ME62CH05-McEwen ARI 1 August 2010 2:42

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Stress- and Allostasis-Induced

Brain Plasticity
Bruce S. McEwen1 and Peter J. Gianaros2
1
Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller
University, New York, New York 10065; email: [email protected]
2
Departments of Psychiatry and Psychology, University of Pittsburgh, Pittsburgh,
Pennsylvania 15213

Annu. Rev. Med. 2011. 62:5.1–5.15 Key Words

The Annual Review of Medicine is online at
med.annualreviews.org brain-body medicine, brain plasticity, hippocampus, amygdala,
prefrontal cortex
This article’s doi:
10.1146/annurev-med-052209-100430
Abstract
Copyright  c 2011 by Annual Reviews.
All rights reserved The brain is the key organ of stress processes. It determines what indi-
viduals will experience as stressful, it orchestrates how individuals will
0066-4219/11/0218-0001$20.00
cope with stressful experiences, and it changes both functionally and
structurally as a result of stressful experiences. Within the brain, a dis-
tributed, dynamic, and plastic neural circuitry coordinates, monitors,
and calibrates behavioral and physiological stress response systems to
meet the demands imposed by particular stressors. These allodynamic
processes can be adaptive in the short term (allostasis) and maladaptive
in the long term (allostatic load). Critically, these processes involve bidi-
rectional signaling between the brain and body. Consequently, allosta-
sis and allostatic load can jointly affect vulnerability to brain-dependent
and stress-related mental and physical health conditions. This review
focuses on the role of brain plasticity in adaptation to, and pathophysiol-
ogy resulting from, stressful experiences. It also considers interventions
to prevent and treat chronic and prevalent health conditions via allody-
namic brain mechanisms.

5.1
ME62CH05-McEwen ARI 1 August 2010 2:42

INTRODUCTION and beneficial forms of learning that promote

resiliency and good health. By contrast, other
Stress and stressful experiences have long been formar
stressful experiences can foster a proliferation
Brain plasticity: the implicated in the etiology and pathophysiology
mutability of brain of recursive neural, physiological, behavioral,
of chronic physical and mental health condi-
structure and function cognitive, and emotional changes that increase
tions that now pose a great threat to public
as a result of vulnerability to ill health and premature death
health (1). Historically, disciplinary variation
experience by several chronic medical conditions (5).
in defining and studying stress and stressful
Here, we highlight translational animal and
experiences posed both methodological and
human evidence demonstrating that the brain
conceptual challenges to the medical commu-
is the central mediator and target of stress re-
nity’s understanding of how an individual’s
siliency and vulnerability processes. We em-
health status could be affected by such complex
phasize that the brain (a) determines what is
processes over the life course. These challenges
threatening, and hence stressful, to the indi-
have been addressed by current perspectives,
vidual; (b) regulates the physiological, behav-
which build on recent advances in translational
ioral, cognitive, and emotional responses that
animal and human research and emphasize that
an individual will deploy in order to cope
the relationships between stressful experiences
with a given stressor; and (c) changes in its
and health status depend on a dynamic interac-
plasticity both adaptively and maladaptively as
tion between genetic liability and exposure to
a result of coping with stressful experiences
environmental factors. This interaction begins sublinhamos
(Figure 1). We underscore the organizing con-
in utero and continues until death (2).
cepts of allostasis and allostatic load, which can
Canonically, we can label a stressful experi-
aid in our understanding of how forms of stress-
ence as “good,” “tolerable,” or “toxic” depend-
related brain plasticity impact mental and phys-
ing on the extent to which an individual has
ical health. We then consider the potential of
control over a given stressor and has support
social and personal interventions to prevent and
systems and resources in place for coping with it
treat chronic and prevalent health conditions
(3, 4). Meeting the demands imposed by stress-
via plastic and allodynamic brain mechanisms.
ful experiences can lead to growth, adaptation,

Major life events

ssors
Environmental stressors Trau
Trauma/abuse
rhood)
(work, home, neighborhood)

Perceived stress
(threat or no threat,
helplessness, vigilance)

Individual differences Behavioral responses

(genes, development, [fight or flight, personal
experience) behavior (e.g., diet, smoking,
drinking, exercise)]

Physiologic responses

Allostasis Adaptation

Allostatic load

Figure 1
Central role of the brain in allostasis and the behavioral and physiological response to stressors. Redrawn
from Reference 5 with permission.

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STRESS, BRAIN PLASTICITY, variability as a means of promoting adaptation.

AND HEALTH: THE ROLES Allostasis is essential for maintaining homeosta-
OF ALLOSTASIS AND sis in the face of external and internal demands
Homeostasis:
ALLOSTATIC LOAD that are registered by the brain. Critically, how- a process wherein
ever, allodynamic adaptation has a price, and physiological
The brain processes not only external sen-
the cost of this adaptation is called allostatic parameters, such as
sory inputs from the environment but also desgaste
load—the wear-and-tear on the body and brain blood oxygen and pH,
internal inputs from the body. This parallel are maintained in a
(5, 8).
processing enables the brain to control and narrow range
Allostatic systems promote adaptation to
coordinate behavioral and physiological adjust- HPA: hypothalamic-
stressful experiences and are generally most
ments engendered by external or internal chal- pituitary-adrenal
useful when rapidly mobilized and terminated.
lenges to homeostasis. These adjustments can Allostasis: the active
When they are prolonged or not terminated
promote adaptation, such as calibrating car- process of responding
promptly, allostatic systems undermine mental to a challenge to the
diac output and peripheral vascular resistance to
and physical health—primarily because of their body by triggering
provide hemodynamic and metabolic support
effects on brain plasticity (see below). The in- chemical mediators of
for large muscle groups needed for immediate
ability to engage allostatic systems when needed adaptation (HPA,
or anticipated action (e.g., escape from a preda- autonomic, metabolic,
also produces a load on the body, because the
tor). The biological systems that promote such immune) that operate
normal protection afforded by these systems is in a nonlinear network.
adaptation include the hypothalamic-pituitary-
lacking. Allostasis is essential
adrenal (HPA) axis, the autonomic nervous sys-
An important aspect of allostasis and allo- for maintaining
tem, the metabolic system, the gut, the kidneys,
static load is the notion of anticipation. Here, homeostasis in the face
and the immune system (including the network of challenges or
anticipation implies psychological states, such
of cytokine-producing cells throughout the demands imposed by
as apprehension, worry, andpróximo/futuro
anxiety, as well as changes in (a) the
body). The chief biomediators of these systems
cognitive preparation for a forthcoming event. environment and (b) an
(e.g., cortisol, sympathetic and parasympathetic
Anticipation arising from neural activity within individual’s behavioral
transmitters, cytokines, metabolic hormones)
the brain can drive the output of allostatic bio- state that are
operate within a nonlinear, dynamic, and inter- registered by the brain
mediators, and it is likely that states of pro-
active network in which mediators down- and
longed anxiety and anticipation can result in Allostatic load: the
upregulate each other, depending on such fac- wear-and-tear on the
allostatic load (9). Other important aspects of
tors as their concentration, location in the body, body and brain that
individual responses to stress in relation to al- results from chronic
and sequential temporal patterning (6). Impor-
lostasis and allostatic load are health-damaging dysregulation
tantly, the activities of these systems and me-
and health-promoting behaviors such as smok- (overactivity or
diators are influenced by the genetic make-up,
ing, alcohol consumption, sleep, diet, and inactivity) of mediators
developmental history, and current behavioral of allostasis
physical activity, collectively called lifestyle be-
and psychological states of the individual.
haviors. These may be embodied within the
Adjustments of the aforementioned biolog-
overall notion of allostasis—i.e., how individ-
ical systems thus enable protection and adap-
uals adapt to and cope with a challenge—and
tation of the individual to particular chal-
they also contribute to allostatic load. For ex-
lenges by a process called allostasis (7). Whereas
ample, a Western diet accelerates atherosclero-
many physiological parameters, such as blood
sis and progression to type II diabetes; smoking
oxygen and pH, are maintained in a nar-
accelerates atherogenesis; exercise and restora-
row homeostatic range, many other parame-
tive sleep promote cognitive functioning and
ters vary in their functionality with time of
health (6).
day and in response to external and internal
Within the framework presented above and
demands. Dynamic mediators of allostasis ex-
detailed elsewhere (5), there are four types of
pressing marked variability, therefore, facilitate
allodynamic and physiological responses that
adaptation, whereas the parameters associated
may contribute to and reflect allostatic load
with homeostasis do not express comparable
(Figure 2). These include (a) repeated “hits”

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ME62CH05-McEwen ARI 1 August 2010 2:42

from multiple stressors, (b) a lack of adapta-

tion or habituation, (c) prolonged response due
Normal to delayed shutdown, and (d ) inadequate re-
sponse that leads to compensatory hyperactiv-
Physiologic response

ity of other mediators. As discussed next, these

Stress
forms of allodynamic response, which can con-
tribute to allostatic load, are mediated by the
brain and target the brain. Importantly, con-
ditions of allostatic load that adversely affect
Activity Recovery
the brain are associated with forms of neural
Time plasticity that are amenable to prevention and
intervention.
Allostatic load

BRAIN SYSTEMS MEDIATING

a Repeated “hits” b Lack of adaptation AND TARGETED BY
ALLODYNAMIC PROCESSES
Physiologic response

Physiologic response

The brain is the central organ of stress processes

and allodynamic adaptation, and it is a key tar-
get of allostatic load (Figure 1). Within the
brain, a distributed, dynamic, and plastic neural
Normal response repeated over time Normal adaptation circuitry coordinates, monitors, and calibrates
behavioral and allodynamic response systems
Time Time lidar
to cope with the demands of particular stres-
c Prolonged response d Inadequate response sors. This circuitry includes the hippocampus
and amygdala, which are limbic brain struc-
Physiologic response

Physiologic response

tures that process experiences by interfacing

with lower vegetative brain areas (such as the
hypothalamus and brainstem) and higher cor-
tical areas, particularly the prefrontal cortex.
No recovery Hence, the hippocampus, amygdala, and pre-
frontal cortex can be viewed as coordinating
Time Time behavior with allodynamic response systems in
Figure 2 the service of coping with external and inter-
Types of allostasis and allostatic load. (a) Repeated “hits” from multiple nal challenges or perceived threats to home-
stressors. Individuals who are repeatedly exposed to stressors over their life ostasis and well-being. They also serve im-
course and who also experience large surges in blood pressure and
portant functions in cognition, emotions, and
cardiovascular activity, which depend on the engagement of the HPA and
autonomic axes, are more likely to show premature hypertension and impulse control, and they help to interpret,
atherosclerotic heart disease. (b) Lack of adaptation. A failure to habituate to a on the basis of current and past experiences,
repetition of the same stressor results in a persistent elevation of mediators such whether an event is threatening or otherwise
as cortisol. This was first described in individuals who failed to habituate in their stressful—thus influencing allostatic responses.
cortisol response to a public-speaking stressor (5, 71). (c) Prolonged response
Next, we review translational animal and hu-
due to delayed shutdown. Adaptive autonomic and neuroendocrine responses
are slow to terminate; e.g., blood-pressure elevations are sustained during man studies focusing on these areas, particularly
repetitive, time-pressured work. (d ) Inadequate response leads to compensatory in the context of their importance for mediating
hyperactivity of other mediators. For example, autoimmunity and inflammation allodynamic processes important for health.
can be associated with inadequate endogenous glucocorticoid responses, as in The hippocampus has been found in animal
the Lewis rat and possibly also in chronic fatigue syndrome and fibromyalgia.
models to show remarkable structural plasticity,

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including remodeling of dendrites and synaptic Complementing animal studies of stress-

connections and a limited amount of neuroge- related processes mediated by and affecting
nesis. The hippocampus contains receptors for plasticity in the hippocampus, a growing num-
Hippocampus:
adrenal steroids and for major metabolic hor- ber of human neuroimaging studies have begun a brain region in the
mones that have functional effects on the hip- to examine stress processes in association with medial temporal lobe
pocampus. Specifically, these biomediators can aspects of gross hippocampal morphology. For that is instrumental for
enhance cognitive processes, affect mood and example, individuals with stress-related psychi- learning and
remembering
motivation, and promote excitability and neu- atric disorders, such as major depressive dis-
declarative and spatial
roprotection. Yet, these same biomediators can order and posttraumatic stress disorder, show information,
have deleterious effects on the hippocampus un- volumetric reductions in the hippocampus (see processing the
der conditions of chronic stress and allostatic 11, 12). Reduced hippocampal volume has also contextual aspects of
load (2). been found in Cushing’s disease (13). Interest- emotional events, and
regulating visceral
Animal studies of the hippocampus have ingly, in Cushing’s disease, surgical correction
functions, including
revealed a mechanism by which repeated or of hypercortisolemia has been reported to par- the HPA axis
chronic stress exposure causes a plastic remod- tially reverse hippocampal volume reduction, as
Amygdala: a brain
eling of hippocampal circuitry: shortening of well as ameliorate mood and memory deficits region in the medial
dendrites, loss of spine synapses, and suppres- (14, 15). In depression, there is evidence of vol- anterior temporal
sion of the neurogenesis that occurs in the den- umetric increase in the hippocampus after an- lobe, adjacent to the
tate gyrus region of the hippocampal formation tidepressant treatment (16), suggesting that the hippocampus. It
rapidly assigns
up to young adulthood. This is a reversible re- deficits in depression are potentially reversible.
emotional significance
sponse to stress exposure lasting a number of Moreover, there is increasing support for the to environmental
weeks, and it is mediated not only by circulat- notion that targeting the plasticity of the hip- events, and it regulates
ing glucocorticoids but also by excitatory amino pocampus in depression and mood disorders physiological and
acid neurotransmitters and other endogenous may underpin pharmacological and nonphar- behavioral responses
to those events
mediators and modulators. Because of these macological treatment efficacy (17, 18).
two interrelated roles of the hippocampus— In addition to disease studies, there is emerg- Prefrontal cortex:
a large brain region
supporting aspects of memory and regulat- ing evidence from otherwise healthy individuals
occupying the anterior
ing HPA activity—impairment of hippocam- for a relationship between chronic stressful portion of the frontal
pal function through changes in excitability, re- experiences and changes in hippocampal lobe, connected with
versible plasticity, or permanent damage may morphology. Among postmenopausal women, the hippocampus. It is
be expected to have two effects. The first is to for example, higher levels of chronic perceived broadly involved in
higher cognitive
impair hippocampal involvement in episodic, stress, as measured over an approximate 20-year
functions (e.g.,
declarative, contextual, and spatial memory. period of life, have been associated with reduced working memory and
Impairments of these functions are likely to de- gray matter volume in the hippocampus and in a executive control), as
bilitate an individual’s ability to process infor- region of the lateral prefrontal cortex (19). Fur- well as the control of
mation in new situations and to make decisions ther, more than three years after the terrorist emotion, mood, stress
functions, and
about how to deal with new challenges or stres- attacks on the World Trade Center buildings
impulsive actions
sors. The second effect is to impair hippocam- on September 11, 2001, otherwise healthy
pal regulation of HPA activity, particularly the adults living near the site of the attacks showed
termination of the stress response, leading to a reduction in gray matter volume in the hip-
elevated HPA activity and further exacerbating pocampus, as well as in anatomically networked
the actions of adrenal steroids in the long-term areas of the amygdala and prefrontal cortex (20).
effects of repeated and chronic stress exposure. In humans, as well as in animal models, there
This concept, first called the “glucocorticoid appears to be a heritable component of stress-
cascade hypothesis” of hippocampal aging (10), related plasticity in the hippocampus. For ex-
is crucial to the notions of allostasis and allo- ample, human carriers of the methionine (met)
static load and the central role of the brain in allele of the valine (val) 66met brain-derived
stress plasticity processes. neurotrophic factor (BDNF) polymorphism

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ME62CH05-McEwen ARI 1 August 2010 2:42

express lower gray matter volume in the hip- gray matter volume and cognition in humans
pocampus and prefrontal cortex compared with are not yet known, as are their implications for
carriers of the val/val allele (21–23). In animal stress-related processes involved in mediating
models, chronic stress downregulates BDNF, brain plasticity.
possibly contributing to cellular remodeling Related to inflammation are metabolic im-
(24). Given that the met allele is associated with balance, oxidative stress (32), and the con-
relatively reduced activity-dependent secretion sequences of diabetes for cognitive function
and intracellular trafficking of pro-BDNF, this and the hippocampus. Studies of type II dia-
allele could plausibly affect the contribution of betes have revealed reduced hippocampal vol-
BDNF to signaling cascades mediating synaptic ume that is larger in those subjects with the
or cellular plasticity and, potentially, neuroge- greatest elevations of glycosylated hemoglobin,
nesis in response to stress exposure. In aggre- indicative of elevated blood glucose levels (33).
gate, these studies reveal both vulnerability and Mild cognitive impairment in aging is also as-
experience-dependent patterns of hippocampal sociated with hippocampal volume reduction
morphology relevant to stress-related risk for that is in turn related to elevated glycosylated
and resilience against ill health. hemoglobin levels below the threshold for type
Within the context of the allostatic load II diabetes (34). One of the interventions that
model presented in Figure 2, there are can prevent type II diabetes is physical activ-
several additional immune-mediated mecha- ity, and a recent study shows that fit individu-
nisms involving bidirectional brain-body and als have larger hippocampal volumes than unfit
body-brain communication patterns that may individuals (35).
further account for individual differences in The amygdala is also involved in and affected
hippocampal plasticity. Growing evidence by allostatic processes. This region comprises
supports an association between peripheral cell groups in the medial anterior temporal
immune activation and behavioral, affective, lobe, adjacent to the hippocampus. One func-
and cognitive disturbances. Peripheral proin- tion of the amygdala in stressor-related pro-
flammatory cytokines, such as interleukin cessing is the rapid assignment of emotional
(IL)-6, represent plausible mediators of these salience to environmental events (36). Hence,
effects, as they can penetrate the blood-brain the amygdala is thought to interrelate percep-
barrier (25) feedback to the brain via visceral tual and cortical processes supporting the coor-
afferent transmission along the vagus nerve dination of stressor-evoked changes in behavior
(26, 27) to stimulate the production of central and peripheral physiological reactivity, partic-
proinflammatory cytokines, including IL-6, ularly within the context of adverse environ-
which are expressed in the hippocampus along mental conditions and stressors that negatively
with their receptors (28, 29). affect health (12).
Moreover, this central inflammation may Interestingly, the same stressors may affect
adversely affect learning and memory through the hippocampus and amygdala differently. For
processes related to neurodegeneration and example, animal studies of amygdala plasticity
structural remodeling of the hippocampus in have shown that chronic immobilization stress
particular. In humans, there is evidence for an of the type that causes retraction of dendrites in
inverse association between peripheral levels the CA3 region of the hippocampus produces
of IL-6, a relatively stable marker of systemic dendritic growth in neurons in the basolateral
inflammation, and memory function in midlife amygdala (37). Moreover, chronic stress
adults (30). In extension, peripheral levels of this type not only impairs hippocampus-
of IL-6 have been found to covary inversely dependent cognitive function but also enhances
with hippocampal and prefrontal gray matter amygdala-dependent unlearned fear and fear
volume (31). However, the mechanisms by conditioning processes (38), consistent with
which peripheral IL-6 relates to hippocampal the opposite effects of stress on hippocampal

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ME62CH05-McEwen ARI 1 August 2010 2:42

and amygdala structures. Chronic stress also Areas of the prefrontal cortex that are
increases aggression between animals living strongly implicated in allostatic processes are
in the same cage, and this is likely to reflect the orbital and medial prefrontal cortex and
hyperactivity of the amygdala (39). Moreover, the anterior cingulate cortex. Along with many
chronic corticosterone treatment in drinking other brain regions, the prefrontal cortex has
water has an anxiogenic effect in mice (40), adrenal steroid receptors (12); however, the
which could be due to the glucocorticoid role of adrenal steroids, excitatory amino acids,
enhancement of corticotrophin-releasing and other mediators has not yet been studied
factor expression in the amygdala (41). Thus, in detail in the prefrontal cortex, in contrast
animal studies on the amygdala reveal stress- to the hippocampus. Nevertheless, glucocorti-
induced plasticity that relates to aggression and coids do appear to play a role: Three weeks of
anxiety. chronic corticosterone treatment produced re-
There is human neuroimaging evidence traction of dendrites in medial prefrontal cor-
that the amygdala is involved in mediating tex (49), although there were subtle qualitative
forms of peripheral or allodynamic stress differences from the effect of chronic restraint
reactivity that have been linked to prevalent stress (50). Another study determined the effect
physical health outcomes. For example, in- of adrenalectomy, compared to four weeks of
dividual differences in amygdala reactivity to chronic treatment with either corticosterone or
emotionally salient stimuli have been shown to dexamethasone, on volume and neuron number
covary with physiological parameters associ- in the prefrontal cortex (51). Dexamethasone
ated with cardiovascular disease risk, including treatment at a dose that may have been high
basal levels of autonomic-cardiac control (42), enough to enter the brain (although this was not
stressor-evoked changes in blood pressure directly measured) caused a loss of neurons in
(43), and diurnal variations in the secretion Layer II of the infralimbic, prelimbic, and cin-
of the stress hormone, cortisol (44). Recently, gulate cortex, whereas corticosterone treatment
it has been demonstrated that individuals reduced the volume but not the neuron number
who express greater amygdala reactivity to of these cortical regions (51). Dexamethasone
threatening social cues (angry and fearful treatment was particularly effective in impair-
facial expressions) also exhibit higher levels ing working memory and cognitive flexibility,
of preclinical atherosclerosis (Figure 3) (45). as measured by a working-memory task in a
In that study, individuals who showed lower Morris water maze (51). Effects of chronic stress
levels of preclinical atherosclerosis exhibited were not investigated in this study. These data
a pattern of dynamic functional connectivity notwithstanding, the cautions expressed above
(correlated activity) between the amygdala and concerning differences between chronic stress
prefrontal cortex that suggested a potentially and chronic glucocorticoid treatment must be
greater regulation of amydala activity by the kept in mind for the prefrontal cortex, as well
prefrontal cortex during threat processing. as the amygdala, which has not been studied yet
These findings are noteworthy from a clinical in this regard.
perspective because the amygdala and its func- Behavioral correlates of remodeling induced
tional interactions with the prefrontal cortex by chronic restraint stress in the prefrontal cor-
have long been implicated in conferring risk for tex include impairments in cognitive flexibility
psychopathologies of mood and anxiety (46), and decision making, possibly reflecting struc-
which are highly comorbid with atherosclerotic tural remodeling in the medial prefrontal cor-
cardiovascular disease (47). Further, functional tex (52, 53). Thus, animal studies on the pre-
aspects of the prefrontal cortex in particular frontal cortex reveal stress-induced changes in
have been recently implicated in atherogenesis neuronal structure and connectivity. The me-
in a primate model of comorbid depression dial prefrontal cortex shows reduced neuronal
and cardiovascular disease (48). complexity and loss of synaptic connections as a

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ME62CH05-McEwen ARI 1 August 2010 2:42

a b c
1 cm

0.3
d e Right: r = 0.53**
Left: r = 0.53**
0.2

Adjacent intima-media
thickness (mm)
0.1

0.0

–0.1

–0.2
y = –6
<Left – Right> –0.3
–3.0 –2.0 –1.0 0.0 1.0 2.0 3.0
Amygdala activation (z units)
2.20 t-value 3.75

Figure 3
In a functional neuroimaging study, a measure of preclinical atherosclerosis was related to activation of the
amygdala in response to threatening facial expressions. Carotid intima-media thickness (IMT) was assessed
by B-mode ultrasonography. (a) A trained vascular technologist imaged the carotid arteries. (b) An image of
the carotid artery with the common carotid segment visible at right and the beginning of the carotid bulb
visible at left; arrow indicates a point along the far wall of the common carotid artery, which is shown at
higher magnification in panel c. (c) Magnified point of the far wall of the common carotid artery illustrating
the lumen-intima and media-adventitia interfaces. IMT was measured by averaging the IMT (the distance
between two lines tracking the lumen-intima and media-adventitia interfaces, not illustrated here) in 1-mm
increments along the distal 1 cm of the far wall of the common carotid artery, the far wall of the carotid bulb,
and the first centimeter of the internal carotid artery. As assessed by this ultrasound procedure, carotid IMT
covaried positively with amygdala reactivity to angry and fearful facial expressions in an adult sample of
otherwise healthy humans. (d ) Statistical parametric maps from a regression analysis identifying regions of
the left and right amygdala where carotid IMT covaried with amygdala reactivity after controlling for age,
sex, resting systolic blood pressure, and family income. (e) Adjusted IMT values are shown as a function of
amygdala activation values of the left (L, open circles) and right (R, closed circles) amygdala areas profiled in
panel d. Insets in panel e illustrate sample trials from the facial-expression protocol designed to elicit
amygdala reactivity. ∗∗ p < 0.001.

result of repeated stress, whereas the or- United States, which is thought to be a corre-
bitofrontal cortex shows greater neuronal com- late of chronic stress, show a reduced gray mat-
plexity as a result of chronic stress (52). ter volume in the anterior cingulate portion of
From a translational perspective developed the prefrontal cortex (54).
within the context of these animal findings,
stress-related dimensions of human life could
thus plausibly covary with changes in the mor- INTERVENTIONS FOR
phology of the prefrontal cortex in humans. In ALLOSTATIC LOAD AND
support of this notion, there is structural neu- BRAIN-BODY MEDICINE
roimaging evidence in humans that individuals The concept that the brain is the central organ
who report holding a low social standing in the of stress, with downward influences on many

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physiological processes involved in adaptation, individuals (35). In contrast to these beneficial

provides a basis for understanding how inter- effects of exercise, gaining greater amounts of
ventions that are integrative (or “holistic” in- weight in middle age is associated with reduced
Social integration:
sofar as they stimulate the entire body to help brain tissue volume (57). an individual’s effortful
itself to function normally) can have enormous In addition to aerobic exercise, dimensions engagement in social
preventative and therapeutic benefits by target- of social relationships have long been linked to activities and
ing a person’s interpersonal relationships and longevity and aspects of physical and mental relationships, cognitive
construal of her or his
lifestyle. Other interventions can alter the so- health (58; for review, see 12). These include
communality, and
cial environment through policies of the gov- social network composition, social support, so- identification with
ernment and private sector that provide groups cial interaction frequency and quality, and the diverse social roles
of individuals with access to and control over experience of isolation and loneliness accompa- Social support:
environmental, social, and material resources nying deficient or broken social relationships. psychological and
that are important for health and well-being. One important dimension of social life is social material resources
Two of the most important interventional integration. Epidemiological studies have asso- provided by one’s
social ties
approaches target physical activity and social ciated measures of social integration with lifes-
integration. Whereas a sedentary lifestyle is a pan, trajectories of cognitive aging and risk for
major risk factor for many of the diseases of dementia, severity of subclinical cardiovascular
modern life, including obesity, diabetes, car- disease, risk for stroke, survival times in patients
diovascular disease, depression, and dementia, with cardiovascular disease, and the recurrence
moderate physical activity can be beneficial for of cancer (12, 58). In addition to social integra-
the brain and the cardiovascular and metabolic tion, social support helps individuals cope more
systems (see 12 for review). In animal models, adaptively with acute and chronic stressors. For
voluntary physical activity has been shown to example, the social support provided by fam-
increase expression of neurotrophic growth fac- ily or health professionals who offer emotional
tors in the cortex and hippocampus, as well as support and useful information has been shown
to increase neurogenesis in the dentate gyrus to reduce an epidemiological summary mea-
of both young and aging animals (see 2 for sure of allostatic load, which encompasses key
review). Besides improving memory, physical physiological markers related to chronic stress
activity appears to have antidepressant effects, and a potentially health-damaging lifestyle (59).
similar to the actions of antidepressant drugs Social support also ameliorates reported levels
(12). of chronic stress in caregivers, who show a re-
An increasing number of human neuroimag- duced length of telomeres in white blood cells
ing studies are beginning to examine these pro- (60).
cesses in relation to human cognition and brain For the individual, lifestyle behaviors and
structure and function (12). An aerobic exercise habits may be hard to change, and it is often
program, involving regular and brisk walking necessary to turn to pharmacological interven-
over 6–12 months, improved cognitive perfor- tions. Sleeping pills, anxiolytics, beta blockers,
mance and postintervention patterns of brain and antidepressants are all used to counteract
activation in the prefrontal and parietal cor- problems associated with allostatic overload.
tices that were comparable to those displayed Likewise, drugs that reduce oxidative stress
by a much younger control group. More re- or inflammation, block cholesterol synthesis
cent neuroimaging studies report an increase in or absorption, and treat insulin resistance or
the volume of gray matter in the prefrontal and chronic pain can help deal with the metabolic
temporal cortices (55), increased cerebral blood and neurological consequences of chronically
volume in the dentate gyrus of the hippocampus stressful experiences. All of these agents have
among middle-aged individuals who completed value, but each one has side effects and limita-
a three-month aerobic exercise program (56), tions that are based in part on the fact that all of
and larger hippocampal volumes in fit than unfit the systems that are dysregulated in allostatic

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ME62CH05-McEwen ARI 1 August 2010 2:42

overload interact with each other and perform to be beneficial across a number of domains
normal functions when properly regulated. (63, 64).
In promoting interventions that affect brain- A program that exemplifies combin-
body health, employers have a powerful role. ing education, physical activity, and social
For example, businesses that encourage healthy engagement—along with one other ingredient
lifestyle practices among their employees could that is hard to quantify, namely, finding
have a dramatic impact on the prevalence meaning and purpose in life—is the Experience
and course of many costly medical conditions, Corps. This program trains elderly volunteers
thus reducing health insurance costs and per- as teachers’ assistants for younger children
haps even gaining a more loyal workforce (61, in neighborhood schools. Not only does
62). Governmental policies regarding educa- this program improve the education of the
tion, housing, taxation, a minimum wage, oc- children, it also benefits elderly volunteers and
cupational health and safety, and environmen- improves their physical and mental health.
tal pollution may all affect brain-body health A pilot study (65) reports gains in executive
at a population level; these effects are likely function and prefrontal cortical activity in the
to be especially powerful for the health of older adult volunteers who are at elevated risk
children, impacting cognitive development, fu- for cognitive impairment. Holistic programs,
ture academic achievement, and physical health such as this, should serve as models of the kinds
(see 12). For the elderly, community centers of interventions that can dramatically affect
and activities that promote social interactions the course of chronic and prevalent health
and physical activity have been demonstrated conditions via allodynamic brain mechanisms.

SUMMARY POINTS
1. Stressful experiences affect risk for and resilience against physical and mental illnesses
that are both prevalent and often comorbid with one another. Stressful experiences are
not uniformly health impairing. In the short term, they can lead to growth, adaptation,
and new learning. In the long term, however, they become problematic for health when
they are chronic, uncontrollable, unpredictable, and difficult to cope with because of a
lack of supportive personal, social, and environmental resources.
2. Allostatic systems enable the individual to cope with stressful experiences. They are
adaptive when rapidly mobilized and terminated. However, when the activity of allostatic
systems is sluggish, ineffective, prolonged, or not terminated promptly, allostatic systems
can impair mental and physical health through their maladaptive effects on brain plasticity
and metabolic, immune, and cardiovascular pathophysiology (allostatic load).
3. The adult, as well as the developing, brain shows structural as well as neurochemical
plasticity and resilience with all experiences, including those that are stressful. Animal
models of brain plasticity are providing neuroanatomical details, as well as evidence
for regional specificity and cellular and molecular mechanisms. Modern neuroimaging
techniques are providing converging details and evidence in the human brain. Loss of
resilience is a key feature of disorders of stress adaptation, e.g., anxiety, depression.
Reversibility of maladaptive forms of stress-related brain plasticity is possible, and this
reversibility may underpin many forms of treatment efficacy.

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4. The brain is the central organ of stress and adaptation. It regulates and responds to the
mediators of allostasis, which are normally involved in adaptation but which, when dys-
regulated and overused, lead to wear-and-tear on the brain and body (allostatic load).
Interventions to alleviate allostatic load include improving diet, promoting regular phys-
ical activity, increasing access to social support and integration, and changing policies
of the government and private sector to improve quality of life, particularly for the
disadvantaged.
5. Specific areas of the brain that show several forms of plasticity, are involved in allostasis,
are affected by allostatic load, and are implicated in stress-related vulnerability to chronic
health conditions include regions of the prefrontal cortex, hippocampus, and amygdala.
These brain areas represent the primary targets of preventative and intervention efforts
to reduce the public health burden of mental and physical illnesses.

FUTURE ISSUES
1. As illustrated by its response to increased physical activity, the human brain has a con-
siderable degree of plasticity and resilience. An important task for future research will be
to delineate the biological pathways by which physical activity affects aging and health
in the brain and body.
2. Cognitive behavioral therapy has been demonstrated to be as efficacious as several medi-
cation regimens aimed at treating disorders of mood, particularly depression; moreover,
cognitive therapy and medication appear to affect many of the same or overlapping neural
mechanisms (68). There is recent evidence that successful cognitive therapy can produce
changes in brain morphology that parallel those of physical activity, particularly within
the context of chronic fatigue syndrome—a brain-body disorder characterized by un-
abating or recurrent fatigue adversely affecting allostatic control systems (69). Studies
on animal models reveal that the amygdala shows neuronal growth after chronic stress,
and imaging studies on the human brain demonstrate hyperactive amygdala function
in mood and anxiety disorders. A recent longitudinal magnetic resonance imaging study
investigated the relationship between changes in the perceived stress scale and changes in
amygdala gray matter density following a stress-reduction intervention (70). Reductions
in perceived stress correlated positively with decreases in right basolateral amygdala gray
matter density, a finding that is consistent with the reported ability of chronic stress to
increase dendritic branching in the basolateral amygdala. Therefore, further longitudinal
studies of how the brain is changed by behavioral, as well as by pharmaceutical, therapies
are important future directions.
3. There are currently limited data on whether and how social integration, social support,
or other social factors may benefit human brain circuits that are affected by chronic
stress and allostatic load, although it is clear that these factors are linked to mood, overall
mental health, and related brain-based processes (58). An important direction for future
research will be to delineate the pathways by which dimensions of social relationships
and networks may affect brain and bodily aging and health, and to design interventions
impacting health-related aspects of social ties.

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ME62CH05-McEwen ARI 1 August 2010 2:42

DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS
B.S.M. is supported by National Institutes of Health (NIH) grants R01 MH41256 and 5P01
MH58911. P.J.G. is supported by NIH grants K01 MH070616 and R01 HL089850. The authors
are grateful for the support and comments of members of the John D. and Catherine T. MacArthur
Research Network on Socioeconomic Status and Health.

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RELATED RESOURCES
1. Online documentation regarding available measurement methods for the study of health behav-
ior, sleep, and behavioral and biological aspects of stress are available through the Pittsburgh
Mind-Body Center, http://pmbcii.psy.cmu.edu/.
2. Online documentation regarding available measurement methods for the study of stress and
health processes linked to socioeconomic status are available through the MacArthur Research
Network on Socioeconomic Status and Health, http://www.macses.ucsf.edu/.
3. Online documentation regarding brain health in relation to healthy brain development and the
lasting effects of adverse early life experiences may be found through the National Scientific
Council on the Developing Child, http://developingchild.harvard.edu/initiatives/council/.

www.annualreviews.org • Brain Plasticity, Stress, and Allostasis 5.15