Neurobiology of Resilience

Charney & Nestler's Neurobiology of Mental Illness (5 edn)
Dennis S. Charney et al.
https://doi.org/10.1093/med/9780190681425.001.0001
Published: 2017 Online ISBN: 9780190698850 Print ISBN: 9780190681425
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CHAPTER
38. The Neurobiology of Resilience 

Adriana Feder, Sarah R. Horn, Margaret Haglund, Steven M. Southwick, Dennis S. Charney
https://doi.org/10.1093/med/9780190681425.003.0038
Published: November 2017
Abstract
Resilience is the ability to adapt successfully in the face of severe stress, trauma, or adversity. Over the
past several decades, a wide range of studies in children and later in adults identi ed several key
psychosocial characteristics associated with resilience, including emotion regulation, cognitive
exibility, positive emotions, and the availability of social support, among others. More recent studies
are increasingly employing integrative approaches, incorporating genomic, neuroendocrine, and
neuroimaging data to the study of resilience. This chapter reviews our current understanding of the
neurobiology of resilience from genomic, developmental, psychosocial, neuroendocrine, brain
circuitry, and integrative perspectives, and includes a nal section focusing on implications for
prevention and treatment of stress-related psychopathology.
Keywords: resilience, genomics, development, early life environment, psychobiology, neurobiology,

stress response systems, immune system, neural circuitry.
Subject: Neurology, Psychiatry
Collection: Oxford Medicine Online
Introduction
Resilience is the ability to adapt successfully in the face of severe stress, trauma or adversity (Horn et al.,
2016; Southwick and Charney, 2012a). Resilient individuals are those who are able to demonstrate healthy
psychological and physiological stress responses when facing extreme stress or trauma exposure, thus
maintaining “psychobiological allostasis” (Karatsoreos and McEwen, 2013). Historically, most research on
the e ects of severe stress focused on its deleterious e ects on well-being. The study of resilience began in
the 1970s with the study of children exposed to signi cant adversity during development (Masten and
Tellegen, 2012), later extending to the study of trauma-exposed adults (Alim et al., 2008; Bonanno, 2004;
Pietrzak and Southwick, 2011). Epidemiological studies also examined longitudinal trajectories of
posttraumatic stress disorder (PTSD) symptoms and resilience over time (e.g., Pietrzak et al., 2014). Rather
than being present or absent, however, resilience can be conceptualized as existing on a continuum, present
to di ering degrees across di erent domains of life, for example in the workplace or relationships with
others (Pietrzak and Southwick, 2011). An individual’s degree of resilience might change over time at
di erent phases of development. Response to stress and trauma may also vary depending on the resilience
and resources of the individual’s family, surrounding community, and societal context (Southwick et al.,
2014).
A large body of research identifying a range of psychosocial characteristics and factors associated with
resilience has been followed by an ever growing number of studies seeking to understand the neurobiology
of resilience. Supplementing studies in humans, animal studies are greatly advancing our understanding of
neural and molecular mechanisms underlying resilience to stress (Pfau and Russo, 2015; Southwick and
Charney, 2012a). Understanding the neurobiology of resilience adds to our knowledge of psychological and
social factors associated with resilience, and enables researchers and clinicians to develop new therapies for
the prevention and treatment of stress-induced psychopathology.
This chapter outlines the current understanding of resilience from genetic, epigenetic, developmental,
psychological, and neurobiological perspectives, and presents promising new therapies for the promotion
of resilience to stress.
Prevalence of Resilience
The majority of individuals are exposed to trauma during their lifetime: in the United States, lifetime risk of
at least one signi cant traumatic event, such as sudden unexpected death of a loved one, injury in a motor
vehicle accident, or experiencing assault, is estimated at over 70%. (Benjet et al., 2016). The prevalence of
resilience depends on the particular de nition and measure(s) used, on the population studied, and
importantly on the severity and chronicity of stress or trauma exposure. In the words of Rutter (2012),
“resilience is an inference based on evidence that some individuals have a better outcome than others who
have experienced a comparable level of adversity,” and is best operationalized as a continuous outcome
(Soutwick et al., 2015).
Population studies in the United States have estimated the lifetime prevalence of PTSD at approximately
8%. Certain types of trauma, however, are signi cantly more likely to cause PTSD, particularly rape for both
sexes (46% to 65%) and physical abuse (48.5%) for women. In US Army and National Guard soldiers, the
prevalence of PTSD and depression following combat in Iraq ranged from 9% to 31%, depending on the
severity of associated functional impairment (Thomas et al., 2010).
In general, traumatic events that are severe and unpredictable, intentionally caused by other human beings
(such as assaultive trauma), and result in loss (of a loved one, property, or physical integrity) are most likely
to lead to PTSD. In a study of a high-risk primary care sample, the resilient group had a signi cantly lower
lifetime prevalence of assaultive trauma (46.8% vs. 75.6%) as well as a signi cantly lower mean number of
lifetime experienced trauma types (3.4% vs. 5.1%) than the group with current psychiatric disorders (Alim
et al., 2008). Further, studies have shown that the degree of control that an individual has over a stressor or
trauma is a key factor in modulating the impact of a stressor (Fleshner et al., 2011).
Longitudinal trajectories studies have employed latent growth mixture modeling, a statistical approach that
identi es clusters of individuals following distinct courses of longitudinal symptom development without
assuming a priori trajectory types. In these studies, the prevalence of resilience has ranged widely
depending on the population studied. For example, the resilience trajectory represented over 80% of the
p. 488 sample in a study of deployed US military service members (Bonanno et al., 2012), whereas it was 35.6%
(resistance and resilience trajectories combined) in a sample under ongoing threat of terrorism and rocket
attacks (Hobfoll et al., 2009). Of note, the second study used PTSD and depressive symptom measures to
de ne resilience, whereas the rst one only measured PTSD symptoms. In studies of rescue and recovery
workers following the 9/11 World Trade Center attacks evaluating predominant PTSD symptom trajectories,
police responders were more likely than nontraditional responders (e.g., construction workers) to be
classi ed in a resistant/resilient trajectory (Pietrzak et al., 2014). Despite di erences in prevalence across
studies, research has shown that a signi cant percentage of individuals are resilient to the e ects of
extreme stress.
Genomics and Resilience
It has long been known that stress-related disorders are at least partially heritable. For example, studies of
combat-exposed men enrolled in the Vietnam Twin Registry have found that PTSD, panic disorder, and
general anxiety disorder, frequently comorbid conditions, all have signi cant genetic contributions. It has
been estimated that up to 40% of the variance in occurrence of these disorders is accounted for by genetic
factors rather than by situation or trauma-related factors (Cornelis et al., 2010). Genetic factors are not only
important in determining an individual’s response to a stressful event, but also in uence the likelihood of
exposure to that event.
Research ndings indicate that complex interactions between genetic contributions and an individual’s
particular history of exposure to environmental stressors yield a unique pro le of adaptability of
neurochemical stress responses and neural circuitry function upon exposure to new stressors. Further, as
discussed later, epigenetic modi cations are now understood to modulate stress reactivity by regulating
gene expression at the molecular level. More recent research has advanced to genome-wide association
studies (GWAS), requiring large sample sizes to scan the genome for small variations in multiple genes that
might increase risk for PTSD and other stress-related disorders.
To date, the most frequently utilized genomics approach to study resilience has been the candidate gene
approach (Logue et al., 2015a). An extensively studied candidate gene of relevance to resilience is the gene
coding for FK506 binding protein 5 (FKBP5), a chaperone protein that modulates glucocorticoid receptor
(GR) sensitivity. FKBP5 is a key regulator of the hypothalamic-pituitary-adrenal (HPA) axis, a hormonal
system involved stress responses. For example, genetic variation in FKBP5 has been found to a ect the
e ciency of recovery of HPA axis activation after exposure to the Trier Social Stress Test in healthy
individuals, and to interact with severity of childhood abuse in predicting PTSD symptom severity in adults
(Klengel and Binder, 2015). Further, genetic variation in FKBP5 has been found to in uence epigenetic
modi cations of this gene, resulting in di erential risk for PTSD as discussed (Klengel and Binder, 2015). A
range of studies have identi ed other speci c genetic polymorphisms a ecting the HPA axis and stress
reactivity that might contribute to di erential stress vulnerability.
Variation in serotonergic system genes has also been found to a ect susceptibility to stress-induced
psychopathology. The short (S) allele of the serotonin (5-HT) transporter promoter gene (5HTTLPR), which
compared with the long (L) allele results in decreased transporter availability and lower uptake of 5-HT
from synaptic clefts, has been linked to heightened activation in brain regions implicated in fear processing,
including the amygdala, thalamus, and dorsomedial prefrontal cortex (dmPFC), and decreased coupling
between the amygdala and the regulatory perigenual cingulate region while viewing fearful or aversive
stimuli (Klumpers et al., 2015). Interestingly, studies have found that youth homozygous for the short allele
of 5HTTLPR were not only more vulnerable to negative parenting but also more responsive to supportive
parenting, showing higher levels of positive a ect if parenting was supportive.
Genetic polymorphisms a ecting resilience to stress have also been identi ed in the noradrenergic system.
Functional polymorphisms in the gene that produces catechol-O-methyltransferase (COMT), an enzyme
that degrades dopamine (DA) and norepinephrine (NE), have been found to a ect response to stress.
Individuals with the low-functioning Met allele for the enzyme, and hence higher circulating levels of DA
and NE, tend to exhibit more anxious behaviors and lower resilience against negative moods than carriers of
the high-functioning allele, and to avoid novelty-seeking behaviors. They have also been found to show
greater plasma endocrine responses to stressful tasks and heightened reactivity of corticolimbic circuits to
aversive stimuli. Polymorphisms in DA receptors and in the DA transporter gene have also been associated
with vulnerability to depression and PTSD.
Polymorphisms in other relevant systems have been identi ed, including a polymorphism (Val66Met) in
the gene for brain-derived neurotrophic factor (BDNF), a widely expressed protein that stimulates
neurogenesis and promotes learning and memory, which has been linked to increased likelihood of
su ering stress-induced depression, and with increased amygdala reactivity in response to emotional
stimuli in healthy females. A recent study in 780 Chinese Han adolescents demonstrated that Val carriers
experienced less depressive symptoms than Met homozygotes when maternal parenting was positive;
however, they experienced more symptoms when mothering was negative (Zhang et al., 2016). A single
nucleotide polymorphism (rs1617) located in the promoter region of the gene coding for neuropeptide Y
(NPY), a peptide released during stress that appears to mitigate the negative e ects of the stress response,
alters NPY expression and was found to di erentially a ect stress responses and neural activation to
emotional probes. Overall, ndings from gene × environment studies suggest that some genetic variations
might increase an individual’s responsivity to environmental in uence, whether good or bad, potentially
boosting or decreasing resilience depending on the quality of the environment during development
(Homberg and Lesch, 2011).
Recent research in genetics of stress-related disorders has advanced to large collaborative GWAS, including
p. 489 studies of PTSD and depression. Large-scale GWAS studies of PTSD are challenging, as heterogeneous
samples di er by trauma exposure and ancestry (Logue et al., 2015a). As sample sizes grow through
collaborative e orts, genome-wide loci are beginning to emerge in association with PTSD, and await future
replication.
Epigenetics and Gene Expression
Prenatal and early postnatal environments regulate developmental processes at the molecular level via
epigenetic modi cations (to the DNA itself or to histone proteins, the latter a ecting DNA organization into
chromatin), without changing the DNA sequence. Epigenetic changes in turn in uence gene expression
(Nestler, 2014). Initial studies in rodents showed that high maternal care early in development can lead to a
“permanent increase” in glucocorticoid (GR) expression in the hippocampus, resulting from lower GR
promoter DNA methylation, and thereby lowering sensitivity to circulating glucocorticoids. Further
epigenetic changes can occur in response to experiences including drug use, social interactions, and
exposure to stress during critical development periods (Dudley et al., 2011).
Stress reactivity in adult animals is partially a result of epigenetic changes stemming from di erential early
life experience, such as methylation levels of promoter regions in genes of central importance to stress
responses (e.g., GR, BDNF) and located in key regions of the brain (e.g., hippocampus, prefrontal cortex).
Similarly, prenatal stress can also result in epigenetic changes, which in turn impact stress reactivity; on the
other hand, early evidence suggests that some of these changes are potentially reversible by optimal
postnatal experience (Dudley et al., 2011). Studies in humans have begun to identify the role of epigenetic
changes, as exempli ed by a report of di erential methylation of the GR gene in newborn babies of mothers
with prenatal depression. In-depth studies of the FKBP5 gene have also shown that allele type can in uence
epigenetic changes upon trauma exposure during development. Exposure to childhood trauma was found to
be associated with a reduction in DNA methylation of FKBP5, but only in risk allele carriers, illustrating the
complexity of these interactions (Klengel and Binder, 2015). Other epigenetic changes are likely the result of
stochastic events during development (Nestler, 2014).
Further, the word epigenetics is used in many ways, encompassing both short-term changes in gene
expression and life-long changes in gene expression that occur in the brain in response to behavioral
experience described. Other examples of epigenetic changes include di erential histone acetylation or
methylation associated with stress resilience versus vulnerability following several days of chronic social
defeat stress in mice (Nestler, 2014). Additionally, chromatin remodeling occurs after synaptic
transmission, via phosphorylation of the transcription factor cyclic AMP response element binding protein
(CREB), leading to quick changes in histone acetylation that result in activation of gene expression.
Epigenetic changes of this kind are very dynamic and regulate changes in gene expression in response to
stress, exercise, drug use, medications, and other in uences. For example, epigenetic reprogramming
might underlie the resilience-boosting e ects of physical exercise, as suggested by ndings from a recent
study of physical exercise in rats, showing increased levels of hippocampal NPY mRNA due to epigenetic
reprogramming of the NPY gene by physical activity (wheel running). Novel animal studies are employing
engineered transcription factors targeting epigenetic remodeling of speci c genes, for example in brain
reward regions, attempting to elucidate the role of such epigenetic regulation in neuropsychiatric illness.
Epigenetic mechanisms thus yield di erential gene expression patterns that are increasingly understood to
mediate resilience or vulnerability to stress (McEwen et al., 2015). The quest to uncover epigenetic changes
and di erential gene expression patterns that mediate di erential stress reactivity, as well as to understand
why some epigenetic changes in the brain are short-lived and others long-lasting, is a major area of
research (Klengel and Binder, 2015; Nestler, 2014). Epigenetic changes can also occur in sperm or ova and
might potentially in uence o spring behavior through intergenerational transmission, although this
mechanism is less well established. A recent study reported evidence of intergenerational transmission of
epigenetic changes (FKBP5 methylation) from Holocaust-exposed parents to their o spring, measured in
blood samples; yet as the authors point out, this study does not reveal the mechanisms of intergenerational
transmission, and additional research is needed.
Animal studies involving genome-wide expression pro ling in blood and speci c brain regions (e.g.,
amygdala, hippocampus) have begun to identify di erences in gene expression patterns within signaling
pathways of known relevance to PTSD (Logue et al., 2015b). Additional studies have identi ed di erential
expression of in ammatory response genes in association with high levels of well-being, of relevance to
resilience.
The Development of Resilience: Role of Early Life Environment
The developmental environment is a key contributor to resilience. The study of resilience from a
developmental perspective dates back to the early 1970s (Masten and Tellegen, 2012). An important
discovery to emerge from this research is that resilience is common, even in children who su ered severe
adversity in early life. Studies of adolescents whose development was stunted in childhood due to traumatic
experiences such as being orphaned have found that the majority of children rapidly demonstrate
“developmental catch-up” when placed in safe and nurturing environments. It seems that, under the right
circumstances, neural circuits involved in resilience are modi able for many years after birth, possibly even
into adulthood.
The nding that children are often able to thrive despite exposure to severe stress led to innovative studies
p. 490 searching for protective factors in resilient children (Masten and Tellegen, 2012). Consistently, e ective
parenting and positive bonding with caregivers or other adults emerged as key predictors of child
competence and resilience. Children’s natural disposition and behavior can also in uence the quality of
parenting they receive (Pastorelli et al., 2015). Additional personal and psychosocial protective factors
linked to resilience in children include advanced maturity, rapid response to danger, information-seeking
skills, positive relationships with peers, optimism, self-discipline, and higher cognitive functioning (Horn
et al., 2016; Masten and Tellegen, 2012). In studies of children exposed to the extreme adversity of war and
related traumas (e.g., child soldiers, bombings), positive bonding with caregivers, strong social support
networks, a shared sense of values, humor, altruism, and religious beliefs that identify meaning in su ering
all emerged as protective factors associated with resilience (Werner, 2012).
Nevertheless, severely traumatic experiences in early life can negatively a ect the development of stress
response systems, in some cases doing long-lasting damage. Studies of rodents and nonhuman primates
indicate that animals abused by their mothers during the rst few weeks after birth have delayed
independence and a decreased ability to manage stress later in life, demonstrated by high levels of
behavioral anxiety, a hyperactive HPA axis, and increased basal levels of the anxiogenic corticotropin-
releasing hormone (CRH) in the cerebrospinal uid. Furthermore, nonhuman primates who su ered
damage to their stress response systems as a result of abuse in infancy seem more likely to mistreat their
own infants, perpetuating the e ects of abuse across generations.
Studies of human survivors of early life stress and abuse have also found long-lasting alterations in central
nervous system circuits and structures involved in psychological well-being. Developmental timing,
severity, and duration of early life stress are of key importance to resilience. For example, children raised in
orphanages and later adopted into stable families fare considerably better when adopted earlier (Rutter,
2013). Infancy and adolescence are developmental periods of particular susceptibility to positive and
negative environmental in uences, in part due to heightened brain plasticity during these stages (Gee and
Casey, 2015). In infancy, severe prenatal stress and early childhood abuse have been linked to increased HPA
axis activity later in life, putting survivors at risk for the adverse e ects of chronic hypercortisolemia.
Developmental environment also in uences the adult functioning of the locus coeruleus–norepinephrine
(LC–NE) system, with severe stress in early life leading to its hyperfunctioning. For instance, one study
found that police recruits with a history of childhood trauma had signi cantly higher levels of a salivary
metabolite of NE in response to viewing aversive videos than did healthy controls. Other research has found
that physical or sexual abuse in childhood can lead to smaller-than-average hippocampal volumes;
decreased hippocampal volume is commonly seen in individuals with depression or chronic stress disorders.
Thus, early abuse can cause longstanding changes in brain structures and circuits associated with resilience.
Although early exposure to unpredictable and uncontrollable stress or trauma commonly leads to later
psychopathology, exposure to moderately stressful events that can be mastered to an extent (e.g., family
relocation, illness of a parent, or loss of a friendship) seems to enable children to e ectively regulate their
stress response systems. Children who experienced successful coping with di cult situations reap bene ts
when faced with stressors later in life, experiencing less physiological and psychological distress. It seems
that the experience of mastering stress provides a form of immunity against later challenges. This
phenomenon is known as stress inoculation, based on the analogy to vaccine-induced inoculation against
disease. Just as exposure to a low dose of a pathogen enables the body to mount a long-lasting immune
response, exposure to moderate amounts of stress enables organisms to conquer and ght o future
stressors.
Research in rodents and primates supports the stress inoculation hypothesis and provides insight into its
neurobiological mechanisms. Young monkeys presented with a manageable stressor in the form of periodic
short maternal separations from postnatal weeks 17 to 27 experience acute distress during the separation
periods, manifested by behavioral agitation and temporarily increased cortisol levels. Later in life, however,
the same monkeys demonstrate lower anxiety (e.g., increased exploratory behavior in novel environments)
and lower basal stress hormone levels at nine months of age than monkeys who never underwent periods of
maternal separation. Furthermore, these stress-inoculated monkeys demonstrate higher cognitive control
assessed at 1.5 years, higher curiosity in a stress-free situation at 2.5 years, and larger ventromedial
prefrontal cortex (PFC) volume assessed with neuroimaging at age 3.3 years compared with their non–
stress-inoculated peers (Lyons et al., 2009). Poor cognitive control has been associated with depression in
humans. Of note, the size of the ventromedial PFC in humans predicts lower impulsivity, lower harm
avoidance, and greater retention of learned fear extinction (Lyons et al., 2009).
Just as in humans, the degree of control that an animal has over a stressor plays a key role in determining
whether the event will lead to subsequent vulnerability or resilience to stress. Animals administered
unavoidable and unpredictable shocks tend to develop exaggerated fear responses, heightened anxiety
states, and de cits in active coping when faced with subsequent stressors: this condition is known as
learned helplessness. The phenomenon of learned helplessness is a well-known animal model for depression
and is thought to lead to dysregulation of the serotonergic neurons in the dorsal raphé nuclei, as well as to
reduce hippocampal cell proliferation. Because 5-HT has far-reaching e ects in the limbic system, the
dysregulations created by learned helplessness likely have serious negative e ects on cognition and mood.
In contrast, animals that are administered shocks and given the ability to avoid them by modifying their
behavior do not develop learned helplessness. Furthermore, animals that have at one time experienced
behavioral control over predictable tail shocks are less likely than naïve animals to develop learned
helplessness if they are subsequently exposed to unpredictable and inescapable shocks. Similarly, human
beings that have been “stress inoculated” to one type of stressor by successfully managing the stressor
appear to acquire resilience to a broad range of other subsequent stressors. As noted by Rutter (2012),
limited evidence from human studies suggests that steeling might occur via the acquisition of self-e cacy
and mastery.
p. 491 It is important to note that even among animals administered unpredictable and unavoidable shocks, not all
develop learned helplessness. Similarly, in humans exposed to severe, unpredictable, and uncontrollable
traumas, not all go on to develop PTSD or other anxiety or panic disorders. Clearly, genomic factors interact
with environmental exposures to a ect resilience. A genetic pro le characterized by the presence of
protective alleles of polymorphisms in genes impacting stress reactivity are thought to confer an advantage
in the face of adverse developmental circumstances. Overall, multifaceted interactions between individual
genetic makeup, trauma characteristics, and other environmental factors in uence individual responses to
stress, even milder forms of stress, in complex ways.
Psychobiological Features of Resilience
Traits and Behaviors
Positive Emotions
Positive emotions play an integral role in the capacity to tolerate stress. The broaden-and-build theory
holds that positive emotions enable broader psychological and behavioral responses, ultimately building
enduring resources (Fredrickson, 2001). Positive a ect is associated with health-protecting factors
including greater social connectedness and adaptive coping mechanisms. Positive emotions also appear to
decrease autonomic arousal and facilitate cardiovascular recovery after negative arousal in response to a
stressor, leading to better physical health. Positive a ect has been associated with reduced use of medical
services; fewer stress-related illnesses; and decreased neuroendocrine, cardiovascular, and in ammatory
reactivity. More recently, dispositional positive a ect was found to predict lower in ammatory cytokine
levels in healthy college students, and a meditation exercise designed to generate positive emotions
increased perceptions of positive social connections in study participants and improved vagal tone, an index
of physical health (Kok et al., 2013). Similarly, dispositional optimism has been found to be associated with
greater psychological well-being, life satisfaction, health, and longevity, as well as with greater perceived
social support and constructive problem solving (Carver and Scheier, 2014). An optimistic disposition is
thought to be in large part inherited; however, motivated individuals can increase their optimism with
practice. Optimists maintain positive emotions even in the face of adversity because they tend to view
problems as temporary and limited in scope. Pessimists, on the other hand, tend to think of their problems
as permanent and pervasive and consequently are more prone to depression (Box 38.1). Positive appraisal
style is likely a core mechanism in resilience. Rather than overly positive appraisal of all stimuli, however,
resilience might be fostered by generally positive appraisals that are also accurate and realistic, leading to
appropriate responses (Southwick et al., 2015). Optimists are thought to have robust brain reward circuits,
which is discussed in further detail later in the chapter. Dispositional gratitude, another positive emotion
related to a generally appreciative outlook toward life, was shown in longitudinal studies to foster social
support and protect individuals from stress and depression.
Box 38.1 Selected Psychological Resilience Factors: Attitudes and Behaviors that
Can Help Maintain Well-Being During Stress
1. Positive emotions, positive and realistic appraisal style
Optimism is strongly related to resilience.
Optimism is in part inherited but can be learned through therapy.
Putative neurobiological mechanisms: robust brain reward circuits, decreased autonomic arousal.
2. Cognitive flexibility and reappraisal
Finding meaning or value in adversity.
Traumatic experiences can be reevaluated through a more positive lens.
Trauma can lead to growth: learn to reappraise or reframe adversity, finding its benefits; assimilate the event into
personal history; accept its occurrence; and recover.
Recognize that failure is an essential ingredient for growth.
Putative neurobiological mechanisms: memory reconsolidation, cognitive control over emotions.
3. Moral compass: embrace a set of core beliefs that few things can shatter
Live by a set of guiding principles.
For many, moral compass means religious or spiritual faith.
Altruism strongly associated with resilience: selfless acts increase our own well-being.
Putative neurobiological mechanisms: spirituality/religiosity associated with strong serotonergic system. Oxytocin can
enhance spirituality.
Morality has neural basis, likely evolved because adaptive.
4. Finding a resilient role model/mentor
Role models and mentors can help teach resilience: imitation is powerful mode of learning.
Putative neurobiological mechanisms: oxytocin mediates initial bonding/attachment. “Mirror”/Von Economo
neurons involved in neuronal imprinting of human values.
5. Facing fears: learning to move through fear
Fear is normal and can be used as a guide for action.
Facing and overcoming fears can increase self-esteem and sense of self-e icacy.
Practice undertaking and completing challenging or anxiety-inducing tasks.
Putative neurobiological mechanisms: promotes fear extinction, stress inoculation.
6. Active coping: seeking solutions, managing emotions
Resilient individuals use active rather than passive coping skills (dealing with problem and with emotions versus
resignation or avoidance).
Can be learned: work on minimizing appraisal of threat, developing positive views about oneself, focusing on aspects
that can be changed.
Putative neurobiological mechanisms: prevents fear conditioning and learned helplessness, promotes fear extinction.
7. Establishing and nurturing a supportive social network
Establish and nurture a supportive social network.

Very few can “go it alone”; resilient individuals derive strength from close relationships.
Social support is safety net during stress.
Putative neurobiological mechanisms: oxytocin mediates bonding/attachment, neural networks subserve automatic
emotional responses and voluntary emotion regulation during social interactions.
8. Physical exercise and attending to physical well-being
Physical exercise has positive e ects on physical and psychological hardiness.
E ective at increasing mood and self-esteem.
Putative neurobiological mechanisms: promotes neurogenesis, improves cognition, attenuates HPA activity, aids in
regulation of emotion, boosts immune system.
9. Other resilience factors
Training regularly (emotionally and physically), discipline.
Recognizing oneʼs own strengths and fostering them.
Modified and reprinted with permission from Cambridge University Press. © 2007, Cambridge University Press. In-depth
discussion in Southwick and Charney, 2012a.
Positive Cognitive Reappraisal

Cognitive reappraisal, or the ability to nd the silver lining in every cloud, is closely related to optimism and
strongly associated with resilience (Gross, 2002). The technique, also known as cognitive exibility or
cognitive reframing, refers to the purposeful, conscious transformation of emotional experience. Cognitive
reframing is the reinterpretation of traumatic events to nd their positive meaning, value, or the new
opportunity that they provide. It stands in contrast to suppression, which signi es conscious attempts to
forget traumatic events. Individuals who use cognitive reappraisal when dealing with trauma have less
anger and physiologic arousal than those who use suppression techniques (Gross, 2002). It is thought that
cognitive reappraisal works in part by attenuating biological stress responses.
The ability to nd personal meaning in tragedy is extraordinarily helpful in successfully overcoming

trauma. Viktor Frankl, psychiatrist and Holocaust survivor, attributes his survival of concentration camps
largely to this process of “meaning making”; in fact, meaning making became the basis for the school of
psychotherapy that he founded, known as logotherapy. On a long enforced march, weak from hunger and
cold, he wrote, “I forced my thoughts to turn to another subject. Suddenly I saw myself standing on the
platform of a well-lit, warm and pleasant lecture room. . . . I was giving a lecture on the psychology of the
concentration camp!” (Frankl, 1959/2006: p. 73). The conscious construction of this narrative and of the
meaning he would derive from his experiences provided Dr. Frankl with the psychological endurance to
survive his days in concentration camps.
The importance of integrating traumatic events into one’s personal life narrative was described over a
century ago by Pierre Janet, the French neurologist. Janet noted that his patients with posttraumatic
pathology had failed to integrate their traumatic memories into a cohesive story. Janet stressed the
necessity of cognitive reappraisal in preventing or overcoming posttraumatic stress: traumatic memories
“needed to be modi ed and transformed, that is, placed in their proper context and reconstructed into
neutral or meaningful narratives.” (van der Kolk and van der Hart, 1989).
Purpose in Life
A closely related concept to that of nding meaning is having a sense of purpose in life. Several cross-
sectional studies have documented an association between higher self-reported purpose in life and
resilience or recovery from psychiatric illness in traumatized populations (e.g., Alim et al., 2008; Feder et
al., 2013). Higher purpose in life was signi cantly associated with psychological well-being in a study of
veterans living with spinal cord injury, with resilience (compared to PTSD) in Operation Enduring Freedom-
Operation Iraqi Freedom (OEF-OIF) veterans (Pietrzak and Southwick, 2011), and less symptomatic PTSD
p. 492 symptom trajectories in World Trade
p. 493
Center rescue and recovery workers over a decade after the 9/11 attacks (Feder et al., 2016). In an
experimental study in an adult sample, higher purpose in life (assessed over two years earlier) predicted
better emotional recovery after viewing negative pictures, measured by the eyeblink startle re ex after
controlling for initial reactivity to the stimuli, suggesting a mechanism whereby purpose in life might
enhance resilience to stress (Schaefer et al., 2013).
Active Coping Styles

Active coping means deploying productive strategies for solving problems, managing stress, and regulating
negative emotions that may arise in the aftermath of adverse events. Active coping behaviors include
acknowledging and trying to solve problems, accepting that which cannot be changed, facing fears, using
humor and physical exercise to alleviate stress, and seeking out social support and role models. Active
coping has repeatedly been associated with hardiness and psychological resilience in various populations. In
contrast, passive coping, including the blunting of emotions through substance use, denial, disengagement,
or resignation, is associated with depression and lower levels of hardiness. Resilient adolescents exposed to
war in Gaza were more likely to use task-oriented and problem-solving approaches than avoidance and
venting. Several studies have shown an association between avoidance coping and psychopathology (e.g.,
Feder et al., 2016; Thompson et al., 2011).
Acceptance
Acceptance is an adaptive coping strategy commonly found among people who are able to tolerate extreme
and uncontrollable stress. Acceptance involves recognizing the uncontrollable aspects of certain stressors,
changing expectations about outcome based on reality, and focusing on controllable aspects of the stressor.
Not to be confused with resignation, which is giving up or coping passively, acceptance has been linked with
better physical and psychological health, lower levels of distress, and greater psychological adjustment after
trauma exposure (Thompson et al., 2011). Individuals who reported using acceptance as a coping style had
fewer PTSD symptoms following the terrorist attacks of September 11, 2001. In a new study, World Trade
Center rescue and recovery workers with improving or low PTSD symptom levels were more likely to report
using emotion-focused coping, including acceptance and positive reframing, than those in worsening or
chronic PTSD symptom groups (Feder et al., 2016).
Facing Fears
Facing fears is a key component of the active coping paradigm. Fear conditioning, which is discussed in
greater detail later in the chapter, plays a major role in the development and maintenance of posttraumatic
psychopathology. Individuals with PTSD avoid a wide variety of life’s opportunities (people, places, events,
etc.) that may serve as reminders of the trauma; thus, conditioned fear is maintained rather than
extinguished. In contrast, resilient individuals are more adept at managing fear, using it as a guide to
critically appraise threat and to select appropriate action. Results from an fMRI study in healthy volunteers
suggest that the ability of fear responses to adapt exibly as threat shifts from one stimulus to another is
mediated in particular by the ventromedial PFC.
Active coping at the time of trauma or when exposed to trauma reminders appears to attenuate fear
conditioning, likely by redirecting activity in the lateral and central nuclei of the amygdala away from the
brainstem and toward the motor circuits in the ventral striatum. This has the e ect of reducing brainstem-
mediated responses to fear, such as freezing behavior and autonomic and endocrine responses, and
enabling productive action. Resilient individuals have learned to face fears and actively cope with them; by
moving through fear, they avoid fear conditioning and are less likely to develop psychopathology and
functional impairments in the aftermath of trauma.
Humor
Humor, frequently used by resilient individuals, has been identi ed as an adaptive coping style and mature
defense mechanism. It appears that humor decreases the probability of developing stress-induced
depression. The use of humor has been studied in resilient Vietnam veterans, surgical patients, cancer
patients, and at-risk children, and has been shown to be protective against distress. Humor is thought to
diminish the threatening nature and negative emotional impact of stressful situations, fostering a more
positive perspective on challenging circumstances. A study of adult twin pairs found positive correlations
between positive humor styles (a liative, self-enhancing) and global mental toughness (e.g., emotional
control, con dence); these correlations were attributable to common genetic and nonshared environmental
factors. The use of humor also relieves tension and discomfort, and attracts social support. Humor is
thought to activate a network of subcortical regions that are critically involved in the dopaminergic reward
system (Mobbs et al., 2003).
Physical Exercise
Physical exercise has consistently been shown to have positive e ects on physical hardiness, mood, and
self-esteem. Individuals who exercise regularly report lower depression scores than those who do not
exercise. Physical exercise has e ects on a number of neurobiological factors that a ect resilience. It
attenuates the HPA axis response to stress, increases release of endorphins, and increases levels of plasma
monoamines and the 5-HT precursor tryptophan. It has also been found to induce the expression of genes
coding for trophic factors, in particular BDNF in the hippocampus, thus promoting neuroplasticity and
neurogenesis. Exercise also appears to enhance expression the gene coding for galanin (a neuromodulatory
peptide and trophic factor) in the locus coeruleus, and the NPY gene in the hippocampus, as reviewed. Other
animal studies have shown that exercise helps contain the stress response via central sympathetic,
serotonergic, and dopaminergic reward pathways, resulting in protection from stress-induced
p. 494 immunosuppression, cytokine elevation, and a ective dysregulation (Fleshner et al., 2011). In human
studies, exercise has been shown to reduce the rate of cognitive decline that normally occurs with aging, as
well as the risk of Alzheimer’s disease and other dementias.
Social Support
Higher levels of social support have been associated with better mental and physical health outcomes
following a wide variety of stressors (Southwick et al., 2016). In a study of survivors of the 2005 earthquake
in Pakistan, higher perceived social support was associated with higher self-reported positive emotions,
after adjusting for PTSD symptom severity (Feder et al., 2013). Conversely, lower levels of social support
have been linked to PTSD and other psychiatric disorders. In a study of OEF-OIF veterans, resilience was
associated with self-reports of greater family support and understanding (Pietrzak and Southwick, 2011).
Social support is thought to decrease appraisals of threat, counteract feelings of loneliness, increase sense
of self-e cacy, and reduce functional impairment. Role models and mentors form a valuable part of a
strong social support network. In a study mentioned, increased perceptions of social connections with
others were found to mediate the e ect of enhancing positive emotions on physical health (Kok et al., 2013).
On the other hand, social isolation and lack of social support are associated with higher rates of mood and
anxiety disorders, higher levels of stress, and increased morbidity and mortality from medical illness.
Individuals who are able to seek and nurture a supportive social network during times of stress tend to fare
better in the face of adversity than individuals who are socially isolated.
Moral Compass: A Set of Guiding Ethical Principles

Moral compass, an internal framework of belief about right and wrong, is another feature common to
resilient individuals (Southwick and Charney, 2012a). This construct may, but does not have to, include
adherence to a religious or spiritual system.
Religion and spirituality seem to have a protective e ect on physical and psychological well-being. A meta-
analysis of 126,000 individuals from 42 independent samples found religious practice or involvement to be
associated with lower risk of mortality from all causes (McCullough et al., 2000). In addition, higher levels
of religious belief have been correlated with lower incidence of depression and higher rates of remission
from depression in a number of populations. Interestingly, one’s particular religious a liation is not
implicated in the overall relationship between religiousness and improved psychological and physical
health.
Some evidence suggests that spiritual or self-transcendent experiences are associated with increased
density of 5-HT1A receptors in the dorsal raphé nuclei, hippocampus, and neocortex. Chronic stress appears
to lead to a downregulation of 5HT1A receptors; spirituality and religiosity may enhance the functioning of
the 5-HT system, fostering resilience and protecting against the development of posttraumatic mental
illness. A new study found that intranasally administered oxytocin increased self-reported spirituality, and
that this increase was moderated by oxytocin-related genotypes (Van Cappellen, et al., 2016).
Religious faith or spirituality is not an essential ingredient in a strong moral compass. In fact, morality
appears to have a neural basis and is likely intrinsic to human nature. The idea that morality is inherent to
human beings can be traced back to Epictetus, a Greek philosopher living in Rome in the rst century A.D .
Moral sense likely developed early in human evolution as our ancestors organized into societies: the
successful functioning of society requires cooperation and trust between members. Many studies support
the notion that principles of cooperation and reciprocity are ingrained within human nature. Games
designed to test participants’ morality repeatedly nd that human beings act according to the rule that
fairness to others should supersede self-interest. For example, in games in which participants are given
money to divide between themselves and strangers, most participants choose to divide the money equally
among players. Furthermore, participants who play fairly in such games tend to show heightened activation
of their dopaminergic reward systems on imaging studies. These ndings provide support for the
hypothesis that people know what is right and derive ful llment from acting accordingly.
Altruism
Altruism, or putting one’s moral compass into action, is a powerful contributor to resilience. For example,
research on the behavior of citizens after bombing attacks during World War II showed that those who
demonstrated altruism by caring for others su ered fewer trauma-related mood and anxiety symptoms
than would be expected. Furthermore, individuals who had been symptomatic pre-attack experienced a
meaningful decrease in psychological distress. It appears that, similar to acting fairly, performing acts of
altruism activates brain reward circuits. Several fMRI studies have shown activation of reward-related brain
regions, such as the striatum, during charitable donation tasks, while dysfunctional reward processing has
been reported in studies of individuals with PTSD or subthreshold PTSD (Wei et al., 2013).
Some individuals are able to nd meaning in personal tragedy by embracing a survivor mission to help
others. Rape survivors who go public with their experience to raise social awareness through events such as
Take Back the Night, and the mothers who founded Mothers Against Drunk Driving after their children were
injured or killed in drunk driving accidents, are examples of this phenomenon.
Neurobiological Profile of Resilience
A complex web of neurotransmitters, neuropeptides, and hormones, as well as immune system signaling
molecules, has been implicated in acute and long-term adaptation to stress. A comprehensive review of the
many functions and e ects of these factors is beyond the scope of this chapter; we focus speci cally on the
p. 496 factors’ role in mediating the stress response (Table 38.1, Figure 38.1).
p. 495
Table 38.1 The Neurochemical Response Patterns to Acute Stress
Neurochemical Acute E ects Brain Region Key Functional Association with Association with
Interactions Resilience Psychopathology Potential
for Treatment?
CRH Activated fear Prefrontal cortex, cingulated CRH-1 receptor Reduced CRH
Persistently increased CRH
behaviors, increased cortex, amygdala, nucleus anxiogenic, CRH-2 release, adaptive
concentration may predispose
arousal, increased accumbens, hippocampus, receptor anxiolytic, changes in CRH-1
to PTSD and mood disorders as
motor activity, inhibited hypothalamus, bed nucleus of increases cortisol and CRH-2
well as stress-related
neurovegetative the stria terminalis, and DHEA, activates receptors
gastrointestinal disorders.
function, reduced periaqueductal gray matter, locus coeruleus–
reward expectations locus coeruleus, dorsal raphé norepinephrine CRH receptor antagonists
nuclei system investigated to date as
treatments for stress-related
disorders not associated with
significant symptom
improvement.
Cortisol Mobilized energy, Prefrontal cortex, Increases amygdala Stress-induced

Dysregulated cortisol systems
increased arousal, hippocampus, amygdala, corticotrophin- increase rapidly
(excessive cortisol release,
focused attention hypothalamus releasing hormone constrained by
improperly functioning
(CRH), increases negative
negative feedback systems)
hypothalamic CRH feedback
seen in mood disorders and
mechanisms
PTSD.
Hydrocortisone augmentation
of exposure therapy under
investigation.
Dehydroepi- Counteracts deleterious Largely unknown; Antiglucocorticoid High DHEA- Low DHEA response to stress
androsterone e ects of high cortisol hypothalamus actions cortisol ratios may predispose to PTSD and
(DHEA) Neuroprotective may prevent/ depression and sensitize to the
Positive mood e ects lessen severity of e ects of hypercortisolemia.
PTSD and DHEA supplementation has
depression. shown beneficial e ects on
depressive symptoms.
Locus coeruleus– General alarm function Prefrontal cortex, amygdala, Activates Reduced
Unrestrained functioning of
norepinephrine activated by extrinsic hippocampus, hypothalamus sympathetic axis, responsiveness of
locus coeruleus–
system and intrinsic threat; inhibits locus coeruleus–
norepinephrine system, seen
increased arousal, parasympathetic norepinephrine
in some patients with PTSD,
increased attention, fear outflow, stimulates system
leads to chronic anxiety,
memory formation, hypothalamic CRH
hypervigilance, and intrusive
facilitated motor
memories.
response
Beta-receptor blockade shortly
a er trauma exposure has
yielded mixed results; under
investigation to disrupt
memory reconsolidation.
Neuropeptide Y Amygdala, hippocampus, Reduces CRH- Adaptive increase

Anxiolytic Low NPY associated with PTSD
(NPY) hypothalamus, septum, related actions at in amygdala
Improves performance periaqueductal gray matter, amygdala, reduces neuropeptide Y is Y-l and Y-2 receptors may be
under stress locus coeruleus rate of firing of locus associated with targets for treating mood and
coeruleus. reduced stress- anxiety disorders. NPY
induced anxiety administration may protect
and depression. against stress.
Serotonin (5-HT) Mixed e ects: 5-HT Prefrontal cortex, amygdala, High levels of High activity of Low activity of postsynaptic 5-
stimulation of 5-HT2 hippocampus, dorsal raphé cortisol decrease 5- postsynaptic 5- HT1A receptors may predispose
receptors is anxiogenic; HT1A receptors. HT1A receptors to anxiety and depression.
5-HT stimulation of 5- may facilitate
HT1A receptors is recovery.
anxiolytic
Dopamine High prefrontal cortex Prefrontal cortex, nucleus Reciprocal Within optimal
Excessive mesocortical
and low nucleus accumbens, amygdala interactions window of
dopamine release associated
accumbens dopamine between cortical activity,
with vulnerability to stress
levels are associated and subcortical preserves
with anhedonic and dopamine systems functions Persistently high levels of
helpless behaviors involving reward prefrontal cortical dopamine
and extinction of associated with chronic
fear anxiety and fear
Low levels of circulating
dopamine linked to
depression.
Brain-Derived Supports neuronal Hippocampus, cerebral cortex, Exerts di erent High level of Antidepressants can reverse
Neurotrophic growth, di erentiation striatum functions in BDNF in stress-induced decrease in
Factor (BDNF) and survival; involved in di erent brain hippocampus BDNF expression in
fear conditioning, regions promotes stress hippocampus.
extinction, and (antidepressant and resilience
inhibitory learning depression-like
e ects)
Glutamate Excitatory synaptic Frontal cortex, amygdala, Primary receptors Increased AMPA NMDA receptor antagonism
signaling hippocampus, cingulate cortex NMDA and AMPA; receptor and AMPA receptor activation
memory formation activation may are novel approaches to
and learning promote depression and PTSD
antidepressant treatment.
e ects
Oxytocin Modulates stress Hypothalamus, nucleus Reduces amygdala Modulates stress Intranasal oxytocin
responses and social accumbens, amygdala, bed reactivity, enhances reactivity, administration under
emotional functions, nucleus of the stria terminalis, functional increases social investigation for treatment of
facilitates emotion prefrontal cortex connectivity of connectedness, anxiety and other disorders;
recognition, increases amygdala with mediates social potential in PTSD treatment.
prosocial behavior insula and ACC reward
Endocannabinoids Regulate HPA axis Prefrontal cortex, Actions at CB1 and Optimal function Enhanced action of
(eCBs) activity under basal and hypothalamus, amygdala, CB2 receptors; of endocannabinoids at the CB1
stressful conditions hippocampus regulation of HPA endocannabinoid receptor might reduce
axis activity signaling excessive stress responses.
regulates stress
hormone
responses
AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; CRH, corticotrophin-releasing hormone; NMDA, N-methyl-D -aspartate; PTSD, posttraumatic
stress disorder.
Modified and reprinted with permission from Cambridge University Press. © 2007, Cambridge University Press
Figure 38.1
Neurochemical response patterns to acute stress. This figure illustrates some of the key brain structures involved in the
neurochemical response patterns following acute psychological stress. The functional interactions among the di erent
neurotransmitters, neuropeptides, and hormones are emphasized. The functional status of brain regions such as the amygdala
(neuropeptide Y [NPY], glutamate, corticotropin-releasing hormone [CRH], cortisol, endocannabinoids [eCBs], oxytocin,
dopamine, norepinephrine, and galanin), hippocampus (cortisol, eCBs, serotonin, norepinephrine, brain-derived neurotrophic
factor [BDNF], glutamate, and NPY), locus coeruleus (norepinephrine, galanin, NPY, and CRH), and prefrontal cortex (serotonin,
dopamine, norepinephrine, galanin, CRH, cortisol, eCBs, glutamate, BDNF, and oxytocin) depends upon the balance among
multiple inhibitory and excitatory neurochemical inputs. Functional e ects may vary depending on the brain region. For
example, cortisol increases CRH concentrations in the amygdala and decreases concentrations in the paraventricular nucleus of
the hypothalamus. As described in the text, these neurochemical response patterns may relate to resilience and vulnerability to
the e ects of extreme psychological stress. (Modified and reprinted with permission from Cambridge University Press, 2007.)
p. 497 Corticotropin-Releasing Hormone

The hypothalamus releases CRH in conditions of stress, activating the pituitary-adrenal axis and triggering
the release of cortisol and dehydroepiandrosterone (DHEA). CRH also has important direct e ects in the
central nervous system; CRH-containing neurons and CRH receptors are distributed widely throughout the
brain and gut. Activation of CRH neurons in the amygdala triggers fear-related behaviors, whereas
activation of cortical CRH neurons reduces expectation of rewards. Excessive stress in early life can result in
abnormally elevated CRH activity in the adult brain.
Corticotropin-releasing hormone acts via two G-coupled receptors, CRH-1 and CRH-2. These receptors
appear to have opposite e ects in the response to stress; the CRH-1 receptor primarily activates the
behavioral, endocrine, and visceral responses to stress. Elevated hippocampal CRH–CRH-1 interaction may
contribute to the structural and cognitive impairments associated with early life stress. CRH-1 receptor gene
single nucleotide polymorphism rs110402 was found to moderate neural responses to emotional stimuli,
thereby potentially increasing vulnerability for the development of psychiatric disorders. The CRH-2
receptor generally serves to dampen these e ects. However, activation of the CRH-2 receptor does produce
some anxiogenic e ects, for example, enhancing CRH-1 mediated suppression of feeding behavior. More
research is necessary to determine the precise role of both receptors.
Abnormally high CRH levels in the cerebrospinal uid have been linked to major depression and PTSD.
Resilient individuals likely have the capacity to e ectively regulate CRH levels and/or the relative activity of
both receptor subtypes. Gender di erences in corticotropin response to CRH challenge may explain
di erential gender susceptibility to psychopathology following early life trauma (DeSantis et al., 2011).
Although initial studies showed promise for the use of CRH-1 receptor antagonists as potential new
pharmacotherapies for anxiety and mood disorders as well as for stress-related gastrointestinal disorders
such as irritable bowel syndrome, subsequent clinical trials failed to show a bene cial e ect of these
compounds in patients with major depression, generalized anxiety disorder, or PTSD.
Cortisol
Many forms of psychological stress increase the synthesis and release of cortisol, which leads to increased
arousal, vigilance, inhibition of growth and reproduction, and containment of the immune response. In
resilient individuals, the stress-induced increase in cortisol is e ectively constrained via an elaborate
negative feedback system involving GR and mineralocorticoid receptors. Excessive and sustained cortisol
secretion can have serious adverse e ects, including osteoporosis, immunosuppression, hypertension,
metabolic syndrome, depression, and anxiety (Karatsoreos and McEwen, 2013).
p. 498 Cortisol has important regulatory e ects on the hippocampus, amygdala, and PFC. It plays a role in the
formation, processing, and retrieval of memories, particularly fearful memories. Cortisol levels tend to be
dysregulated in depression and PTSD. Patients with major depressive disorder tend to have higher than
normal levels of cortisol and a blunted suppression of cortisol secretion in response to the dexamethasone
suppression test. In contrast, basal circulating cortisol levels are generally lower in individuals with PTSD
than in healthy individuals (Daskalakis et al., 2013). A prospective study of soldiers before and at 12 months
post-deployment found that lower hair cortisol concentrations and lower cortisol stress reactivity at
baseline were predictive of a greater increase in PTSD symptomatology after trauma exposure.
Correspondingly, individuals with PTSD tend to show higher-than-average cortisol suppression during the
dexamethasone suppression test, implying that their HPA axis GRs are hypersensitive. Altered HPA axis
function is associated with impaired fear inhibition in subjects with PTSD. Women with PTSD having lower
basal salivary cortisol levels than men with PTSD might contribute to the gender di erence in PTSD
prevalence between men and women.
That patients with PTSD might have lower-than-average basal cortisol levels suggests that the disorder
may develop in the setting of abnormally low cortisol; this hypothesis is supported by a number of studies
showing that steroid administration inhibits traumatic memory formation, as well as more recent and
ongoing studies of high-dose glucocorticoid administration in the acute aftermath of trauma aimed at
preventing PTSD (Daskalakis et al., 2013). Patients who were pretreated with stress doses of glucocorticoids
before surgery and/or hospitalization in the intensive care unit were less likely to have traumatic memories
of their hospital stay after discharge than patients treated with placebo.
Although there are a great deal of data suggesting that patients with PTSD have lower basal cortisol than
healthy controls and that PTSD may develop in the setting of low glucocorticoid levels, there is also
con icting evidence. Some studies have found no di erence in cortisol levels between patients with PTSD
and healthy controls, and some have even found that patients with PTSD have higher-than-average basal
cortisol levels, and that elevated cortisol at the time of trauma may predict subsequent PTSD development.
In summary, though it is clear that cortisol is implicated in the encoding of traumatic memories and in the
subsequent development of posttraumatic psychopathology, the exact nature of this e ect is still under
investigation. Undoubtedly though, dysregulation of cortisol secretion has adverse e ects on resilience to
stress.
Treatment aimed at enhancing resilience may also normalize cortisol rhythms. For example, intervention
programs targeting children and families at risk (e.g., Child Protective Service (CPS) referrals, foster care)
have been shown to normalize cortisol rhythms (e.g., Bernard et al., 2015). In a study of prolonged exposure
therapy for military veterans, cortisol augmentation (hydrocortisone) was associated with greater reduction
in total PTSD symptoms compared to placebo (Yehuda et al., 2015). Additionally, pending further research,
it may be possible to utilize cortisol reactivity as predictor of treatment outcome.
Dehydroepiandrosterone
Like cortisol, dehydroepiandrosterone (DHEA) is an adrenal steroid released under stress; in contrast to
cortisol, DHEA protects against the negative e ects of excessive stress. DHEA is secreted episodically and
synchronously with cortisol and has antiglucocorticoid activity in the brain. DHEA and its metabolites
interfere with the normal uptake of GRs in the hippocampus, preventing corticosteroid-induced
hippocampal neurotoxicity. DHEA derivatives also amplify long-term potentiation of hippocampal neurons,
likely by modulating transmission at the N-methylD - aspartate (NMDA) receptor. DHEA and uoxetine
were found to have synergistic e ects in promoting hippocampal progenitor cell proliferation. The steroid’s
neuroprotective and potentiating e ects in the hippocampus help to facilitate learning and memory.
Studies have shown that DHEA is released under both acute and chronic stress, and that higher levels of
DHEA are associated with PTSD and comorbid depression, whereas a higher DHEA-to-cortisol ratio may
mitigate symptom severity). However, one study found no evidence for PTSD-related alterations in cortisol
or DHEA secretion in response to stimulation by low doses of adrenocorticotropic hormone (ACTH),
indicating normal adrenocortical responsiveness in PTSD.
DHEA appears to enhance cognition and performance under stress. In a study of soldiers undergoing
rigorous training as part of military survival school, DHEA-S (dehydroepiandrosterone sulfate) to cortisol
ratios were highest in those soldiers who demonstrated the best performance during training. Thus, DHEA-
S to cortisol ratios may index the degree to which an individual is bu ered against the negative e ects of
stress. In another study, DHEA and DHEA-S levels predicted superior performance in active duty soldiers
undergoing an underwater navigation exam. Recovery from severe stress in PTSD patients also appears to
be facilitated by high levels of DHEA. In a cross-sectional study of a nonclinical sample, a positive
association was observed between resilience (assessed by the 25-item Connor-Davidson Resilience Scale)
and DHEA levels in saliva (Petros et al., 2013).
Other studies have also found a negative correlation between plasma DHEA levels and depressive symptoms.
Studies of DHEA supplementation have shown some bene cial e ects on depressive and PTSD symptoms,
but further research is needed. Animal studies suggest that the antidepressant action of DHEA is mediated
via GABAergic modulation of the mesolimbic system. In a study of military men participating in survival
training, low-dose DHEA supplementation was found to enhance anabolic balance but did not result in
di erences in subjective distress. A recent meta-analysis of clinical studies reported lower DHEA-S levels in
depressed individuals; however, this pattern was not observed in Caucasian or Asian depressed patients in
further analyses strati ed by ethnicity. More research is needed to determine whether DHEA could enhance
resilience if administered prior to trauma exposure.
p. 499 The Locus Coeruleus–Norepinephrine System
Stress activates the locus coeruleus (LC), which results in increased norepinephrine (NE) release in
projection sites of the LC, including the amygdala, PFC, and hippocampus. The LC is activated by a variety of
stressors, intrinsic (e.g., hypoglycemia, hypotension) and extrinsic (environmental threats). Such activation
serves as a general alarm function and is adaptive in a life-threatening situation. Activation of the LC
contributes to the sympathetic nervous system and HPA axis stimulation and inhibits parasympathetic
out ow and neurovegetative function, including eating and sleep. A high level of activation of the LC–NE
system inhibits function of the PFC, thereby favoring instinctual responses over more complex cognition. A
study in rats showed that during early adolescence, social stress in the form of a resident intruder led to
elevated activity of LC neurons, promoting defensive behaviors in this particular age group. A recent study’s
ndings suggest that this result may be speci c to adolescence. The study demonstrated that social stress in
adolescent rats led to elevated LC neuronal and network activity, which remained elevated in the absence of
the stressor. However, the LC neuron activity of adult rats was relatively inhibited in the absence of the
stressor, providing preliminary evidence that adaptive mechanisms promoting stress recovery in the LC–
NE system may not be fully developed during adolescence (Zitnik et al., 2016).
The activation of the HPA and LC–NE systems under acute stress facilitates the encoding and relay of
aversively charged emotional memories, beginning at the amygdala. Animal studies have shown that
injections of NE into the amygdala enhance memory consolidation; on the other hand, blocking NE activity
during stress impedes the encoding of fearful memories. In rats, blocking the lateral nucleus of the
amygdala to the e ects of NE during reactivation of a fearful memory prevents the process of memory
reconsolidation and appears to permanently impair that memory. If unchecked, persistent
hyperresponsiveness of the LC–NE system contributes to chronic anxiety, fear, intrusive memories, and an
increased risk of cardiovascular disease and hypertension. Findings from an imaging study in humans
suggest that disinhibited endogenous NE signaling may contribute to the etiology of PTSD by eliciting
exaggerated basolateral amygdala (BLA) responses to fear stimuli. Noradrenergic activation in the BLA is
also involved in the facilitating e ects of stress hormones (such as CRH) on the consolidation of emotional
memory. Interestingly, norepinephrine was shown to directly activate multipotent neural precursors in the
hippocampus of adult mice via β3 adrenoreceptors, thus facilitating hippocampal neurogenesis; these
ndings may pave the way for the development of new types of antidepressants. A cross-sectional study
utilizing positron emission tomography (PET) imaging built upon preclinical ndings to demonstrate that
PTSD is associated with decreased NE transporter (NET) availability in the LC compared to healthy controls.
Interestingly, within the PTSD group, greater NET availability in the LC was also independently and
positively associated with increased severity of anxious arousal symptoms (e.g., hypervigilance), providing
preliminary support that a dysregulated LC–NE system may underlie anxious arousal symptoms in PTSD
(Pietrzak et al., 2013).
In rat studies, exercise (wheel running) has been found to enhance expression of the neuropeptide galanin
in the LC and suppress LC norepinephrine activity induced by stress. Galanin has been shown to be involved
in a number of physiological and behavioral functions, including anxiety, stress, and alcohol intake, and
appears to mitigate the e ects of stress. A recent series of experiments in rats suggest that galanin mediates
the promotion of resilience by exercise; both exercise and intracerebral administration of galanin prevented
anxiety responses to stress, as well as loss of dendritic spines in the mPFC.
Neuropeptide Y
Neuropeptide Y (NPY) is an abundant peptide that is widely distributed throughout the brain and acts via at
least four G-protein coupled receptors (Y1, Y2, Y4, Y5). The Y3 receptor has yet to be cloned, and the y6
receptor is a truncated receptor in humans (Wu et al., 2011). Neuropeptide Y produces anxiolytic e ects and
appears to enhance cognitive functioning under stress. There are important functional interactions between
NPY and CRH. NPY counteracts the anxiogenic e ects of CRH at various locations within the stress/anxiety
circuit, including the amygdala, hippocampus, hypothalamus, and LC. It may be that the balance between
NPY and CRH neurotransmission is critical to maintaining a homeostatic emotional state during stress. A
recent study in rats, evaluating the impact of stress exposure at di erent time points in the circadian cycle
of corticosterone release, has further clari ed the role of NPY in enhancing resilience to stress.
High levels of NPY appear to protect against depression and anxiety, with the Y1 and Y2 receptors playing
important roles in the peptide’s e ects on mood. The Y1 receptor was found to be anxiolytic, whereas the Y2
receptor, a presynaptic autoreceptor, was found to be anxiogenic (Wu et al., 2011). Neuropeptide Y activation
of the Y1 receptor inhibits several metabolic and behavioral stress responses, including gastrointestinal
distress, anxious behavior, and decreased sleep. Antidepressant drugs and electroconvulsive therapy
increase NPY in rodent brains as they decrease depression; this e ect is likely mediated by the Y1 receptor. A
variety of antidepressant drugs increase NPY levels in humans as well.
The potential role of NPY in fear conditioning is under investigation. In one study, central administration of
NPY in rats inhibited fear-potentiated startle and enhanced its extinction; the latter e ect was counteracted
by the Y1 receptor antagonist BIBO3304. In another study, however, whereas fear conditioning was
attenuated by exogenous NPY administration, BIBO3304 had no e ect on conditioned fear; thus the role of
endogenous NPY is more uncertain. In a more recent study, intracerebral administration of low doses of
NPY in rats was associated with marked inhibition of contextual fear conditioning, an e ect at least partially
mediated by the Y1 receptor.
Y2 knockout mice exhibit fewer anxious and depressed behaviors and reduced neuronal activation in
p. 500 response to the emotional stressors, and are more adventurous. Site-speci c deletion of the Y2 receptor
gene in the central and basolateral amygdala, but not in any other amygdaloid nucleus, results in anxiolytic
and antidepressant-like e ects, suggesting a possible mechanism for Y2 receptor-mediated regulation of
anxiety and depression. The Y1- and Y2-receptors may therefore be useful targets for treating mood and
anxiety disorders in humans.
Elevated NPY levels are associated with better performance under stress. In human studies, preliminary
work with special operations soldiers under extreme training stress showed an association between high
NPY levels and better performance. The Y1 receptor in the BLA has been implicated in the mediation e ects
of NPY on stress and may serve as a therapeutic target for the treatment of PTSD. The role of NPY has been
investigated further in animal models of depression and of PTSD. In a genetic model of depression in rats,
allele-speci c epigenetic changes were reported in the NPY gene, which might underlie NPY dysregulation
in the rat hippocampus. Recent animal studies have begun to examine stress-induced changes in NPY gene
expression in the brain (Reichmann and Holzer, 2016).
In a rat model of PTSD, NPY treatment after exposure to predator scent stress was associated with
behavioral resilience (Cohen et al., 2012). Using a di erent rat model of PTSD, namely, single prolonged
stress (SPS), intranasal administration of NPY attenuated dysregulation of HPA axis and LC–NE activity as
well as the development of PTSD-like symptoms (Serova et al., 2013). Intranasal NPY administration also
reversed behavioral symptoms emerging after SPS and prevented HPA axis dysregulation when
administered immediately after SPS. Altogether, ndings from these studies suggest that the
administration of NPY could be an e ective intervention for the treatment of depression, anxiety disorders,
and PTSD, and for enhancing resilience to stress. However, in order to translate preclinical ndings into a
treatment or preventive intervention, it will rst be necessary to optimize a drug delivery method that
enables the peptide to penetrate into the CSF; intranasal NPY administration in humans is being
investigated.
Serotonin
Serotonin (5-HT) is well known as one of the neurotransmitters most relevant to mood. As a
neuromodulator, 5-HT also regulates other neurotransmitter systems involved in mood and anxiety, and
dysregulation of the 5-HT system may cause a cascade of changes in brain chemistry. The role of 5-HT as a
neuromodulator is demonstrated in tryptophan depletion studies, whereby serotonin levels are lowered by
ingestion of a tryptophan-free amino acid mixture. For example, tryptophan depletion led to failure to
inhibit appropriate responses to punishing outcomes in healthy females, and uncovered a potential
vulnerability in never-depressed young adults at high familial risk for depression, who showed increased
bias toward negative words while performing an a ective go/no-go task in the depletion condition
compared to low-risk controls.
Acute stress results in increased 5-HT turnover in the PFC, nucleus accumbens, amygdala, and lateral
hypothalamus. Serotonin release may have anxiogenic and anxiolytic e ects, depending on the region of the
forebrain involved and the receptor subtype activated. 5-HT1A receptors are anxiolytic and may be
responsible for adaptive responses to aversive events, whereas anxiogenic e ects appear to be mediated by
5-HT2A receptors. Absence of 5HT1A receptor signaling during early stages of brain maturation predisposes
an organism to a ective dysfunction later in life. 5HT1A knockout mice show an increase in anxiety-like
behaviors, including behavioral inhibition in ambiguous environments (settings that contain neutral and
fear-conditioned cues). This type of behavior represents an inappropriate generalization of fearful
behavior, a phenomenon that occurs in some human anxiety disorders, including panic disorder, speci c
phobias, and PTSD. Therefore, lower-than-normal activation of 5HT1A receptors may be involved in the
pathophysiology of human anxiety disorders. On the other hand, antagonism of 5HT2A receptor has been
shown to prevent the emergence of anxiety behavior and dysregulated stress response following early life
stress.
A scenario has been proposed in which early life stress increases CRH and cortisol levels, which, in turn,
downregulate 5HT1A receptors, resulting in a lower threshold for tolerating stressful life events. Consistent
with ndings in rodents and nonhuman primates, a negative association is found between plasma cortisol
levels and 5HT1A receptor distribution in humans (Lanzenberger et al., 2010). Alternatively, 5HT1A receptor
density may be partly genetic. Data so far have been mixed. A PET study scanning receptor status in
individuals with PTSD found no di erences in 5HT1A receptor distribution, binding potential, or tracer
delivery, whereas a more recent PET study in Rhesus monkeys showed that reduced 5HT1A receptor density
during development might be a factor increasing vulnerability to stress-related neuropsychiatric disorders.
The cholinergic system, comprised of nerve cells that use acetylcholine in the transduction of action
potentials, may act synergistically with the 5-HT system; for example, nicotinic acetylcholine receptor
(nAChR) blockers are known to potentiate the e ects of SSRIs, particularly in treatment-refractory
depression. A recent preclinical study found that expression of the 5HT1A serotonin receptor in the
hippocampus was necessary to observe both the antidepressant e ects and social stress resilience behaviors
induced by a nicotinic acetylcholine receptor partial agonist, cytisine.
The Brain–Gut Axis
The brain–gut axis refers to the bidirectional communication system between the central nervous system
and the gastrointestinal tract; serotonin is a key neurotransmitter on both terminals of the axis. Recently,
research has focused on the gut microbiome, in particular the microbial regulation of tryptophan
metabolism and the serotonergic system, and how gut microbiota in uences brain function and behavior
(Kennedy et al., 2017). The serotonergic system may be vulnerable to distinct microbial colonization
patterns prior to the establishment of a stable adult-like gut microbiota.
Known gut functions of 5-HT include epithelial secretion, satiation, pain, and discomfort. Novel
gastrointestinal functions of 5-HT continue to be researched. Within the gut, 5-HT promotes in ammation
p. 501 and serves as a trophic factor to enhance the development and maintenance of neurons. Experimental
and preliminary clinical data have indicated that an imbalanced gut microbiota in early life may have
enduring immune and physiologic e ects that in turn could heighten susceptibilty to developing PTSD
following a traumatic event (Leclercq et al., 2016). To note, much of the current research on the gut
microbiota has been completed in preclinical models, and the translational applications of these new
ndings are still in progress. Therapeutic targeting of the gut microbiota may be a novel strategy for the
treatment of serotonin-related stress disorders.
Dopamine
Dopamine (DA) is released in some areas of the brain and inhibited in others during extreme stress. Stress
activates DA release in the mPFC and inhibits DA release in the nucleus accumbens, one of the regions
associated with human experience of pleasure and reward. Lesions of the amygdala in a conditioned stress
model block stress-induced DA activation in the mPFC, implying amygdalar control over stress-induced DA
release. DA D1 receptors were shown to be responsible for stress-induced de cits of emotional learning and
memory. The degree to which an individual’s DA system is activated by stress is in part genetically
determined, and individuals whose genetic pro le results in excessive mesocortical DA release after
stressful events may have a tendency toward vulnerability to stress. Variation in the dopamine transporter
gene may contribute to one heritable path toward the development of PTSD. Polymorphisms in the
dopamine D2 receptor gene might also contribute to susceptibility to PTSD. As mentioned in the earlier
discussion on NE, studies of individuals with low-functioning variants of the COMT gene, leading to less DA
degradation, display higher anxiety and lower resistance to stress. A recent study (Li et al., 2016)
demonstrated that dopamine transporter gene haplotypes in children interact with early parenting quality
to predict children’s e ortful control (EC), an important dimension of temperament critical to children’s
resilience and adjustment.
In animal studies employing the social defeat stress paradigm, susceptible and resilient phenotypes
emerging after ten days of the stress were found to be causally related to di erential molecular changes in
the mesolimbic DA pathway, comprising the ventral tegmental area (VTA) and its terminals projecting to
the nucleus accumbens (Wook Koo et al., 2016). Only in resilient mice did social defeat stress lead to
di erential regulation of synaptic strength in medium spiny neurons expressing certain subtypes of DA
receptor in the nucleus accumbens, a neuroadaptive mechanism that might mediate active coping and
resilience to stress.
Other studies in rodents have identi ed a central role of DA in facilitating extinction learning, by
consolidating the fear extinction memory in the mPFC. Thus underactivity of dopaminergic neurons in the
PFC might be implicated in sustaining PTSD. In a study of PTSD patients compared to trauma-exposed
controls, dopamine transporter density was found to be greater in PTSD patients, possibly re ecting higher
dopamine turnover in PTSD, in turn contributing to perpetuating heightened fear responses to trauma
reminders. Reduced levels of circulating DA have also been implicated in depression in a number of studies.
Brain-Derived Neurotrophic Factor

Brain-derived neurotrophic factor (BDNF) is an important neurotrophic factor that is active in brain regions
including the hippocampus, cortex, and basal forebrain. BDNF helps support neuronal growth,
di erentiation, and survival, and has an important role in synaptic plasticity (Mahan and Ressler, 2012).
BDNF interacts with tyrosine receptor kinase B (TrkB) and p75 as its two main receptors. The BDNF-TrkB
pathway has been implicated in both PTSD in humans and in animal models of fear conditioning, extinction,
and inhibitory learning (Mahan and Ressler, 2012). Of note, in ammatory cytokines also in uence BDNF
receptor (TrkB) phosphorylation, interfering with BDNF signaling. Inhibition of BDNF signaling in the
amygdala can lead to impairment of acquisition and consolidation of fear conditioning, and to consolidation
of extinction learning.
BDNF exerts di erent functions in di erent brain regions. Animal studies have shown that hippocampal
BDNF expression plays a critical role in resilience to chronic stress. In animal studies, stress decreases BDNF
expression in the hippocampus, which is reversible by antidepressant treatment. On the other hand,
increased BDNF expression in the nucleus accumbens following social defeat stress mediates the susceptible
phenotype in mice, characterized by depressive-like symptoms (Wook Koo et al., 2016).
There is some evidence for an association between a single nucleotide polymorphism in the BDNF gene
(Val66Met) and various psychiatric disorders including depression and PTSD. This polymorphism was
found to alter BDNF stability and activity-dependent secretion, and might result in activation of the limbic
system during memory formation and emotionally relevant learning (Mahan and Ressler, 2012). Studies in
Val66Met knock-in mice revealed that mice with the Met/Met genotype exhibited increased anxiety-related
behaviors. A recent meta-analysis, however, did not support an association between the BDNF Val66Met
polymorphism and vulnerability to PTSD, and larger-scale studies are needed.
Glutamate
Glutamate is the most widely distributed excitatory neurotransmitter in the brain. Glutamate functions via
activation of its receptors, including ionotropic NMDA, Kainate, and AMPA receptors, as well as
metabotropic receptors. Glutamate, together with its downstream product GABA, the chief inhibitory
neurotransmitter in the nervous system, plays an important role in neuroplasticity and in modulating
cognitive and a ective responses to stress.
Acute exposure to stress rapidly increases glutamate release in limbic and cortical brain regions including
the hippocampus, amygdala, and prefrontal cortex, areas associated with memory, learning, and a ect.
Glutamate system dysregulation has been implicated in the pathophysiology of stress-related disorders. A
series of studies have found an important role of glutamate in the mediation of stress responsivity,
p. 502 formation of traumatic memories, and the pathophysiology of PTSD (Steckler and Risbrough, 2012).
More recently, increased in ammation has been found to be associated with altered glutamate system
function in basal ganglia and dorsal anterior cingulate cortex (ACC) in depressed patients.
Studies employing stress paradigms in mice have uncovered di erences in glutamate receptor function in
vulnerable compared with resilient animals, which cope better with stress. In one study, induction of
DeltaFosB in the nucleus accumbens mediated resilience in response to chronic social defeat stress, an
e ect produced in part through induction of the GluR2 AMPA subunit of the glutamate receptor, decreasing
nucleus accumbens neuron responsiveness to glutamate. In another study, deletion of AMPA receptor
subunit GluR-A in mice was associated with increased depression-like symptoms such as learned
helplessness, and decreased serotonin and norepinephrine levels. In a more recent study, compared with
resilient mice, vulnerable mice in both acute stress and chronic unpredictable stress paradigms showed
reduced expression of hippocampal presynaptic mGlu2 receptors, which inhibit glutamate release. Drug
development targeting the glutamatergic system remains an active area of research. The NMDA receptor
antagonist ketamine has demonstrated antidepressant e ects in patients with treatment-resistant
depression (Murrough, 2015). Additionally, in a proof-of-concept randomized controlled trial (RCT), a
single dose of intravenous (IV) ketamine was superior to IV midazolam in rapidly reducing PTSD symptom
levels in patients with chronic PTSD (Feder et al., 2014). It is thought that NMDA receptor antagonist
antidepressant e ect may be related to a rapid increase in glutamate release, resulting in activation of
AMPA receptors and ultimately in changes in synaptic signaling and protein synthesis, and formation of
new dendritic spine synapses in the PFC (Duman and Duman, 2015). Antagonism of metabotropic glutamate
receptors has also been shown to produce antidepressant-like e ects (Murrough, 2015). Findings from
recent animal studies, described further, suggest that ketamine might protect against the e ects of stress,
as it was shown to blunt biological responses to uncontrollable stress when administered prophylactically
up to two weeks prior to stress exposure.
Oxytocin
Oxytocin is a nine aminoacid peptide hormone released by neurons within the brain, and also into the
bloodstream via the posterior pituitary after synthesis in the paraventricular and supraoptic nuclei of the
hypothalamus. This peptide hormone has gained increased attention in the study of resilience, as it has
been shown to modulate stress responses and social emotional functions (Gobrogge and Wang, 2015).
First described in rodent studies, the function of oxytocin has more recently also been studied in humans.
Intranasal administration of oxytocin has been shown to increase prosocial behavior and improve emotion
recognition; reduce amygdala activation to fearful facial expressions; reduce anxiety; and improve social
cognition (Ma et al., 2016). In studies of healthy volunteers and patients with anxiety disorders, intranasal
oxytocin administration reduced anxiety during performance of the Trier Social Stress Test (TSST). In
patients with social anxiety disorder, intranasal oxytocin dampened amygdala reactivity, while enhancing
functional connectivity between the amygdala and other regions involved in emotional responses, including
the insula and cingulate gyrus, during viewing of fearful facial expressions. In patients with PTSD,
intranasal oxytocin administration reduced amygdala reactivity to emotional facial expressions and, by
contrast, enhanced amygdala reactivity in healthy controls (Koch et al., 2015).
Genetic studies have begun to report associations between oxytocin receptor gene polymorphisms and
di erential risk for anxiety, depression, and stress in survivors of early life stress. Lower methylation of this
gene has additionally been linked to social anxiety disorder and increased amygdala reactivity during
processing of socially relevant words.
Endocannabinoids
Endocannabinoids including anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are substances
naturally produced from within the body that activate cannabinoid receptors such as G-protein coupled CB1
and CB2 receptors. The endocannabinoid system is widely distributed throughout neural regions that
regulate mood and emotion, and has emerged as a key modulator of stress responses and emotional
behavior (McLaughlin et al., 2014). The CB1 receptor and endocannabinoid ligands are found at high
densities in regions including the prefrontal cortex, hypothalamus, amygdala, and hippocampus. Activation
of CB1 receptors in these limbic areas can result in both excitatory and inhibitory neurotransmission, as well
as the release of monoamines and neuropeptides. The CB2 receptor is located predominantly in peripheral
immune cells and organs. A growing body of evidence demonstrates that de cits in endocannabinoid
signaling may result in depressive and anxiogenic behavioral responses, which could be ameliorated by
pharmacological augmentation of endocannabinoid signaling (McLaughlin et al., 2014).
Preclinical studies have shown that CB1 receptor knockout mice exhibit increased susceptibility to the
anhedonic e ects of chronic stress, as well as increased passive stress coping behaviors in forced swim test
and tail suspension test, suggesting that the loss of CB1 receptor signaling promotes a depressive
phenotype. Endocannabinoid system disruption has also been found to impair fear extinction.
Studies in humans also suggest a potential link between disruption of endocannabinoid signaling and
vulnerability to mood and anxiety disorders. For example, healthy carriers of a genetic polymorphism linked
to lower CB1 receptor expression showed impaired fear extinction, potentially underlying di erential
resilience to stress. In clinical studies in patients with medical conditions, the use of CB1 receptor
antagonists rimonabant and taranabant was associated with anxiety and depressive symptoms as adverse
e ects. Reduction in circulating endocannabinoid levels has been reported in individuals with major
depression and PTSD. Pharmacologic interventions targeting the endocannabinoid system are currently
under investigation in these patients, including cannabidiol (a Cannabis sativa constituent), synthetic
p. 503 cannabinoids, and inhibitors of the catabolic enzyme fatty acid amide hydrolase.
The Immune System

Animal and human studies have established that the immune system communicates bidirectionally with the
central nervous and endocrine systems. The brain communicates with the immune system via the
autonomic nervous system (ANS), which innervates immune system organs such as the spleen, and via
release of HPA axis hormones, which also in uence immune system organs and cells. Stress activates the
ANS and HPA axis, thereby in uencing immune system function downstream. These interactions are
bidirectional, as the immune system in turn regulates central nervous system function via production of
cytokines, a ecting function in brain areas including the amygdala, PFC, ACC, and ventral striatum, among
others (Irwin and Cole, 2011).
A recent surge of research is investigating the role of in ammatory disturbances in stress-related
psychiatric disorders, and in animal models of resilience and stress vulnerability. For example, a study in
mice using a chronic social defeat stress paradigm showed that leukocyte-derived peripheral IL-6 was both
necessary and su cient to induce a depressive-like behavioral phenotype, and that IL-6 was upregulated in
mice that developed the susceptible phenotype but not in resilient mice (Hodes et al., 2014). Several human
studies have established a relationship between elevated in ammatory markers (e.g., C-reactive protein,
IL-6) and both depression and PTSD. Abnormal in ammatory pro les in Gulf War veterans were linked to
higher PTSD symptom severity and reduced hippocampal volume, suggesting that in ammation might alter
brain function. Additionally, one study reported a di erential in ammatory pro le in resilient individuals
versus those with PTSD, with resilient individuals showing similar pro les to those of unexposed controls.
In ammatory markers as potential biomarkers of resilience, disease trajectory, diagnosis, and treatment
response are currently being investigated. One prospective study in motor vehicle accident survivors found
that children with higher IL-6 levels within 24 hours of the accident were more likely to develop PTSD six
months later. Of relevance to resilience is a recent report that lower cytokine reactivity to a laboratory
stressor, an emotionally evocative video, in healthy young adult women was associated with better
cognitive control of emotional information assessed with an emotional Stroop task. Overall, further
research is needed to explore the complex role of the immune system in resilience and its potential role as a
biomarker of resilience (Walker et al., 2017).
Neural Circuitry of Reward: How Reward Pathways Impact Resilience

to Stress
A stable and well-functioning system of reward pathways and response to pleasant stimuli is a prerequisite
for dealing successfully with stress and traumatic life experiences. The ability to respond appropriately to
positive events and situations is vital to the preservation of reward expectation, optimism, and positive
self-concept following stress or trauma. Resilient individuals likely have a robust reward system, which is
strongly responsive to reward and/or resistant to change (Table 38.2, Figure 38.2.
Table 38.2 Neural Mechanisms Related to Resilience and Vulnerability to Extreme Stress
Mechanism Neurochemical Systems Brain Regions Association with Association with

Resilience Psychopathology
Reward Dopamine, dopamine Medial prefrontal In resilient Stress-induced reduction in

receptors, glutamate, N- cortex, orbital individuals, dopamine and increases in
methyl-D -aspartic acid frontal cortex, stress does not cAMP response element
(NMDA) receptors, γ- nucleus produce binding protein transcription
aminobutyric acid (GABA), accumbens, impairment in produces a dysfunction in
opioids, cAMP response amygdala, neurochemical or reward circuitry leading to
element binding protein, hippocampus, transcription anhedonia and hopelessness.
AFosB ventral tegmental factor-mediated
area, hypothalamus reward.
Reconsolidation Glutamate, NMDA Amygdala, The lability of the Repeated reactivation and
receptors, norepinephrine, hippocampus memory trace reconsolidation may further
β-adrenergic receptors, allows a strengthen the memory trace
cAMP response element reorganization of and lead to persistence of
binding protein original memory trauma-related symptoms.
that is less
traumatic
Extinction Glutamate, NMDA Medial prefrontal An ability to Failure in neural mechanisms

receptors, voltage-gated sensory cortex, quickly attenuate of extinction may relate to
calcium channels, amygdala learned fear persistent traumatic
norepinephrine, through a memories, reexperiencing
dopamine, GABA powerful symptoms, hyperarousal, and
extinction phobic behaviors.
process
cAMP, cyclic adenosine monophosphate; NMDA, N-methyl-D -aspartate.
(Modified and reprinted with permission from Cambridge University Press 2007).
Figure 38.2
Neural circuits associated with reward, fear conditioning, and social behavior. The figure depicts a simplified summary of some
of the brain structures and relevant neurochemistry mediating the neural mechanisms of reward (purple paths), fear
conditioning and extinction (yellow paths), and social behaviors (blue paths). Only a subset of the many known interconnections
among these various regions is shown, and relevant interneurons are not illustrated, yet it can be seen there is considerable
overlap in the brain structures associated with these neural mechanisms. This suggests that there may be clinically relevant
functional interactions among the circuits. For example, a properly functioning reward circuit may be necessary for the
reinforcement of positive social behaviors. An overly responsive fear circuit or impaired extinction process may negatively
influence functioning of the reward system. The assessment of these neural mechanisms must be considered in the context of
their neurochemical regulation. Alterations in one neurotransmitter, neuropeptide, or hormone system will a ect more than one
circuit. Several receptors that may be targeted by new anti-anxiety and antidepressant drugs are illustrated. The functional
status of these circuits has important influences on stress-related psychopathology and the discovery of novel therapeutics (see
text). (Modified and reprinted with permission from Cambridge University Press, 2007.)
p. 504 The dopaminergic system is involved in mediating elements of the reward system, including motivation,
incentive, and hedonic tone. Dopaminergic neurons increase ring when rewards are unexpected or better
than expected, and decrease their rate of ring when rewards are absent or less than predicted. Imaging
research suggests that the anticipation of reward involves mesolimbic DA pathways through the ventral
striatum and other subcortical limbic structures including the dorsal striatum, amygdala, and midbrain
VTA.
The roles of the orbitofrontal cortex (OFC) and mPFC in reward are somewhat more complex. The OFC,
taking input from the nucleus accumbens, assists in discriminating the motivational value of rewarding
stimuli. The mPFC appears to be involved in assessing the likelihood of receiving a given reward (as opposed
to its magnitude) and providing feedback along glutamatergic projections to the nucleus accumbens and the
VTA. The anterior insula is involved in producing aversion to risks in the pursuit of reward. In making
decisions about behavior, it appears that a stimulus’s potential rewards are assessed in subcortical areas
before being analyzed in the mPFC.
Strength, persistence, and emotional value of reward memory are modulated by circuits formed by the
amygdala, subiculum, bed nucleus of the stria terminalis, nucleus accumbens, and mPFC. Speci cally, the
cyclic adenosine monophosphate (cAMP) pathway and expression of the transcription factor cAMP response
element binding protein (CREB) in the amygdala strengthen positive as well as negative associations.
Rodents have been shown to develop persistent anhedonia when increased cAMP response element binding
is present in the nucleus accumbens.
Stresses, chronic and acute, are correlated with decreased sensitivity to rewarding stimuli and increased
sensitivity to aversive stimuli (Nestler, 2015). Evidence from animal models provides insight into potential
mechanisms. In rodent models, chronic exposure to stressful stimuli leads to an enduring aversion to social
contact. Researchers have found that knocking out BDNF in the mesolimbic DA system of the rodents seems
to produce a reward system that has lost its plasticity, remaining resistant to change when the rats are
subsequently presented with stressors. Studies of the social defeat paradigm in mice, whereby mice are
p. 505 exposed to a dominant intruder placed in their cage, have demonstrated that resilient mice, who show
appropriate anxiety responses but no defeat, upregulate K+ channels in the VTA, thereby preventing an
increase in neuronal excitability and associated BDNF release onto the nucleus accumbens, observed by
contrast in vulnerable mice.
Candidate gene studies in humans have also found associations between reward responsivity and stress
vulnerability. During performance of a probabilistic reward task, high school student carriers of the S allele
of the 5HTTLPR gene showed a larger stress-related reduction in responsiveness to reward as school nals
approached, compared with L allele homozygotes. This e ect was observed only in males. In a di erent
study, reward learning under a stressful condition was di erentially in uenced in healthy female
participants depending on their CRH receptor type 1 genotype, and was associated with di erential
activation to reward in the ACC and OFC. Although exposure to acute stress has the potential to alter reward
circuits, decreasing positive response to reward, ndings from these studies suggest that some people are
more sensitive to the e ects of stress, and other, potentially more resilient individuals show reduced stress
sensitivity, maintaining highly functional reward systems under adverse conditions.
Less is known about reward neural circuitry function in individuals who have demonstrated resilience to
trauma. Few brain imaging studies have examined reward responses in PTSD patients compared to trauma-
exposed individuals without PTSD (resilient). In one fMRI study, individuals with PTSD rated happy facial
expressions as less intense, and showed lower activation in the ventral striatum, a key reward-processing
region, than trauma controls while viewing these faces (Felmingham et al., 2014). An informative
prospective fMRI study of 24 healthy soldiers pre- and post-exposure to stressful military service, using an
interactive game that included risky and rewarding intervals, found that increased PTSD symptoms post-
exposure were associated with decreased response to reward in the nucleus accumbens—but only post-
exposure (Admon et al., 2013). By contrast, PTSD symptoms post-exposure were associated with greater
amygdala response to risk both pre- and post-exposure. In this study, reduced reward responsivity seems
to emerge with the development of PTSD symptoms.
A unique fMRI of highly resilient individuals compared 11 active duty male Special Forces (SF) soldiers to 11
age- and sex-matched civilians who were not trauma-exposed, during performance of a monetary
incentive delay task. While the civilians showed greater right subgenual PFC and right nucleus accumbens
activation during reward anticipation, the SF soldiers showed no activation di erences in reward-
processing regions between the reward and no-reward conditions. These ndings suggest a “sturdy”
reward system in highly resilient individuals, but additional research is necessary (Vythilingam et al., 2009).
These ndings highlight the major role of the reward system’s plasticity in mediating resilience, and
indicate possible mechanisms through which a resistant reward system plays a part in allowing resilient
individuals to endure hardships without developing posttraumatic psychopathology.
The Neural Circuitry of Anxiety and Fear: The Role of Fear Learning in
Resilience to Stress
Fear is an adaptive response to threatening stimuli, increasing vigilance and triggering defensive responses
against danger. In a study of healthy volunteers viewing fearful faces under threat of receiving an
unpredictable foot shock, anxiety was associated with increased connectivity between amygdala and dmPFC
and with faster recognition of fearful faces. At the same time, this increased connectivity was associated
with higher self-reported trait anxiety, suggesting that while adaptive, this response might also underlie
vulnerability to anxiety disorders when it is more pronounced. Findings from other studies also suggest that
individual variation in initial attention, perception, and intensity of emotional responses to threatening
stimuli underlies di erences in vulnerability and resilience to stress. For example, in healthy young adults
followed longitudinally, higher amygdala reactivity to threatening stimuli at baseline predicted
psychological vulnerability to future stressful life events (Swartz et al., 2014).
In a di erent study of soldiers studied before and after deployment to a combat zone, it was degree of
perceived threat, and not actual trauma exposure severity, that predicted degree of coupling between the
amygdala and both the insula and dorsal ACC (van Wingen et al., 2011). Of note, degree of perceived threat is
known to be associated with increased risk for PTSD from published meta-analyses. Interestingly, results
from a di erent study of healthy soldiers after a one-year intensive and stressful military training suggests
that neural mechanisms underlying resilience might di er in individuals with high and low trait anxiety. In
this study, attentional threat avoidance (compared to attentional vigilance) was associated with lower PTSD
symptoms only in high anxious, and not in low anxious, soldiers. In the high anxious group, attentional
threat avoidance was associated with higher hippocampal activation to threat stimuli (Lin et al., 2015).
Fear Conditioning
Individuals with PTSD su er distress when they encounter traumatic reminders. Over time, patients
su ering from PTSD tend to “overgeneralize” fear cues: they begin to associate more and more features in
their environment with their past traumas. Often, fear cues are objectively nonthreatening and unrelated to
trauma. The process through which previously neutral stimuli become fear inducing is known as fear
conditioning. In the terminology of fear conditioning, previously neutral stimuli become “conditioned”
stimuli by virtue of their association with aversive (unconditioned) stimuli.
Cue-speci c conditioned stimuli are transmitted to the thalamus by external and visceral pathways.
A erents reach the lateral amygdala by means of two parallel circuits: a rapid subcortical path directly from
the dorsal (sensory) thalamus and a slower regulatory cortical pathway encompassing the primary
p. 506 somatosensory cortices, the insula, and the ACC/PFC. Contextual conditioned stimuli are projected to the
lateral amygdala from the hippocampus and the bed nucleus of the stria terminalis. The lateral nucleus of
the amygdala is required for threat learning and memory. The existence of the long loop pathway (passing
through cortical regions) indicates that sensory information relayed to the amygdala undergoes substantial
higher-level processing, thereby enabling assignment of signi cance based on prior exposure to stimuli.
This higher-level processing of conditioned stimuli is important because it implies that there is potential
for modifying the processing of fear-conditioned stimuli with cognitive therapies.
The lateral amygdala, once engaged, projects to the central nucleus of the amygdala, which is the primary
output nucleus involved in initial memory consolidation. The central nucleus projects to the hypothalamus
and brain stem, triggering the cascade of autonomic, endocrine, and behavioral responses associated with
fear (Sears et al., 2014). The molecular processes underlying fear conditioning has been an area of active
investigation. Consolidation of fear conditioning occurs via long-term potentiation of synapses in the
lateral amygdala, where a series of cellular and molecular studies have identi ed many of the molecular
pathways involved. Activation of NMDA receptors appears to be central to plasticity and threat memory
formation in the amygdala, leading to calcium entry into the cell and initiating the molecular processes to
consolidate synaptic changes into long-term memory. Understanding these adaptive molecular
mechanisms and their disruption in conditions such as PTSD is crucial for developing new preventive and
treatment interventions (Sears et al., 2014). Because NMDA receptors are critical in fear learning, mediated
by glutamate acting in the central nucleus of the amygdala, we may be able to impair fear learning by
blocking NMDA receptors in the amygdala during stress, which has been demonstrated in studies of
rodents.
Reconsolidation and Extinction

Existing memories, when retrieved or “reactivated” by remembering, become labile and prone to change.
Reactivated memories may go down one of two pathways: they may be strengthened by reconsolidation or
weakened by extinction. While these processes have been considered mutually exclusive, this “strict
dichotomy” is now being questioned (Clem and Schiller, 2016). The processes of memory reactivation,
reconsolidation, and extinction involve NMDA and β-adrenergic receptors and require CREB induction,
indicating that nuclear protein synthesis is necessary. Reconsolidation and extinction are impaired by
NMDA and β-adrenergic blockade, and enhanced by the NMDA partial agonist D -cycloserine (Sears et al.,
2014). Reconsolidation and extinction of a memory are a ected by the age of the memory in question. As
would be expected, younger memories are more prone to being altered by either process, although
intensifying the memory reactivation process helps enhance the lability of older memories.
Similarly, the process of extinction changes over time. Extinction induced immediately after fear acquisition
(between 10 minutes and 1 hour later) is thought to occur by “erasing” the learned fear. However, extinction
induced 24–72 hours after initial fear training appears to be a new form of learning altogether. The
extinction that is achieved during this later time period involves new learning, namely the formation of a
new, safe association with the original fear cue; this new association is placed over the older fear
association. The original fear association still exists underneath, and extinguished fears often return
spontaneously.
The central nucleus of the amygdala and hippocampus are involved in initial memory consolidation, the
lateral amygdala in reconsolidation, and the basal lateral amygdala in extinction. The mPFC is a critical
structure in extinction. Since the 1980s, studies have found that lesions of the mPFC result in an impairment
of normal extinction. Failure to achieve an adequate level of activation of the mPFC might lead to persistent
fear responses. Individuals with the capacity to function well after high-stress experiences may have potent
mPFC inhibition of amygdala responsiveness. In contrast, patients with PTSD have been shown to exhibit
increased left amygdala activation during fear acquisition and decreased activity of the mPFC/anterior
cingulate during extinction.
Reconsolidation and extinction of traumatic memories are implicated in vulnerability and resilience to
extreme stress. Individuals who are able to attenuate learned fear through extinction are likely highly
stress-resilient. Further, in exposure-based psychotherapy for individuals with PTSD, reduction of fear is
thought to occur via extinction learning. In an fMRI study of volunteer policemen who were all exposed to
the same traumatic event, during which the police force was under gun re attack, resilient policemen
exhibited signi cantly higher mPFC and lower amygdala activity during traumatic memory retrieval
compared to policemen with subsyndromal PTSD (Peres et al., 2011). Resilience traits in the resilient group
included self-e cacy, empathy, and optimism. After a course of exposure-based and cognitive
restructuring psychotherapy, lower amygdala and increased mPFC activity in participants with
subsyndromal PTSD was associated with improvement on the Clinician-Administered PTSD Scale and the
Traumatic Memory Inventory. The authors hypothesize that psychotherapy might help integrate
fragmented traumatic memories into coherent narratives, thereby enhancing resilience, and posit a role of
the mPFC in this process (Peres et al., 2011).
Due to our growing understanding of the mechanisms of memory processing, there will likely be ever more
possibilities for helping trauma survivors manage their traumatic memories. In particular, a series of
studies have led to the discovery that during reconsolidation, previously stored information becomes labile
after retrieval and thus amenable to change as new information is incorporated (Schiller et al., 2010). Recent
studies in healthy volunteers, whereby participants underwent extinction during the reconsolidation
window, incorporating nonfearful information to the old fear memory, have successfully prevented the
expression of fear responses (Schiller et al., 2010). This e ect was shown to last for at least one year and was
replicated by a di erent group. A recent fMRI study in humans demonstrated that suppression of a fear
memory by conducting extinction training during the reconsolidation window works by erasing the fear
p. 507 memory representation in the amygdala (Agren et al., 2012). Emerging evidence thus suggests that
extinction training during reconsolidation might be a potentially e ective treatment approach. These
exciting ndings might lead to new interventions for individuals with PTSD.
Additional Neural Circuitry Relevant in Resilience
Stress resilience has been related to a greater capacity for emotion regulation (Masten and Tellegen, 2012).
Brain imaging studies have identi ed several regions mediating emotion regulation, including the ventral
ACC, vmPFC, and lateral prefrontal and parietal cortices (Etkin et al., 2015). As discussed earlier, studies
have linked genetic variation with di erential amygdala reactivity to negative stimuli, as well as altered
functional coupling between the PFC and the amygdala, a possible mechanism mediating di erential
vulnerability to stress. In addition, studies of o spring at high and low familial risk for depression have
found di erences in neural responses to emotional stimuli and in attention to negative emotional stimuli
during tryptophan depletion. In a study of acutely traumatized individuals, higher trait resilience measured
by the Connor-Davidson Resilience Scale was positively correlated with activation in the right thalamus and
the inferior and middle frontal gyri (BA 47), additional areas involved in emotion regulation (Daniels et al.,
2012).
In another fMRI study, healthy male re ghters were recruited from a re ghter training center prior to
trauma exposure. Higher scores on the Dispositional Resilience Scale (DRS15), which measures hardiness,
correlated with higher right amygdala and left orbitofrontal (OFC) activations during script-driven imagery
of a traumatic event, compared to a relaxing script (Reynaud et al., 2013). A possible interpretation is that
resilience is associated with more appropriate emotional responses to a stressful situation (Reynaud et al.,
2013).
The neural basis of a particular form of emotion regulation, cognitive reappraisal, has been examined in
several imaging studies. Activation of the dmPFC, as well as dorsolateral (dlPFC) and ventrolateral (vlPFC)
—regions involved in self-monitoring, working memory, and response inhibition and selection—has been
linked to reappraisal success (Silvers et al., 2015). Further, greater use of reappraisal in everyday life was
found to correlate with lower amygdala and greater PFC activation to negative stimuli.
Other imaging studies have begun to delineate neural circuits relevant for social behavior, for example
neural circuitry mediating the capacity for empathy, thought to be comprised of the mirror neuron system
in interaction with limbic brain regions. As discussed, social contact and support are known to promote
health and well-being (Southwick et al., 2016).
Accurate perception of facial emotional expressions is a key component of healthy social interactions. Using
a morphed faces paradigm, healthy volunteers with higher self-reported general self-e cacy, which has
been likened to resilience, showed bias toward recognizing and remembering happy facial expressions when
morphed with angry expressions, suggesting that they are “tuned to ‘happy others’ ” (Tanzer et al., 2014).
Further, participants with higher perceived social support were less accurate in recognizing angry facial
expressions, even after exposure to a stressful situation. These perceptual biases identi ed in individuals
possessing psychological characteristics previously linked to resilience shed some light on underlying
mechanisms that might enable individuals to shape their social environment (Tanzer et al., 2014). Imaging
studies have begun to uncover the neural mechanisms mediating reduced responses to stress in the
presence of social support. In a study employing fMRI, higher functional amygdala–mPFC connectivity was
associated with higher social network size.
Implications for Prevention and Treatment of Stress-Related

Psychopathology
Our growing understanding of genetic, developmental, psychological, and neurobiological resilience factors
continues to lead to the development of therapeutic interventions for enhancing resilience to stress
(Southwick and Charney, 2012b; Horn et al., 2016).
An intervention to enhance resilience is stress inoculation training, with a strong tradition in the military
and in rst responder groups such as police or re ghters in the form of training programs designed to
maximize coping self-e cacy and mastery. This training is accomplished by means of exposure to
manageable stressors including physical and mental challenges, providing opportunities for mastery by
repeated practice and gradual exposure to increasingly challenging situations. A similar approach is applied
in outdoor education programs for children and adolescents, such as Outward Bound.
Cognitive-behavioral therapies emphasize cognitive reappraisal of negatively viewed circumstances into

more positive perspectives, and have shown results across a broad range of populations. Other therapies
employing cognitive reappraisal include hardiness training and well-being therapy, the latter also showing
promising results in school interventions.
Positive psychology-based exercises, including re ecting daily on things that went well that day, were
shown to increase positive a ect and decrease depression levels in adults (Seligman et al., 2005). Similarly,
gratitude interventions, whereby individuals are instructed to identify several things that they are grateful
or thankful for in their life, have been associated with increased reports of well-being and positive a ect in
various populations. In children and adolescents, the Positive Youth Development (PYD) movement draws
from positive psychology with an emphasis on well-being and positive outcomes during development. PYD-
based programs highlight strong bonds with healthy adults and involvement in positive community
activities to enhance resilience. A community-based intervention, Communities That Care (CTC), focusing
p. 508 on enhancing prosocial involvement in the community, in school, and with peers, was tested in 5th
graders from 24 communities in seven states, followed through 8th grade. In analyses of protective factors
in 8th grade, CTC communities had signi cantly higher levels of community opportunities and school
recognition for prosocial involvement, interaction with prosocial peers, and social skills compared to
control communities (Kim et al., 2015).
Mindfulness-based interventions have also been studied in diverse populations. Mindfulness training for
individuals with residual depressive symptoms successfully increased their ability to experience positive
emotions and was associated with a reduction in residual depressive symptoms, compared with a waitlist
control condition. The Mindful Awareness and Resilience Skills Training (MARST) program is designed to
enhance resilience in human service professionals through mindfulness, positive cognitive appraisal skills,
and awareness of positive emotions. Yoga and meditation have also been applied as treatments for PTSD and
are thought to enhance resilience. Yoga integrates physical exercise, which protects against dysregulation of
stress responses, and is being studied for the treatment of PTSD. Mindfulness meditation has been linked to
increases in positive a ect and left-sided anterior temporal activation, as well as improved immune system
functioning.
Meaning-making interventions have been applied to help patients with breast or colorectal cancer,
resulting in increases in self-esteem, optimism, and self-e cacy, in comparison with a control group.
Meaning making is particularly relevant to PTSD; incorporating a traumatic experience into one’s broader
belief system may enhance resilience and facilitate recovery. Meaning making is incorporated in Integrative
Testimonial Therapy (ITT) for individuals with posttraumatic stress. ITT, which utilizes a biographical
approach to help trauma survivors with persistent PTSD symptoms integrate their traumatic experiences
into their life narrative, was associated with PTSD symptom improvement and posttraumatic growth in
German elderly survivors of World War II, maintained at three-month follow-up. In another study of
survivors of a range of traumas, symptom improvement was maintained at follow-up 18 months later
(Knaevelsrud and Maercker, 2010). ITT has been compared to a waitlist control condition; an RCT with an
active comparison condition is under way.
An active area of research is focused on developing preventive interventions to be administered shortly
following a traumatic experience, to mitigate or stem the emergence of PTSD symptoms. Despite earlier
discouraging results from studies of psychological debrie ng administered immediately post-trauma, a
recent pilot study of three modi ed prolonged exposure sessions administered in the emergency room only
hours after trauma exposure mitigated the risk of emerging posttraumatic stress reactions, particularly in
rape survivors; interestingly, it was most successful in those at highest risk for PTSD based on particular
genetic polymorphisms (Rothbaum et al., 2014). A potential pharmacologic intervention under study for
administration shortly after trauma exposure is hydrocortisone, a glucocorticoid receptor agonist. Trials of
hydrocortisone in intensive care unit patients with septic shock or undergoing cardiac surgery, and in
trauma-exposed patients recruited from the emergency department, have shown promising results in
reducing the emergence of PTSD symptoms or improving quality of life. The NPY-ergic system also
continues to be of active interest in the development of novel interventions. Intranasal NPY administration
immediately prior to or following exposure to traumatic stress in rodent models of PTSD has shown
preliminary support for protective e ects at the behavioral, neuroendocrine, and molecular levels (Serova et
al., 2013).
Some pharmacologic interventions with demonstrated e ectiveness in clinical populations might help
enhance resilience when administered to healthy individuals prior to trauma exposure. For example
ketamine, a glutamate NMDA receptor antagonist known to enhance synaptic plasticity, with demonstrated
e cacy in treatment-resistant depression and preliminary evidence of e cacy in PTSD, has been shown in
recent animal studies to blunt biological stress responses when administered up to two weeks prior to
exposure to uncontrollable stress. Human studies of ketamine administration to healthy volunteers are
underway, with potential applications in the military and rst responder groups if shown to be e ective in
mitigating acute responses to stress.
A series of recent studies has focused on trying to harness the mechanisms of fear extinction and
reconsolidation, reviewed, to enhance resilience or as potential treatment interventions. Recent studies
have centered on re ning windows of opportunity during memory retrieval when fear memories and
responses are more receptive to extinction training, with the goal of developing novel therapeutic
interventions. Interventions under study include pharmacologic agents administered in close proximity to
memory retrieval, psychotherapeutic interventions, or their combination. Because antagonizing β receptors
disrupts the process of consolidation, several trials have investigated the e cacy of β-blockers, in
particular propranolol, in disrupting initial consolidation of traumatic memories shortly after trauma
exposure, with mixed results (Hoge et al., 2012). Recent studies investigating pharmacologic blockade of
memory reconsolidation with propranolol or mifepristone in individuals with PTSD have yielded negative
results. In a recent promising study of individuals already su ering from spider phobia, however, a single
dose of propranolol administered after brief exposure to a tarantula appeared to successfully disrupt fear
memory reconsolidation, with adaptive changes persisting at least one year post-intervention. (Soeter and
Kindt, 2015).
Pharmacologic agents to block reconsolidation or enhance extinction are under investigation, including the
N-methyl D -aspartate (NMDA) receptor partial agonist D -cycloserine, with promising but mixed results in
anxiety disorders (McGuire et al., 2017). Other agents targeting the glutamate system are under
investigation in animal studies; disruption of contextual fear reconsolidation by NMDA receptor antagonist
ketamine has been recently demonstrated in rats and awaits further study (Duclot, et al., 2016). Cognitive
enhancers that might a ect fear extinction are also under investigation in preclinical trials, for example
agents modulating GABAergic transmission and compounds targeting endocannabinoid receptors to
p. 509 facilitate fear extinction (Hill and Tasker, 2012). Other receptors known to be involved in extinction, such
as the BDNF receptor tyrosine kinase b, have also been targeted in preclinical trials.
Continued progress in understanding the genetic, developmental, neurobiological, and psychological
underpinnings of resilience and vulnerability to stress, as well as the interactions between these factors,
will aid in moving the eld toward the identi cation of those at risk of developing stress-related
psychopathology, and the development of novel preventive and treatment interventions.
Disclosures
Dr. Feder is named co-inventor with Dr. Charney (Dean of Icahn School of Medicine at Mount Sinai) and the
Icahn School of Medicine at Mount Sinai on a use patent application led by Mount Sinai for the use of
ketamine as a treatment for posttraumatic stress disorder (PTSD) (patent pending). If ketamine were shown
to be e ective for the treatment of PTSD, Drs. Charney and Feder, and the Icahn School of Medicine at
Mount Sinai could bene t nancially.
Dr. Feder’s research is funded by CDC/NIOSH and the Brain and Behavior Research Foundation.
Ms. Horn has no con icts of interest or disclosures.
Dr. Haglund has no con icts of interest or disclosures.
Dr. Southwick has no con icts of interest or disclosures. His research is funded by, CDC/NIOSH and the
Department of Veterans A airs.
Dr. Charney:
Issued Patent:Ketamine—Intranasal Administration of Ketamine to Treat Depression(issued July 22, 2014).Dr.

Charney (Dean of Icahn School of Medicine at Mount Sinai) has been named as a co-inventor on a use patent
of ketamine as a treatment for depression. The Icahn School of Medicine at Mount Sinai has entered into a
licensing agreement with a biopharmaceutical company and will receive payments related to the use of
ketamine for the treatment of depression. Dr. Charney is entitled to a portion of these payments.
Patents (pending):
*Ketamine—As a Rapid Treatment for PTSD. As mentioned, Dr. Charney and the Icahn School of Medicine at
Mount Sinai are named co-inventors on a use patent application led by Mount Sinai for the use of
ketamine as a treatment for posttraumatic stress disorder (PTSD). If ketamine were shown to be e ective
for the treatment of PTSD, Dr. Charney and the Icahn School of Medicine at Mount Sinai could bene t
nancially. There is often a link between PTSD and depression.
*Intranasal Neuropeptide Y (NPY)—for the Treatment of Mood and Anxiety Disorders. Dr. Charney and the
Icahn School of Medicine at Mount Sinai are named co-inventors on a use patent application for the study
drug NPY for the Treatment of Mood and Anxiety Disorders. If Intranasal NPY were shown to be e ective for
the Treatment of Mood and Anxiety Disorders, Dr. Charney and the Icahn School of Medicine at Mount Sinai
could bene t nancially.
*Method of Maintaining the Anti-Depressant E ect of Ketamine with Lithium. Dr. Charney is a named co-
inventor on patent applications led by Mount Sinai on a combination of ketamine plus lithium related to
the treatment of depression and the treatment of suicidal ideation.
*Method of Reducing Risk of Suicidal Ideation with Combined Ketamine/Lithium Therapy. Dr. Charney is a
named co-inventor on patent applications led by Mount Sinai on a combination of ketamine plus lithium
related to the treatment of depression and the treatment of suicidal ideations.
Dr. Charney’s research is funded by NIH and NIH/NIMH. He has no other disclosures.
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Charney & Nestler's Neurobiology of Mental Illness (5 edn)

Dennis S. Charney et al.

38. The Neurobiology of Resilience 

Keywords: resilience, genomics, development, early life environment, psychobiology, neurobiology,

Genomics and Resilience

The Development of Resilience: Role of Early Life Environment

Psychobiological Features of Resilience

Traits and Behaviors

1. Positive emotions, positive and realistic appraisal style

Optimism is strongly related to resilience.

Optimism is in part inherited but can be learned through therapy.

2. Cognitive flexibility and reappraisal

Finding meaning or value in adversity.

Traumatic experiences can be reevaluated through a more positive lens.

Recognize that failure is an essential ingredient for growth.

Putative neurobiological mechanisms: memory reconsolidation, cognitive control over emotions.

Live by a set of guiding principles.

For many, moral compass means religious or spiritual faith.

Morality has neural basis, likely evolved because adaptive.

4. Finding a resilient role model/mentor

Putative neurobiological mechanisms: oxytocin mediates initial bonding/attachment. “Mirror”/Von Economo

neurons involved in neuronal imprinting of human values.

5. Facing fears: learning to move through fear

Fear is normal and can be used as a guide for action.

Practice undertaking and completing challenging or anxiety-inducing tasks.

Putative neurobiological mechanisms: promotes fear extinction, stress inoculation.

6. Active coping: seeking solutions, managing emotions

7. Establishing and nurturing a supportive social network

Establish and nurture a supportive social network.

Social support is safety net during stress.

8. Physical exercise and attending to physical well-being

Physical exercise has positive e ects on physical and psychological hardiness.

9. Other resilience factors

Training regularly (emotionally and physically), discipline.

Recognizing oneʼs own strengths and fostering them.

Positive Cognitive Reappraisal

The ability to nd personal meaning in tragedy is extraordinarily helpful in successfully overcoming

Active Coping Styles

Moral Compass: A Set of Guiding Ethical Principles

Neurobiological Profile of Resilience

Cortisol Mobilized energy, Prefrontal cortex, Increases amygdala Stress-induced

Neuropeptide Y Amygdala, hippocampus, Reduces CRH- Adaptive increase

p. 497 Corticotropin-Releasing Hormone

The Brain–Gut Axis

Brain-Derived Neurotrophic Factor

The Immune System

Neural Circuitry of Reward: How Reward Pathways Impact Resilience

Mechanism Neurochemical Systems Brain Regions Association with Association with

Reward Dopamine, dopamine Medial prefrontal In resilient Stress-induced reduction in

Extinction Glutamate, NMDA Medial prefrontal An ability to Failure in neural mechanisms

cAMP, cyclic adenosine monophosphate; NMDA, N-methyl-D -aspartate.

Reconsolidation and Extinction

Additional Neural Circuitry Relevant in Resilience

Implications for Prevention and Treatment of Stress-Related

Cognitive-behavioral therapies emphasize cognitive reappraisal of negatively viewed circumstances into

Ms. Horn has no con icts of interest or disclosures.

Dr. Haglund has no con icts of interest or disclosures.

Issued Patent:Ketamine—Intranasal Administration of Ketamine to Treat Depression(issued July 22, 2014).Dr.

Rutter, M. (2012). Resilience as a dynamic concept. Dev Psychopathol 24:335–344. 10.1017/S0954579412000028

© Oxford University Press

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