their targets:  the neutrophil and macrophage

….general response by these cells is inflammation

…..macrophages n particular also release communication molecules or cytokines that have broad effects on organism, including fevers, and promote wound healing (include interleukin (IL)-1, !L-6, and tumor necrosis factor alpha (TNF[alpha])

……..other granulocytes include mast cell and the cosinophil involved in parasitic defense and allergy  – Segerstrom & Miller, 2004 p 602

another cell involved in natural immunity – natural killer cell – “Recognize the lack of a self-tissue molecule on the surface of cells (characteristic of many kinds of virally infected and some [malignant self-cells] cancerous cells) and lyse those cells by releasing toxic substances on them….. Segerstrom & Miller, 2004 p 602

family of complement proteins also involved in natural immunity

SPECIFIC IMMUNITY

Greater specificity and slower speed than natural immune response –

……..lymphocytes have receptor sites on their cell surfaces, fits with one and only one small molecular shape, or antigen, on given invader, responds to one and only one kind of invader – these antigen-specific cells divide to create a population of cells with same antigen specificity – have to be continually supported daily – creates a delay before full defense is ready, body has to rely on natural immunity meanwhile

……..3 types of cells that mediate specific immunity

– T-helper cells – produces protein cytokines that direct and amplify rest of the immune response-

– T-cytotoxic cells – recognizes and lyses compromised cells

–         B cells – produces proteins called antibody (5 kinds) that perform a number of functions  – Segerstrom & Miller, 2004 p 603

PATHWAYS BETWEEN STRESS AND THE IMMUNE SYSTEM

How stress “gets into the body” to influence immune system

….1st “…sympathetic fibers descend from the brain into both primary (bone marrow and thymus) and secondary (spleen and lymph nodes)lymphoid tissues….can release a wide variety of substances that influence immune responses by binding to receptors on white blood cells.”  Segerstrom & Miller, 2004 p 604

……all lymphocytes have adrenergic receptors; differences in density and sensitivity can affect responsiveness to stress among cell subsets

…2nd “…the hypothalamic-pituitary-adrenal axis, the sympathetic-adrenal-medullary axis, and the hypothalamic-pituitary-ovarian axis secrete the adrenal hormones epinephrine, norepinephrine, and cortisol; the pituitary hormones prolactin and growth hormone; and the brain peptides melatonin, [beta]-endorphin, and enkephalin.  These substances bind to specific receptors on white blood cells and have diverse regulatory effects on their distribution and function….” Segerstrom & Miller, 2004 p 604

…3rd “…people’s efforts to manage the demands of stressful experience sometimes lead them to engage in behaviors – such as alcohol use or changes in sleeping patterns – that also could modify immune system processes….behavior represents a potentially important pathway linking stress with the immune system.”  Segerstrom & Miller, 2004 p 604

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Maier & Watkins 1998

Abstract – [referred to in Segerstrom & Miller, 2004 p 604]

The brain and immune system form a bidirectional communication network in which the immune system operates as a diffuse sense organ,

informing the brain about events in the body.  This allows the activation of immune cells to produce physiological, behavioral, affective, and cognitive changes that are collectively called sickness, which function to promote recuperation.”

“Fight-flight evolved later and coopted this immune-brain-circuitry both because many of the needs of fight-flight were met by this circuitry and this cooptation allowed the immune system to respond to potential injury in anticipatory fashion.”

“Many sequelae of exposure to stressors can be understood from this view and can take on the role of adaptive responses rather than pathological manifestations.”

“Finally, it is argued that activation of immune-brain pathways is important for understanding diverse phenomena related to stress such as depression and suppression of specific immunity.”

Very interesting – so mother was sick in the truest sense – as I now am.  She had ‘sickness behavior’ – I can see where this might be “the big umbrella!” that everything else I am writing about fits under.

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www.authoratory.com/authors/2003/433861925/1/all.htm

Steven F. Maier – summary for 2003

Key opinion leader in many areas of study, including stress, electroshock, behavior, animal, raphe nuclei, escape reaction – professional interests focused around dorsal raphe nucleus, inhibit drn 5-ht, behavioral consequences uncontrollable, proinflammatory cytokine, or drn 5-ht – 5-ht

total grant awards in support of Maier’s work totaled $10,458,480.between 1992 and 2003

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IMMUNE SYSTEM RESPONSE TO STRESS

Maier and Watkins (1998) [see above] proposed an even closer relationship between stress and immune function: that the

immunological changes associated with stress were adapted from the immunological changes in response to infection.

Immunological activation in mammals results in a syndrome called

sickness behavior,

which consists of behavioral changes such as reduction in activity, social interaction, and sexual activity, as well as increased responsiveness to pain, anorexia, and depressed mood.

This syndrome is probably adaptive in that it results in energy conservation at a time when such energy is best direct toward fighting infection.

Maier and Watkins drew parallels between the behavioral, neuroendocrine, and thermoregulatory responses to sickness and stress.  The common thread between the two is the energy mobilization and redirection that is necessary to fight attackers both within and without.”  Segerstrom & Miller, 2004 p 604

++

paradox that chronic stress is linked to both disease outcomes associated with inadequate immunity (infectious and neoplastic disease) and disease outcomes associated with excessive immune activity (allergic and autoimmune disease)

model of stress:  cytokine shift of balance model – chronic stress elicits simultaneous enhancement and suppression of immune response by altering patterns of cytokine [Th1/cellular & Th2/humoral] secretion (Marshall et al, 1998) – “This shift can occur via the effects of stress hormones such as cortisol (Chiappelli, Manfrini, Franceschi, Cossarizza, & Black, 1994).”  Segerstrom & Miller, 2004 p 605

this model reconciles patterns of stress-related immune change with patterns of stress-related disease outcomes – Segerstrom & Miller, 2004 p 605

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“…there is little or no evidence linking stress-related immune change in healthy humans to disease vulnerability….the immune system is remarkably flexible and capable of substantial change without compromising an otherwise healthy host.”  Segerstrom & Miller, 2004 p 605

“…the flexibility of the immune system can be compromised by age and disease….The decreased ability of the immune system to respond to stimulation is one indicator of its loss of flexibility.”  Segerstrom & Miller, 2004 p 605

“Loss of self-regulation is also characteristic of disease states….the change in the immune system from flexible and balanced to inflexible and unbalanced suggests increased vulnerability to stress-related immune dysregulation….”  Segerstrom & Miller, 2004 p 605————and severe stress can by itself lead to loss of self-regulation!?

Performed meta-analysis of published results linking stress and the immune system

……..studies not included that used anxiety as a proxy for stress – studies had to study stress!

…….stressors had to be psychosocial rather than physical

……studies had to include measure of the immune system

meta-analysis is based on effect sizes derived from 293 independent studies reported in 319 separate articles in peer-reviewed scientific journals

…..represented a total of 18,941 individuals, mean age 34.8 – examined 292 distinct immune system outcomes

ACUTE TIME-LIMITED STRESSORS:

………effects on the immune system included increases in immune parameters, especially natural im- (607) munity – marked increase in number of natural killer cells and large granular lymphocytes in peripheral blood – consistent with view that acute stressors will cause immune cells to redistribute into the compartments where they will be most effective – though other types of lymphocytes did not show robust redistribution effects:  B cells and T-helper cells showed very little change – Segerstrom & Miller, 2004 p 610

…”The data for acute stressors, therefore, support an upregulation of natural immunity, as reflected by increased number of natural (610) killer cells in peripheral blood, and potential downregulation of specific immunity, as reflected by decreased proliferation responses. Segerstrom & Miller, 2004 p 611

BRIEF NATURALISTIC STRESSORS:

“In contrast to the acute time-limited stressors, examination stress did not markedly affect the number or percentage of cells in peripheral blood.  Instead, the largest effects were on functional parameters, particularly changes in cytokine production that indicate a shift away from cellular immunity (Th1) and toward humoral immunity (Th2).”  Segerstrom & Miller, 2004 p 612

……..”…evidence that age contributed to vulnerability to stress-related immune change during brief naturalistic stressors, even within a limited range of relatively young ages [mean age range 15.7 to 35.0].   – surprising finding

STRESSFUL EVENT SEQUENCES:

“…indicate that stressful event sequences are not associated with reliable immune changes…

…………”Studies of healthy adults generally fell into two categories that yielded disparate patterns of immune findings.  The largest group of studies focused on the death of a spouse as a stressor and, as such, used samples consisting primarily of older women.  Collectively…losing a spouse was associated with a reliable decline in natural killer cell cytotoxity …but not with alterations in stimulated-lymphocyte proliferation by the mitogens.”  Segerstrom & Miller, 2004 p 613

…………….”The next largest group of studies in this area examined immune responses to disasters, which may have different neuroendocrine consequences than loss; whereas loss is generally associated with increases in cortisol, trauma may be associated with decreases in cortisol….Natural disaster samples tended to focus on middle-aged adults of both sexes who were direct victims of the disaster, rescue works at the scene, or personnel at nearby medical centers.  There were medium-size effects suggesting increases in natural killer cell cytotoxicity…and stimulated-lymphocyte proliferation by the mitogens…as well as decreases in the number of T-helper lymphocytes …and T-cytotoxic lymphocytes…in the circulation….none of them statistically significant because of the small number of studies involved, and therefore these effects should be considered suggestive but not reliable.”  Segerstrom & Miller, 2004 p 613

CHRONIC STRESSORS:

..nonacute stressors –  had “…negative effects on almost all functional measures of the immune system….Both natural and specific immunity were negatively affected, as were Th1…and Th2…parameters…changes equally strong across ages and genders

DISTANT STRESSORS:

…traumatic events such as combat exposure or abuse occurring years prior to immune assessment – “The only immune outcome that has been examined regularly in this literature is natural killer cell cytotoxicity, and it is not reliably altered in persons who report a distant traumatic experience.”  Segerstrom & Miller, 2004 p 614

“…persons who are in the midst of a specific event sequence or a chronic stressor.  To the extent that they appraise their lives as stressful or report the occurrence of intrusive thoughts, these individuals exhibit a significant reduction in natural killer cell cytotoxicity.  Although this effect does not extend to the number of T-helper and T-cytotoxic lymphocytes in the circulation, it suggests that a person’s subjective representation of a stressor may be a determinant of its impact on the immune response.”  Segerstrom & Miller, 2004 p 615

DISCUSSION:

The immune system, once thought to be autonomous, is now known to respond to signals from many other systems in the body, particularly the nervous system and the endocrine system.  As a consequence, environmental events to which the nervous system and endocrine system respond can also elicit responses from the immune system.”  Segerstrom & Miller, 2004 p 617

“The results of meta-analysis of the hundreds of research reports generated by this hypothesis indicate that stressful events reliably associate with changes in the immune system and that characteristics of those events are important in determining the kind of change that occurs.”  Segerstrom & Miller, 2004 p 617

results support balance between cellular and humoral immunity – “Depending on the time frame, stressors triggered adaptive upregulation of natural immunity and suppression of specific immunity (acute time-limited), cytokine shift (brief naturalistic), or global immunosuppression (chronic).” Segerstrom & Miller, 2004 p 617

ACUTE AND TIME LIMITED STRESSORS:

When stressors were acute and time-limited – that is, they generally followed the temporal parameters of fight-or-flight stressors – there was evidence for adaptive redistribution of cells and preparation of the natural immune system for possible infection, injury, or both.  In evolution, stressor-related changes in the immune system that prepared the organism for infections resulting from bites, puncture wounds, scrapes, or other challenges to the integrity of the skin and blood could be selected for.  This process would be most adaptive when it was also efficient and did not divert excess energy from fight-or-flight behavior. Indeed, changes in the immune system following acute stress conformed to this pattern of efficiency and energy conservation.  Acute stress upregulated parameters of natural immunity, the branch of the immune system in which most changes occurred, which requires only minimal time and energy investment to act against invaders and is also subject to the fewest inhibitory constraints on acting quickly (Dopp et al, 2000; Sapolsky, 1998).”  Segerstrom & Miller, 2004 p 617

In contrast, energy may actually be directed away from the specific immune response, as indexed by the decrease in the proliferative response.

The specific immune response in general and proliferation in particular demand time and energy; therefore, this decrease might indicate a redirection away from this function.

Similar redirection occurs during (617) flight-or-flight stressors with regard to other nonessential, future-oriented processes such as digestion and reproduction.

As stressors became more chronic, the potential adaptiveness of the immune changes decreased.

he effect of brief stressors such as examinations was to change the potency of different arms of specific immunity – specifically, to switch away from cellular (Th1) immunity and toward humoral (Th2) immunity.”  Segerstrom & Miller, 2004 p 618

I see this implicated in PTSD, where there is NO TIME, not enough energy – resources – no time for anything nonessential or future-oriented –

STRESSFUL EVENT SEQUENCES

Fell into two main categories – bereavement and trauma

“The different results for loss and trauma mirror neuroendocrine effects of these two types of adverse events.

……..”Lossmaternal separation in nonhuman animals and bereavement in humans – is commonly associated with increased cortisol production.”

……..”In contrast, trauma and posttraumatic stress disorder are commonly associated with decreased cortisol production….To the degree that cortisol suppresses immune function such as natural killer cell cytotoxicity, these results have the potential to explain the different effects of loss and trauma event sequences.”  Segerstrom & Miller, 2004 p 618

“The most chronic stressors were associated with the most global immunosuppression, as they were associated with reliable decreases in almost all functional immune measures examined.  Increasing stressor duration, therefore, resulted in a shift from potentially adaptive changes to potentially detrimental changes, initially in cellular immunity and then in immune function more broadly.”  Segerstrom & Miller, 2004 p 618

“It is important to recognize that although the effects of chronic stressors may be due to their duration, the most chronic stressors were associated with changes in identity or social roles (e.g., acquiring the role of caregiver or refugee or losing the role of employee).  These chronic stressors may also be more persistent, that is, constantly rather than intermittently present.”  Segerstrom & Miller, 2004 p 618 – I would think that retirement for some, and empty nest that both redefine a “role” would fit in here for some – me included

“Finally, chronic stressors may be less controllable and afford less hope for control in the future.  These qualities could contribute to the severity of the stressor in terms of both its psychological and physiological impact.” Segerstrom & Miller, 2004 p 618

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“The meta-analytic results indicate that organismic variables such as age and disease status moderate vulnerability to stress-related decreases in functional immune measures….also associated with disruption of neuroendocrine inputs to the immune system…The loss of self-regulation in disease and aging likely makes affected people more susceptible to negative immunological effects of stress.”  Segerstrom & Miller, 2004 p 619

++

AFFECT

“Virtually nothing is known about the psychological pathways linking stressors with the immune system.  Many theorists have argued that affect is a final common pathway for stressors…yet studies have enjoyed limited success in attempting to explain people’s immune response to life experiences on the basis of their emotional states alone….Furthermore, many studies have focused on the immune effects of emotional valence…., but the immune syste may be even more closely linked to emotional arousal (e.g. stimulated vs. still), especially during acute stressors….Finally, it is possible that emotion will prove to be relatively unimportant and that other mental processes such as motivational states or cognitive appraisals will prove to be the critical psychological mechanisms linking stress and the immune system….”  Segerstrom & Miller, 2004 p 619

biologic mechanisms…”activation of the sympathetic nervous system was responsible for the immune system effects of acute stressors….Apart from these findings, however, little is known about biological mechanisms, especially with regard to more enduring stressors that occur in the real world.  Studies that have attempted to identify hormonal pathways linking stressors and the immune system have enjoyed limited success, perhaps because they have utilized snapshot assessments of hormones circulating in blood.  Future studies can maximize their chances of identifying relevant mediators by utilizing more integrated measures of hormonal output, such as 24-hr urine collections or diurnal profiles generated through saliva collections spaced throughout the day….”  Segerstrom & Miller, 2004 p 619

“Cytokine expression represents a relatively new and promising example of an avenue for research linking stress, immune change, and disease.  For example, chronic stress may elicit prolonged secretion of cortisol, to which white blood cells mount a counterregulatory response by down regulating their cortisol receptors.  This downregulation, in turn, reduces the cells; capacity to respond to anti-inflammatory signals and allows cytokine-mediated inflammatory processes to flourish (Milelr, Cohen, & Richey, 2002).  Stress therefore might contribute to the course of diseases involving excessive nonspecific inflammation (e.g. multiple sclerosis, rheumatoid arthritis, coronary hart disease) and thereby increase risk for excess morbidity and mortality….”  Segerstrom & Miller, 2004 p 620

CONCLUSIONS

“Stressors with the temporal parameters of the fight-or-flight situations faced by humans’ evolutionary ancestors elicited potentially beneficial changes in the immune system.  The more a stressor deviated from those parameters by becoming more chronic, however, the more components of the immune system were affected in a potentially detrimental way.”  Segerstrom & Miller, 2004 p 620

“Further research is needed to support two other ideas elicited by this quote:  the idea that subjective experience such as worry is more likely to result in stress-related immune change than objective experience and the idea that stress-related immune change results in stress-related disease…..We hope that these results will inform investigations that go beyond the relationship between a stressful event and an immune parameter to investigate the psychological phenomena that mediate that relationship.” Segerstrom & Miller, 2004 p 620

“Finally, these results can also inform investigations into stress, immunity, and disease process.  Whether the disease is characterized by natural or specific immunity, its cytokine profile, and its regulation by anti-inflammatory agents such as cortisol, may determine the disparate effects of different kinds of stressors.”  Segerstrom & Miller, 2004 p 620

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APAonline – no author

“Stress Weakens the Immune System”

chronic feelings of loneliness can help predict health status – This feeling can originate all the way back to birth, from inadequate caregiver interactions – and can reflect a lifetime pattern of inability to “feel felt” and lack of mirroring interactions with others.

How do we disentangle the relationship between symptom and cause?  Social isolation is seen as a symptom when in actuality I believe it is most often reflective of a cause.

“conscientious stress management” – helps combat effects of long-term stressors

including “social network” – see Singer and Lyff 1999 – above

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Lowry et al 2007

Article – UK – online paginations

Emotions, serotonin, emotional regulation, immune response – COPING AREA AFFECTED

Peripheral immune activation – profound physiological and behavioral effects – induction of fever and sickness behavior  Lowry 2007, 756

…….mechanism – immune activation or immunomodulation – affect physiology and behavior – via actions on brainstem neuromodulatory systems – such as serotonergic system

………….mice dorsal raphe nucleus (DRI) – experimental manipulation, activation of immune system with bacteria, associated with increases in serotonin metabolism within serotonergic systems

“The effects of immune activation were associated with increases in serotonin metabolism within the ventromedial prefrontal cortex, consistent with an effect of immune activation on mesolimbocortical serotonergic systems.”

…………temporary reductions in immobility, alteration stress-related emotional behavior….

“These findings suggest that the immune-responsive subpopulation of serotonergic neurons in the CRI is likely to play an important role in the neural mechanisms underlying regulation of the physiological and pathophysiological responses to both acute and chronic immune activation, including regulation of mood during health and disease states.”

………..raise possibility that “…immune stimulation activates a functionally and anatomically distinct subset of serotonergic neurons, different from the subset of serotonergic neurons activated by anxiogenic stimuli or uncontrollable stressors.  Consequently, selective activation of specific subsets of serotonergic neurons may have distinct behavioral outcomes.”

…..MAJORITY OF SEROTONERGIC NEURONS – type I – high spontaneous firing rate during active waking states, progressively lower spontaneous firing rate during inactive states, complete cessation of activity during rapid eye movement (REM) sleep

…….interesting paradox after acute immune activation – behavioral activity dramatically decreases while serotonergic activity – [spontaneous neuron firing]  increases particularly in limbic brain regions associated with mood regulation

subpopulation of serotonergic neurons – referred to as Type II – unique electrophysiological properties and behavioral correlates — firing rates independent of level of behavioral arousal – are restricted to highly confined region of brainstem raphe complex at caudal interface of the dorsal and median raphe nuclei, between the medial longitudinal fasciculi, region defined in mice, rats & primates as the interfascicular part of the DRI ——that give rise to projections to limbic forebrain regions……not clear if this region contains both Type I & II serotonergic neurons or only Type II

SUMMARY AND CONCLUSIONS of mouse experiment:

Observed effects on serotonergic metabolism in mesolimbocortical serotonergic systems – those in medial prefrontal cortex thought to play an important role in regulation of coping responses and behavioral responses to uncontrollable stress

That sounds early trauma, abuse, PTSD related

“Consequently, dysregulation of DRI serotonergic systems may contribute to the dysregulation of coping mechanisms in some stress-related neuropsychiatric disorders, including major depression.  The effects of immune activation were dependent on the type of immune activation, suggesting that modulations of the balance of immune signaling in the periphery will have important consequences for brain serotonergic function.  Identification of DRI serotonin neurons as uniquely responsive to peripheral immune activation provides a novel hypothetical framework for investigating the relationships among immune activation, serotonergic systems, and mental health.”

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Ryff, Singer & Love 2004

“Our prior work has…probed the connections between long-term social relational profiles and allostatic load, a measure of wear and tear on multiple physiological systems (Singer & Ryff 1999), showing that men and women with more positive relationship profiles from childhood to adulthood had a lower likelihood of having high allostatic load in adulthood.”  Ryff, Singer & Love 2004, 1391

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Reagan, Grillo & Piroli 2008

Article

ACUTE STRESS RESPONSE

Protective and adaptive in nature

Activation of the hypothalamic-pituitary-adrenal (HPA) axis

Leading to release of epinephrine and glucocorticoids from the adrenal gland

Once released, epinephrine and glucocorticoids produce wide variety of effects

….in periphery ranging from increases in cardiovascular activities, decreases in gastrointestinal and immune function, increasing energy mobilization

..stress hormones, also critical functional roles in central nervous system(CNS), including facilitation and consolidation of strong emotional memories that involves glucocorticoid binding and activation of glucocorticoid receptors in limbic regions such as hippocampus and amygdala

CHRONIC STRESS

Elicits neurochemical, neuroanatomical and cellular changes that may have negative consequences upon higher brain functioning

Exposure to stress levels of glucocorticoids and HPA axis dysfunction are critical mediators in disease states in periphery and CNS

……….for example – among other peripheral disorders, chronic stress proposed to contribute to etiology/progression  of cardiovascular disease, hypertension, cancer metastasis, immune impairments

…..Impairments in HPA axis function and elevated basal glucocorticoids also implicated in peripheral complications of type 1 & 2 diabetes

….contributes to major depressive disorder and PTSD

glucocorticoids may be common mechanistic mediators in pathophysiological consequences of diabetes and stress-related disorders

hippocampus volume decrease in depressive illness – major depressive illness one of most common psychiatric disorders, estimated 12-15% of general pop –

………amygdala implicated in depressive illness, volume maybe increased or decreased

hippocampus and amygdala major sites of glucocorticoid action in the CNS

depressive illness is a stress related disorder

regulation of glutaminergic [check spelling on this word in article] system in chronic stress models – relation to limbic system plasticity

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Boscarino 2006

Abstract – PA

15,288 male U.S. Army veterans 30 years after military service, 16 years after completion of a telephone survey – included in national random sample of veterans from the Vietnam War Era — with and without PTSD

“Our findings indicated that adjusted postwar mortality for all-cause, cardiovascular, cancer, and external causes of death (including motor vehicle accidents, accidental poisonings, suicides, homicides, injuries of undetermined intent) was associated with PTSD among Vietnam Theater veterans (N=7,924)….For Vietnam Era veterans with no Vietnam service (N=7,364), PTSD was associated with all-cause mortality….PTSD-positive era veterans also appeared to have an increase in external-cause mortality as well….”

CONCLUSIONS:

“Our study suggests that Vietnam veterans with PTSD may be an increased risk of death from multiple causes.  The reasons for this increased mortality are unclear but may be related to biological, psychological, or behavioral factors associated with PTSD and warrant further investigation.”

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Boscarino 2008

Abstract – PA

4462 male veterans 30 years after military service were examined, including for PTSD, cortisol/DHEA-s rate, white blood cell count, etc

during baseline in 1985 10.2% of 2490 Vietnam theatre [combat] veterans had PTSD, at follow-up in 2000 10.2% of theater veterans were deceased

during baseline 3.4% of 1,972 non combatant Vietnam era veterans had PTSD

at follow-up only 5% of these non theatre veterans were deceased

“Analyses suggested that having PTSD, a high ESR [erthrocyte sedimentation rate], and a high WBC [white blood count], and a high cortisol/DHEA-s ratio at baseline were associated with all-cause disease mortality at follow-up.”

…………with the exception of cortisol/DHEA-s ration, these factors also predicted cardiovascular mortality

Depression not consistently associated with mortality

Noteworthy:  having PTSD had an impact on mortality nearly comparable to common indicators of disease in medicine, such as an ESR

“This study suggests that the morbidity associated with PTSD may be comparable to laboratory measures of disease pathology in common use and warrants further investigation and surveillance among at risk populations.”

Veterans suffering from PTSD are as likely to have long-term health problems as people with chronic disease risk factors – few healthcare providers screen for PTSD in same was as for other choric disease risk factors — PTSD is just as good an indicator of a person’s long-term health status as elevated white blood cell count can indicate major infection or serious blood disorder – study also showed veterans with high erythrocyte sedimentation rate (ESR), which indicates inflammation, were also at risk \.there was similar finding for a possible indicator of serious neuroendocrine problems – disease markers measured with blood test

.does not have to be extensive, but therapy should occur shortly after person has experienced a traumatic event – early treatment may be critical to avoiding depression, PTSD  and substance abuse problems following trauma exposure – and long-term serious health problems associated with  PTSD

PTSD is a medical warning sign for long-term health problems

++++

Kubzansky et al 2007

Article – Harvard

Study:  is PTSD associated with increased risk for coronary heart disease (CHD)?  Do they share common pathways or is PTSD a risk factor for CHD?

…..various correlates of PTSD, such as high levels of sympathetic activation and HPA axis dysregulation, linked to arterial damage and coronary heart disease (CHD)

“Levels of PTSD symptoms in this cohort were low to moderate.  Men (older white men who had served in military) with preexisting  CHD at baseline were excluded, and PTSD was measured …for Combat-Related PTSD.  For each SD [standard deviation] increase in symptom level, men had age-adjusted relative risks of 1.26 for nonfatal myocardial infarction and fatal CHD combined and 1.21…for all of the CHD outcomes combined (nonfatal myocardial infarction, fatal CHD, and angina).”

….results suggest that a higher level of PTSD symptoms may increase the risk of incident CHD in older men.

PTSD reflects dysregulation of the stress response system –

…..PTSD more likely to have atrioventricular conduction defects and infarctions

……combat-related PTSD – elevated concentrations of serum lipids and a higher aarteriosclerosis index

recent work suggests PTSD rather than combat (or trauma) exposure alone may serve as a mediating factor between trauma and the risk of adverse health outcomes

…….accumulated evidence that chronic stress in various forms, including caregiving strain, marital stress, and work stress, may increase the risk of CHD – research to date suggests that there may be a role for prolonged or chronic stress in the development of CHD

“Posttraumatic stress disorder has been identified as a marker of extreme distress in response to a potentially traumatic event, and it may also be indicative of a chronic stress in the development of CHD.”  Kubzansky et al 2007, 110

…… “…PTSD differs in important ways from depression and anxiety.  Depressive and anxiety disorders are defined by chronic or recurring symptoms occurring over an extended period, which may or may not arise in response to a discrete event.  Posttraumatic stress disorder is defined by the long-term sequelae (symptom occurrence) of an acute stress exposure.  The time course of PTSD can follow 1 of several patterns, where high levels of symptoms after traumatic exposure are followed by recovery, chronic symptoms persist over time, or symptoms are relapsing-remitting…It is unclear what duration or chronicity of PTSD is necessary to initiate pathophysiological processes.  Effects of the different patterns of PTSD will need to be determined and may depend on the toxicity of PTSD symptoms and the reversibility of their effects.”  Kubzansky et al 2007, 110

“In relation to CHD, effects of PTSD are likely to be most comparable to those of chronic stress and distress, particularly when PTSD follows a pattern of persisting or recurring symptoms over time.” Kubzansky et al 2007, 110

“…individuals with higher levels of PTSD symptoms are not simply prone to reporting higher levels of chest pain or other physical symptoms but may well be at higher risk for developing CHD…If effects of symptoms are cumulative, with more symptoms conferring increased risk….We might expect individuals with clinically relevant levels of PTSD symptoms to be at an even greater risk for developing CHD..”  Kubzansky et al 2007, 114

………other research:  psychosocial factors may have their strongest effects on CHD in younger populations

“Other work has considered the neuroendocrinology of PTSD and suggested that it is characterized in many adults by enhanced negative feedback sensitivity of glucocorticoid receptors in the stress response system and lower-than-normal urinary and plasma cortisol levels.  Exaggerated catecholamine responses to trauma-related stimuli have also been found in adult patients with PTSD….Catecholamine release may lead to injury of the intimal endothelium of the coronary arteries by hemodynamic and/or biochemical processes and may also encourage the release of fatty acids above levels needed for metabolic requirements.  These processes may eventually cause or exacerbate endothelial damage and promote the development of atherosclerosis, especially near bifurcations in major arteries….Animal research has also demonstrated that stress and emotional arousal may aggravate atherosclerosis by mechanisms associated with flow-related arterial injury….”  Kubzansky et al 2007, 114

“These results are provocative and suggest that exposure to trauma and prolonged stress not only may increase the risk for serious mental health problems but are also cardiotoxic.”  Kubzansky et al 2007, 115

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Vidovic et al 2007

Abstract – Croatia

38 PTSD compared to 24 healthy civilians

found higher lymphocyte counts in PTSD, and positive correlation between lymphocyte glucocorticoid receptor expression and number of years passed from the traumatic experience

……..Lymphocyte glucocorticoid receptor expression positively correlated with serum cortisol concentration both in PTSD patients and healthy controls

………….study confirmed that the immune system was affected in course of chronic PTSD

…also that the HPA axis profile in PTSD associated with the duration of the disorder

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McEwen 2006

Abstract

The mind involves the whole body

and two-way communication between the brain and the cardiovascular, immune, and other systems via neural and endocrine mechanisms.”

Stress is a condition of the mind-body interaction,

and a factor in the expression of disease that differs among individuals.  It is not just the dramatic stressful events that exact their toll,

but rather the many events of daily life that elevate and sustain activities of physiological systems

and cause sleep deprivation, overeating [and under eating!], and other health-damaging behaviors, producing the feeling of being “stressed out.”  Over time, this results in wear and tear on the body which is called “allostatic load,” and it reflects not only the

impact of life experiences but also of

genetic load,

individual lifestyle habits reflecting items such as diet, exercise, and substance abuse, and developmental experiences that set life-long patterns of behavior and physiological reactivity.”

“Hormones associated with stress and allostatic load protect the body in the short run and promote adaptation by the process known as allostasis,

but in the long run allostatic load causes changes in the body that can lead to disease.”

The brain is the key organ of stress, allostasis, and allostatic load, because it determines what is threatening and therefore stressful, and also determines the physiological and behavioral response.”

Brain regions such as the hippocampus, amygdala, and prefrontal cortex respond to acute and chronic stress by undergoing

structural remodeling,

which alters behavioral and physiological responses.”

If there is stress from abuse and maltreatment during the developmental stages of childhood, as Teicher states, many other brain regions in addition to these mentioned here undergo “structural remodeling” to adapt to life in a malevolent, toxic environment.

These alterations are in response to what the BODY and the brain determine are toxic and a threat to ongoing life  In these cases, the allostatic load is greater and one may not even leave early childhood without already being under the burden of allostatic overload.

“Translational studies in humans with structural and functional imaging reveal smaller hippocampal volume in stress-related conditions [some not all!], such as mile cognitive impairment in aging and prolonged major depressive illness, as well as in individuals with low self-esteem [this is the first I’ve seen this one!].”

“Alterations in amygdala and prefrontal cortex are also reported.”

“Besides pharmaceuticals, approaches to alleviate chronic stress and reduce allostatic load and the incidence of diseases of modern life include lifestyle change, and policies of government and business that would improve the ability of individuals to reduce their own chronic stress burden.”

I would like my writing to be of assistance here – people being informed and educated especially about the early childhood stress contributions to allostatic overload!  Perhaps  inspiring hope, understanding and motivation – Oprah here we come!

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McEwen 2008

Abstract – need to call in this article

Stress begins in the brain and affects the brain, as well as the rest of the body.”

“Acute stress responses promote adaptation and survival via responses of neural, cardiovascular, autonomic, immune and metabolic systems.”

“Chronic stress can promote and exacerbate pathophysiology through the same systems that are dysregulated.”

“The burden of chronic stress and accompanying changes in personal behaviors (smoking, eating too much [or too little!], drinking, poor quality sleep; otherwise referred to as “lifestyle”) is called allostatic overload.”

“Brain regions such as hippocampus, prefrontal cortex and amygdala respond to acute and chronic stress and show changes in morphology and chemistry that are largely reversible if the chronic stress lasts for weeks.  However, it is not clear whether prolonged stress for many moths or years may have irreversible effects on the brain.”

“The adaptive plasticity of chronic stress involves many mediators, including

glucocorticoids,

excitatory amino acids,

endogenous factors such as brain neurotrophic factor (BDNF),

polysialated neural cell adhesion molecule (PSA-NCAM) and

tissue plasminogen activator (tPA).”

…this stress-induced remodeling of neural circuitry – implications for psychiatric illnesses

..top-down – regulation of cognitive, autonomic and neuroendocrine function — view of minimizing the burden of chronic stress and related lifestyle (i.e. allostatic overload)

………”This concept leads to a different way of regarding more holistic manipulations, such as physical activity and social support as important complement to pharmaceutical therapy in treatment of the common phenomenon of being “stressed out”.

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