mecanismos psicobiologicos de la resilencia

35

Most people are exposed to one or more traumatic events during their lifetime, and many must endure stressful conditions that persist over time. Although historically most research has focused on the negative impact of stressful life events, the past several years have witnessed a surge of new information on the psychological and neurobiological mechanisms involved in promoting resilient responses to stress. The construct of resil-ience refers to the ability of individuals to adapt successfully in the face of acute stress, trauma, or chronic adversity, maintaining or rapidly regaining psychological well-being and physiological homeostasis (Charney, 2004). Resilience is not just the absence of psychopathology; adaptive responses to stress can be promoted by strengthening potential protective factors. Recent studies suggest that genetic influences on biological processes are larger than influences on com-plex behavioral responses, and thus easier to identify and to study (Hasler, Drevets, Manji,

& Charney, 2004; Zhou et al., 2008). An integrative model of resilience incorporating information from multiple phenotypic levels, including the behavioral and psychological, is likely to yield a range of preventive and treatment strategies for stress- related dis-orders (Charney, 2004; Zhou et al., 2008). This chapter reviews current perspectives on psychosocial, developmental, neurochemi-cal, genetic, and neural factors associated with resilient responses to stress. We con-clude with a review of promising preventive and therapeutic strategies.

Psychosocial factors associated with Resilience

Studies have identified a range of psychosocial factors that promote successful adaptation to stress, including active coping strategies, positive emotionality, cognitive reappraisal, the presence of social supports, and a sense of purpose in life, among others.

2Psychobiological Mechanisms of Resilience to Stress

Adriana FederEric J. NestlerMaren WestphalDennis S. Charney

36 BASIC DIMENSIONS OF RESILIENCE

Active Coping and Facing Fears

Active coping strategies, such as planning and problem solving, have been linked to a higher degree of well-being and capacity to handle stress, trauma, and medical ill-ness (Southwick, Vythilingam, & Charney, 2005). Active coping involves facing one’s fears. Resilient individuals are more likely to utilize fear as a guide to appraise threat and direct appropriate action. By contrast, mal-adaptive strategies involving escape/avoid-ance of stressful situations—such as denial and behavioral disengagement—have been linked to higher distress levels (Carver, 1997; Folkman & Moskowitz, 2004; Southwick et al., 2005). Individuals with posttraumatic stress disorder (PTSD) avoid facing remind-ers of the trauma, which might contribute to maintenance of conditioned fear.

Positive Emotions and Optimism

An increasing number of studies have pro-vided evidence for the key role of disposi-tional optimism and positive emotions in enhancing psychological resilience (Ong, Bergeman, Bisconti, & Wallace, 2006; Tu-gade & Fredrickson, 2004). Positive emo-tions frequently co-occur with negative emo-tions in the face of highly stressful personal situations (Ong et al., 2006). According to the broaden-and-build model (Fredrickson, 2001), positive emotions provide a buffer against the adverse consequences of stress by decreasing the autonomic arousal pro-duced by negative emotions, and by increas-ing flexibility of thinking and problem solv-ing. In fact, studies have shown that positive emotions are associated with faster cardio-vascular recovery from negative emotional arousal and decreased stress reactivity (Tu-gade & Fredrickson, 2004).

Cognitive Reappraisal

The capacity for cognitive reappraisal al-lows individuals to reevaluate or reframe adverse experiences in a more positive light.

Meaning- making processes open multiple al-ternative avenues to well-being, further dis-cussed below (Seligman, 2005). The ability of resilient individuals to infuse stressful life events with positive meaning, as well as the use of humor, might help to regulate negative emotions (Folkman & Moskowitz, 2000).

Social Support

A large number of studies have documented the importance of social support as a protec-tive variable in stress- related disorders such as PTSD (Charuvastra & Cloitre, 2008). Research has shown that affiliative behav-iors in animals and humans alleviate the ef-fects of stress, injury, and infection (DeVr-ies, Glasper, & Detillion, 2003; Robles & Kiecolt- Glaser, 2003). Secure attachment relationships help to reduce negative affect and physical arousal in stressful situations (Bowlby, 1982; Charuvastra & Cloitre, 2008; Mikulincer, Shaver, & Pereg, 2003).

Purpose in Life, Moral Compass, and Spirituality

A sense of purpose in life and the presence of an internal set of beliefs about right and wrong have been linked to resilience. Trau-matic events may deeply affect a person’s be-liefs and sense of meaning (Janoff- Bulman, 1992). Regaining a sense of purpose might be central for the process of recovery. In a re-cent cross- sectional study of African Ameri-can individuals exposed to severe trauma, a sense of purpose in life was significantly associated with psychological resilience, as well as recovery from psychiatric disorders (Alim et al., 2008). Counseling sessions focused on meaning making with cancer patients were found to decrease depression and increase life satisfaction in another study (Lee, Cohen, Edgar, Laizner, & Ga-gnon, 2004). For many individuals, religious or spiritual beliefs and practices provide a framework that facilitates recovery and find-ing meaning after traumatic or highly stress-ful experiences (Pargament, Smith, Koenig, & Perez, 1998).

Psychobiological Mechanisms of Resilience to Stress 37

Resilience and early life environment

Adverse early life experiences are known to increase risk for depression and PTSD in adulthood by producing long- lasting hormonal, neurotransmitter, and central nervous system changes that may affect re-sistance to later stress (Heim & Nemeroff, 2001; Vythilingam et al., 2002). Similarly, animal studies have shown enduring effects of early, prolonged maternal separation (Heim & Nemeroff, 2001). In contrast, there are many examples of resilient development despite early exposure to severe stress, as ex-emplified by studies of Romanian children adopted away from institutional orphanages into stable homes (Masten, 2001; Rutter, 1998), and by animal studies showing that exposure to an enriched environment can make rodents less vulnerable to stress and to drugs of abuse (Green, Gehrke, & Bardo, 2002), and can reverse some of the behav-ioral impairments induced by early mater-nal separation (Francis, Diorio, Plotsky, & Meaney, 2002).

A key factor identified in children who are able to overcome adversity is a close relationship with a caring adult (Luthar, Sawyer, & Brown, 2006; Masten, Best, & Garmezy, 1991). For example, the quality of caregiving that children receive after the loss of a parent can mitigate risk for depression. Children are also able to adapt better in the context of war or disasters when they are not separated from their parents (Masten et al., 1991). Conversely, problematic paren-tal bonding characterized by affectionless control has been identified as a risk factor for depression in adulthood (Parker, 1983). Of note, this important risk predictor has shown robust intergenerational transmission in women, thus providing an opportunity for early intervention (Miller, Kramer, War-ner, Wickramaratne, & Weissman, 1997). Rodent studies have shown that early posi-tive maternal care in the form of high levels of licking/grooming and arched-back nurs-ing produces offspring who are less fearful as adults and show attenuated hormonal

responses to stress (Weaver et al., 2004). Cross- fostering experiments have demon-strated that these effects are transmitted be-haviorally, and recent research has suggested an epigenetic basis of this phenomenon (see below; McGowan et al., 2009; Meaney & Szyf, 2005; Weaver et al., 2004). Other fac-tors associated with resilience during de-velopment include social competence and agreeableness, positive emotionality, and the capacity for self- regulation (Masten & Coatsworth, 1998).

Less well researched is the finding that prior exposure to mild or “manageable” stress during development might actually promote more adaptive responses to stress in the future. For example, some stud-ies suggest that adults cope better with a range of stressors, including work- related stressors, spousal loss, or accidents, if they previously have experienced and coped suc-cessfully with stressors as children or ado-lescents (Lyons & Parker, 2007). Lyons and colleagues (Parker, Buckmaster, Schatzberg, & Lyons, 2004) have examined this phe-nomenon of stress inoculation in young squirrel monkeys. Exposure of young squir-rel monkeys to short-term isolation from other monkeys induces better social and emotional functioning upon later exposure to mild stressors. Similarly, brief maternal separation of rat pups reduces behavioral and hormonal responses to stress later in life (Meaney & Szyf, 2005) . Importantly, the degree of behavioral control an animal has over stress is a key determinant of whether an individual’s response is adaptive or mal-adaptive: the more control, the more resilient the individual (Maier, Amat, Baratta, Paul, & Watkins, 2006).

neurochemical stress Responses associated with Resilience

The term allostasis, coined by Sterling and Eyer (1988), denotes the dynamic process through which the body adapts to daily stressors and maintains homeostasis. When


faced with unexpected, sudden stressful events, the brain responds by releasing cat-echolamines and other stress hormones that prepare the organism to cope with the situ-ation and avert harm to the organism. In-terindividual variability in stress resilience depends on differences in the coordinated function of numerous hormones, neu-rotransmitters and neuropeptides involved in the stress response.

Hypothalamic– Pituitary– Adrenal Axis

Secreted by the hypothalamus in response to stress, the corticotropin- releasing hormone (CRH) activates the release of the adreno-corticotropic hormone (ACTH) from the an-terior pituitary gland, which in turn stimu-lates the synthesis and secretion of cortisol by the adrenal cortex. Cortisol inhibits the release of CRH and ACTH through a com-plex negative feedback system that keeps in check stress- induced increases in cortisol (de Kloet, DeRijk, & Meijer, 2007). Elevation in hypothalamic– pituitary– adrenal (HPA) axis activity in response to stress sets off a cascade of hormonal processes that facili-tate cognitive, metabolic, immunological, and behavioral adaptations to environmen-tal demands (Sapolsky, Romero, & Munck, 2000; Weiner, 1992). The same chemical mediators that promote survival, however, may produce negative health consequences when the stressors become chronic or are perceived as overwhelming, resulting in al-lostatic overload (McEwen & Wingfield, 2003). In the brain, excessive cortisol is as-sociated with complex structural effects in the hippocampus and amygdala in humans and animals, including atropic effects in cer-tain neuronal cell types (McEwen & Milner, 2007). Studies have shown that early life stress is associated with chronic elevation of CRH levels lasting into adulthood (Heim & Nemeroff, 2001). Disturbances in HPA axis function seem to differ between psychiatric disorders. For example, whereas patients with major depressive disorder have elevated cerebrospinal fluid CRH and plasma corti-

sol levels, patients with PTSD have elevated CRH but reduced cortisol levels (de Kloet, Joels, & Holsboer, 2005). Resilience is as-sociated with the rapid activation and effi-cient termination of the stress response, and is thought to involve an optimal balance of glucocorticoid and mineralocorticoid recep-tor function (Charney, 2004; de Kloet et al., 2005, 2007).

Dehydroepiandrosterone (DHEA), an adrenal steroid released concurrently with cortisol in response to stress, may increase stress resistance by protecting against neural damage resulting from prolonged HPA axis activity. DHEA and its metabolites counter-act corticosteroid- induced neurotoxicity in the hippocampus (Morfin & Starka, 2001). In studies of patients with PTSD, higher plasma DHEA and DHEA-sulfate levels, and higher capacity for adrenal release of DHEA, have been linked to reduced illness severity and greater symptom improvement (Rasmusson et al., 2004; Yehuda, Brand, Golier, & Yang, 2006). Higher DHEA-sulfate– cortisol ratios during stress might be protective in healthy individuals; in a group of soldiers participating in military survival school, higher DHEA-sulfate– cortisol ra-tios were associated with fewer dissociative symptoms and better performance under stress (Morgan et al., 2004).

The Locus Ceruleus– Norepinephrine System

Another neural system that affects sympa-thetic nervous system functioning and HPA axis responses to stress is the locus ceruleus– norepinephrine (LC-NE) system. The LC serves a general alarm function within the body, responding to potential threats by trig-gering the release of NE within the amygda-la, nucleus accumbens, prefrontal cortex (PFC), and hippocampus. Activation of the LC also inhibits neurovegetative functions, such as sleep and feeding behavior. A chron-ically hyperresponsive LC-NE is thought to predispose the organism to heightened anxi-ety by inhibiting PFC function, thus interfer-ing with more complex cognitive, emotion


regulation processes, and leading to cardio-vascular problems (Charney, 2003, 2004). Blockade of beta- adrenergic receptors in the amygdala can oppose the development of aversive memories in animals and humans (Charney, 2003; McGaugh, 2004). Collec-tively, these findings suggest that resilience might be associated with reduced respon-siveness of the LC-NE system.

The Serotonergic System

Serotonin (5-HT) neurons project widely in the brain. Acute stress is associated with in-creased 5-HT turnover in several brain re-gions, including the amygdala, the nucleus accumbens, and the PFC. 5-HT has neuro-modulatory effects on other neurotransmit-ter systems that are implicated in mood and anxiety. Depending on the forebrain region involved and which receptor subtype is acti-vated, the release of 5-HT may have anxio-genic or anxiolytic effects (Charney, 2004). Early life stress may lead to diminished stress tolerance in later life by increasing CRH and cortisol levels, which in turn lower 5-HT1A receptor activity. Levels of 5-HT1A receptor during early postnatal development, par-ticularly in frontal cortex and hippocampal regions, may influence anxiety thresholds in adulthood (Lanzenberger et al., 2007). Re-search using a transgenic mice model sug-gests that 5-HT1A receptor expression may shape development of anxiety during criti-cal developmental periods (Gross & Hen, 2004).

The Dopaminergic System

Dopamine neurons are activated by reward-ing stimuli and inhibited by aversive stimuli. Stress activates dopamine release in the me-dial PFC (mPFC) and inhibits its release in the nucleus accumbens, a key component of the reward circuitry. Animal and human studies have provided evidence that balance between mesocortical and mesoaccumbens dopamine responses to stress might be cru-cial in protecting against the negative impact

of stress on mood and physical well-being (Cabib, Ventura, & Puglisi- Allegra, 2002). Excessive mesocortical dopamine release after stressful events might be associated with increased vulnerability (Cabib et al., 2002). Dopamine signaling facilitates fear extinction, but its role in resilience per se is unclear.

Neuropeptide Y

There is increasing evidence that neuropep-tide Y (NPY), a neuropeptide that is widely distributed in the brain, might have a stabi-lizing effect on neural circuits that are impli-cated in the regulation of emotional and be-havioral responses to stress. NPY is thought to reduce anxiety by counteracting the anx-iogenic effects of CRH in the amygdala, hip-pocampus, hypothalamus, and LC (Britton, Akwa, Spina, & Koob, 2000; Heilig, Koob, Ekman, & Britton, 1994). Balance between NPY and CRH neurotransmission appears to be crucial to maintaining emotional ho-meostasis under stress (Sajdyk, Shekhar, & Gehlert, 2004), and might thus be related to resilience.

Studies of combat veterans have revealed an association between low NPY levels and PTSD (Rasmusson et al., 2000; Yehuda, Brand, & Yang, 2006). Findings from a study of Special Forces soldiers undergoing rigorous military training suggest that el-evated NPY levels might be associated with better performance under stressful condi-tions (Morgan et al., 2000). These findings are consistent with those of animal stud-ies, showing that direct injection of NPY into the central nucleus of the amygdala in rats inhibits fear conditioning, results in increased efforts to initiate contact with a stranger, and promotes resilient responses to stress (Sajdyk et al., 2008).

Brain- Derived Neurotrophic Factor

Brain- derived neurotrophic factor (BDNF), an important nerve growth factor, is ex-pressed at high levels in the brain. Although


animal and human postmortem studies have shown that BDNF exerts a protective function in the hippocampus, it has very different effects in other brain regions. For example, whereas stress decreases BDNF expression in the hippocampus (Duman & Monteggia, 2006), it increases BDNF levels in the nucleus accumbens in rodents, and this increase is associated with depression-like effects (Berton et al., 2006; Eisch et al., 2003). Resilient animals, however, show no increase in BDNF levels in this latter brain region (Krishnan et al., 2007). These find-ings are consistent with human studies of depressed patients, who also show increased BDNF in the nucleus accumbens (Krishnan et al., 2007). Less is known about the effects of stress in other brain regions.

Galanin

Another abundant neuropeptide, galanin, is coreleased with NE in response to stress (Barrera et al., 2006). It has been shown to be involved in a variety of physiological and behavioral functions, including regulation of food intake, metabolism, anxiety, and stress. Starting in the LC, the dense galanin fiber system innervates multiple structures in the forebrain and midbrain that form part of the emotional circuitry, including the hippocam-pus, hypothalamus, amygdala, and PFC (Perez, Wynick, Steiner, & Mufson, 2001). Galanin coexists and functionally interacts with several neurotransmitter systems that are involved in the pathophysiology of mood and anxiety disorders, including NE and 5-HT (Holmes, Yang, & Crawley, 2002). Galanin recruitment might help to down- regulate negative emotional states that may result from stress- induced noradrenergic hy-peractivation (Karlsson & Holmes, 2006). In a recent rodent study, low behavioral disrup-tion upon exposure to predator scent stress was associated with upregulation of galanin messenger RNA (mRNA) in the hippocam-pus (Kozlovsky, Matar, Kaplan, Zohar, & Cohen, 2009).

Genetic, epigenetic, and transcriptional Mechanisms associated with Resilience

Genetic susceptibility to most psychiatric disorders involves allelic variations or poly-morphisms that are common in the general population. Each allelic variation, however, is associated with a small increase in disor-der risk (Rutter, Moffitt, & Caspi, 2006). Thus, each gene might contribute to the causal pathway of psychiatric disorders in combination with other genes, and with en-vironmental influences (Rutter et al., 2006). Recent scientific and technological advances have made it possible to examine genetic in-fluences on not only complex behavioral re-sponses but also underlying biological pro-cesses, such as endocrine responses to stress or neural responses to affective stimuli mea-sured with brain imaging.

Gene– environment interactions seem to play a crucial role in determining the degree of adaptability of stress response systems to acute or chronic stressors, both during development and in adulthood (McEwen, 1998). Certain alleles might be associated with hypersensitivity to stress (DeRijk et al., 2006) and might eventually increase risk for developing psychiatric disorders such as PTSD or depression in the wake of stress-ful life events. The best-known example of gene– environment interaction involves a polymorphism in the serotonin transporter gene promoter region (5-HTTLPR) in hu-mans. This polymorphism has been linked to differential risk for major depression upon exposure to stressful life events in some (Caspi et al., 2003; Kendler, Kuhn, Vittum, Prescott, & Riley, 2005) but not all stud-ies (Gillespie, Whitfield, Williams, Heath, & Martin, 2005; Munafo, Durrant, Lewis, & Flint, 2009; Risch et al., 2009), and to differential amygdala reactivity (Hariri et al., 2005; Munafo, Brown, & Hariri, 2008) and amygdala– cingulate connectivity (Peza-was et al., 2005) in healthy volunteers. Re-cent studies have begun to identify several polymorphisms in other genes of relevance


for resilience, including genes affecting HPA axis function, and the genes coding for cate-chol-O-methyltransferase (COMT), BDNF, and NPY, among others. In these studies, genetic polymorphisms have been linked to differences in anxiety responses, endocrine function, and differential activation of brain

regions to negative stimuli, as summarized in Table 2.1. In addition, studies have identi-fied gene × gene interactions modifying the function of stress response systems, summa-rized in Table 2.2.

Epigenetics refers to stable changes in chromatin structure that underlie long-

TABLE 2.1. Genetic Polymorphisms Affecting Stress Response Systems

Gene Examples of studies Finding

5-HTTLPR Caspi et al. (2003) Kendler et al. (2005)

Short allele carriers have increased risk for depression upon exposure to stressful life events.

Hariri et al. (2005) Short allele carriers show increased amygdala reactivity to threat-related facial expressions.

Pezawas et al. (2005) Short allele carriers show decreased amygdala–perigenual cingulate connectivity.

Kaufman et al. (2004) Social support mitigates effect of short allele on risk for depression.

Munafo et al. (2008, 2009) Risch et al. (2009)

Recent meta-analyses.

CRH type 1 receptor

Bradley et al. (2008) Certain alleles and haplotypes moderate the influence of childhood abuse on depressive symptoms during adulthood.

MR and GR DeRijk & de Kloet (2008) Carriers of the N363S variant of the GR gene exhibit higher cortisol responses to the Trier Social Stress Test.

FKBP5 Binder et al. (2008) Four SNPs of this gene coding for a “chaperone” protein that regulates GR receptor sensitivity interact with childhood abuse severity in predicting PTSD symptoms in adults.

COMT Heinz & Smolka (2006) Low-functioning Met 158 allele is associated with higher circulating levels of dopamine and norepinephrine, higher anxiety levels, and increased limbic reactivity to unpleasant stimuli.

Schmack et al. (2008) Val158Met polymorphism is associated with interindividual variability in neural responses to reward anticipation.

BDNF Chen et al. (2006) Val66Met polymorphism alters anxiety-related behaviors.

Egan et al. (2003) Val66Met polymorphism affects human episodic memory and hippocampal function.

Krishnan et al. (2007) In mice, the Met BDNF allele is associated with reduced BDNF function, greater anxiety-like behavior, and impaired hippocampal-dependent learning, but increased resilience to chronic stress.

NPY Zhou et al. (2008) Low expression diplotype is associated with increased trait anxiety and increased amygdala reactivity to threat-related facial expressions.

Note. 5-HTTLPR, serotonin transporter promoter polymorphism; CRH, corticotropin-releasing hormone; MR, miner-alocorticoid receptor; GR, glucocorticoid receptor; FKBP5, FK506 binding protein 5; COMT, catechol-O-methyltrans-ferase; BDNF, brain-derived neurotrophic factor; NPY, neuropeptide Y.


lasting alterations in gene expression without altering the deoxyribonucleic acid (DNA) sequence (Tsankova, Renthal, Kumar, & Nestler, 2007). Histones constitute the main protein components of chromatin and can be visualized as spheres around which the DNA is wound. Epigenetic mechanisms in-volve the differential acetylation or methyla-tion of histones by a variety of chromatin- modifying enzymes, as well as differential DNA methylation. The resulting changes in nucleosome properties make the DNA more or less accessible for transcription, thereby mediating the impact of environmental stim-uli on gene expression. For example, animal models have shown that drugs of addiction and chronic stress can gradually reduce the activity of histone deacetylase 5 (HDAC5) in the nucleus accumbens, a key brain reward region, leading to increased transcription of genes associated with heightened vulner-ability to stress (Renthal et al., 2007). Stud-ies performed in genetically identical mice raised in strictly defined environments dem-onstrate wide variability in stress responses and degree of resilience. This finding points to the role of chromatin remodeling events, such as histone acetylation or methylation (Krishnan et al., 2007). As mentioned earli-er, epigenetic changes can also occur during development and are capable of mediating differential sensitivity to stress, as demon-

strated by a series of studies conducted by Meaney and Szyf (2005).

Animal studies are beginning to elucidate the molecular mechanisms associated with resilience. A series of studies focusing on the ventral tegmental area (VTA)–nucleus ac-cumbens reward circuitry demonstrate that resilience is not just the absence of vulner-ability, but is associated with a unique set of adaptive changes. C57BI/6 mice were subjected to social defeat by being placed in the home cage of a larger CD1 mouse daily for 10 days. A subset of mice demonstrated resilient responses, characterized only by anxiety-like symptoms, but no social avoid-ance, anhedonia, or metabolic disturbances (demonstrated by vulnerable mice). Resilient mice not only lacked the changes in gene expression observed in the VTA–nucleus ac-cumbens of vulnerable mice but they also showed induction of distinct changes in gene expression present only in this subset of mice (Krishnan et al., 2007). These changes included, among many others, the induc-tion of several K+ channel subunits in VTA dopamine neurons, which prevents changes seen in vulnerable mice in response to stress, including increased VTA excitability and as-sociated release of BDNF into the nucleus accumbens. A related study showed that individual variability in the development of learned helplessness in mice was related

TABLE 2.2. Gene–Gene Interactions Affecting Stress Response Systems

Interaction Study Finding

MAOA by COMT Jabbi et al. (2007) Affects endocrine responses to psychological challenge task

5-HTTLPR by COMT by stressful life events

Mandelli et al. (2007) Affects risk for depression

COMT by 5-HTTLPR Smolka et al. (2007) Affects limbic reactivity to unpleasant stimuli in healthy individuals

5-HTTLPR by BDNF Val66Met by stressful life events

Kaufman et al. (2006)

Predicts risk for depression in children

Kim et al. (2007) Predicts risk for depression in older adults

Note. MAOA, monoamine oxidase A; COMT, catechol-O-methyltransferase; 5-HTTLPR, serotonin transporter promoter polymorphism; BDNF, brain-derived neurotrophic factor.


to the induction of delta-FosB transcription factor in the midbrain, which ultimately re-sulted in reduced substance P transmission to the nucleus accumbens, associated with resilience (Berton et al., 2007). Many other molecular and transcriptional changes like these are being elucidated in subsets of resil-ient animals, and may ultimately lead to the development of new treatments for stress- related disorders.

neural circuits and Resilience

Animal studies and human neuroimaging studies have begun to identify a number of interconnected brain circuits that medi-ate different aspects of mood and emotion under normal circumstances and in various pathological conditions that are indicative of low resilience. The field has identified sev-eral limbic regions in the forebrain that are highly interconnected and function as a se-ries of integrated parallel circuits that regu-late emotional states. Each of these regions is heavily innervated by the brain’s monoam-inergic systems (norepinephrine, dopamine, and 5-HT), which are thought to modulate their activity. The amygdala, located in the temporal lobe, is particularly important for conditioned aspects of learning and mem-ory, for example, establishing associations between environmental cues and emotional stimuli. While it is best understood for its role in fear conditioning and aversive learning, it has an analogous function with respect to reward- related learning (Davis & Whalen, 2001; Everitt, Cardinal, Parkinson, & Rob-bins, 2003). The nucleus accumbens, part of the ventral striatum, is best understood as a key reward region of the brain that regulates an individual’s responses to natural rewards (e.g., food, sex, social interaction), and that mediates the addicting actions of drugs of abuse. It is thought to function as a key link between motivation for rewarding stimuli and the motor responses needed to obtain re-wards (Hyman, Malenka, & Nestler, 2006). More recent research has demonstrated that

it serves an analogous function in avoiding aversive stimuli (Nestler & Carlezon, 2006). The hippocampus, in the temporal lobe, is best characterized for its crucial role in de-clarative memory—the memory of persons, places, and things in time. However, it likely functions more broadly in regulating emo-tional behavior (Bast, 2007), although the specifics are poorly understood. The hypo-thalamus is responsible for coordinating the body’s peripheral hormonal and metabolic responses with the environment. Its control over the HPA axis and numerous other fac-tors is thought to exert pervasive effects on mood (Nestler & Carlezon, 2006). Probably the most important, but least understood, are regions of PFC, such as medial PFC, anterior cingulate cortex (ACC), and orbito-frontal cortex, among others, which medi-ate working memory, and provide executive control over planning and execution of all activities. In the sections that follow, we re-view how these various regions, and several others, integrate to mediate distinct emo-tional behaviors related to resilience.

Neural Circuitry of Fear

The neural circuitry of fear involves primar-ily the amygdala, the hippocampus, and the ventromedial PFC (vmPFC). The amygdala is a key structure in mediating fear condition-ing, the process by which a previously neu-tral stimulus, such as a tone, becomes fear inducing or “conditioned” after being paired with a naturally aversive or “unconditioned” stimulus, such as a foot shock (Delgado, Olsson, & Phelps, 2006). The hippocampus mediates the contextual and temporal as-pects of fear conditioning (Bast, 2007). Fear conditioning is thought to occur via long-term potentiation of synapses in the lateral amygdala and hippocampus. Over time, ex-isting memories may become reactivated and strengthened by reconsolidation, or weak-ened by extinction. Both the amygdala and vmPFC are involved in successful extinction, a process that involves new memory forma-tion (Delgado et al., 2006).


The pathophysiology of PTSD might in-volve abnormal fear learning and underly-ing dysfunction of fear circuits (Liberzon & Sripada, 2008; Rauch, Shin, & Phelps, 2006; Yehuda & LeDoux, 2007). Individu-als with PTSD tend to overgeneralize from specific conditioned stimuli to other stimuli in their environment, which also become as-sociated with their original trauma and are thus fear inducing. Resilience might involve the capacity of avoid overgeneralization of fear cues, as reflected in differential func-tioning of fear conditioning and extinction processes. For example, enhanced inhibi-tion of the amygdala by the vmPFC may enable more controlled responses to acute stressors (Liberzon & Sripada, 2008). In a recent functional magnetic resonance im-aging (fMRI) study of healthy volunteers, the vmPFC became active as fear responses shifted when initially threatening stimuli became safe during the experiment (Schiller, Levy, Niv, LeDoux, & Phelps, 2008). Pre-liminary findings from a study in patients with PTSD suggest that exposure therapy might work at least in part by increasing rostral ACC and reducing amygdala activa-tion during fear processing (Felmingham et al., 2007). Although fear circuitry function is important in resilience, it has not been carefully studied in resilient individuals. A recent study in healthy individuals suggests that the lateral PFC, activated by cognitive regulation of emotions, might act through vmPFC connections to the amygdala to di-minish fear responses (Delgado, Nearing, LeDoux, & Phelps, 2008).

Neural Circuitry of Reward

The nucleus accumbens, part of the ventral striatum, regulates an individual’s responses to natural rewards and also mediates addic-tive behaviors. The mesolimbic dopamine system, the best understood reward circuit, has been increasingly studied in animal models. This system comprises dopaminer-gic neurons in the VTA, located in the mid-brain, that project to the nucleus accumbens

and other limbic regions. A recent study using the social defeat stress model in mice showed a relationship between resilience and the ability of some animals to up- regulate potassium channels in the VTA, preventing a stress- induced increase in neuronal excit-ability and resulting BDNF release in this region, both associated with vulnerability to stress (Krishnan et al., 2007, 2008).

Human fMRI studies have found evidence of reward system dysfunction in both psy-chiatric and trauma- exposed populations (Dillon et al., 2009; Drevets, Price, & Furey, 2008). Altered neural reward processing has been reported in patients with major depres-sion (Forbes et al., 2009) and PTSD (Sailer et al., 2008), and in young adults with a histo-ry of childhood maltreatment (Dillon et al., 2009). In a study using a monetary reward task, healthy adolescents showed greater striatal reactivity during reward anticipation and outcome than did depressed adolescents (Forbes et al., 2009). Furthermore, degree of striatal activation was correlated with level of positive affect measured in naturalistic settings with the Positive and Negative Af-fect Scale (PANAS), demonstrating a link between positive emotions and reward sys-tem function (Forbes et al., 2009).

As mentioned earlier, positive emotion-ality and optimism have been linked to resilience. In a recent fMRI study, Sharot, Riccardi, Raio, and Phelps (2007) dem-onstrated increased amygdala and rostral ACC activation while participants were imagining future autobiographical positive events (compared with negative events). Of note, degree of rostral ACC activation was positively correlated with dispositional op-timism, measured with the Life Orientation Test— Revised (LOT-R). These results sug-gest a mechanism through which resilient in-dividuals might be better able to maintain an optimistic outlook even while facing stress-ful situations. Little is known about reward system function in resilient individuals. A preliminary study in Special Forces soldiers, however, showed differential reactivity of reward- processing regions, including the


nucleus accumbens and subgenual PFC, in these highly resilient individuals compared to civilian healthy controls (Vythilingam et al., 2009).

Neural Circuitry of Emotion Regulation

Stress resilience has been related to a greater capacity for emotion regulation (Masten & Coatsworth, 1998), whereas psychopathol-ogy might be associated with abnormalities in emotion regulation systems (Johnstone, van Reekum, Urry, Kalin, & Davidson, 2007; Masten & Coatsworth, 1998). Phil-lips, Drevets, Rauch, and Lane (2003a) have described a neural model of emotion regula-tion that comprises a ventral system (includ-ing the amygdala, insula, ventral striatum, and ventral ACC and PFC) and a dorsal system (including the hippocampus and dorsal ACC and PFC). The ventral system is important for identification of emotional stimuli and production of an appropriate emotional response, whereas the dorsal sys-tem is important for effortful regulation of emotional responses (Phillips et al., 2003a). Distinct patterns of abnormalities in these systems are associated with different psychi-atric disorders (Phillips, Drevets, Rauch, & Lane, 2003b). Studies in mood and anxiety disorders have most consistently identified abnormalities in amygdala, hippocampus, subgenual ACC, and PFC function (Ressler & Mayberg, 2007).

Imaging genomic studies suggest that differential amygdala reactivity to negative stimuli might represent an intermediate phe-notype associated with differential vulner-ability to anxiety and depressive disorders (Smolka et al., 2007). For example, studies in healthy individuals have identified a link between polymorphisms in the 5-HT trans-porter and the COMT genes, and increased vulnerability to anxiety and negative moods, as well as increased amygdala reactivity to negative stimuli, and differential coupling between amygdala and cortical regulatory regions (Drabant et al., 2006; Hariri et al., 2005; Pezawas et al., 2005).

As discussed earlier, cognitive reappraisal is a mechanism through which resilient in-dividuals may successfully reduce or control emotional responses to stressful situations. Cognitive reappraisal has received increased attention in recent fMRI studies. Findings from studies instructing participants to re-appraise the meaning of negative images point to the involvement of the lateral and medial PFC in regulating emotional respons-es through top-down regulation of amygda-la activation during cognitive reappraisal (Goldin, McRae, Ramel, & Gross, 2008; Ochsner et al., 2004). A recent study suggests that the PFC may act on both the amygdala and the nucleus accumbens, with differen-tial effects on reappraisal success (Wager, Davidson, Hughes, Lindquist, & Ochsner, 2008). Greater use of reappraisal in every-day life has also been linked to greater PFC and lower amygdala activation to negative stimuli (Drabant, McRae, Manuck, Hariri, & Gross, 2009), suggesting a possible neural mechanism through which reappraisal might increase stress resistance. Limited informa-tion is available on central emotion regula-tion systems in trauma- exposed resilient individuals. In a recent fMRI study of resil-ient women with a history of sexual assault but absence of psychopathology, resilience was associated with an increased capacity for cognitive enhancement of emotional re-sponses to negative pictures, a finding that merits further study (New et al., in press).

Additional Neural Circuitry Relevant to Social Behavior

Research suggests that oxytocin and argi-nine vasopressin, neuropeptides implicated in prosocial behaviors and neuroendocrine responses to stress in animals, might me-diate some of the protective and anxiety- reducing effects of affiliative behaviors (Ko-sfeld, Heinrichs, Zak, Fischbacher, & Fehr, 2005; Young & Wang, 2004). Receptors for these two neuropeptides are spread across a network of cortical and subcortical neural systems related to emotion in monogamous


nonhuman mammals (Insel, 1997). Support-ive intimate gestures, such as handholding and other types of soothing physical contact, produce an increase in endogeneous opioid activity by triggering the release of oxyto-cin from the paraventricular nuclei of the hypothalamus (Uvnas- Moberg, 1998). In an fMRI study of married women, handhold-ing with their husband attenuated neural responses to the threat of receiving a shock (Coan, Schaefer, & Davidson, 2006).

Animal studies have shown that intrave-nous administration of oxytocin attenuates stress responses in the central nervous sys-tem (Izzo et al., 1999). In humans, it appears that the combination of social support and oxytocin is most effective in reducing anxi-ety and HPA reactivity in response to psy-chosocial stress. Thus, in an experimental study by Heinrichs, Baumgartner, Kirsch-baum, and Ehlert (2003) participants who received both social support and oxytocin had lower levels of cortisol, and reported greater calmness and lower anxiety during the Trier Social Stress Test than the placebo group, with and without social support, and the oxytocin-only group.

Oxytocin might also facilitate an indi-vidual’s ability to infer the mental states of others (Domes, Heinrichs, Michel, Berger, & Herpertz, 2007). The capacity for empa-thy might be related to social competence, a characteristic of resilient individuals (Iar-occi, Yager, & Elfers, 2007; Schulte- Ruther, Markowitsch, Fink, & Piefke, 2007). Mir-ror neurons are a group of cortical neurons that become activated both when an animal performs an action and when it observes the action performed by another animal of the same species (Rizzolatti & Craighero, 2004). The mirror neuron system might play a role in understanding others’ emotions and intentions, working together with limbic brain regions, as suggested by preliminary findings from a study of children instructed to imitate emotional faces (Pfeifer, Iacoboni, Mazziotta, & Dapretto, 2008). As discussed earlier, social competence and use of social supports have been linked with increased re-

silience to adversity. Further study is needed to clarify the relationship between the capac-ity for empathy and resilience to stress, and to elucidate further the underlying neural mechanisms mediating the protective effects of social support on stress responses.

Resilience interventions

More information is available about treat-ment interventions with clinical populations than about interventions that might foster resilience and prevent the development of psychopathology upon exposure to stress or trauma. Structured psychological treatments for PTSD, such as prolonged exposure ther-apy, cognitive- behavioral therapy, and inter-personal psychotherapy, have been shown to be effective in helping patients practice cog-nitive reappraisal and other coping strategies to confront memories of traumatic events and associated emotions (Butler, Chapman, Forman, & Beck, 2006). Psychotherapeutic approaches with trauma survivors include establishing safety, gradually facing fears in a safe environment, memory consolidation, making meaning, helping patients establish social supports that may have been disrupted or lost in the aftermath of the trauma, and supporting a gradual shift from helplessness to personal agency.

Prolonged exposure therapy, a form of cognitive- behavior therapy based on prin-ciples of learning theory (habituation and extinction), was developed specifically for PTSD and has shown the most efficacy for this disorder (Foa et al., 1999; Schnurr et al., 2007). This form of therapy includes ima-ginal exposure to traumatic memories and in vivo exposure to previously avoided situ-ations. More general cognitive- behavioral techniques include addressing previously distorted cognitions and maladaptive behav-iors, and focusing on increasing positive so-cial supports and improving problem- solving abilities. Interpersonal psychotherapy focus-es on restructuring negative interpersonal relationships and promoting positive social


interactions to decrease negative affect and cognitions (Bleiberg & Markowitz, 2005). Regular physical exercise has also been shown to have positive effects on physical hardiness, mood, and self- esteem, and has been linked to neurobiological effects that promote resilience (Cotman & Berchtold, 2002).

Mindfulness-based approaches to stress reduction may help individuals become more emotionally aware, and have been shown to be effective in reducing anxiety and dyspho-ria in both healthy (Astin, 1997; Shapiro, Schwartz, & Bonner, 1998) and clinical populations (Speca, Carlson, Goodey, & Angen, 2000; Teasdale, Williams, Ridge-way, Soulsby, & Lau, 2000). Davidson and colleagues (2003) found that healthy individ-uals who participated in an 8-week mindful-ness meditation program showed increased left-sided anterior activation (which is asso-ciated with positive affect), measured with electroencephalography, and increased anti-body titers to influenza vaccine from base-line, compared to subjects in a waiting-list control group. Approaches based on positive psychology are also promising in promoting psychological resilience (Seligman & Csik-szentmihalyi, 2000).

Neuroimaging studies have demonstrated that participation in psychotherapy for mood and anxiety disorders can result in measur-able changes in brain activity in neural areas implicated in emotion regulation and posi-tive reappraisal (Beauregard, 2007; Roff-man, Marci, Glick, Dougherty, & Rauch, 2005). Further research is needed to examine whether treatment- related changes in neural functioning can also reduce the likelihood of developing psychopathology in response to future stressors.

Progress in understanding the neuro-biological underpinnings of resilience and vulnerability to stress- related illnesses will also broaden pharmacological treatment approaches. Medications can target respon-siveness to reward, hypervigilance to threat, and dysregulated physiological responses. Drug trials currently under way are evaluat-

ing a range of compounds, including NPY enhancers, substance P antagonists, N-meth-yl-D-aspartic acid (NMDA) antagonists, antiadrenergics, and compounds that down- regulate glucocorticoid receptors (Friedman, 2000). Recent data suggest that D-cycloser-ine, an NMDA receptor partial agonist, can facilitate fear extinction when used in con-junction with exposure therapy (Norberg, Krystal, & Tolin, 2008). Although beta- adrenergic antagonists have been tested in trauma- exposed patients, studies have yield-ed mixed results (Stein, Kerridge, Dimsdale, & Hoyt, 2007).

Stress resilience reflects an individual’s ca-pacity for successful adaptation in the face of acute stress, trauma, or more chronic forms of adversity. Resilience is an active process—not just the absence of pathology—that can be promoted by enhancing potentially pro-tective factors. Novel intervention modali-ties may become possible with increased understanding of psychological predictors of resilience and the associated underlying genetic, neural, and neurochemical influenc-es that shape these observable psychological strengths.

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