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Available online at www.sciencedirect.com

Metabolism
www.metabolismjournal.com

Biomarkers for assessing population and individual

health and disease related to stress and adaptation
Bruce S. McEwen
Harold and Margaret Milliken Hatch, Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY 10065

A R T I C LE I N FO

AB S T R A C T

Keywords:

Biomarkers are important in stress biology in relation to assessing individual and

Allostatic load

population health. They facilitate tapping meaningfully into the complex, non-linear

Mood disorders

interactions that affect the brain and multiple systems of the body and promote adaptation

Hippocampus

or, when dysregulated, they can accelerate disease processes. This has demanded a

Amygdala

multifactorial approach to the choice of biomarkers. This is necessary in order to

Prefrontal cortex

adequately describe and predict how an individual embedded in a particular social and
physical environment, and with a unique genotype and set of lifetime experiences, will fare
in terms of health and disease risk, as well as how that individual will respond to an
intervention. Yet, at the same time, single biomarkers can have a predictive or diagnostic
value when combined with carefully designed longitudinal assessment of behavior and
disease related to stress. Moreover, the methods of brain imaging, themselves the reflection
of the complexity of brain functional architecture, have provided new ways of diagnosing,
and possibly differentiating, subtypes of depressive illness and anxiety disorders that are
precipitated or exacerbated by stress. Furthermore, postmortem assessment of brain
biomarkers provides important clues about individual vulnerability for suicide related to
depression and this may lead to predictive biomarkers to better treat individuals with
suicidal depression. Once biomarkers are available, approaches to prevention and
treatment should take advantage of the emerging evidence that activating brain plasticity
together with targeted behavioral interventions is a promising strategy.
2015 Elsevier Inc. All rights reserved.

1.

Introduction

Until recently, biomedicine focused on the functioning of

individual organ systems as they are affected by the genotype
and impacted by the physical environment. Each organ
system or disorder was viewed, at least from a therapeutic
perspective, somewhat in isolation from other systems of the
body. Functioning of the brain was left to the separate
domains of neurology, neurosurgery, psychology and psychiatry, largely separated from medicine. Furthermore, the
biological influences of the social environment, including
daily stressors and stressful life events, on brain and body
Tel.: +1 212 327 8624; fax: + 1 212 327 8634.
E-mail address: mcewen@rockefeller.edu.
http://dx.doi.org/10.1016/j.metabol.2014.10.029
0026-0495/ 2015 Elsevier Inc. All rights reserved.

functioning fell between the cracks. What was investigated

in that regard was largely the domain of sociology, social
epidemiology and social psychology, with little understanding of the biological and neurobiological implications.
However, this has changed in very significant ways. We now
recognize gradients of physical and mental health that are a
function of socioeconomic status (SES) and the steepness of the
differences between rich and poor in a particular society [1]. This
recognition has demanded a closer examination of the mechanisms by which the social, as well as physical, environments, get
under the skin and affect brain and body health (see pdf
downloads in http://www.macses.ucsf.edu/). Furthermore, we

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now recognize that children are particularly vulnerable and that

adverse, as well as positive, early life experiences can have a
profound and lasting influence on both physical and mental
health over the life course. This has demanded that biomedical
and social sciences include a life course perspective [24].
In addition, the rise of epigenetics in its current, as opposed
to original, meaning [5] has revitalized the nature-nurture
discussion. It has placed a high priority on understanding how
experiences and environmental factors regulate gene expression through mechanisms such as DNA methylation, histone
modifications, and microRNAs [6]. These operate on allelic
variation of genes that are highly reactive, or less reactive, to
those influences in terms of the final endophenotype; this has
been referred to as biological sensitivity to context [79].
Moreover, neuroscience has returned to its roots in
physiology to go beyond a brain-centric view and incorporate
brainbody interactions and elaborate mechanisms by which
neuroendocrine, autonomic, immune and metabolic systems
communicate with each other and with the brain. The brain
has emerged as the central organ of adaptation and maladaptation in response to stressors in the social and physical
environments [10,11]. Finally, the existence of developmentally programmed sex differences in many aspects of brain
function, along with discovery of subtle sex differences in
brain architecture and function, demands that we consider
the implications for health and disease of this important
example of gene environment interactions [1214].
In order to make progress in connecting the mechanistic
world of biomedicine with the domains of epidemiology, the
social sciences with intervention science and policy, biomarkers are needed that tap meaningfully into relevant
mediators and primary, secondary and tertiary consequences
of their action. This has demanded a multifactorial approach to
the choice of biomarkers in order to adequately describe and
predict how an individual embedded in a particular social and
physical environment, and with a unique genotype and set of
lifetime experiences [15], will fare in terms of health and
disease risk, as well as how that individual will respond to an
intervention. Biomarkers are also important in population
studies to explore how, for example, SES and race and ethnicity
impact biological functioning and physical and mental health.
Yet, at the same time, single biological measures can have a
predictive or diagnostic value. Moreover, given the importance
of the brain as the central organ of stress and adaptation [10],
the methods of brain imaging have provided new ways of
diagnosing mental health disorders, as will be illustrated for
anxiety disorders and depressive illness. This review will
provide examples of biomarkers in these various contexts as
they pertain to the domain of stress biology, mental health and
brainbody interactions. It will, therefore, broaden the more
traditional definition of such markers to include measures from
brain imaging and gene arrays, as well as biological indicators
from other parts of the body, including blood and urine.

2.

Criteria for a biomarker

What are the selection criteria for a biomarker? First,

biomarkers must be chosen and evaluated in terms of their
functional significance in biological pathways, including both

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primary and secondary mediators and the secondary and

tertiary consequences of their actions. Moreover, primary
mediators (such as cortisol and adrenalin; see below) show
inverted U shaped actions and there are regulatory interactions between the mediators that result in non-linearity [16].
This brings us to the concepts of allostasis and allostatic load
that look at the protective, as well as potentially damaging,
effects of the mediators of stress and adaptation. This view
takes a life course perspective that recognizes the power of
the social environment and individual life style [4]; it also
considers genetic contributions [9] and recognizes the central
role of the brain and the importance of reciprocal brainbody
interactions [10]. To adequately describe and analyze these
multiple factors and their interactions, biomarkers are
needed that tap into multiple interactive systems and look
at the brain, as well as systemic physiology.
In the concepts of allostasis and allostatic load [17,18] the
goal is to tap into measures of the multiple interacting
mediators that affect many body systems concurrently. This
is referred to as an allostatic load battery. These include
measures of blood pressure, metabolic parameters (glucose,
insulin, lipid profiles, and waist circumference), markers of
inflammation (interleukin-6, C-reactive protein, and fibrinogen), heart rate variability, sympathetic nervous system
activity (12-hour urinary norepinephrine and epinephrine)
and hypothalamicpituitaryadrenal axis activity (diurnal
salivary free cortisol) [18]. In some studies, DHEA and IGF-1
were also used as positive markers of health. Choice of
markers is limited by their cost and accessibility in studies
involving large numbers of subjects. Telomeres and telomerase have been added as another endpoint of cumulative
effect and have shown to be adversely affected by caregiving
stress, adverse early life experiences, depression, cardiovascular disease, diabetes and other conditions [1921] and may
be improved by an intensive lifestyle intervention [22].
These biomarkers fall into different classes: primary,
secondary, tertiary [23]. Primary mediators include cortisol,
sympathetic and parasympathetic activity, pro- and antiinflammatory cytokines, metabolic hormones and neurotransmitters and neuromodulators in the nervous system.
Secondary mediators are those that reflect the cumulative
actions of the primary mediators in a tissue/organ-specific
manner, often reflecting the actions of more than one
primary mediator such as those described above: e.g. those
that reflect abnormal metabolism and risk for cardiovascular
disease, such as waist-hip ratio (WHR), blood pressure,
glycosylated hemoglobin, cholesterol/HDL ratio, HDL cholesterol, as well as telomere length and telomerase activity. As
noted by McEwen and Seeman [23], WHR and glycosylated
hemoglobin both reflect the effects of sustained elevations in
glucose and the insulin resistance that develops as a result of
elevated cortisol and elevated sympathetic nervous system
activity. Blood pressure elevation is part of the pathophysiological pathway of the metabolic syndrome, but is also a more
primary indication of the allostatic load that can lead to
accelerated atherosclerosis, as well as insulin resistance.
Cholesterol and HDL cholesterol are measures of metabolic
imbalance in relation to obesity and atherosclerosis and also
reflect the operation of the same primary mediators, as well
as other metabolic hormones.

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In the realm of neuroimaging, functional activation of a set

of brain regions that appear to define subtypes of anxiety
disorder [24], and hypo- or hyperactivation of the insula
region of the brain that defines antidepressant responsiveness [25], are novel examples of secondary outcomes. They
will be discussed further below. In the case of telomeres and
telomerase, which are secondary outcomes, oxidative stress
and inflammatory processes are primary mediators that
appear to cause these changes [20,26].
Tertiary outcomes are actual diseases or disorders that are
the result of allostatic load that is predicted from the extreme
values of the secondary outcomes and of the primary mediators
[23], as will be discussed below. Cardiovascular disease,
decreased physical capacity, and severe cognitive decline have
been used as outcomes in the successful aging studies [23].
However, as noted by [23] cognitive function could be
classified as a secondary outcome, although Alzheimer's
disease or vascular dementia would be tertiary outcomes
when there is clearly a serious and permanent disease. By the
same token, cancer would be a tertiary outcome, whereas the
common cold would be a secondary outcome and an indirect
measure, in part, of immune system efficacy.
In summary, McEwen and Seeman state that this new
classification of the existing measures of allostatic load
should permit the following next steps: 1) relating progression of pathophysiology from primary mediators to secondary outcomes and then to tertiary, that is, disease outcomes;
2) identifying clusters of secondary outcomes that are
relevant to particular diseases; and 3) moving to earlier
ages in measuring allostatic load by relying more on
secondary outcomes that are known to be risk factors for
later disease; tertiary outcomes generally appear later in life,
at least for dementia and cardiovascular disease, and an
important question for future studies is whether secondary
outcomes in younger subjects can be used as a surrogate for
tertiary outcomes.

3.
How can the biomarkers collected in living
subjects be analyzed and used as a predictive tool?
For assessing and using the allostatic load battery, the
simplest approach for prediction of outcomes was to divide
values for each marker into quartiles and score anyone with
markers in the most extreme quartile (e.g., highest quartile
for negative markers like blood pressure and IL-6; lowest
quartiles for positive markers like IGF-1 or DHEA). For 10
markers, for example, the highest score would be 10 and the
lowest, zero [23]. In later work, a metafactor model of AL as
an aggregate measure of six underlying latent biological
subfactors was found to fit the data, with the metafactor
structure capturing 84% of variance of all pair-wise associations
among biological subsystems [17,18]. Another method of
analysis involves recursive partitioning [27] which was used to
identify a set of pathways, composed of combinations of
different biomarkers, that were associated with and predictive
of a high-risk of mortality over the 12-year period. Of the 13
biomarkers examined, almost all entered into one or more highrisk pathways although combinations of neuroendocrine and
immune markers appeared frequently in high-risk pathways in

men, and systolic blood pressure was present in combination

with other biomarkers in all high-risk pathways in women.
What the application of the allostatic load battery has
revealed thus far are correlations with behavioral and other
outcomes, including predictions of outcomes over time
[17,18]. In the MacArthur Successful Aging study, higher
allostatic load scores predicted increased mortality 7 years
later. Higher education was consistently associated with
lower allostatic load scores, while African-Americans, in
general, have higher AL scores and a flatter gradient across
education. Neighborhood poverty has been found to be
associated with higher allostatic load scores among the
residents [28]. As might be expected, higher allostatic load is
associated with increased social conflict, whereas positive
social support and social connectedness are linked to lower
AL scores [17,18].
A recent review of allostatic load in relation to health
disparities [29] supports its utility and states: The results
revealed considerable heterogeneity in the operationalization
of allostatic load (AL) and the measurement of AL biomarkers,
making interpretations and comparisons across studies
challenging. There is, however, empirical substantiation for
the relationships between AL and socioeconomic status,
social relationships, workplace, lifestyle, race/ethnicity, gender, stress exposure, and genetic factors. The literature also
demonstrated associations between AL and physical and
mental health and all-cause mortality. Targeting the antecedents of AL during key developmental periods is essential
for improving public health. Priorities for future research
include conducting prospective longitudinal studies, examining a broad range of antecedent allostatic challenges, and
collecting reliable measures of multisystem dysregulation
explicitly designed to assess AL, at multiple time points, in
population-representative samples. In addition, one might
also add, future work should use a standardized allostatic
load battery along the lines used by Seeman and colleagues
[18] and summarized above, so as to make easier comparisons
across studies.
A similar approach to scoring of multiple adverse childhood experiences (ACE) was used to relate those experiences
to tertiary outcomes such as cardiovascular disease, diabetes,
substance abuse, antisocial behavior and depression, among
other life-long consequences of ACE [30]. As in the case of the
allostatic load battery, having an ACE score reflecting multiple
adverse experiences has an almost exponential effect on the
subsequent behavioral and physical health problems ranging
from depression and antisocial behavior to substance abuse
and cardiovascular disease and obesity [2] which are, then,
measurable using the biomarkers of allostatic load. The
allostatic load profile is distorted by elevated inflammatory
biomarkers, as will be discussed below.

4.

Allostatic load in personalized medicine?

However can the use of an allostatic load battery also be

implemented for personalized medicine? The concept of
multiple interacting mediators has the potential to enable
physicians and their patients to gain a better insight into
individual health than the simpler assessments of blood

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pressure, cholesterol levels, HDL and LDL, which do not tap into
all the important mediators and health-related indices but
which can be part of a broader array of biomarkers. This has
resulted in commercial and non-commercial efforts such as
ALLOSTATIX (http://www.allostatix.com/) and Optimal Health
and Prevention Research Foundation (http://optimalhealth.org/
index.php/about/), respectively, to apply this type of multifactorial analysis to programs intended to monitor and help
individuals improve health behaviors and overall health,
while at the same time attempting to use distortions of the
allostatic load profile (e.g. high inflammation or low cortisol or
high inflammation plus high cortisol, indicating glucocorticoid
resistance; high sympathetic and low parasympathetic tone) as
not only as predictors of disease risk, but also predictors of the
most effective treatment/prevention strategy. Time will tell if
these approaches, such as in Howard County, Maryland (http://
www.healthyhowardmd.org/healthy-howard), can catch on
and become useful. Such programs emphasize prevention
strategies using health coaches (http://en.wikipedia.org/wiki/
Health_coaching) and other methods that get individuals
involved in promoting a healthy lifestyle for themselves and
others, and the allostatic load battery may be able to provide a
longitudinal index of the success of such interventions.

5.
The diagnostic and predictive value of
structural and functional brain imaging as a biomarker
The brain is the central organ of stress and adaptation to
stressors via activity of brain regions that control behavior.
These brain regions also regulate systemic physiology
through autonomic, neuroendocrine, immune and metabolic
activity. The dysregulation of these interactions, and particularly the dysregulation of neural function, is a signature of
brain and body pathophysiology [11]. Both structural and
functional brain imaging are becoming useful as biomarkers.
Structural imaging of the brain (MRI) has been used to
assess the effects of regular physical activity and demonstrate
its ability to enlarge the hippocampus due to structural
remodeling, including neurogenesis [31]. Previous work by
the same group had shown that regular aerobic physical
activity increased blood flow in the prefrontal and parietal
cortices, measured by functional imaging, and enhanced
executive function [32,33]. Using longitudinal MRI of the
brains of individuals with anxiety disorders, mindfulness
based stress reduction was shown to decrease amygdala
volume in those patients who showed reduced chronic
anxiety [34]. Amygdala enlargement and hyperactivity are
features of chronic anxiety [35]. A similar approach was used
to show the efficacy of cognitive behavioral therapy for
chronic fatigue, showing increased gray matter volume of
the medial prefrontal cortex via MRI in those individuals
whose symptoms had improved with treatment [36].
Although complex and believed to measure cerebral blood
flow, functional brain imaging (fMRI) signatures have been
used to predict antidepressant outcome [25] and to subtype
anxiety disorders [24]. Patients with post-traumatic stress
disorder (PTSD) showed hyperactivity during processing of
emotions in the amygdala, parahippocampal gyrus, insula,
inferior parietal lobule, mid-cingulate, and precuneus, while

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patients with social anxiety disorder also showed hyperactivity in the amygdala, parahippocampal gyrus, and insula, but
also in the fusiform gyrus, globus pallidus, inferior frontal
gyrus, and superior temporal gyrus. In contrast, patients with
specific phobia displayed hyperactivity in the amygdala and
insula, as in the other disorders, but also in fusiform gyrus,
substantia nigra and mid-cingulate. Thus, hyperactivity was
observed in all three disorders in only two structuresthe
amygdala and the insula, and the other areas of activation
begin to provide a unique signature for each disorder.
Further differentiation was found during fear conditioning
of healthy subjects and subjects with different anxiety
disorders [24]. In healthy individuals, fear conditioning
increased activity in the amygdala and bilateral insula.
Compared to healthy subjects, less activation was seen only
in PTSD, specifically in the inferior occipital gyrus, ventromedial prefrontal cortex, rostral anterior cingulate cortex,
parahippocampal gyrus, lingual gyrus, dorsal amygdala and
anterior hippocampus, orbitofrontal cortex, putamen, middle
occipital gyrus, dorsomedial prefrontal cortex, dorsal anterior
cingulate cortex, and mid-cingulate. In fact, symptom severity
of PTSD was related to degree of hypoactivation in the medial
prefrontal cortex. Hyperactivation in the amygdala and
insular cortices of patients was found more frequently in
social anxiety disorder and specific phobia than in PTSD.
However, hypoactivation of rostral anterior cingulate cortex,
dorsal anterior cingulate cortex, and ventromedial prefrontal
cortex was seen more frequently in PTSD than in either social
anxiety disorder or specific phobia, and thalamic hypoactivity
was also more commonly seen in PTSD than either social
anxiety disorder or specific phobia [24]. Unfortunately, the
complexity of these patterns of activation and variability
between subjects with the particular disorder make it difficult
to use this as a routine diagnostic procedure [37].
In spite of the potential variability of brain imaging as
noted above, a new study using positron imaging tomography
(PET) for brain glucose metabolism has provided clues as to
brain regions, the activity of which may predict response or
lack of response to antidepressant therapies [25]. Brain
glucose metabolism was measured with PET prior to treatment randomization to either escitalopram oxalate or cognitive behavior therapy for 12 weeks. Patients who did not remit
on completion of their phase 1 treatment were offered
enrollment in phase 2 comprising an additional 12 weeks of
treatment with combination escitalopram and cognitive
behavior therapy [25]. What these authors found were both
positive and negative predictors of remission. Of six limbic
and cortical regions that were identified, the right anterior
insula showed the most robust discriminant properties across
groups in which insula hypometabolism (relative to wholebrain mean) was associated with remission to cognitive
behavior therapy and poor response to escitalopram, while
insula hypermetabolism was associated with remission to
escitalopram and poor response to cognitive behavior therapy. The insula is also a brain region where direct intracranial
brain stimulation has been shown to relieve depression [38].
Another use of imaging involves the diagnosis and
treatment of social anxiety disorders with cognitive behavioral therapy [39]. Response to angry vs neutral and emotional
vs neutral faces was used to probe individuals before CBT.

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According to the authors, Pretreatment responses significantly predicted subsequent treatment outcome of patients
selectively for social stimuli and particularly in regions of
higher-order visual cortex. Combining the brain measures
with information on clinical severity accounted for more than
40% of the variance in treatment response and substantially
exceeded predictions based on clinical measures at baseline.
Prediction success was unaffected by testing for potential
confounding factors such as depression severity at baseline.
Such successes indicate that proper use of brain imaging
biomarkers will continue to be very useful in clinical practice.

6.
Measuring functional activity of single
mediators and interpreting the results
In addition to the methods for dealing with complexity of
interacting mediators via the allostatic load battery, there are
measures of certain mediators that have predictive validity by
themselves, and a number of examples will illustrate this. The
first two examples concern cortisol, and the third involves
inflammatory mediators. First, low normal cortisol has been
linked to increased risk for PTSD in both animal models and
humans after trauma, and this has led to the use of glucocorticoids as a preventative treatment for the development of
PTSD symptoms [4043]. This highlights the important adaptive
and protective function of cortisol which is often measured and
interpreted in terms of negative consequences of stress. Indeed,
cortisol has many positive functions that include facilitating,
during acute stress, acquired immune responses [44] and
promoting plasticity at the synaptic structural level [45,46].
Second, failure to habituate cortisol responsiveness to a
repeated public speaking challenge is indicative of low self
esteem and poor locus of control and this was linked to a smaller
hippocampal volume [4749]. This assessment requires repeated
testing under a defined stressor and is of particular interest
because a smaller hippocampus and low self esteem are both
risk factors associated with PTSD [50,51]. By the same token,
repeated sampling of cortisol around the day is diagnostic for
whether an individual has a flat diurnal rhythm that is a factor in
such conditions as depression and burnout [52,53]. A flat cortisol
diurnal rhythm, as shown in animal models, is associated with a
sluggish turning-on and turning-off of the cortisol response to
stress, which is maladaptive [54,55]. Both of these measures of
cortisol emphasize a basic principle of allostasis, namely, that
efficiently turning on a stress sensitive mediator, in this case a
cortisol response, when needed, and efficiently turning it off
again when not needed, is a key to successful adaptation with
minimal allostatic load. Moreover, a normal diurnal cortisol
rhythm is important to program many behaviors and brain
functions, including an efficient HPA stress response [54].
Third, inflammatory markers have been very informative
when measured in the context of studies of early life adversity
(abuse, neglect by parents or caregivers in childhood). Along
with telomere shortening in the case of exposure to violence
[56], increased levels of inflammatory cytokines and Creactive protein (CRP), along with obesity as a secondary
outcome, are seen to persist into adulthood along with
increased incidence of depression, substance abuse, cardiovascular disease and diabetes [2,30,57,58]. Some hopeful

indications that a cognitively based compassion intervention

can ameliorate some of these consequences are based upon a
reduction in inflammatory markers [59].
While individual biomarkers may have a particularly strong
association with a pathophysiological condition, and in the case
of PTSD, where low cortisol at time of trauma indicates a possible
prevention strategy by giving cortisol immediately afterwards,
the entire allostatic load network is distorted, leading to the
likelihood of systemic disorders, as already noted for adverse
childhood experiences. For example, telomere shortening is
attributed to increased oxidative and inflammatory stress in
which there are distortions of other mediator systems [20,26].

7.
Molecular biomarkers for translation and
reverse translation
There are also biomarkers that are only available after the
fact, e.g., as correlates of depression with suicide as determined post mortem in rigorously collected and preserved
human brain samples. These may provide a better understanding of the etiology of depressive illness and lead to
preventative treatments. For depression that led to suicide,
low levels of fibroblast growth factor 2 (FGF2) and FGF receptor
2 were found in the anterior cingulate (ACC) or dorsolateral
prefrontal cortex (DLPFC), along with reduced levels of FGF1,
FGFR2, and FGFR3 and elevated levels of FGF9 and FGF12
[60,61]. Similar changes were found in other brain regions,
such as hippocampus where FGFR2 was reduced even as FGF2
itself was elevated, and animal models that show depressiveand anxiety-like behaviors also show similar patterns. Indeed, administration of FGF2 in adults, or neonatally in those
animal models, protects against these behaviors [60,62].
Furthermore, using the same rigorously collected brain
samples as in the FGF studies, a pathway analysis revealed
alterations of serotonergic signaling in the DLPFC and
alternations of glucocorticoid signaling in the ACC and NAcc
[63]. Also deficient in suicide brains was the 5-HT2A gene in
the DLPFC, previously associated both with suicide and mood
disorders. Moreover, in the ACC, 6 metallothionein genes
were down-regulated in suicide (MT1E, MT1F, MT1G, MT1H,
MT1X, MT2A) and three were down-regulated in the NAcc in
suicide (MT1F, MT1G, MT1H). Thus, 5-HT2A and members of
the metallothionein subfamilies MT 1 and 2, which are downregulated in suicide completers, are normally protective
factors following stress and glucocorticoid stimulation [63].
In order to fully utilize the power of such post-mortem
biomarker studies in prevention of suicide and better treatment
of depression, humanized animal models with alleles of
genes that represent vulnerability for depression, such as the
BDNF val66met alleles, can provide important insights into
plasticity of neural architecture in relation to anxiety-like
behavior and the efficacy of antidepressant medications [64,65].

8.

How can we change the brain?

When we have biomarkers that give us some idea of risk for a

stress-related disorder, what can be done to remediate it?
Interventions may involve pharmaceutical, as well as

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behavioral, or top-down, interventions (i.e., interventions

that involve integrated CNS activity, as opposed to pharmacological agents) that include cognitive-behavioral therapy,
physical activity and programs that promote social support
and integration and meaning and purpose in life [66]. More
targeted interventions for emotional and cognitive dysfunction may arise from fundamental studies of such developmental processes as the reversal of amblyopia and other
conditions by releasing the brakes that retard structural and
functional plasticity [67].
It should be noted that many of these interventions that
are intended to promote plasticity and slow decline with age,
such as physical activity and positive social interactions that
give meaning and purpose, are also useful for promoting
positive health and eudamonia [6870] independently of
any notable disorder and within the range of normal behavior
and physiology.
A powerful top down therapy (defined as an activity,
usually voluntary, involving activation of integrated nervous
system activity, as opposed to pharmacological therapy
which has a more limited target and may interfere with
beneficial processes) is regular physical activity, which has
actions that improve prefrontal and parietal cortex blood flow
and enhance executive function [33]. Moreover, regular
physical activity, consisting of walking an hour a day, 5 out
of 7 days a week, increases hippocampal volume in previously sedentary adults [31]. This finding complements work
showing that fit individuals have larger hippocampal volumes than sedentary adults of the same age-range [71]. It is
also well known that regular physical activity is an effective
antidepressant and protects again cardiovascular disease,
diabetes and dementia [72,73]. Moreover, extensive learning
has also been shown to increase volume of the human
hippocampus [74].
Social integration and support and finding meaning and
purpose in life are known to be protective against allostatic
load [75] and dementia [76], and programs such as the
Experience Corps give meaning and purpose to retirees
along with providing increased physical activity and social
support and have been shown to slow the decline of physical
and mental health and to improve prefrontal cortical blood
flow [77,78].
Depression and anxiety disorders are examples of a loss of
resilience, in the sense that changes in brain circuitry and
function, caused by the stressors that precipitate the disorder,
become locked in a particular state and thus need external
intervention. Indeed, prolonged depression is associated with
shrinkage of the hippocampus [79,80] and prefrontal cortex
[81]. While there appears to be no neuronal loss, there is
evidence for glial cell loss and smaller neuronal cell nuclei
[82,83], which is consistent with a shrinking of the dendritic
tree described above after chronic stress. Indeed, a few
studies indicate that pharmacological treatment may reverse
the decreased hippocampal volume in unipolar [84] and
bipolar [85] depression, but the possible influence of concurrent cognitive-behavioral therapy in these studies is unclear.
Depression is more prevalent in individuals who have had
adverse early life experiences [2]. Reduced brain-derived
neurotrophic factor (BDNF) may be a key feature of the
depressive state and elevation of BDNF by diverse treatments

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ranging from antidepressant drugs to regular physical activity

may be one part of treatment response [86]. Yet, there are other
potential uses of increased plasticity, such as the recently
reported ability of fluoxetine to enhance recovery from stroke
[87]. However, a key aspect of this new view [88] is that the drug
is opening a window of opportunity that may be capitalized
by a positive behavioral intervention, e.g., behavioral therapy in
the case of depression or the intensive physiotherapy to
promote neuroplasticity to counteract the effects of a stroke.
This is consistent with animal model work that shows
that ocular dominance imbalance from early monocular
deprivation can be reversed by patterned light exposure in
adulthood that can be facilitated by fluoxetine, on the one
hand [89] and by food restriction, on the other hand, [90], in
which reducing inhibitory neuronal activity appears to play a
key role [67]. Investigations of underlying mechanisms for
the re-establishment of a new window of plasticity are
focusing on the balance between excitatory and inhibitory
transmission and removing molecules that put the brakes
on such plasticity [67]. Moreover cortisol, which mimics food
restriction [90], has been shown to promote synapse turnover
[45] and, in so doing, ultradian and diurnal fluctuations of
cortisol play a role in motor learning [46].
In this connection, it is important to reiterate that
successful behavioral therapy, which is tailored to individual
needs, is reported to produce volumetric changes in both
prefrontal cortex in the case of chronic fatigue [36], and in
amygdala, in the case of chronic anxiety [34]. This reinforces
two important messages: first, that plasticity-facilitating
treatments should be given within the framework of a
positive behavioral or physical therapy intervention; and
secondly, that negative experiences during the window may
even make matters worse [88]. In that connection, it should be
noted that BDNF also has the ability to promote pathophysiology, as in seizures [9193].

9.

Conclusion and future directions

This article has examined how biomarkers are being used for
diagnosis and treatment of stress-related mental and physical health disorders. Moreover, studies on postmortem brain
tissue are showing that certain gene products can be useful to
better understand brain mechanisms, hopefully leading to
treatment of suicidal depression. This article has also noted
that, in some cases, single biomarkers can be very informative
when measured in the context of careful longitudinal
behavioral assessment. Examples include the use of cortisol
in relation to diagnosing the physiological consequence of
low self-esteem and vulnerability for PTSD, and for PTSD's
preventative treatment. Furthermore, inflammatory cytokines,
obesity and telomere length are useful biomarkers in relation to
the impact of adverse childhood experiences [56,57].
Yet, even if only one or just a few biomarkers are
measured, it should be kept in mind that in all of these
pathophysiological conditions, there are perturbations of the
whole network of allostasis, which is indicative of systemic
allostatic load affecting many body systems and functions
concurrently. For multi-systems interactions of biological
mediators of stress and adaptation, it is important, therefore,

S8

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if possible, to monitor the non-linear interacting mediators of

the neuroendocrine, autonomic, immune and metabolic
systems, in which case, the use of an allostatic load battery
can be useful in population studies and possibly also for
monitoring individual health.
Moreover, once biomarkers are in hand, this article
suggests that, rather than trying to find magic bullet
drugs that do it all, therapies for treating these disorders
should consider top down interventions that take advantage of the wisdom of the body to correct itself when given
the opportunity. Together with pharmacological agents like
fluoxetine, but also using regular physical activity and
caloric restriction in order to enhance brain plasticity,
driving that plasticity with a targeted behavioral intervention should be an effective way to improve mental and
physical health.

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[16]

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