Child abuse and neglect

C H A P T E R

13 Child abuse and neglect: stress responsivity and resilience Shariful A. Syed1, Matthew Cranshaw2, Charles B. Nemeroff1 1

Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, Miami, FL, United States; 2University of Miami, Miller School of Medicine, Miami, FL, United States

Child abuse and neglect is one of the most prevalent forms of trauma experienced in the modern world (Anda et al., 2006). In the United States alone there were approximately 4 million reports of child maltreatment in 2015 (increased from 3.4 million in 2012), including 1,585 fatalities, with only 1 in 10 victims receiving any form of postabuse care/service. Furthermore, since 2008, the overall incidence of childhood maltreatment appears to be steadily increasing. Of the child fatalities, 72.9% were neglected children, 43.9% physically abused, and 1.2% sexually abused (Health USDo and Human S, 2015). National reports (Fig. 13.1) have consistently shown that early-life trauma predisposes individuals to develop a number of psychiatric syndromes, particular mood and anxiety disorders, and as such, is a significant public health problem (Molnar et al., 2001). The mechanisms by which various forms of child abuse increase the risk of developing psychiatric disorders are believed to stem from their profound short- and long-term effects on the central nervous system (CNS) and a multitude of peripheral organ systems (Heim et al., 2000a). The neurobiological mechanisms that mediate the consequences of early developmental stress have been studied in humans and laboratory animals. The increased rates of several psychiatric disorders after exposure to early-life stress (ELS) suggest a persistent sensitivity to the effects of stress in later life (Heim and Binder, 2012). More specifically, child abuse and neglect have been posited to permanently sensitize and dysregulate various components of the stress response, both centrally and peripherally. Although the goal of this book is to generate a neurobiological paradigm of stress resilience, in this chapter we focus on one of the most pivotal aspects of this paradigm, namely stress responsivity and how we may discern resilience mechanisms from the stress neurobiology of childhood abuse and neglect. To begin, we present the functional definition of “stress responsivity” to be “variability in reaction to stressful stimuli.” We have chosen such a definition, as it appears to be congruent

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FIGURE 13.1 Number of cases of child abuse in the United States in 2015, according to the type of abuse. Adapted from the U.S. Department of Health and Human Services.

with the theory of evolution as well as the physiology subserving the human stress response. A challenge, which we will elaborate on later in the chapter, although necessary to address from the start, is the difficulty of developing a generalizable definition for “resilience.” To date, the field of stress neurobiology has largely presumed it to mean the absence of psychopathology after extreme stress. This is, in part, a product of the simple fact that we are still in the early stages of “stress resilience” neurobiological research. As the scientific community continues to further elucidate mechanisms via advancement in methodological approaches as well as innovative methods of investigation, we are optimistic that a more refined and comprehensible definition will be operationalized. Before delving into the various mechanisms involved in stress responsivity, a brief overview of the two major systems, which mediate the human stress response, is necessary, namely, the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic adrenomedullary (SAM) system. Before beginning this discussion, we would highlight a fact of the utmost importance. The age group most vulnerable to abuse (neonatesdchildren aged 2 years) is also the group abused the most (Health USDo and Human S, 2015).

Stress responsivity physiology The two main components of the mammalian stress response are the SAM system and the HPA axis (Gunnar and Quevedo, 2007). CNS circuits involving areas of the prefrontal cortex, hippocampus, amygdala, hypothalamic, and brain stem nuclei modulate both systems. Corticotropin-releasing factor (CRF)eproducing neurons oversee the entire mammalian stress response, coordinating the autonomic, endocrine, immune, and behavioral responses to stress (Arborelius et al., 1999). The highest concentrations of CRF are found in the paraventricular nucleus (PVN) of the hypothalamus, which primarily regulates the HPA axis

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response to stress (Antoni et al., 1983). CRF-producing neurons located in the central nucleus of the amygdala are involved in processing emotional stress responses and the SAM response as well. CRF neurons in the central nucleus of the amygdala project to locus coeruleus norepinephrine cells, which in turn project to the lateral thalamus, leading to subsequent activation of the sympathetic preganglionic neurons that ultimately stimulate release of epinephrine from the adrenal medulla. CRF cells of the central nucleus of amygdala are involved in stress-induced activation of the HPA axis (Shekhar et al., 2005), via an indirect pathway through the bed nucleus of the stria terminalis, where CRF neuronal projections innervate the PVN neurons of the hypothalamus (Herman and Cullinan, 1997; Herman et al., 2002; Swanson and Sawchenko, 1983). Following activation of the HPA axis, CRF is released from the PVN in to the adenohypophysial-portal circulation from nerve terminals in the median eminence where it stimulates adrenocorticotropin hormone (ACTH) release from the anterior pituitary. ACTH in turn stimulates release of glucocorticoids (GCs) from the adrenal cortex (Gutman and Nemeroff, 2002). Able to permeate the blood-brain barrier, GCs reduce activation of the HPA axis via stimulation of GC receptors (GRs) within the hippocampus, hypothalamus, and anterior pituitary (Jacobson and Sapolsky, 1991). The critical role of amygdalar CRF has brought to attention the widespread localization of CRF receptors throughout the CNS and their converging pathways in orchestrating stress reactions (Swiergiel et al., 1993; Nemeroff, 1996). Two G proteinecoupled subtypes of CRF receptors, CRFR1 and CRFR2, have been found in the anterior pituitary, as well as in subcortical and cortical brain areas (Chalmers et al., 1996; Steckler and Holsboer, 1999). In general, the stress response appears to be mediated largely by CRFR1 receptors, whereas CRFR2 activation appears to actually diminish the stress response (see Chapter 16 for more information). The response to psychosocial stress, of which ELS represents a specific subtype, also involves “higher appraisal” by cortical and subcortical regions of brain containing CRFR1 receptors, namely, cingulate cortex, orbital/medial prefrontal cortex, and hippocampus (Bale and Vale, 2004); all these areas comprise part of the converging pathways described above. Much evidence points to the role for CRF as a neurotransmitter coordinating immune, autonomic, endocrine, and behavioral stress responses, supported by the finding that CRFR1 receptors are more abundant in corticolimbic pathways that mediate fear- and anxiety-related behaviors (Sanchez et al., 1999). With this basic framework of stress response neurobiology, the concept of “stress responsivity” may be viewed through a model of posttraumatic stress disorder (PTSD). In many ways, as discussed in more detail in other chapters of this book, individuals diagnosed with PTSD exhibit dysregulation of the stress response system. Criteria D for diagnosing PTSD in DSM5 requires that an individual demonstrates “marked alterations in arousal and reactivity associated with traumatic event(s)” in the form of hypervigilance, exaggerated startle response, increased irritability, problems with concentration, and/or sleep disturbance. The fact that many individuals with PTSD have experienced traumatic events that occurred in the form of child abuse and neglect comes as little surprise and further strengthens the argument for using PTSD-derived neurobiological research in developing the construct of “stress responsivity.”

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In the space below, we will examine in further detail the available evidence from human studies on the role of child abuse and neglect that contribute toward a model of “stress responsivity.”

Hypothalamic-pituitary-adrenal axis physiology The HPA axis represents the major neuroendocrine stress response system that serves to adapt the organism to change in life demands and thereby maintain homeostasis (McEwen, 2004). Studies of the influence of ELS on HPA axis activity have shown that the effects of child abuse and neglect are variable in that it is associated with either increased or decreased HPA axis activity. This variability is dependent on several factors including age at the time of the trauma, subtype of abuse/neglect, magnitude, duration, etc.

Childhood maltreatment influence on hypothalamic-pituitary-adrenal/ sympathetic nervous system response to stress Using various validated human stress models of provocative adrenal testing, HPA axis hyperactivity was demonstrated in depressed women and men with ELS by increases in both the ACTH and cortisol response as well as increased cerebrospinal fluid (CSF) CRF concentrations (Heim and Nemeroff, 2001; Heim et al., 2000b, 2002; Carpenter et al., 2004). In an early study, we tested the hypothesis that ELS in humans is associated with persistent sensitization of the HPA axis (Heim et al., 2003). To induce stress, we employed a standardized psychosocial stress protocol, the Trier Social Stress Test (TSST) that consists of public speaking and mental arithmetic tasks in front of an “audience” that has been shown to reliably induce HPA axis and sympathetic nervous system activation (Kirschbaum et al., 1993). Parallel to results from animal models, women with a history of childhood abuse (with and without) current major depressive disorder (MDD) exhibited increased ACTH responses to stress compared with controls. Overall the ACTH response was more than sixfold greater in abused women with current MDD than in controls. These women also demonstrated increased cortisol and heart rate responses to psychosocial stress. Abused women who were not currently depressed exhibited normal cortisol responses, despite their increased ACTH response, perhaps suggesting adrenal adaptation to central sensitization as a marker of resilience against depression after early stress. Depressed women without abuse demonstrated normal neuroendocrine responses. Our findings suggested that HPA axis and autonomic nervous system hyperactivity, likely due to CRF hypersecretion, may be a persistent consequence of childhood abuse that may contribute to the diathesis for adulthood psychopathology (Monroe and Simons, 1991). In a study of patients with MDD and borderline personality disorder, higher baseline and postdexamethasone cortisol concentrations were found in those who had a history of childhood trauma (Fernando et al., 2012). In a nonclinical sample of women with minimal or no current psychopathology, childhood physical abuse was associated with a blunted cortisol response to psychosocial stress task (Carpenter et al., 2011). In another sample of 230 adults without a primary affective disorder,

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a history of self-reported childhood emotional abuse predicted a significantly diminished cortisol response after administration of the dexamethasone/CRF test (Carpenter et al., 2009). In contrast, individuals with child abuse have been reported to exhibit reduced basal cortisol levels, as well as a blunted cortisol response to provocative stimuli (Carpenter et al., 2007). Likewise, ELS is well documented to increase the risk for development of PTSD, which is characterized by an “endocrine signature” of GR hypersensitivity and reduced cortisol signaling (Bradley and Blakely, 1997).

Sympathetic nervous system Perceived threat activates the sympathetic (SNS) and parasympathetic (PNS) nervous systems and recurrent high levels of threat exposure, particularly early in life, can significantly affect an individual’s long-term ability to modulate the SNS and PNS response to future stressors (McEwen, 1998). Although the majority of studies have been focused on the HPA axis, others have examined childhood abuse and SNS reactivity. Of these, some report increased SNS reactivity following high levels of family adversity, whereas others observe no such association (Ellis et al., 2005; Oosterman et al., 2010; El-Sheikh, 2005; Elzinga et al., 2008). Women with a history of childhood sexual abuse also demonstrate relatively high SNS activity (Weiss et al., 1999), particularly in response to sexual cues (Rellini and Meston, 2006). Child abuse is associated with maladaptive patterns of cardiovascular reactivity to psychosocial stress in adolescence (McLaughlin et al., 2014). Taken together, these described HPA axis and SNS changes are consistent with an abnormal increase of CNS CRF activity as a function of childhood abuse and neglect. In fact, childhood stress has been suggested to be more predictive of increased CSF CRF concentrations than either a syndromal diagnosis of a depressive disorder or a suicide attempt (De Bellis and Thomas, 2003). Further highlighting the importance of the timing of stressors, Carpenter et al. (2004) reported that a history of adverse life events before age 6 years predicted elevated CSF CRF concentrations better than the diagnosis of MDD (Schoedl et al., 2010).

Glucocorticoid feedback regulation of stress responsivity Enhanced stress responsiveness after childhood trauma might be further influenced by changes in GC-mediated feedback control of the HPA axis. In an initial study, we observed increased suppression of cortisol in a low-dose dexamethasone suppression test in abused women with depression and concurrent PTSD (Newport et al., 2004). Such hypersuppression indicates enhanced sensitivity of the pituitary to negative feedback and is a prominent finding in PTSD, believed to contribute to stress sensitization (Yehuda, 2006). In fact, the results found in this study might be best attributable to comorbidity with PTSD. We sought to determine the effects of childhood abuse on results in the dexamethasone/CRF test in adult men with and without current MDD. Abused men demonstrated markedly increased cortisol

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responses to dexamethasone/CRF administration when compared with nonabused men, regardless of diagnosis. When stratifying groups by MDD and childhood trauma, only those abused men with current MDD, but not depressed men without childhood trauma, demonstrated increased cortisol responses. Increased response was associated with exposure to both sexual and physical abuse and the severity of the abuse (Heim et al., 2008). Importantly, this effect was not attributable to comorbid PTSD. These results suggest that childhood trauma is associated with impaired GC-mediated feedback control of the HPA axis during stimulated conditions (Heim et al., 2008).

Epigenetics of stress responsivity It is firmly established that genetics contribute to the risk for the development of major psychiatric disorders. In addition, child abuse and neglect serve as important risk factors for the development of psychiatric disorders (Agid et al., 1999; Nestler et al., 2002). A novel approach utilized in recent years tests the hypothesis that gene variants may modulate the effect of ELS on the longitudinal risk for mental illness. Diathesis-stress theories of depression suggest that individual’s sensitivity to stressful events depends, in part, on their genotype (Costello et al., 2002). Investigations to date have largely supported this theory, with many studies demonstrating gene  environment (G  E) interactions that predict psychiatric disorder risk. A handful of such genetic polymorphisms are reviewed here: serotonin transporterelinked polymorphic region (5HTTLPR), monoamine oxidase A (MAOA), FK506-binding protein 51 (FKBP51), CRFR1, brain-derived neurotrophic factor (BDNF), and opioid-related nociceptin receptor 1 (OPRL1). Much research has focused on the interaction between serotonin transporter polymorphisms, ELS, and depression. In a pioneering study using the Dunedin cohort, Caspi et al. (2003) were the first to demonstrate an association between depression, ELS, and the 5-HTTLPR genotype. Individuals exposed to childhood maltreatment, possessing the s/s genotype, were shown to have the highest probability of developing a MDD episode and/or exhibit suicidality, followed by the s/l genotype. The l/l genotype was associated with resiliencedno increased risk for depression or suicide even in the presence of severe childhood abuse or neglect. In a general population study, a three-way interaction among childhood abuse  adult traumatic experience  s allele carrier status was found to be associated with higher Beck Depression Inventory-II (BDI-II) scores (Grabe et al., 2012). A meta-analysis by Karg et al. (2011) found strong evidence supporting the association between childhood maltreatment and the s allele and increased stress sensitivity. This G  E discovery leads to an interesting question, namely, whether we can use a patient’s genotype for the serotonin transporter promoter polymorphism, as well as other polymorphisms coupled with a history of child abuse/neglect as criteria for early intervention to prevent the development of MDD in vulnerable individuals. Caspi et al. (2002) were also among the first to suggest that individual differences at a functional polymorphism in the promoter region of the MAOA gene may modulate children’s response to maltreatment.

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As noted previously, the association between child abuse and adult PTSD is well established (Bremner et al., 1993). Given that PTSD is strongly associated with long-lasting alterations in HPA axis sensitivity and increased GR sensitivity, a natural extension of GE research has examined whether HPA axis gene candidates mediate the increased susceptibility to PTSD after ELS (Yehuda, 2001; Yehuda et al., 1991). FKBP51 codes for a cochaperone protein that modules signal transduction of the GR. Four FKBP51 SNPs were found to significantly predict the PTSD Symptom Score (PSS) in individuals with a history of child abuse. All four SNPs have been associated with the presence of higher levels of FKBP51, consistent with the physiological mechanisms mediating GC sensitivity (Binder et al., 2008). Bradley et al. (2008) demonstrated that genetic variants of the CRFR1 moderate the effect of child abuse on adult depressive symptoms. Laucht et al. (2013) found that the impact of childhood maltreatment on adult depressive symptoms was higher in individuals with two copies of the CRFR1 TAT haplotype. A haplotype of three SNPs in intron 1 of the CRFR1 gene was associated with a diminished effect of child abuse on adult depressive symptoms (Bradley et al., 2008). Thus, a genotype/haplotype may serve as a predictor of risk/resilience in those with history of child abuse and neglect. Ressler et al. found that variants in the 5-HTTLPR interact with CRFR1 genotypes to predict current adult depressive symptoms. Individuals carrying a “risk” allele in both genes demonstrated more severe depressive symptoms at lower levels of child abuse (Ressler et al., 2010). Another GG interaction with implications of vulnerability to depression is between 5-HTTLPR and BDNF. Meta-analyses have suggested that alteration in serotonergic activity may serve as a prodrome for later changes in neural plasticity of which BDNF is essential (Munafo et al., 2005; Urani et al., 2005). One study suggested that the BDNF Met allele may serve as a protection against the adverse effects associated with the 5-HTTLPR s allele in healthy individuals. However, in maltreated children, the combination of BDNF Met with the 5-HTTLPR s allele was associated with an increased risk for MDD (Kaufman et al., 2006).

Stress responsivity neural circuits That ELS, including child abuse and neglect, produces persistent increases in CSF CRF concentrations, a measure of activity of CRF-containing neural circuits, a hallmark of HPA axis hyperactivity, and dysregulation of corticolimbic circuits places it in a position of fundamental importance in exploring pathogenic mechanisms that may underlie major psychiatric illnesses such as MDD and PTSD. Within the context of ELS, emerging data are all congruent in demonstrating persistent structural and functional changes to CNS structures and circuits including the prefrontal cortex, hippocampus, amygdala, and other cortical/ subcortical areas of brain, with increasing evidence that the ELS-specific subtypes result in specific neuroanatomical alterations. The hippocampus has long been an area of interest for a multitude of reasons, one being that it is known to play a pivotal role in efficient termination of the HPA axis stress response by its rich density of GRs.

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Moreover, hippocampal volume reductions have been repeatedly reported in those suffering from MDD, PTSD, and other psychiatric disorders. Reports of reduced hippocampal volume in depressed women with a history of childhood maltreatment but not in equally depressed women without ELS have also been confirmed by others (Vythilingam et al., 2002; Buss et al., 2007; Frodl et al., 2010) and in a comprehensive meta-analysis (Nanni et al., 2012). Teicher et al. (2012) found that childhood maltreatment was significantly associated with reduced volume in the hippocampal dentate gyrus, subiculum, and subfield CA3. Another study compared depressed patients and age- and sex-matched healthy controls and found that childhood maltreatment, but not depression, was associated with hippocampal atrophy (Opel et al., 2014). Victims of childhood sexual and emotional abuse showed marked thinning in specific areas of cortical representation, respectively, suggesting that type-specific ELS has select effects on neural plasticity that persist into adulthood (Heim et al., 2013). The preeminent role of the amygdala in stress responsivity has appropriately rendered it a central focus in research on mood and anxiety disorders. Both amygdala volume and responsiveness to stressors in those exposed to child abuse and neglect versus controls have been explored. Childhood maltreatment (assessed by the Childhood Trauma Questionnaire) was shown to be positively associated with amygdala responsiveness in a standard emotional face-matching paradigm. This effect was not confounded by recent life stressors, current depression, or sociodemographic factors (Dannlowski et al., 2012).

Stress responsivity and inflammation A neurodegenerative hypothesis of depression and psychiatric disorders of which inflammation is central has started to gain significant support in the stress neurobiology literature (Maes et al., 2009). Briefly, the mechanisms of action of cytokines on the brain include the ability to mediate “sickness” behavior, alterations in serotonergic/glutamatergic/dopaminergic neurotransmission, reduction in neurotrophic factors (e.g., BDNF), and increased neuronal glutamate excitotoxicity, as well as neuronal vulnerability to oxidative reactive species (Maes et al., 1993, 2009, 2011; Raison et al., 2006, 2010; Qin et al., 2007; Irwin and Miller, 2007; Borland and Michael, 2004; Zhu et al., 2010; Neurauter et al., 2008; Felger et al., 2013; Steiner et al., 2011; Raison and Miller, 2003; Krügel et al., 2013). This has refined the original monoamine hypothesis of depression (Reichenberg et al., 2001; Maes, 1995; Capuron et al., 2002; Harrison et al., 2009; Bonaccorso et al., 2002) with a chronic neuroinflammatory and neurodegenerative theory of depression (Maes et al., 2009). Childhood abuse has been convincingly shown to produce a proinflammatory state (Coelho et al., 2014). Individuals with depression and a history of childhood maltreatment were more likely to have elevated C-reactive protein concentrations compared with controls (Danese et al., 2007, 2011). In response to daily stressors, child abuse history moderated levels of IL-6; those with a positive history of childhood abuse had IL-6 levels 2.35 times greater than those without any early abuse history. Childhood abuse was significantly associated with increased NF-kb pathway activity in individuals with PTSD, providing additional pathways to the previously discussed HPA axis alterations in the context of child abuse and neglect (Pace et al., 2012).

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Stress responsivity and resilience As discussed earlier, the concept of resilience has proven remarkably challenging to operationalize, as it encompasses a variety of behavioral phenotypes, which further complicates the characterization of neurobiological mechanisms in resilient individuals (Russo et al., 2012). If we consider resilience to be an active process of adaptation that precludes the development of psychopathology in the context of extreme duress, then the study of stress responsivity may be one pathway to advancing our understanding of resilience. To date, it is clear that the scientific literature has amassed a considerate database on the neurobiological consequences of child abuse and neglect and its associated cascade of perturbations associated with increased vulnerability to developing affective and anxiety disorders. However, it may be that through the elucidation of “risk neurobiology,” we may indirectly arrive at ways to reduce risk and thus increase resilience. In several animal models and in some human studies, resilience is associated with rapid activation of the stress response and its efficient termination (DeRijk and de Kloet, 2005; De Kloet et al., 2005) and is further characterized by the capacity to constrain stress-induced increases in CRF and cortisol through an elaborate negative feedback system. There are clinical data in select populations that exemplify stress resilience (i.e., military personnel, victims of trauma), of which there are multiple biological factors that appear to play a role: CRFR1, 5HTLLPR, BDNF, neuropeptide Y (NPY), and dehydroepiandrosterone (DHEA) to name a few.

Resilient stress responses: CRFR1/OPRL1/5HTLPR/BDNF/NPY/DHEA Mediating the bulk of the CNS action of CRF, the CRFR1 receptor gene has demonstrated a haplotype of three SNPs in intron 1 of the CRFR1 gene that was associated with a diminished effect of child abuse on adult depressive symptoms (Bradley et al., 2008). Specific CRFR1 polymorphisms appeared to uniquely moderate the effect of child abuse on the prospective risk for depressive symptoms in adulthood. Thus, a genotype/haplotype may serve as a predictor of both risk and resilience in those with history of child abuse and neglect. To add to the ELS-HPA axis gene interaction story, an SNP found in the opioid receptore like 1 (Oprl1) gene in patients with PTSD symptoms after a traumatic event is associated with a self-reported history of childhood trauma (Andero et al., 2013). The same SNP is associated with altered fear learning and fear discrimination, mechanisms including differential amygdala-insula functional connectivity that has been linked to PTSD (Stein et al., 2007). Kaufman et al. (2004) showed that a supportive environment protected children with the s/s serotonin transporter promoter genotype and a history of maltreatment from developing depression. BDNF, a vital growth factor, promotes healthy function of the adult hippocampus. Induction of BDNF has been implicated in relative vulnerability and resilience to stress (Krishnan et al., 2007). NPY is a peptide neurotransmitter that modulates the acute stress response, and laboratory animal studies have provided evidence that increased NPY

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signaling in the central nucleus of the amygdala is associated with lower anxiety levels (Rasmusson et al., 2003). DHEA is released with cortisol from the adrenal cortex, and studies suggest it may play an antiinflammatory/antioxidant role during an acute stress response. DHEA increased under acute stress and a higher DHEA-to-cortisol ratio is associated with fewer dissociative symptoms in healthy subjects during military survival training (Rasmusson et al., 2003; Mulchahey et al., 2001). There is evidence to suggest that testosterone promotes resilient behavior in males with MDD and PTSD, an observation congruent with the epidemiological data that women are at significantly higher risk than men to develop such disorders (Pope et al., 2003). One area of work that will significantly advance resilience research will be human brain imaging, as the elucidation of brain circuits involved in stress resilience is vital. Although this avenue of exploration still remains in its infancy in human studies, there already are some promising findings. Steffens et al. (2017), in the NBOLD study, have found significant differences in the Default Mode Network vmPFC/dlPFC that are thought to play a regulatory role in corticolimbic circuits mediating stress vulnerability (Steffens et al., 2017).

Treatment/implications/future Stress resilience neurobiology research, at its core, deals with the human evaluational response to verbal and nonverbal stimuli (aka “stressors”) in connection with their unique meanings to the “person.” Maladaptive evaluations result in abnormal stress responses, which lead to a cascade of negative consequences including poor coping skills, reduced tolerance for stressful stimuli, and higher risk of developing a psychiatric disorder (Hammen et al., 1985). As briefly discussed in this chapter, and further elaborated upon in others, genetic variants appear to interact with environmental variables to modulate how a human’s reaction to stress predisposes or protects against development of psychiatric disturbances. Studies suggest that the molecular mechanisms of childhood abuse and neglect as well as other forms of early-life adversity are potentially reversible in adulthood (Meaney and Szyf, 2005). That behavioral interventions have been shown to directly affect 5-HT neurotransmission, leading to changes in GR expression, which allow for effective termination of stress response bodes well for the field of stress resilience research. Not to be excluded, exercise training has also had consistently positive results suggesting utility in the area of stress resilience, specifically for those with clinical depression (Martinsen et al., 1985; Blumenthal et al., 1999; Singh et al., 2001). Exercise monotherapy for mild to moderate depression showed comparable rates of remission to the SSRI monotherapy group. Furthermore, during the follow-up period, those who exercised on their own had a 50% reduction in probability of relapse compared with those who did not continue exercise after study completion (Babyak et al., 2000; Salmon, 2001). In relation to stress responsivity, it is of interest that exercise-trained individuals showed attenuated HPA axis responses to mental stress (Luger et al., 1987) and that exercise has been shown to prevent stress-induced changes in gene expression of neurotrophic factors vital to hippocampal function (Russo-Neustadt et al., 2001).

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The neurobiology of stress resilience will hopefully make possible the induction of natural mechanisms of resilience in vulnerable populations including victims of child abuse and neglect. One of the intrinsic and unavoidable challenges that researchers must navigate in the realm of stress resilience neurobiological research is that those who are able to maintain a high level of function and psychiatric stability despite exposure to trauma do not come to the attention of clinicians. As a result, other than some studies in niche populations (military personnel), the field remains challenged to discern resilient mechanisms from those that have been shown to have higher risk/vulnerability such as those who develop MDD/ PTSD in the context of childhood abuse and neglect. A plausible methodological approach that may better demonstrate the neurobiological mechanisms mediating resilient behavior would include a model that prospectively examines the impact of a stressor such as natural disaster with comparisons to nonetrauma-exposed individuals. Determining what factors contribute to psychiatric vulnerability and morbidity in these two groups in a long-term longitudinal paradigm is of interest. Decreasing the CRF response both centrally and peripherally to stress represents an important component of the therapeutic response in mood and anxiety disorders (Nemeroff and Vale, 2005). Alternatively, discovery of resilience biomarkers that translate into novel interventions that can alleviate the suffering of those afflicted by stress-related disorders and/or prevention is the ultimate goal.

Financial Disclosures The author(s) declared the following financial relationships over the past 3 years. Charles B. Nemeroff, MD, PhD, Research/Grants: National Institutes of Health (NIH), Stanley Foundation. Consulting: Xhale, Takeda, Mitsubishi Tanabe Pharma Development America, Taisho Pharmaceutical Inc., Navitor, Intracellular therapeutics, Bracket (Clintara), Gerson Lehrman Group (GLG) Healthcare & Biomedical Council, Sunovion Pharmaceuticals Inc., TC-MSO, Janssen Research & Development, LLC, Magstim, Inc.; Stockholder (or options): Xhale, Celgene, Seattle Genetics, Abbvie, OPKO Health, Inc., Bracket Intermediate Holding Corp., Network Life Sciences Inc.; Scientific Advisory Boards: American Foundation for Suicide Prevention (AFSP), Brain and Behavior Research Foundation (BBRF) (formerly named National Alliance for Research on Schizophrenia and Depression [NARSAD]), Xhale, Anxiety Disorders Association of America (ADAA), Skyland Trail, Bracket (Clintara), Laureate Institute for Brain Research, Inc.; Board of Directors: AFSP, Gratitude America, ADAA; Income sources or equity of US$10,000 or more: American Psychiatric Publishing, Xhale, Bracket (Clintara), CME Outfitters, Takeda; Patents: Method and devices for transdermal delivery of lithium (US 6,375,990B1) and method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2).

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