Abstract
Experience of early life stress (ELS) and trauma is highly prevalent in the general population and has a high public health impact, as it can trigger a health-related risk cascade and lead to impaired homeostatic balance and elevated cacostatic load even decades later. The prolonged neuropsychobiological impact of ELS can, thus, be conceptualized as a common developmental risk factor for disease associated with increased physical and mental morbidity in later life. ELS during critical periods of brain development with elevated neuroplasticity could exert a programming effect on particular neuronal networks related to the stress response and lead to enduring neuroendocrine alterations, i.e., hyper- or hypoactivation of the stress system, associated with adult hypothalamic-pituitary-adrenal axis and glucocorticoid signaling dysregulation. This paper reviews the pathophysiology of the human stress response and provides evidence from human research on the most acknowledged stress axis-related neuroendocrine pathways exerting the enduring adverse effects of ELS and mediating the cumulative long-term risk of disease vulnerability in adulthood.
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Introduction
The developmental origins hypothesis suggests that the roots of adult disease are to be found among disruptions of physiological developmental processes in early life [1, 2]. The term “early life stress” (ELS) has been used to describe a broad spectrum of adverse exposures during fetal and neonatal life, early and late childhood, and adolescence (e.g., childhood trauma, maltreatment, neglect, separation, abuse, parental loss, and starvation). Experience of such disrupting early life adversities occurs at disturbingly high rates in the general population (over 30–40% of the adult population have experienced some form of ELS) and constitutes a major public health problem [3, 4]. ELS during critical phases of perinatal and juvenile brain development is associated with higher levels of cacostatic load and reduced adaptability to stress in adult life, leading to enhanced vulnerability to disease [5].
Many studies have reported a negative impact of ELS and trauma on adult general mental and physical health-related quality of life. Particularly, a higher risk of psychiatric disorders (e.g., depression, posttraumatic stress disorder, and schizophrenia) and their unfavorable outcomes has been recurrently associated with ELS experience in several retrospective [6,7,8,9] but also prospective [10] studies. In addition, risk behavior patterns such as substance use and, especially, tobacco and alcohol consumption are considered significantly increased in individuals with ELS history [11,12,13]. A recent meta-analysis by Zatti et al. also confirmed the close association of ELS and suicide attempts in later life [14]. Nevertheless, the chronic physical health consequences of childhood adversities may be as substantial as mental health consequences [7, 15]. Several studies and meta-analyses of related research point to a distinct association of ELS with cardiovascular, gastrointestinal, neurological, musculoskeletal, pulmonary, and metabolic diseases; chronic inflammatory and pain syndromes; frequency of medical consultations, and number of medical diagnoses [7, 16,17,18,19,20,21]. These findings indicate that ELS experience not only alters neurobiological systems resulting in an increased risk of mental disorders but may also have a long-lasting effect on a number of organ systems.
ELS rarely occurs as a single event but frequently consists of prolonged or repetitive experience of one or more types of malicious acts. Several negative risk factors may also coexist (e.g., poverty, parental psychopathology, and drug addiction), contributing to a complex milieu of multiple chronic stressors, which calls for specialized assessment [22]. In particular, the seriousness of physical and psychological consequences has often been linked to the number of ELS events experienced [23,24,25,26]. In several studies, the number of ELS experiences has been associated with a higher adult risk of psychiatric symptom complexity and severity, psychiatric comorbidities, prescribed psychotropic medication, poor mental and physical quality of life, as well as several physical conditions (e.g., heart disease, asthma, diabetes mellitus, arthritis, chronic spinal pain, and chronic headache) [7, 9, 27,28,29,30].
The long-term effects of ELS may, thus, be conceptualized as a common developmental risk factor triggering a health-related risk cascade and mediating cumulative health risk leading to increased physical and mental morbidity and all-cause mortality in later life [1, 3, 23, 31,32,33]. Furthermore, genetic factors, the specific nature of ELS and particularly its exact timing, presence of caregivers and psychological support, family history of major psychiatric disorders, as well as additional traumatic stress experiences in adulthood may all greatly influence downstream biological pathways and further influence the individual vulnerability for later disease [34]. Although the number of studies assessing the causal relations between ELS and its long-term adverse health-related effects is constantly on the rise, little is known about the exact neurobiological pathways through which ELS is translated into biological health risk.
Among all the systems involved though, the most apparent link between ELS and adult disease is neuroendocrine alterations reflecting a chronic dysregulation of the stress system [34]. This paper reviews the pathophysiology of the human stress response and provides evidence from human research on the most acknowledged stress-related neuroendocrine trajectories, mediating the cumulative long-term risk of disease vulnerability in later life after ELS exposure (cf. Fig. 1).
Schematic model of developmental neuroendocrine aspects of prolonged stress system dysregulation after early life stress exposure
The biology of stress
Stress, homeostasis, and cacostatic load
Τhe capacity to maintain a state of complex dynamic balance and constant fluctuation around an ideal homeostatic condition (non-equilibrium homeodynamic state) serves self-regulation and adaptability of the organism to ongoing challenges [35, 36]. This optimal state is constantly challenged by intrinsic or extrinsic, real or perceived altering conditions or stimuli, defined as stressors. When stressors exceed a certain severity or temporal threshold, perceived stressor-related information initiates a complex stress response, redirecting energy according to the current needs [5, 37,38,39,40]. The organism’s total response to these ongoing demands is defined as allostatic load and mirrors a state of disharmony. Thus, stress is defined as the state of threatened homeostasis [5, 41].
Repeated, ephemeral, and motivating stress states lead to response habituation and are fairly beneficial, while inadequate, aversive, excessive, or prolonged stress may surpass the natural regulatory capacity and adjustive resources of the organism and majorly affect adaptive responses [5]. Cumulative or excessive stress exposure, especially in developmental stages of particular stress sensitivity and plasticity (e.g., early childhood), but also following a single but extreme stress experience (e.g., traumatic stress) may oversensitize neuroendocrine responses to stress. This can lead to excessive and prolonged activation of the stress system or, in a subgroup of individuals, to chronic hypoactivation of this system and a vulnerable phenotype with disrupted stress reactivity. This chronic condition can result in an altered homeodynamic state, called allostasis or, more accurately, cacostasis (i.e., negatively altered homeodynamic state, dyshomeostasis), and accumulated cacostatic load which is related to chronic physical and mental morbidity [5]. In the long run, secondary biological alterations with profound and debilitating effects on homeodynamic balance, health, and development are the sequelae of this state [42,43,44,45,46].
The human stress system and the stress response
The human stress system includes central and peripheral components. The central, greatly interconnected components of the stress system are located in the hypothalamus and the brain stem and include the following: (a) the parvocellular neurons of corticotropin-releasing hormone (CRH), (b) the arginine-vasopressin (AVP) neurons of the hypothalamic paraventricular nuclei (PVN), (c) the CRH neurons of the paragigantocellular and parabranchial nuclei of the medulla and the locus coeruleus (LC), (d) the arcuate nucleus proopiomelanocortin-derived peptides alpha-melanocyte-stimulating hormone (MSH) and beta-endorphin, (e) other mostly noradrenergic (NE) cell groups in the medulla and pons (LC/NE system), and (f) the central nuclei of the autonomic nervous system (ANS). The peripheral components of the stress system include (a) the hypothalamic-pituitary-adrenal (HPA) axis and (b) the limbs of the ANS comprising (i) the sympathetic nervous system (SNS) and sympatho-adrenomedullary (SAM) system and (ii) the parasympathetic system (PNS).
Activation of the stress system through perception of a threat by the limbic system (i.e., PVN) leads to a normally adaptive and time-limited micro-, meso-, and macrophysiologic compensatory response, redirecting energy according to the current needs [5, 37,38,39,40]. Together, these responses through different stress effector tissues produce an orchestrated “symphony” enabling a fine-tuned response to challenge in both the central nervous system (CNS) and the somatic periphery [47]. The stress response is remarkably consistent in its qualitative presentation. The principal peripheral effector molecules are the HPA axis-regulated glucocorticoids (GCs) and the SAM-regulated catecholamines (CAs) NE and epinephrine. GCs participate in early direct and non-genomic molecular events as well as in transcriptional cellular procedures [5, 37,38,39,40,41, 48] and are essential to the maintenance, duration, and downregulation of the stress response mainly through GC binding to glucocorticoid receptors (GRs) in the hippocampus [49, 50].
Pathophysiology of the stress response
Traumatic and long-term stress exposure is considered to lead to sustainable alterations in stress regulation and psychophysiological reactivity [1, 3, 15, 19, 23, 31,32,33, 51,52,53], impaired GC signaling [54,55,56], and changes in ANS function, the HPA axis, and the SAM system [57, 58]. Previous results have pointed to a particularly crucial role of GC signaling in the pathophysiology of chronic stress. Insufficient glucocorticoid signaling, although through dysregulations at different levels (resulting from either hyper- or hypoactivation of the HPA axis), may have similar devastating effects on the organisms’ physiology [55]. Such effects may be related to the particular role of GC signaling in the regulation of the immune system and the ANS [54]. The typical example of chronic hyperactivation of the stress system is observed in melancholic depression [5, 48], with chronic hypersecretion of CRH/AVP by the hypothalamus and hypersecretion of ACTH by the pituitary [49], resulting in repeated activation of the stress system and increased peripheral cortisol levels due to an insensitive negative GC feedback of the HPA axis loop [59]. Similarly, other conditions, such as anorexia nervosa, obsessive–compulsive disorder, panic disorder, alcohol withdrawal, excessive exercising, poorly controlled diabetes mellitus, and hyperthyroidism among others, may also be associated with increased cortisol levels through hyperactivation of the HPA axis [60]. On the other hand, repeated or chronic stress may also result in hypoactivation of the HPA axis (rather than sustained activation), with lower peripheral cortisol levels, possibly reflecting a compensatory physiologic adaptation [56, 60, 61]. Patients with atypical depression, chronic fatigue syndrome, fibromyalgia, hypothyroidism, nicotine withdrawal syndrome, and PTSD fall into this category. This diminished secretion seems to be the result of a negative feedback hypersensitivity of GCs associated with an upregulated leukocyte GR number and sensitivity [62,63,64,65,66], downregulated secretion of CRF/AVP to the pituitary [49], or a long-lasting dropping of glucocorticoid catabolism to increase the persistence of active cortisol in the liver and kidney without elevation of circulating levels [67]. These effects appear even greater in individuals with ELS history, suggesting a developmental programming through GC signaling.
ELS and the stress system
Preclinical and clinical studies have shown that ELS can irreversibly disrupt central neurobiological systems crucial for growth and puberty in the most vulnerable periods of human development and, thus, lead to long-lasting altered neuroendocrine stress responses [64, 68, 69]. Because of their pivotal role in the regulation of the dynamic stress response, the HPA axis and ANS have received the closest scrutiny in relation to other systems that may be longitudinally affected by ELS [34, 70]. However, progress in this research area is hampered by the complex and often conflicting associations found between markers of HPA axis function (i.e., both increased and decreased HPA axis activity) and ELS [5, 70], as well as the broad definition of ELS (i.e., broad time window of 0–18 years of age). For example, ELS has been repeatedly positively associated with HPA axis hyperactivity not only in adults with depression and PTSD but also in healthy individuals (e.g., increased peripheral cortisol and dehydroepiandrosterone-DHEA levels, enhanced CAR, increased ACTH and cortisol responses to psychosocial stress or endocrine challenges) [71,72,73,74,75,76,77,78,79,80], while several studies have reported HPA axis hypoactivity (e.g., reduced peripheral cortisol levels and blunted cortisol responses to psychosocial stress) in similar populations and study designs [81,82,83,84,85]. Therefore, several factors may have influenced study results, such as the exact subtype of trauma, gender, and the assessment of phasic (e.g., diurnal saliva cortisol and cortisol reactivity to challenge) versus tonic cortisol values (e.g., hair cortisol) [86, 87]. However, probably the most important factor modulating the impact of ELS in later HPA axis activity is its exact timing.
Timing of ELS and HPA axis development
Although the HPA axis develops continuously from infancy to adolescence and adulthood, specific periods of greater plasticity may also represent periods of greater vulnerability and, very likely, profound and enduring consequences [88]. In conjunction with the HPA axis, amygdala, and hippocampus development, there are also evolving non-linear patterns until the age of 25 years, with specific gender differences [89,90,91]. Accordingly, several findings suggest a differential impact of ELS according to specific developmental age of exposure.
One of the most vulnerable periods in CNS development is infancy and early childhood (0–2 years of age) [44, 88, 92, 93]. Animal and human research implies that the HPA axis, after an initial hyperresponsive period, may later transition into a stress hyporesponsive period (SHRP) with blunted basal and stress-induced cortisol [88, 92, 94, 95]. Several longitudinal studies indicate that stress responses in early childhood decrease with age throughout the preschool period [88, 94,95,96]. There are several studies demonstrating that these findings might reflect a particular social buffering of the HPA axis (i.e., blunted response) by a nurturing caregiver, who may operate as a safety signal and help maintain low GC levels [97,98,99]. Interestingly, in a recent review, Struber et al. have also proposed important interactions of GC signaling with oxytocin pathways, which may, in part, explain some of results in early childhood [100]. Collectively, these findings suggest that the shift from a hyper- to a relatively hyporesponsive stress axis during the first 2 years of life within the first 2 years of age may be an important stress-sensitive period, especially in the absence of a nurturing caregiver [92]. ELS accompanied by heightened cortisol during the hyporesponsive period could lead to greater exposure to glucocorticoids and, in turn, to glucocorticoid receptor insensitivity over time, affecting the physiological development of a hyporesponsive HPA axis [88, 101]. Studies from Kuhlman et al. [87, 102] confirm that ELS exposure prior to the age of 2 years was associated with prolonged cortisol responses to an acute social stressor among adolescents. Similarly, in their longitudinal orphan study, McLaughlin et al. [103] reported that youth who had been placed in foster care before the age of 2 showed similar cortisol responses to never-institutionalized children, while youth in prolonged institutionalization exhibited blunted cortisol responses to psychosocial stress. These findings support the hypothesis of a particularly high sensitivity and plasticity during the first 2 years of life.
Another particularly sensitive and vulnerable period is the later developmental stage of adolescence/puberty, which signifies a new major change in HPA axis activity, transitioning from hyporesponsivity to a period of increased activity [88, 104,105,106] with continuously higher basal [95, 99, 107, 108] and reactive [95, 107, 109,110,111] cortisol levels. Interestingly, during this developmental stage, parental support does not seem to buffer HPA axis reactivity in humans [99]. However, the autonomy and sexual maturation characterizing this period in humans may reprogram HPA axis reactivity for the new challenges in interaction with sex and environmental cues [102]. The individual, but also gender-specific onset of gonadal hormone production (pubertal maturation completed around the age of 16 years), plays a pivotal role in stress and HPA axis reactivity, since estrogen secretion suppresses HPA axis hyperactivity in women [112]. Some human studies on ELS during adolescence reported lower baseline cortisol [113] and blunted cortisol responses to psychosocial stress [114], hence pointing to an opposite effect of ELS on HPA axis basal activity and reactivity than in infancy.
Taken together, ELS during the first hyposensitive 2 years of life may lead to a hyperactivity and hyperresponsiveness of the HPA axis and ELS during the hyperactive phase of adolescence to a hypoactive and hyporesponsive HPA axis [88]. The study by Bosch et al. [115] confirms this hypothesis by reporting a particular association between adversities in the first year of life, but not late childhood or adolescence, and heightened cortisol reactivity later in life. In addition, they reported greater cortisol output later in life after experience of adversities during childhood, but lower cortisol output after experience of adversities in adolescence. These age-related differences in HPA axis activity and reactivity seem also to be reflected in the specific risk of developing a mental disorder. Accordingly, after traumatization in early childhood, the risk of developing major depressive disorder in adulthood equals the risk of developing PTSD, while after traumatization in adolescence, the risk of PTSD is greater than that of depression [6].
Interplay between the HPA axis and the ANS
Normally, the HPA axis and the ANS are closely interconnected at several neuroendocrine levels and their activity shows some degree of analogy and complementarity throughout the body. The HPA axis and the ANS are increasingly studied together [116], as integrated and interrelated components of an internal neural regulation system (central autonomic network, CAN). Dysregulation of the central autonomic network [117,118,119] may affect downstream autonomic core centers, from the prefrontal cortex (PFC) via the amygdala and the hypothalamus to the brain stem, thereby altering peripheral ANS activity and overall stress responsiveness [118, 120, 121]. Accordingly, findings suggest that the appropriate regulation of the HPA axis depends, at least in part, on the ANS, especially on vagal influences [122]. On the other hand, ANS activity is heavily implicated in the development of trauma- and stress-related pathophysiological alterations. The significant overlap of the fear/arousal circuitry with the CAN [123] could, at least in part, be responsible for autonomic dysregulation after ELS or trauma exposure [124]. The high comorbidity of stress- and trauma-related psychiatric disorders with cardiovascular disease [125,126,127,128,129,130] confirms an important pathophysiological link between these disorders and autonomic control [131,132,133].
With respect to these findings, some studies have reported increased ANS activity in adults with ELS exposure. For example, Otte et al. [134] have shown increased CA responses to psychological stress in police academy recruits with ELS history, while O’Hare et al. [135] reported a strong association between ELS experience and syncope frequency in adulthood. However, the number of adult ELS-exposed studies is limited in relation to the numerous studies assessing ANS activity in adult PTSD patients and pointing to an increased sympathetic and/or decreased vagal activity as a sequel of trauma [136].
Lately, several pediatric studies have sought to shed some light on the interplay between the HPA axis and the ANS after ELS. De Bellis et al. have reported significantly higher 24-h urinary concentrations of CAs and their metabolites but similar responses to CRH injection in sexually abused girls relative to matched controls [137]. In another pediatric study, Gordis et al. [138] reported an asymmetry between concentrations of salivary alpha-amylase (sAA), an indicator of SNS functioning, and cortisol reactivity to a social stressor, with maltreated youth showing no associations between the peripheral biomarkers of HPA axis and SNS activity. Pervanidou et al. [139] reported a successive normalization of cortisol levels but a continuous increase of CA levels after 6 months of trauma exposure in children with PTSD following a motor vehicle accident, suggesting a lifted cortisol-mediated restraint on the catecholaminergic response in limbic structures (e.g., locus coeruleus and other brain stem centers), resulting in enhanced ANS activity. With respect to these findings, Pervanidou [56] has proposed a progressive divergence of HPA axis and ANS activity following ELS, which may represent another potential pathophysiological pathway leading to the long-term impact of ELS and the preservation of symptoms over the years. Hence, the low cortisol levels and enhanced ANS activity found in adult PTSD patients and some ELS exposed individuals may represent a late event in the natural history of stress-axis divergence in trauma-related disorders [140].
The stress system and immune axis
The central and peripheral limbs of the stress system and the immune axis are implicated in a very complex, two-way neuroimmunoendocrine interplay [141,142,143], which implicates the immune system in stress resilience, influencing peripheral and central stress-related neurobiological and neuroendocrine responses [144]. Acute stress-related adrenergic and CRH-peptidergic stimulation activates the secretion of proinflammatory cytokines, which coordinate further immune responses (e.g., stimulation of systemic acute-phase proteins, such as C-reactive protein, CRP) [45, 145]. Proinflammatory cytokines also stimulate the secretion of GCs, while GCs, in turn, help terminate the inflammatory response [143, 146,147,148]. A dysregulated stress response could, thus, lead to a dysregulation of inflammatory feedback mechanisms, thereby promoting biological aging and the development of inflammatory-related or immunosuppressed medical conditions [54, 64, 149,150,151].
ELS has therefore been increasingly associated with peripheral immune dysregulation and long-term, low-grade inflammatory excess, leading to a proinflammatory phenotype and an increased risk of disease with immune origin in adulthood [19, 33, 88, 152,153,154,155,156]. Although the precise underlying mechanisms involved are still not completely understood [141], the two major limbs of the stress system may play a crucial role. On the one hand, an ELS-related ANS dysregulation with compromised vagal activity could directly enhance inflammation via direct vagal efferent effects of autonomic brain regions [157,158,159]. On the other hand, ELS-related HPA axis dysregulation could affect GR-mediated transcriptional and post-transcriptional responses of immune-related genes and result in reduced recovery capability [54, 160]. Human and preclinical research has confirmed GC resistance and insensitivity in immune cells and, thus, altered inhibitory signaling of GCs [101, 161] following repeated acute and/or chronic stress [162, 163].
Sleep and the circadian system
The human circadian system (CS) enables the temporal organization and coordination of numerous physiologic processes [164], such as the diurnal rhythmicity of the HPA axis and ANS activity [165,166,167,168]. The central and peripheral CS synchronizes hypothalamic CRH- and AVP-secreting neurons, influences adrenal sensitivity to ACTH, stimulates circadian GC hormone secretion, and displays a peripheral 24-h rhythm of target tissue sensitivity to GCs through circadian acetylation and deacetylation of the GRs and peripheral clock gene expression [165, 169,170,171,172,173]. The CS also modulates ANS activity through projections to preautonomic hypothalamic neurons and is essential for the physiologic autonomic diurnal fluctuations seen in humans [174,175,176].
Recent research has focused on a potential causal role of sleep and circadian disruption in the development of the long-term cacostatic effects of trauma exposure [177,178,179]. Circadian disruption represents a critical loss of the strict temporal order at different organizational levels and introduces a breakdown of harmonious functioning of internal biological systems [180,181,182], which may sensitize individuals to stress and increase their vulnerability to stress-related disorders [183, 184]. Acute and chronic physical and/or psychological stress affects the CNS sleep centers [185,186,187,188] and can cause both immediate and long-lasting sleep disruption [189,190,191], which may, in turn, enhance maladaptive stress regulation [192]. Some animal [193], and numerous human, studies have repeatedly confirmed that ELS is independently associated with enduring adult sleep disruption including global sleep pathology (i.e., insomnia), as well as specific types of sleep problems, most likely in a dose-response manner [194,195,196,197,198,199,200,201,202,203,204,205]. Sleep and circadian disruption occurring after trauma exposure could thus represent a core pathway mediating the enduring neurobiological correlates of ELS through stress system dysregulation [177, 178, 190, 206,207,208].
Genetics and epigenetics
Human genetic background, environmental influence, DNA methylation (methylome), and gene expression profiles (transcriptome) are all integral to our understanding of stress-related disorders, as their interaction modulates functional sites controlling the human stress axis and may, hence, increase or decrease the risk of psychobiological maladjustment after exposure to ELS [209, 210].
Gene × environment interactions of gene polymorphisms may influence the acute effects of trauma and modulate long-term risk of disease development. After the first groundbreaking studies on the interaction of ELS with monoamine oxidase A (MAOA) and the promoter region of the serotonin transporter (5-HTTLPR) functional polymorphisms predicting adult outcomes by Caspi et al. [211, 212], more recent studies point to a vital role of further genes involved in HPA axis function and GC sensitivity, in conjunction with exposure to ELS [213]. The two key genes implicated to date are the CRH-releasing hormone receptor 1 (CRHR1) and the GC response elements of the FKBP5 co-chaperone gene [213, 214]. The interaction of ELS with specific single nucleotide polymorphisms (SNPs) of the FKBP5 gene predicts the level of adult PTSD symptoms [215] probably through an allele-specific demethylation in the GC response elements of FKBP5 leading to a resistance of tissues to GCs [216]. Additional studies confirmed that minor alleles of FKBP5 are particularly sensitive and interact with ELS to increase aggressive behavior [217], suicide attempts [218], and depression [219]. The CRHR1 gene plays an important role in the initiation and termination of the stress response as it influences sensitivity of the negative feedback loop of cortisol. The interaction of ELS with specific CRHR1 polymorphisms increased the risk of adult depression and adult suicide attempts [220,221,222]. Finally, imaging studies investigated the potential interaction of specific polymorphisms in candidate genes and ELS with brain development [223]. A number of studies proposed a moderating effect of FKBP5 [224,225,226] and mineralocorticoid receptor genotypes [227] on amygdala volume, reactivity, and connectivity of adult individuals with ELS experience, thus implicating HPA axis-related genes in brain development.
In the interaction of ELS with specific genotypes, epigenetic modifications play a crucial role, as they regulate functional expression of genes by decreasing, silencing, or increasing gene expression [228, 229]. The installment of such epigenetic marks in the transcriptome by early developmental challenges may play a central role in the long-term biological trajectories of ELS through programming effects in stress reactivity [92, 230, 231] and represents a critical factor explaining interindividual variation in vulnerability or resilience. There is accumulating evidence of gene programming and epigenetic regulation of specific genes in the aftermath of trauma in humans [232,233,234,235]. However, gene expression profiles of PTSD patients with and without ELS are 98% non-overlapping [236], suggesting that DNA methylation changes may have a much greater impact during early life and possibly reflect differences in the pathophysiology of PTSD. ELS experience has been especially associated with epigenetic changes and altered gene expression profiles in stress system-related genes in the CNS (e.g., the hippocampus and amygdala) [237,238,239,240]. In particular, several GC signaling-related genes (e.g., GR gene promoter 1F) are subject to stress- and trauma-related epigenetic regulation throughout life and may be useful as future biomarkers [241, 242]. For example, ELS experience is related to postmortem changes in hippocampal neuron-specific GR (NR3C1) promoter DNA methylation status, implying distinct epigenetic ELS effects on hippocampal GR expression [243]. Maternal stress during pregnancy has been associated with epigenetic hypermethylation of the promoter and exon 1F of the human GR gene Nr3c1 and related elevated cortisol stress reactivity in the offspring [244]. On the other hand, in a genome-wide blood DNA methylation analysis, a locus in the Kit ligand gene (KITLG; cg27512205) was shown to strongly modulate the relation between ELS and cortisol stress reactivity [245]. Finally, cross-sectional, large-scale methylation studies have indicated significant ELS-related differences in methylation of a large proportion of genes responsible for HPA axis regulation [246].
Imaging findings
ELS has been associated with remarkable structural and functional brain changes even decades later [213, 223, 247, 248] through alterations in brain development affecting behavioral, cognitive, emotional, and physiologic responses [34, 249]. The two brain structures particularly frequently reported to be impaired in adult victims of ELS are the amygdala and the hippocampus, strongly indicating the vital prefrontal-limbic gray matter effects of ELS. The hippocampus has a special importance due to its role in cognition and its rich density in GR, and the amygdala because of its pivotal role in stress responsivity. Numerous reports and meta-analytic studies confirm the association of ELS with reduced hippocampal volume in adulthood [223, 247, 250,251,252,253,254]. Concerning study results as regards the volumetric effect of ELS on the amygdala, findings are inconclusive [247, 250, 251, 255,256,257,258]. However, with respect to amygdala responsiveness, ELS has been repeatedly associated with facial threat- or negative emotion-related amygdala hyperresponsiveness [223, 247, 259, 260], implying that the risk of adult depression after ELS could be actually mediated by this preceding amygdala hyperactivity [259, 261].
Conclusions
Coordination of the stress system is essential to development, survival, and well-being [5, 41]. The continuum of ELS-provoked aftermath extends from healthy adaptation with high resilience to severe maladjustment with increased physical and mental morbidity in later life. Despite the resilience of many abused children, ELS is highly prevalent in the general population and can, thus, be conceptualized as a common developmental risk factor for disease with high public health impact. ELS during critical phases of perinatal and juvenile brain development with elevated neuroplasticity is associated with impaired homeodynamic balance, elevated cacostatic load, and reduced adaptability to stress in adult life, consequently leading to enhanced vulnerability. ELS disrupts developmental programming of the related neural circuitry and results in alterations in neuroendocrine (re-)activity, i.e., hyper- or hypoactivation of the stress system, associated with the adult HPA axis, glucocorticoid signaling, and ANS dysregulation with related structural and molecular changes both in the brain and in peripheral tissues. Although most studies support a causal relationship between ELS and psychobiological maladjustment in later life, the exact developmental course of such changes and its temporal coincidence have not yet been fully elucidated. Understanding the pathways susceptible to disruption following ELS exposure could provide new insights into the neuroendocrine trajectories linking toxic stress during developmental stages of childhood and adolescence to adult maladjustment. Screening strategies for ELS and trauma therefore need to be improved, in order to better identify an individual’s risk level for disease development and/or help predict his or her response to treatment.
References
Shonkoff JP, Boyce WT, McEwen BS (2009) Neuroscience, molecular biology, and the childhood roots of health disparities: building a new framework for health promotion and disease prevention. JAMA 301(21):2252–2259
Gluckman PD, Hanson MA, Pinal C (2005) The developmental origins of adult disease. Maternal & Child Nutrition 1(3):130–141
Gilbert R, Widom CS, Browne K, Fergusson D, Webb E, Janson S (2009) Burden and consequences of child maltreatment in high-income countries. Lancet 373(9657):68–81
Green JG, McLaughlin KA, Berglund PA et al (2010) Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication I: associations with first onset of DSM-IV disorders. Arch Gen Psychiatry 67(2):113–123
Chrousos GP (2009) Stress and disorders of the stress system. Nat Rev Endocrinol 5(7):374–381
Maercker A, Michael T, Fehm L, Becker ES, Margraf J (2004) Age of traumatisation as a predictor of post-traumatic stress disorder or major depression in young women. Br J Psychiatry 184:482–487
Scott KM, Von Korff M, Angermeyer MC et al (2011) Association of childhood adversities and early-onset mental disorders with adult-onset chronic physical conditions. Arch Gen Psychiatry 68(8):838–844
Nanni V, Uher R, Danese A (2012) Childhood maltreatment predicts unfavorable course of illness and treatment outcome in depression: a meta-analysis. Am J Psychiatry 169(2):141–151
Pirkola S, Isometsa E, Aro H et al (2005) Childhood adversities as risk factors for adult mental disorders: results from the Health 2000 study. Soc Psychiatry Psychiatr Epidemiol 40(10):769–777
Koenen KC, Moffitt TE, Poulton R, Martin J, Caspi A (2007) Early childhood factors associated with the development of post-traumatic stress disorder: results from a longitudinal birth cohort. Psychol Med 37(2):181–192
Khoury L, Tang YL, Bradley B, Cubells JF, Ressler KJ (2010) Substance use, childhood traumatic experience, and posttraumatic stress disorder in an urban civilian population. Depression and Anxiety 27(12):1077–1086
Strine TW, Dube SR, Edwards VJ et al (2012) Associations between adverse childhood experiences, psychological distress, and adult alcohol problems. Am J Health Behav 36(3):408–423
Spratt EG, Back SE, Yeatts SD et al (2009) Relationship between child abuse and adult smoking. Int J Psychiatry Med 39(4):417–426
Zatti C, Rosa V, Barros A et al (2017) Childhood trauma and suicide attempt: a meta-analysis of longitudinal studies from the last decade. Psychiatry Res 256:353–358
Goodwin RD, Stein MB (2004) Association between childhood trauma and physical disorders among adults in the United States. Psychol Med 34(3):509–520
Korkeila J, Vahtera J, Korkeila K et al (2010) Childhood adversities as predictors of incident coronary heart disease and cerebrovascular disease. Heart 96(4):298–303
Tamayo T, Christian H, Rathmann W (2010) Impact of early psychosocial factors (childhood socioeconomic factors and adversities) on future risk of type 2 diabetes, metabolic disturbances and obesity: a systematic review. BMC Public Health 10:525
Stein DJ, Scott K, Haro Abad JM et al (2010) Early childhood adversity and later hypertension: data from the World Mental Health Survey. Ann Clin Psychiatry 22(1):19–28
Dong M, Giles WH, Felitti VJ et al (2004) Insights into causal pathways for ischemic heart disease: Adverse Childhood Experiences Study. Circulation 110(13):1761–1766
Paras ML, Murad MH, Chen LP et al (2009) Sexual abuse and lifetime diagnosis of somatic disorders: a systematic review and meta-analysis. JAMA 302(5):550–561
Wegman HL, Stetler C (2009) A meta-analytic review of the effects of childhood abuse on medical outcomes in adulthood. Psychosom Med 71(8):805–812
Reuben A, Moffitt TE, Caspi A et al (2016) Lest we forget: comparing retrospective and prospective assessments of adverse childhood experiences in the prediction of adult health. J Child Psychol Psychiatry 57(10):1103–1112
Edwards VJ, Holden GW, Felitti VJ, Anda RF (2003) Relationship between multiple forms of childhood maltreatment and adult mental health in community respondents: results from the Adverse Childhood Experiences Study. Am J Psychiatry 160(8):1453–1460
Walker EA, Gelfand A, Katon WJ et al (1999) Adult health status of women with histories of childhood abuse and neglect. Am J Med 107(4):332–339
Huang MC, Schwandt ML, Ramchandani VA, George DT, Heilig M (2012) Impact of multiple types of childhood trauma exposure on risk of psychiatric comorbidity among alcoholic inpatients. Alcohol Clin Exp Res 36(6):1099–1107
Agorastos A, Pittman JO, Angkaw AC et al (2014) The cumulative effect of different childhood trauma types on self-reported symptoms of adult male depression and PTSD, substance abuse and health-related quality of life in a large active-duty military cohort. J Psychiatr Res 58:46–54
Anda RF, Felitti VJ, Bremner JD et al (2006) The enduring effects of abuse and related adverse experiences in childhood. A convergence of evidence from neurobiology and epidemiology. Eur Arch Psychiatry Clin Neurosci 256(3):174–186
Briere J, Kaltman S, Green BL (2008) Accumulated childhood trauma and symptom complexity. J Trauma Stress 21(2):223–226
Suliman S, Mkabile SG, Fincham DS, Ahmed R, Stein DJ, Seedat S (2009) Cumulative effect of multiple trauma on symptoms of posttraumatic stress disorder, anxiety, and depression in adolescents. Compr Psychiatry 50(2):121–127
Anda RF, Brown DW, Felitti VJ, Bremner JD, Dube SR, Giles WH (2007) Adverse childhood experiences and prescribed psychotropic medications in adults. Am J Prev Med 32(5):389–394
Kaufman J, Plotsky PM, Nemeroff CB, Charney DS (2000) Effects of early adverse experiences on brain structure and function: clinical implications. Biol Psychiatry 48(8):778–790
Heim C, Nemeroff CB (1999) The impact of early adverse experiences on brain systems involved in the pathophysiology of anxiety and affective disorders. Biol Psychiatry 46(11):1509–1522
Felitti VJ, Anda RF, Nordenberg D et al (1998) Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults: the Adverse Childhood Experiences (ACE) Study. Am J Prev Med 14(4):245–258
Nemeroff CB (2016) Paradise lost: the neurobiological and clinical consequences of child abuse and neglect. Neuron 89(5):892–909
Buchman TG (2002) The community of the self. Nature 420(6912):246–251
Ikegami T, Suzuki K (2008) From a homeostatic to a homeodynamic self. Biosystems 91(2):388–400
Ulrich-Lai YM, Herman JP (2009) Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci 10(6):397–409
Elenkov IJ, Chrousos GP (2006) Stress system—organization, physiology and immunoregulation. Neuroimmunomodulation 13(5–6):257–267
Nicolaides NC, Kyratzi E, Lamprokostopoulou A, Chrousos GP, Charmandari E (2015) Stress, the stress system and the role of glucocorticoids. Neuroimmunomodulation 22(1–2):6–19
Tsigos C, Chrousos GP (2002) Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res 53(4):865–871
Chrousos GP, Gold PW (1992) The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267(9):1244–1252
Frodl T, O’Keane V (2013) How does the brain deal with cumulative stress? A review with focus on developmental stress, HPA axis function and hippocampal structure in humans. Neurobiol Dis 52:24–37
Seo D, Tsou KA, Ansell EB, Potenza MN, Sinha R (2014) Cumulative adversity sensitizes neural response to acute stress: association with health symptoms. Neuropsychopharmacology 39(3):670–680
Lupien SJ, McEwen BS, Gunnar MR, Heim C (2009) Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10(6):434–445
McEwen BS (1998) Protective and damaging effects of stress mediators. N Engl J Med 338(3):171–179
Koolhaas JM, Bartolomucci A, Buwalda B et al (2011) Stress revisited: a critical evaluation of the stress concept. Neurosci Biobehav Rev 35(5):1291–1301
Joels M, Baram TZ (2009) The neuro-symphony of stress. Nat Rev Neurosci 10(6):459–466
Charmandari E, Tsigos C, Chrousos G (2005) Endocrinology of the stress response. Annu Rev Physiol 67:259–284
Aguilera G, Liu Y (2012) The molecular physiology of CRH neurons. Front Neuroendocrinol 33(1):67–84
Smith SM, Vale WW (2006) The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci 8(4):383–395
Mullen PE, Martin JL, Anderson JC, Romans SE, Herbison GP (1996) The long-term impact of the physical, emotional, and sexual abuse of children: a community study. Child Abuse Negl 20(1):7–21
Pole N, Neylan TC, Otte C et al (2007) Associations between childhood trauma and emotion-modulated psychophysiological responses to startling sounds: a study of police cadets. J Abnorm Psychol 116(2):352–361
Mock SE, Arai SM (2010) Childhood trauma and chronic illness in adulthood: mental health and socioeconomic status as explanatory factors and buffers. Front Psychol 1:246
Raison CL, Miller AH (2003) When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry 160(9):1554–1565
Rohleder N, Wolf JM, Wolf OT (2010) Glucocorticoid sensitivity of cognitive and inflammatory processes in depression and posttraumatic stress disorder. Neurosci Biobehav Rev 35(1):104–114
Pervanidou P (2008) Biology of post-traumatic stress disorder in childhood and adolescence. J Neuroendocrinol 20(5):632–638
Nemeroff CB, Bremner JD, Foa EB, Mayberg HS, North CS, Stein MB (2006) Posttraumatic stress disorder: a state-of-the-science review. J Psychiatr Res 40(1):1–21
Yehuda R (2000) Biology of posttraumatic stress disorder. J Clin Psychiatry 61(Suppl 7):14–21
Stetler C, Miller GE (2011) Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. Psychosom Med 73(2):114–126
Pervanidou P, Chrousos GP (2010) Neuroendocrinology of post-traumatic stress disorder. Prog Brain Res 182:149–160
Ehlert U, Gaab J, Heinrichs M (2001) Psychoneuroendocrinological contributions to the etiology of depression, posttraumatic stress disorder, and stress-related bodily disorders: the role of the hypothalamus-pituitary-adrenal axis. Biol Psychol 57(1–3):141–152
Heim C, Ehlert U, Hellhammer DH (2000) The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders. Psychoneuroendocrinology 25(1):1–35
Heim C, Nemeroff CB (2001) The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry 49(12):1023–1039
Heim C, Newport DJ, Mletzko T, Miller AH, Nemeroff CB (2008) The link between childhood trauma and depression: insights from HPA axis studies in humans. Psychoneuroendocrinology 33(6):693–710
de Kloet CS, Vermetten E, Bikker A et al (2007) Leukocyte glucocorticoid receptor expression and immunoregulation in veterans with and without post-traumatic stress disorder. Mol Psychiatry 12(5):443–453
de Kloet ER, Joels M, Holsboer F (2005) Stress and the brain: from adaptation to disease. Nat Rev Neurosci 6(6):463–475
Yehuda R, Seckl J (2011) Minireview: Stress-related psychiatric disorders with low cortisol levels: a metabolic hypothesis. Endocrinology 152(12):4496–4503
Nemeroff CB (2004) Neurobiological consequences of childhood trauma. J Clin Psychiatry 65(Suppl 1):18–28
Teicher MH, Andersen SL, Polcari A, Anderson CM, Navalta CP (2002) Developmental neurobiology of childhood stress and trauma. The Psychiatric Clinics of North America 25(2):397–426 vii-viii
Heim C, Newport DJ, Miller AH, Nemeroff CB (2000) Long-term neuroendocrine effects of childhood maltreatment. JAMA 284(18):2321
Heim C, Newport DJ, Heit S et al (2000) Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA 284(5):592–597
Heim C, Mletzko T, Purselle D, Musselman DL, Nemeroff CB (2008) The dexamethasone/corticotropin-releasing factor test in men with major depression: role of childhood trauma. Biol Psychiatry 63(4):398–405
Heim C, Newport DJ, Bonsall R, Miller AH, Nemeroff CB (2001) Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse. Am J Psychiatry 158(4):575–581
Lu S, Gao W, Huang M, Li L, Xu Y (2016) In search of the HPA axis activity in unipolar depression patients with childhood trauma: combined cortisol awakening response and dexamethasone suppression test. J Psychiatr Res 78:24–30
Butler K, Klaus K, Edwards L, Pennington K (2017) Elevated cortisol awakening response associated with early life stress and impaired executive function in healthy adult males. Horm Behav 95:13–21
Pesonen AK, Raikkonen K, Feldt K et al (2010) Childhood separation experience predicts HPA axis hormonal responses in late adulthood: a natural experiment of World War II. Psychoneuroendocrinology 35(5):758–767
Muhtz C, Wester M, Yassouridis A, Wiedemann K, Kellner M (2008) A combined dexamethasone/corticotropin-releasing hormone test in patients with chronic PTSD—first preliminary results. J Psychiatr Res 42(8):689–693
Tyrka AR, Wier L, Price LH et al (2008) Childhood parental loss and adult hypothalamic-pituitary-adrenal function. Biol Psychiatry 63(12):1147–1154
Kumari M, Head J, Bartley M, Stansfeld S, Kivimaki M (2013) Maternal separation in childhood and diurnal cortisol patterns in mid-life: findings from the Whitehall II study. Psychol Med 43(3):633–643
Kellner M, Muhtz C, Peter F, Dunker S, Wiedemann K, Yassouridis A (2010) Increased DHEA and DHEA-S plasma levels in patients with post-traumatic stress disorder and a history of childhood abuse. J Psychiatr Res 44(4):215–219
Carpenter LL, Shattuck TT, Tyrka AR, Geracioti TD, Price LH (2011) Effect of childhood physical abuse on cortisol stress response. Psychopharmacology (Berl) 214(1):367–375
Voellmin A, Winzeler K, Hug E et al (2015) Blunted endocrine and cardiovascular reactivity in young healthy women reporting a history of childhood adversity. Psychoneuroendocrinology 51:58–67
Carpenter LL, Tyrka AR, Ross NS, Khoury L, Anderson GM, Price LH (2009) Effect of childhood emotional abuse and age on cortisol responsivity in adulthood. Biol Psychiatry 66(1):69–75
Hinkelmann K, Muhtz C, Dettenborn L et al (2013) Association between childhood trauma and low hair cortisol in depressed patients and healthy control subjects. Biol Psychiatry 74(9):e15–e17
Suzuki A, Poon L, Papadopoulos AS, Kumari V, Cleare AJ (2014) Long term effects of childhood trauma on cortisol stress reactivity in adulthood and relationship to the occurrence of depression. Psychoneuroendocrinology 50:289–299
Schalinski I, Elbert T, Steudte-Schmiedgen S, Kirschbaum C (2015) The cortisol paradox of trauma-related disorders: lower phasic responses but higher tonic levels of cortisol are associated with sexual abuse in childhood. PLoS One 10(8):e0136921
Kuhlman KR, Geiss EG, Vargas I, Lopez-Duran NL (2015) Differential associations between childhood trauma subtypes and adolescent HPA-axis functioning. Psychoneuroendocrinology 54:103–114
Kuhlman KR, Chiang JJ, Horn S, Bower JE (2017) Developmental psychoneuroendocrine and psychoneuroimmune pathways from childhood adversity to disease. Neurosci Biobehav Rev 80:166–184
Uematsu A, Matsui M, Tanaka C et al (2012) Developmental trajectories of amygdala and hippocampus from infancy to early adulthood in healthy individuals. PLoS One 7(10):e46970
Giedd JN (2012) The digital revolution and adolescent brain evolution. J Adolesc Health 51(2):101–105
Qiu A, Mori S, Miller MI (2015) Diffusion tensor imaging for understanding brain development in early life. Annu Rev Psychol 66:853–876
Daskalakis NP, Bagot RC, Parker KJ, Vinkers CH, de Kloet ER (2013) The three-hit concept of vulnerability and resilience: toward understanding adaptation to early-life adversity outcome. Psychoneuroendocrinology 38(9):1858–1873
Gunnar MR (1998) Quality of early care and buffering of neuroendocrine stress reactions: potential effects on the developing human brain. Prev Med 27(2):208–211
Gunnar M, Quevedo K (2007) The neurobiology of stress and development. Annu Rev Psychol 58:145–173
Gunnar MR, Wewerka S, Frenn K, Long JD, Griggs C (2009) Developmental changes in hypothalamus-pituitary-adrenal activity over the transition to adolescence: normative changes and associations with puberty. Dev Psychopathol 21(1):69–85
Davis EP, Granger DA (2009) Developmental differences in infant salivary alpha-amylase and cortisol responses to stress. Psychoneuroendocrinology 34(6):795–804
Hostinar CE, Gunnar MR (2013) Future directions in the study of social relationships as regulators of the HPA axis across development. J Clin Child Adolesc Psychol 42(4):564–575
Hostinar CE, Sullivan RM, Gunnar MR (2014) Psychobiological mechanisms underlying the social buffering of the hypothalamic-pituitary-adrenocortical axis: a review of animal models and human studies across development. Psychol Bull 140(1):256–282
Hostinar CE, Johnson AE, Gunnar MR (2015) Early social deprivation and the social buffering of cortisol stress responses in late childhood: an experimental study. Dev Psychol 51(11):1597–1608
Struber N, Struber D, Roth G (2014) Impact of early adversity on glucocorticoid regulation and later mental disorders. Neurosci Biobehav Rev 38:17–37
Cohen S, Janicki-Deverts D, Doyle WJ et al (2012) Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. Proc Natl Acad Sci U S A 109(16):5995–5999
Kuhlman KR, Vargas I, Geiss EG, Lopez-Duran NL (2015) Age of trauma onset and HPA axis dysregulation among trauma-exposed youth. J Trauma Stress 28(6):572–579
McLaughlin KA, Sheridan MA, Tibu F, Fox NA, Zeanah CH, Nelson CA 3rd (2015) Causal effects of the early caregiving environment on development of stress response systems in children. Proc Natl Acad Sci U S A 112(18):5637–5642
Fuhrmann D, Knoll LJ, Blakemore SJ (2015) Adolescence as a sensitive period of brain development. Trends Cogn Sci 19(10):558–566
Galvan A, McGlennen KM (2013) Enhanced striatal sensitivity to aversive reinforcement in adolescents versus adults. J Cogn Neurosci 25(2):284–296
Somerville LH, Jones RM, Casey BJ (2010) A time of change: behavioral and neural correlates of adolescent sensitivity to appetitive and aversive environmental cues. Brain Cogn 72(1):124–133
Stroud LR, Foster E, Papandonatos GD et al (2009) Stress response and the adolescent transition: performance versus peer rejection stressors. Dev Psychopathol 21(1):47–68
Tornhage CJ (2002) Reference values for morning salivary cortisol concentrations in healthy school-aged children. J Pediatr Endocrinol Metab 15(2):197–204
Blumenthal H, Leen-Feldner EW, Badour CL, Trainor CD, Babson KA (2014) Pubertal maturation and cortisol level in response to a novel social environment among female adolescents. J Adolesc 37(6):893–900
Sumter SR, Bokhorst CL, Miers AC, Van Pelt J, Westenberg PM (2010) Age and puberty differences in stress responses during a public speaking task: do adolescents grow more sensitive to social evaluation? Psychoneuroendocrinology 35(10):1510–1516
van den Bos E, de Rooij M, Miers AC, Bokhorst CL, Westenberg PM (2014) Adolescents’ increasing stress response to social evaluation: pubertal effects on cortisol and alpha-amylase during public speaking. Child Dev 85(1):220–236
Solomon MB, Herman JP (2009) Sex differences in psychopathology: of gonads, adrenals and mental illness. Physiol Behav 97(2):250–258
Vaillancourt T, Duku E, Decatanzaro D, Macmillan H, Muir C, Schmidt LA (2008) Variation in hypothalamic-pituitary-adrenal axis activity among bullied and non-bullied children. Aggress Behav 34(3):294–305
Trickett PK, Gordis E, Peckins MK, Susman EJ (2014) Stress reactivity in maltreated and comparison male and female young adolescents. Child Maltreat 19(1):27–37
Bosch NM, Riese H, Reijneveld SA et al (2012) Timing matters: long term effects of adversities from prenatal period up to adolescence on adolescents’ cortisol stress response. The TRAILS study. Psychoneuroendocrinology 37(9):1439–1447
Licht CM, Vreeburg SA, van Reedt Dortland AK et al (2010) Increased sympathetic and decreased parasympathetic activity rather than changes in hypothalamic-pituitary-adrenal axis activity is associated with metabolic abnormalities. J Clin Endocrinol Metab 95(5):2458–2466
Loewy AD, Spyer KM (1990) Central regulation of autonomic functions. Oxford University Press, Oxford
Davis AM, Natelson BH (1993) Brain-heart interactions. The neurocardiology of arrhythmia and sudden cardiac death. Texas Heart Institute Journal/from the Texas Heart Institute of St. Luke’s Episcopal Hospital, Texas Children’s Hospital 20(3):158–169
Saper CB (2004) Central autonomic system. In: Paxinos G (ed) The rat nervous system, 3rd edn. Elsevier, Amsterdam, pp 761–796
Stiedl O, Youn J, Jansen RF (2010) Cardiovascular conditioning: neural substrates. In: Koob GF, LeMoal M, Thompson RF (eds) Encyclopedia of behavioral neuroscience, vol 1. Elsevier, Amsterdam, pp 226–235
Thayer JF, Lane RD (2009) Claude Bernard and the heart-brain connection: further elaboration of a model of neurovisceral integration. Neurosci Biobehav Rev 33(2):81–88
Thayer JF, Sternberg E (2006) Beyond heart rate variability: vagal regulation of allostatic systems. Ann N Y Acad Sci 1088:361–372
Ter Horst GJ, Hautvast RW, De Jongste MJ, Korf J (1996) Neuroanatomy of cardiac activity-regulating circuitry: a transneuronal retrograde viral labelling study in the rat. Eur J Neurosci 8(10):2029–2041
Agorastos A, Boel JA, Heppner PS et al (2013) Diminished vagal activity and blunted diurnal variation of heart rate dynamics in posttraumatic stress disorder. Stress 16(3):300–310
Kemp AH, Quintana DS (2013) The relationship between mental and physical health: insights from the study of heart rate variability. Int J Psychophysiol 89(3):288–296
Kemp AH, Quintana DS, Gray MA, Felmingham KL, Brown K, Gatt JM (2010) Impact of depression and antidepressant treatment on heart rate variability: a review and meta-analysis. Biol Psychiatry 67(11):1067–1074
Bedi US, Arora R (2007) Cardiovascular manifestations of posttraumatic stress disorder. J Natl Med Assoc 99(6):642–649
Boscarino JA (2004) Posttraumatic stress disorder and physical illness: results from clinical and epidemiologic studies. Ann N Y Acad Sci 1032:141–153
Boscarino JA (2008) A prospective study of PTSD and early-age heart disease mortality among Vietnam veterans: implications for surveillance and prevention. Psychosom Med 70(6):668–676
Gorman JM, Sloan RP (2000) Heart rate variability in depressive and anxiety disorders. Am Heart J 140(4 Suppl):77–83
Carney RM, Freedland KE, Veith RC (2005) Depression, the autonomic nervous system, and coronary heart disease. Psychosom Med 67(Suppl 1):S29–S33
Harrison NA, Cooper E, Voon V, Miles K, Critchley HD (2013) Central autonomic network mediates cardiovascular responses to acute inflammation: relevance to increased cardiovascular risk in depression? Brain Behav Immun 31:189–196
Kamphuis MH, Geerlings MI, Dekker JM et al (2007) Autonomic dysfunction: a link between depression and cardiovascular mortality? The FINE study. Eur J Cardiovasc Prev Rehabil 14(6):796–802
Otte C, Neylan TC, Pole N et al (2005) Association between childhood trauma and catecholamine response to psychological stress in police academy recruits. Biol Psychiatry 57(1):27–32
O’Hare C, McCrory C, O’Leary N, O’Brien H, Kenny RA (2017) Childhood trauma and lifetime syncope burden among older adults. J Psychosom Res 97:63–69
Agorastos A, Kellner M, Baker DG, Stiedl O. Diminished vagal and/or increased sympathetic activity in post-traumatic stress disorder. In: Martin C, Preedy VR, Patel VB, eds. The Comprehensive Guide to Post-Traumatic Stress Disorders. Berlin (in print): Springer; 2015
De Bellis MD, Chrousos GP, Dorn LD et al (1994) Hypothalamic-pituitary-adrenal axis dysregulation in sexually abused girls. J Clin Endocrinol Metab 78(2):249–255
Gordis EB, Granger DA, Susman EJ, Trickett PK (2008) Salivary alpha amylase-cortisol asymmetry in maltreated youth. Horm Behav 53(1):96–103
Pervanidou P, Kolaitis G, Charitaki S et al (2007) Elevated morning serum interleukin (IL)-6 or evening salivary cortisol concentrations predict posttraumatic stress disorder in children and adolescents six months after a motor vehicle accident. Psychoneuroendocrinology 32(8–10):991–999
Pervanidou P, Kolaitis G, Charitaki S et al (2007) The natural history of neuroendocrine changes in pediatric posttraumatic stress disorder (PTSD) after motor vehicle accidents: progressive divergence of noradrenaline and cortisol concentrations over time. Biol Psychiatry 62(10):1095–1102
Pace TW, Heim CM (2011) A short review on the psychoneuroimmunology of posttraumatic stress disorder: from risk factors to medical comorbidities. Brain Behav Immun 25(1):6–13
Pace TW, Hu F, Miller AH (2007) Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behav Immun 21(1):9–19
Cain DW, Cidlowski JA (2017) Immune regulation by glucocorticoids. Nat Rev Immunol. 17(4):233–247
Menard C, Pfau ML, Hodes GE, Russo SJ (2017) Immune and neuroendocrine mechanisms of stress vulnerability and resilience. Neuropsychopharmacology 42(1):62–80
Steptoe A, Hamer M, Chida Y (2007) The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav Immun 21(7):901–912
Chrousos GP (1995) The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med 332(20):1351–1362
Glaser R, Kiecolt-Glaser JK (2005) Stress-induced immune dysfunction: implications for health. Nat Rev Immunol 5(3):243–251
Sternberg EM (2006) Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol 6(4):318–328
Rohleder N, Karl A (2006) Role of endocrine and inflammatory alterations in comorbid somatic diseases of post-traumatic stress disorder. Minerva Endocrinol 31(4):273–288
Gill JM, Saligan L, Woods S, Page G (2009) PTSD is associated with an excess of inflammatory immune activities. Perspect Psychiatr Care 45(4):262–277
Hoge EA, Brandstetter K, Moshier S, Pollack MH, Wong KK, Simon NM (2009) Broad spectrum of cytokine abnormalities in panic disorder and posttraumatic stress disorder. Depression and Anxiety 26(5):447–455
Wei L, Simen A, Mane S, Kaffman A (2012) Early life stress inhibits expression of a novel innate immune pathway in the developing hippocampus. Neuropsychopharmacology 37(2):567–580
Chida Y, Sudo N, Sonoda J, Hiramoto T, Kubo C (2007) Early-life psychological stress exacerbates adult mouse asthma via the hypothalamus-pituitary-adrenal axis. Am J Respir Crit Care Med 175(4):316–322
Danese A, Moffitt TE, Pariante CM, Ambler A, Poulton R, Caspi A (2008) Elevated inflammation levels in depressed adults with a history of childhood maltreatment. Arch Gen Psychiatry 65(4):409–415
Danese A, Pariante CM, Caspi A, Taylor A, Poulton R (2007) Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci U S A 104(4):1319–1324
Danese A, JL S (2017) Psychoneuroimmunology of early-life stress: the hidden wounds of childhood trauma? Neuropsychopharmacology 42(1):99–114
Michopoulos V, Powers A, Gillespie CF, Ressler KJ, Jovanovic T (2017) Inflammation in fear- and anxiety-based disorders: PTSD, GAD, and beyond. Neuropsychopharmacology 42(1):254–270
Matteoli G, Boeckxstaens GE (2013) The vagal innervation of the gut and immune homeostasis. Gut 62(8):1214–1222
Ohira H, Matsunaga M, Osumi T et al (2013) Vagal nerve activity as a moderator of brain-immune relationships. J Neuroimmunol 260(1–2):28–36
Daskalakis NP, Cohen H, Nievergelt CM et al (2016) New translational perspectives for blood-based biomarkers of PTSD: from glucocorticoid to immune mediators of stress susceptibility. Exp Neurol 284(Pt B):133–140
Miller GE, Cohen S, Ritchey AK (2002) Chronic psychological stress and the regulation of pro-inflammatory cytokines: a glucocorticoid-resistance model. Health Psychol 21(6):531–541
Avitsur R, Powell N, Padgett DA, Sheridan JF (2009) Social interactions, stress, and immunity. Immunol Allergy Clin N Am 29(2):285–293
Engler H, Bailey MT, Engler A, Stiner-Jones LM, Quan N, Sheridan JF (2008) Interleukin-1 receptor type 1-deficient mice fail to develop social stress-associated glucocorticoid resistance in the spleen. Psychoneuroendocrinology 33(1):108–117
Saper CB (2013) The central circadian timing system. Curr Opin Neurobiol 23(5):747–751
Dickmeis T (2009) Glucocorticoids and the circadian clock. J Endocrinol 200(1):3–22
Gan EH, Quinton R (2010) Physiological significance of the rhythmic secretion of hypothalamic and pituitary hormones. Prog Brain Res 181:111–126
Nader N, Chrousos GP, Kino T (2010) Interactions of the circadian CLOCK system and the HPA axis. Trends Endocrinol Metab 21(5):277–286
Qian X, Droste SK, Lightman SL, Reul JMHM, Linthorst ACE (2012) Circadian and ultradian rhythms of free glucocorticoid hormone are highly synchronized between the blood, the subcutaneous tissue, and the brain. Endocrinology 153(9):4346–4353
Oster H, Damerow S, Kiessling S et al (2006) The circadian rhythm of glucocorticoids is regulated by a gating mechanism residing in the adrenal cortical clock. Cell Metab 4(2):163–173
Clow A, Hucklebridge F, Stalder T, Evans P, Thorn L (2010) The cortisol awakening response: more than a measure of HPA axis function. Neurosci Biobehav Rev 35(1):97–103
Wu YH, Zhou JN, Balesar R et al (2006) Distribution of MT1 melatonin receptor immunoreactivity in the human hypothalamus and pituitary gland: colocalization of MT1 with vasopressin, oxytocin, and corticotropin-releasing hormone. J Comp Neurol 499(6):897–910
Charmandari E, Chrousos GP, Lambrou GI et al (2011) Peripheral CLOCK regulates target-tissue glucocorticoid receptor transcriptional activity in a circadian fashion in man. PLoS One 6(9):e25612
Chrousos GP, Kino T (2009) Glucocorticoid signaling in the cell. Expanding clinical implications to complex human behavioral and somatic disorders. Ann N Y Acad Sci 1179:153–166
Vandewalle G, Middleton B, Rajaratnam SM et al (2007) Robust circadian rhythm in heart rate and its variability: influence of exogenous melatonin and photoperiod. J Sleep Res 16(2):148–155
Portaluppi F, Tiseo R, Smolensky MH, Hermida RC, Ayala DE, Fabbian F (2012) Circadian rhythms and cardiovascular health. Sleep Med Rev 16(2):151–166
Kalsbeek A, Yi CX, la Fleur SE, Buijs RM, Fliers E. Suprachiasmatic nucleus and autonomic nervous system influences on awakening from sleep. Int Rev Neurobiol 2010;93:91–107
Germain A, Buysse DJ, Nofzinger E (2008) Sleep-specific mechanisms underlying posttraumatic stress disorder: integrative review and neurobiological hypotheses. Sleep Med Rev 12(3):185–195
Mellman TA, Hipolito MM (2006) Sleep disturbances in the aftermath of trauma and posttraumatic stress disorder. CNS Spectrums 11(8):611–615
Agorastos A, Kellner M, Baker DG, Otte C (2014) When time stands still. an integrative review on the role of chronodisruption in PTSD. Current Opinion in Psychiatry 27:385–392
Erren TC, Reiter RJ (2009) Defining chronodisruption. J Pineal Res 46(3):245–247
Zelinski EL, Deibel SH, McDonald RJ (2014) The trouble with circadian clock dysfunction: multiple deleterious effects on the brain and body. Neurosci Biobehav Rev 24(40C):80–101 [Epub ahead of print]
Erren TC, Reiter RJ (2013) Revisiting chronodisruption: when the physiological nexus between internal and external times splits in humans. Naturwissenschaften 100(4):291–298
Meerlo P, Sgoifo A, Suchecki D (2008) Restricted and disrupted sleep: effects on autonomic function, neuroendocrine stress systems and stress responsivity. Sleep Med Rev 12(3):197–210
Weibel L, Maccari S, Van Reeth O (2002) Circadian clock functioning is linked to acute stress reactivity in rats. J Biol Rhythm 17(5):438–446
Pina G, Brun J, Tissot S, Claustrat B (2010) Long-term alteration of daily melatonin, 6-sulfatoxymelatonin, cortisol, and temperature profiles in burn patients: a preliminary report. Chronobiol Int 27(2):378–392
Paredes SD, Sanchez S, Parvez H, Rodriguez AB, Barriga C (2007) Altered circadian rhythms of corticosterone, melatonin, and phagocytic activity in response to stress in rats. Neuro Endocrinol Lett 28(4):489–495
Gogenur I, Ocak U, Altunpinar O, Middleton B, Skene DJ, Rosenberg J (2007) Disturbances in melatonin, cortisol and core body temperature rhythms after major surgery. World J Surg 31(2):290–298
Christiansen S, Bouzinova EV, Palme R, Wiborg O. Circadian activity of the hypothalamic-pituitary-adrenal axis is differentially affected in the rat chronic mild stress model of depression. Stress. 2012
Touma C, Fenzl T, Ruschel J et al (2009) Rhythmicity in mice selected for extremes in stress reactivity: behavioural, endocrine and sleep changes resembling endophenotypes of major depression. PLoS One 4(1):e4325
Lavie P (2001) Sleep disturbances in the wake of traumatic events. N Engl J Med 345(25):1825–1832
Philbert J, Pichat P, Beeske S, Decobert M, Belzung C, Griebel G (2011) Acute inescapable stress exposure induces long-term sleep disturbances and avoidance behavior: a mouse model of post-traumatic stress disorder (PTSD). Behav Brain Res 221(1):149–154
Germain A (2013) Sleep disturbances as the hallmark of PTSD: where are we now? Am J Psychiatry 170(4):372–382
Mrdalj J, Pallesen S, Milde AM et al (2013) Early and later life stress alter brain activity and sleep in rats. PLoS One 8(7):e69923
Schafer V, Bader K (2013) Relationship between early-life stress load and sleep in psychiatric outpatients: a sleep diary and actigraphy study. Stress and Health: journal of the International Society for the Investigation of Stress 29(3):177–189
Greenfield EA, Lee C, Friedman EL, Springer KW (2011) Childhood abuse as a risk factor for sleep problems in adulthood: evidence from a U.S. national study. Ann Behav Med 42(2):245–256
Steine IM, Winje D, Krystal JH et al (2017) Cumulative childhood maltreatment and its dose-response relation with adult symptomatology: findings in a sample of adult survivors of sexual abuse. Child Abuse Negl 65:99–111
Wang Y, Raffeld MR, Slopen N, Hale L, Dunn EC (2016) Childhood adversity and insomnia in adolescence. Sleep Med 21:12–18
Baiden P, Fallon B, den Dunnen W, Boateng GO (2015) The enduring effects of early-childhood adversities and troubled sleep among Canadian adults: a population-based study. Sleep Med 16(6):760–767
Koskenvuo K, Hublin C, Partinen M, Paunio T, Koskenvuo M (2010) Childhood adversities and quality of sleep in adulthood: a population-based study of 26,000 Finns. Sleep Med 11(1):17–22
Taylor DJ, Pruiksma KE, Hale WJ et al (2016) Prevalence, correlates, and predictors of insomnia in the US Army prior to deployment. Sleep 39(10):1795–1806
Thordardottir EB, Hansdottir I, Valdimarsdottir UA, Shipherd JC, Resnick H, Gudmundsdottir B (2016) The manifestations of sleep disturbances 16 years post-trauma. Sleep 39(8):1551–1554
Petrov ME, Davis MC, Belyea MJ, Zautra AJ (2016) Linking childhood abuse and hypertension: sleep disturbance and inflammation as mediators. J Behav Med 39(4):716–726
Lind MJ, Aggen SH, Kendler KS, York TP, Amstadter AB (2016) An epidemiologic study of childhood sexual abuse and adult sleep disturbances. Psychological Trauma: Theory, Research, Practice and Policy 8(2):198–205
Kajeepeta S, Gelaye B, Jackson CL, Williams MA (2015) Adverse childhood experiences are associated with adult sleep disorders: a systematic review. Sleep Med 16(3):320–330
Bader K, Schafer V, Schenkel M, Nissen L, Schwander J (2007) Adverse childhood experiences associated with sleep in primary insomnia. J Sleep Res 16(3):285–296
Mellman TA, Bustamante V, Fins AI, Pigeon WR, Nolan B (2002) REM sleep and the early development of posttraumatic stress disorder. Am J Psychiatry 159(10):1696–1701
Mellman TA, Knorr BR, Pigeon WR, Leiter JC, Akay M (2004) Heart rate variability during sleep and the early development of posttraumatic stress disorder. Biol Psychiatry 55(9):953–956
Spoormaker VI, Montgomery P (2008) Disturbed sleep in post-traumatic stress disorder: secondary symptom or core feature? Sleep Med Rev 12(3):169–184
Malan-Muller S, Seedat S, Hemmings SM (2014) Understanding posttraumatic stress disorder: insights from the methylome. Genes Brain Behav. 13(1):52–68
Skelton K, Ressler KJ, Norrholm SD, Jovanovic T, Bradley-Davino B (2012) PTSD and gene variants: new pathways and new thinking. Neuropharmacology 62(2):628–637
Caspi A, McClay J, Moffitt TE et al (2002) Role of genotype in the cycle of violence in maltreated children. Science 297(5582):851–854
Caspi A, Sugden K, Moffitt TE et al (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301(5631):386–389
Gillespie CF, Phifer J, Bradley B, Ressler KJ (2009) Risk and resilience: genetic and environmental influences on development of the stress response. Depression Anxiety 26(11):984–992
Hauger RL, Olivares-Reyes JA, Dautzenberg FM, Lohr JB, Braun S, Oakley RH (2012) Molecular and cell signaling targets for PTSD pathophysiology and pharmacotherapy. Neuropharmacology 62(2):705–714
Binder EB, Bradley RG, Liu W et al (2008) Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 299(11):1291–1305
Klengel T, Mehta D, Anacker C et al (2013) Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci 16(1):33–41
Bevilacqua L, Carli V, Sarchiapone M et al (2012) Interaction between FKBP5 and childhood trauma and risk of aggressive behavior. Arch Gen Psychiatry 69(1):62–70
Roy A, Gorodetsky E, Yuan Q, Goldman D, Enoch MA (2010) Interaction of FKBP5, a stress-related gene, with childhood trauma increases the risk for attempting suicide. Neuropsychopharmacology 35(8):1674–1683
Zimmermann P, Bruckl T, Nocon A et al (2011) Interaction of FKBP5 gene variants and adverse life events in predicting depression onset: results from a 10-year prospective community study. Am J Psychiatry 168(10):1107–1116
Ben-Efraim YJ, Wasserman D, Wasserman J, Sokolowski M (2011) Gene-environment interactions between CRHR1 variants and physical assault in suicide attempts. Genes Brain Behav 10(6):663–672
Bradley RG, Binder EB, Epstein MP et al (2008) Influence of child abuse on adult depression: moderation by the corticotropin-releasing hormone receptor gene. Arch Gen Psychiatry 65(2):190–200
Heim C, Bradley B, Mletzko TC et al (2009) Effect of childhood trauma on adult depression and neuroendocrine function: sex-specific moderation by CRH receptor 1 gene. Front Behav Neurosci 3:41
Teicher MH, Samson JA, Anderson CM, Ohashi K (2016) The effects of childhood maltreatment on brain structure, function and connectivity. Nat Rev Neurosci 17(10):652–666
White MG, Bogdan R, Fisher PM, Munoz KE, Williamson DE, Hariri AR (2012) FKBP5 and emotional neglect interact to predict individual differences in amygdala reactivity. Genes Brain Behav 11(7):869–878
Holz NE, Buchmann AF, Boecker R et al (2015) Role of FKBP5 in emotion processing: results on amygdala activity, connectivity and volume. Brain Struct Funct 220(3):1355–1368
Grabe HJ, Wittfeld K, Van der Auwera S et al (2016) Effect of the interaction between childhood abuse and rs1360780 of the FKBP5 gene on gray matter volume in a general population sample. Hum Brain Mapp 37(4):1602–1613
Bogdan R, Williamson DE, Hariri AR (2012) Mineralocorticoid receptor Iso/Val (rs5522) genotype moderates the association between previous childhood emotional neglect and amygdala reactivity. Am J Psychiatry 169(5):515–522
Bjornsson HT, Fallin MD, Feinberg AP (2004) An integrated epigenetic and genetic approach to common human disease. Trends Genet 20(8):350–358
Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33(Suppl):245–254
Yehuda R, Bierer LM (2009) The relevance of epigenetics to PTSD: implications for the DSM-V. J Trauma Stress 22(5):427–434
Klengel T, Pape J, Binder EB, Mehta D (2014) The role of DNA methylation in stress-related psychiatric disorders. Neuropharmacology
Schmidt U, Holsboer F, Rein T (2011) Epigenetic aspects of posttraumatic stress disorder. Dis Markers 30(2–3):77–87
Zannas AS, Provencal N, Binder EB (2015) Epigenetics of posttraumatic stress disorder: current evidence, challenges, and future directions. Biol Psychiatry
Almli LM, Stevens JS, Smith AK et al (2015) A genome-wide identified risk variant for PTSD is a methylation quantitative trait locus and confers decreased cortical activation to fearful faces. Am J Med Genet B Neuropsychiatr Genet 168B(5):327–336
Wingo AP, Almli LM, Stevens JJ et al (2015) DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression. Nat Commun 6:10106
Mehta D, Klengel T, Conneely KN et al (2013) Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder. Proc Natl Acad Sci U S A 110(20):8302–8307
Trollope AF, Gutierrez-Mecinas M, Mifsud KR, Collins A, Saunderson EA, Reul JMHM (2012) Stress, epigenetic control of gene expression and memory formation. Exp Neurol 233(1):3–11
Stankiewicz AM, Swiergiel AH, Lisowski P (2013) Epigenetics of stress adaptations in the brain. Brain Res Bull 98:76–92
Reul JMHM (2014) Making memories of stressful events: a journey along epigenetic, gene transcription, and signaling pathways. Front Psychiatry 5:5
McGowan PO (2013) Epigenomic mechanisms of early adversity and HPA dysfunction: considerations for PTSD research. Front Psychiatry 4:110
Yehuda R, Daskalakis NP, Desarnaud F et al (2013) Epigenetic biomarkers as predictors and correlates of symptom improvement following psychotherapy in combat veterans with PTSD. Front Psychiatry 4:118
Yehuda R, Flory JD, Bierer LM et al (2015) Lower methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of veterans with posttraumatic stress disorder. Biol Psychiatry 77(4):356–364
McGowan PO, Sasaki A, D’Alessio AC et al (2009) Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 12(3):342–348
Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM (2008) Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 3(2):97–106
Houtepen LC, Vinkers CH, Carrillo-Roa T et al (2016) Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans. Nat Commun 7:10967
Bick J, Naumova O, Hunter S et al (2012) Childhood adversity and DNA methylation of genes involved in the hypothalamus-pituitary-adrenal axis and immune system: whole-genome and candidate-gene associations. Dev Psychopathol 24(4):1417–1425
Dannlowski U, Stuhrmann A, Beutelmann V et al (2012) Limbic scars: long-term consequences of childhood maltreatment revealed by functional and structural magnetic resonance imaging. Biol Psychiatry 71(4):286–293
Taylor SE (2010) Mechanisms linking early life stress to adult health outcomes. Proc Natl Acad Sci U S A 107(19):8507–8512
Chen Y, Baram TZ (2016) Toward understanding how early-life stress reprograms cognitive and emotional brain networks. Neuropsychopharmacology 41(1):197–206
Grassi-Oliveira R, Ashy M, Stein LM (2008) Psychobiology of childhood maltreatment: effects of allostatic load? Rev Bras Psiquiatr 30(1):60–68
Paquola C, Bennett MR, Lagopoulos J (2016) Understanding heterogeneity in grey matter research of adults with childhood maltreatment—a meta-analysis and review. Neurosci Biobehav Rev 69:299–312
Thomaes K, Dorrepaal E, Draijer N et al (2010) Reduced anterior cingulate and orbitofrontal volumes in child abuse-related complex PTSD. J Clin Psychiatry 71(12):1636–1644
Lim L, Radua J, Rubia K (2014) Gray matter abnormalities in childhood maltreatment: a voxel-wise meta-analysis. Am J Psychiatry 171(8):854–863
Van Dam NT, Rando K, Potenza MN, Tuit K, Sinha R (2014) Childhood maltreatment, altered limbic neurobiology, and substance use relapse severity via trauma-specific reductions in limbic gray matter volume. JAMA Psychiatry 71(8):917–925
van Velzen LS, Schmaal L, Jansen R et al (2016) Effect of childhood maltreatment and brain-derived neurotrophic factor on brain morphology. Soc Cogn Affect Neurosci 11(11):1841–1852
Aust S, Stasch J, Jentschke S et al (2014) Differential effects of early life stress on hippocampus and amygdala volume as a function of emotional abilities. Hippocampus 24(9):1094–1101
Edmiston EE, Wang F, Mazure CM et al (2011) Corticostriatal-limbic gray matter morphology in adolescents with self-reported exposure to childhood maltreatment. Arch Ped Adolesc Med 165(12):1069–1077
Coplan JD, Fathy HM, Jackowski AP et al (2014) Early life stress and macaque amygdala hypertrophy: preliminary evidence for a role for the serotonin transporter gene. Front Behav Neurosci 8:342
Swartz JR, Williamson DE, Hariri AR (2015) Developmental change in amygdala reactivity during adolescence: effects of family history of depression and stressful life events. Am J Psychiatry 172(3):276–283
Dannlowski U, Kugel H, Huber F et al (2013) Childhood maltreatment is associated with an automatic negative emotion processing bias in the amygdala. Hum Brain Mapp 34(11):2899–2909
Grant MM, Cannistraci C, Hollon SD, Gore J, Shelton R (2011) Childhood trauma history differentiates amygdala response to sad faces within MDD. J Psychiatr Res 45(7):886–895
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AA and PP managed all the literature searches. AA wrote the first draft of the paper. GPC, PP, and GK revised the draft for important intellectual content. All authors have contributed to, read, and approved the final version of the manuscript.
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Agorastos, A., Pervanidou, P., Chrousos, G.P. et al. Early life stress and trauma: developmental neuroendocrine aspects of prolonged stress system dysregulation. Hormones 17, 507–520 (2018). https://doi.org/10.1007/s42000-018-0065-x
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DOI: https://doi.org/10.1007/s42000-018-0065-x