Skip to main content

REVIEW article

Front. Psychiatry, 04 September 2018
Sec. Public Mental Health
This article is part of the Research Topic International Public Mental Health Conference 2017: From Fundamentals to Innovations View all 4 articles

Adverse Childhood Experiences and the Consequences on Neurobiological, Psychosocial, and Somatic Conditions Across the Lifespan

  • 1Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
  • 2Department of Psychiatry, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada

Introduction: Adverse childhood experiences (ACE) such as sexual and physical abuse or neglect are frequent in childhood and constitute a massive stressor with long-lasting adverse effects on the brain, mental and physical health.The aim of this qualitative review is to present a concise overview of the present literature on the impact of ACE on neurobiology, mental and somatic health in later adulthood.

Methods: The authors reviewed the existing literature on the impact of ACE on neurobiology, mental and somatic health in later adulthood and summarized the results for a concise qualitative overview.

Results: In adulthood, the history of ACE can result in complex clinical profiles with several co-occurring mental and somatic disorders such as posttraumatic stress disorder, depression, borderline personality disorder, obesity and diabetes. Although a general stress effect in the development of the disorders and neural alterations can be assumed, the role of type and timing of ACE is of particular interest in terms of prevention and treatment of ACE-related mental and somatic conditions. It has been suggested that during certain vulnerable developmental phases the risk for subsequent ACE-related disorders is increased. Moreover, emerging evidence points to sensitive periods and specificity of ACE-subtypes in the development of neurobiological alterations, e.g., volumetric and functional changes in the amygdala and hippocampus.

Conclusion: Longitudinal studies are needed to investigate complex ACE-related characteristics and mechanisms relevant for mental and somatic disorders by integrating state of the art knowledge and methods. By identifying and validating psychosocial and somatic risk factors and diagnostic markers one might improve the development of innovative somatic and psychological treatment options for individuals suffering from ACE-related disorders.

Introduction

Converging evidence from epidemiological and neurobiological studies suggest adverse childhood experiences (ACE) such as sexual and physical abuse and related adverse experiences to be closely related to enduring brain dysfunctions that, in turn, affect physical and mental health throughout the lifespan (13). This is particularly relevant, since community surveys from Europe and worldwide show high prevalence rates of physical (22.9%), emotional (29.1%) and sexual (9.6%) abuse, as well as physical (16.3%) and emotional neglect (18.4%) (4). Unfortunately, these numbers probably under-represents the real dimension of the problem, as they do not account for the high number of unreported cases. Individuals with ACE seem to be at higher risk for the development of mental and somatic disorders throughout the lifespan (2, 58). Psychological and psychosocial mechanisms known to contribute to mental disorders are affected after ACE, comprising disturbances in cognitive and affective processing such as for example heightened attention toward threatening stimuli (9). These alterations are mirrored in functional alterations in key stress–and emotion associated brain regions (anterior cingulate cortex [ACC], amygdala, hippocampus) (917) [for review see: (1820)]. Importantly, these are not restricted to functional, but also mirrored in morphometric changes: Volumetric alterations in amygdala, hippocampal, as well as in the ACC have been reported in several investigations (9, 13, 2127). Several etiological models describe neural alterations and symptom severity usually with a linear function (dose-dependent effect) of cumulative ACE load (multiplicity/number of event types) (3, 2832) or overall severity of exposure (33)). Next to the dose-dependent effect, studies suggest a different impact of type and timing of ACE in terms of neurobiological alterations, mental and somatic consequences (26, 30, 34, 35). The aim of this qualitative review is to present a concise overview of the present literature on the impact of ACE on neurobiology, mental, and somatic health in later adulthood. Therefore, we searched the databases PubMed, Web of science, PsycINFO for literature on the impact of ACE on neurobiology, mental, and somatic health in later adulthood. We included manuscripts based on original research as well as reviews and meta-analyses and summarized the results for a concise qualitative overview.

ACE-Structural and Functional Brain Alterations and the Role of Type and Timing of Exposure

At the present time, there is clear evidence that ACE and ACE-related disorders are associated with enduring effects on the structure and function of neural stress-regulatory circuits such as for example the hippocampus, the amygdala or the ACC (35, 36) and promote alterations in stress sensitivity and emotion regulation in later life. The respective brain regions could be especially vulnerable to the impact of ACE due to a high density of glucorticoid receptors and high vulnerability to the effects of glucorticoids via damage, dendritic atrophy and neurogenesis suppression (37, 38).

Structural Neuroimaging Studies

On balance, many studies point at reduced volume of the hippocampus in individuals after ACE compared to non-maltreated individuals (9, 27, 34, 3945). However, a recent meta-analysis showed that this difference becomes less evident when controlling for gender (37). Moreover, several studies demonstrated greater hippocampus reduction in males than females (4648), suggesting that the increased resilience in women may be associated with a protective effect of estrogen. For those readers interested in the latter, we would recommend the review by Helpman et al. (49) and a recent study by Teicher et al. (50). The amygdala has, next to the hippocampus, a high density of glucocorticoid receptors on stress-susceptible pyramidal cells (36). Interestingly, opposite to the effects of stress on the hippocampus, stress stimulates dendritic arborization on pyramid cells in the amygdala, leading to increasing volume (36, 51). However, studies of ACE on amygdala volume are controversial. Several studies have reported increased amygdala volume in institutionally reared children (13, 52), children with chronically depressed mothers (53) and adult subjects with disturbed attachment bonds as infants (26). Contrary, reduced amygdala volumes were found in adults after ACE with diagnoses of BPD (41, 43, 54), Dissociative Identity Disorder (55) and substance abuse (56). Hence, these results are broadly consistent with the hypothesis that amygdala hypertrophy may be more related to early exposure to emotional and/or physical neglect, whereas decreased amygdala volume rather is reported in adults or older adolescents with a greater degree of psychopathology (e.g., BPD) and with exposure to multiple and very severe abuse (26, 36). Numerous studies have reported attenuated development of the ACC after ACE, for example reduced ACC volume (21, 57) and diminished thickness (58).

Several studies have demonstrated that exposure to specific types of ACE selectively affect sensory systems, which were involved in perceiving the trauma that was experienced (35, 36). For example, the exposure to parental verbal abuse seems to significantly target the arcuate fasciculus, a region which interconnects Broca and Wernicke's area (59). Moreover, witnessing domestic violence seems to affect the inferior longitudinal fasciculus (60), that interconnects visual and limbic systems (35). In line with this, Tomoda et al. (61) reported reduced visual cortex and right lingual gyrus gray matter volume in young adults who were exposed to witnessing domestic violence in childhood. The respective regions were maximally sensitive to exposure between the ages of 11–13 years (61). Heim et al. (58) investigated cortical thickness in healthy women who were exposed to childhood maltreatment. The authors found, that exposure to childhood sexual abuse was associated with thinning of the somatosensory genital field. Contrary, women who were exposed to emotional abuse showed thinning in brain regions associated with self-awareness and self-evaluation. Andersen et al. (34) investigated sensitive time periods of trauma exposure in women with a history of childhood sexual abuse. In this case, the hippocampal volume was found to be maximally susceptible to sexual abuse when individuals were exposed between the ages of 3 and 5 years (34). A study by Pechtel et al. (26) compared healthy controls with exposure to emotional abuse and neglect with healthy controls without a history of ACE and found evidence for increased bilateral amygdala volume. Using the Maltreatment and Abuse Chronology of Exposure Scale [MACE; (62)] for sensitive period analyses, the authors showed that the right amygdala appeared to be most sensitive to maltreatment at 10–11 years of age. In a longitudinal study of subjects with ACE, Whittle et al. (63) reported data of a linear effect of ACE on left amygdala development, such that higher levels of ACE were associated with a suppressive effect on amygdala development over time. These studies are in line with the hypothesis of an initial increase in amygdala volume after ACE, followed by a decrease in volume due to persistent and severe maltreatment in later life (36).

Functional Neuroimaging Studies

In contrast to the high amount of studies investigating structural brain alterations, only a few have examined functional differences related to ACE. Fortunately, over the last decade, an increasing number of studies have been published using functional neuroimaging (fMRI) techniques to examine possible associations between ACE and alterations in neurocognitive systems.

Evidence from animal and human research proposes that the amygdala is critically involved in the detection and processing of salient stimuli, especially in those related to danger (64). Neuroimaging research mainly documents amygdala hyperactivity in response to emotional stimuli in individuals with a history of childhood maltreatment (18, 6569) [for meta-analysis see: (70)]. As this region is highly involved in emotional processes, such as salient detection (esp. stimuli associated with danger) and emotional responses, one can suppose that hyperactivity in this region may be associated with greater risk for the development of dysfunctional behaviors (67). In line with this, hyperactivity in the amygdala is linked to several disorders, including posttraumatic stress disorder (PTSD) (71), anxiety and mood disorders (72) or BPD (54). Moreover, preliminary results suggest that hyperactivation of the amygdala may predict the likelihood of future symptomatology (67, 73, 74). In contrast, several studies reported no differences or even reduced amygdala activity in individuals with ACE compared to control groups when exposed to negative/trauma-related stimuli (7577). This pattern of hypo-activity to threat-related cues has repeatedly been found in patients with PTSD and severe dissociative symptomatology, pointing toward a specific dissociative subtype in PTSD [for further details please see for example: (78)]. Beyond the amygdala, the anterior insula has found to be hyperactive in individuals with ACE when exposed to emotional stimuli compared to neutral stimuli (66, 70). The anterior insula is associated with the detection of salient stimuli and is assumed to be important for effective modulation of attention in the presence of emotional stimuli (79). Like the amygdala, hyperactivity in the anterior insula to trauma-related stimuli has been found in several mental disorders, such as in social anxiety, specific phobia (72) and PTSD (75). Additionally, a recent meta-analysis of 20 studies of emotion processing in maltreatment individuals, revealed that ACE was (next to hyperactivation in the amygdala and insula), associated with hyperactivation in the superior temporal gyrus, and the parahippocampal gyrus (70). The authors suggest that increased activation in the superior temporal gyrus may aid in early detection of threatening stimuli, which may be an adaptive ability in the context of childhood maltreatment. With regard to the hippocampal formation, evidence suggests that alterations in this system are associated with the development of PTSD. However it is unclear if altered hippocampal formation activation may be a risk factor that interacts with ACE to produce PTSD or a consequence of ACE that predispose an individual to later PTSD (70). The literature on functional alterations of the hippocampal formation in PTSD is mixed: hippocampal activation has been found to be both increased and decreased and parahippocampal activation tends to be increased (80). To our knowledge, studies so far did not systematically contrast different types or timing periods of ACE directly in terms of functional brain differences, which would be needed to further characterize the impact of ACE on brain development.

ACE and Psychosocial Consequences

ACE are supposed to affect psychological and psychosocial mechanisms known to contribute to mental disorders, comprising disturbances in cognitive and affective processing such as a heightened attention toward threatening stimuli (9), heightened experience of loneliness (81), as well as social cognitive functioning (19) and social interactions (82) including aggressive behaviors (83). The risk for developing a mental disorder after ACE (in a dose-dependent manner) is highest for depression (3, 84, 85), PTSD (86, 87), borderline personality disorder (BPD) (88), and substance abuse (7, 89). There is growing recognition that individuals with a history of ACE who present with a mental disorder, vary in several respects from individuals within the same diagnostic category without ACE and may therefore represent a specific ecophenotype (35, 67). For example, mental disorders in individuals with ACE are supposed to develop earlier accompanied by more severe symptomatology (90), increased risk of comorbidity (91) and are less likely to respond to standard treatments (92).

A few studies provide evidence that specific types of maltreatment are associated with greater risk for developing psychopathology than other types. In a meta-analysis, Norman et al. (93) reported higher odds ratio for depression when exposed to emotional abuse compared to physical abuse and higher odds ratio for drug abuse when exposed to physical abuse compared to emotional abuse. There is controversial evidence regarding the association between timing of maltreatment and psychopathology. Schoedl et al. (94) examined the relationship between the age of trauma exposure (sexual abuse) and the development of PTSD and depression. The main findings suggest an association between the age of trauma exposure and the likelihood for developing severe depressive or PTSD symptoms in adulthood: Those with earlier exposure (sexual abuse before the age of 12) were at greater risk of having prominent depressive symptoms, while those reporting sexual abuse after the age of 12 were at greater risk of having severe PTSD symptoms. Others have found the opposite effect of maltreatment time and psychopathology (95). Using sensitive time period analyses, Schalinski et al. (30) recently demonstrated that dissociative symptoms (i.e., depersonalization and derealization) were associated with peak vulnerability at 13–14 years of age with emotional neglect being the leading influence followed by other forms of emotional abuse [for further findings regarding clinical outcomes see: (30, 96)]. Moreover, evidence suggest that trauma exposure between 3 and 5 years of age is associated with higher risk for developing PTSD (97), depression and suicidality (98) compared to exposure at 0–2 or 6–8 years. These studies provide evidence that sensitive time periods of risk for psychopathology could be easily missed when comparing broader time frames or overall severity of exposure (30, 96). Finally we have to take into account the question of resilience: Why do two individuals who have experienced very similar patterns of ACE often show very different outcomes? This may be partly due to social environmental or psychological factors but also very likely in part at least due to genetic differences and epigenetic mechanisms. Emerging data suggest that epigenetic mechanisms help to explain the association between ACE and later health problems (99). Researchers have focused on the way in which genetic variants and adverse social environments can interact (gene by environment interaction, GxE) and have shown that a child‘s genotype may partly determine their level of risk and resilience for later psychopathology following ACE including depression (100), bipolar disorder (101) and PTSD (102). Nevertheless, it should be kept in mind that positive environmental influences (e.g., familiar support) can also promote resilience, even in those children carrying “risk” polymorphisms exposed to ACE (103). For further details, we refer to Turecki et al. (99) or Zannas and West (104).

ACE and Somatic Consequences

Emerging evidence suggests that ACE is associated with the development of a wide range of somatic disorders, such as obesity, diabetes, inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn Disease (CD) (2, 6, 105107) as well as abnormal pain perception with and without corresponding somatic pathology (e.g., chronic pain vs. pain during child birth) (108, 109).

Recent studies have suggested a dysregulation of the innate immune system as a possible biological mediator between ACE and adulthood disease. These studies have reported an association between ACE and increased levels of pro-inflammatory markers, most notably of the acute phase protein C-reactive protein (CRP), the cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) (110). IBD are driven by the interaction of the intestinal microflora and environmental factors in a genetically susceptible host. Since childhood is a critical phase for the development of neurobiological systems relevant for IBD, e.g., the mucosal immune system, the intestinal microbiota, and immune tolerance in the gut, ACE may contribute to dysfunctions and this effect may depend on the type and timing of ACE. In light of several non-significant findings as well as a significant amount of heterogeneity in methods, Baumeister et al. (111) examined in a recent meta-analysis, whether early-life adversity contributes to potentially pathogenic pro-inflammatory phenotypes in adult individuals. They found a significant association between childhood trauma and elevated baseline peripheral levels of CRP, IL-6 and TNF-α. They conclude that these results provide strong evidence for ACE significantly impacting on the inflammatory immune system, with trajectories reaching into adulthood, thus offering a potential molecular pathway by which early trauma confers vulnerability to developing mental and somatic disorders later in life. Moreover, subgroup analyses for specific types of trauma (sexual, physical or emotional abuse) revealed that these differentially impact specific inflammatory markers. These results indicate that ACE contribute to a pro-inflammatory state in adulthood, with specific inflammatory profiles depending on the specific type of trauma. Furthermore, ACE are known as predictors for chronicity of low back pain and are associated with enhanced pressure pain sensitivity (112). More precisely, early life social stressors such as emotional abuse are associated with enhanced temporal summation of pain and enhanced touch sensitivity (109). Recent animal experiments indicate that stress itself is able to sensitize nociceptive neurons in the spinal cord (113115) and that altered neuronal responses are accompanied by comparable changes in pain-related behavior. Schneider et al. (115) for example have developed a new animal model on social rejection that mimicks ACE and found that social rejection produces long-lasting effects in pain sensitivity and social behavior that persist into adulthood (115, 116). Moreover, ACE such as parent-child separation have been postulated to be associated with alterations in reproductive traits, prenatal maternal distress, childbirth experience, and labor pain as well as pregnancy outcome (108, 117119). A recent study showed that childbirth experience in women with childhood sexual abuse was more often frightening and attributed more negatively than in controls (108). Moreover, about half of the women experienced dissociation during childbirth, which was also related to reduced labor pain (108). Additionally, ACE and low socioeconomic status of mothers independently predict low birth weight of the offspring (117, 119).

Implications for Research and Clinical Practice

ACE are complex etiological marker, that appear to vary on impact in terms of type, timing and severity of maltreatment, together with a wide range of vulnerability and resilience cofactors. In the last years, there has been a welcome increase of research on consequences of ACE on neurobiological, psychological and somatic issues. Overall, the available studies indicate an enduring effect of ACE on mental and physical health throughout the lifespan (67). However, the results need to be treated with some caution, given many differences in study designs (e.g., defining and measuring maltreatment, small sample sizes) or nearly solely cross-sectional studies. Going forward, we need longitudinal studies to better understand how ACE alter brain structure and function and therefore contribute to psychological and somatic consequences. More precisely, future longitudinal studies would allow the valid identification of the influence of important variables including such as age of exposure, type of maltreatment and duration of maltreatment. To sum up, the significant implication of all findings, we summarized in this qualitative review, is that they provide starting points to (1) develop much more explicitly preventive approaches to reduce a child's risk for maltreatment, (2) to implement interventions, that can reduce long-term risk for mental illness in individuals after ACE prior to the emerge of psychopathology and (3) to develop specific treatments for children and adults with psychopathology.

Author Contributions

JH wrote the article, which CS reviewed and approved for publication.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

1. Anda RF, Felitti VJ, Bremner JD, Walker JD, Whitfield C, Perry BD, et al. The enduring effects of abuse and related adverse experiences in childhood. A convergence of evidence from neurobiology and epidemiology. Eur Arch Psychiatry Clin Neurosci. (2006) 256:174–86. doi: 10.1007/s00406-005-0624-4

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Felitti VJ, Anda RF. The relationship of adverse childhood experiences to adult medical disease, psychiatric disorders and sexual behavior: implications for healthcare. In: Pain C, Vermetten E, Lanius RA, editors, The Impact of Early Life Trauma on Health and Disease: The Hidden Epidemic. Cambridge: Cambridge University Press (2010). p. 77–87.

Google Scholar

3. Felitti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM, Edwards V, et al. 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. (1998) 14:245–58. doi: 10.1016/S0749-3797(98)00017-8

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Sethi D, Bellis MA, Hughes K, Gilbert R, Mitis F, Galea G. European Report on Preventing Child Maltreatment. Copenhagen: World Health Organization Regional Office for Europe (2013).

Google Scholar

5. Anda RF Whitfield CL, Felitti VJ, Chapman D, Edwards VJ, Dube SR, et al. Adverse childhood experiences, alcoholic parents, and later risk of alcoholism and depression. Psychiatr Serv. (2002) 53:1001–9. doi: 10.1176/appi.ps.53.8.1001

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Danese A, Tan M. Childhood maltreatment and obesity: systematic review and meta-analysis. Mol Psychiatr. (2014) 19:544–54. doi: 10.1038/mp.2013.54

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Dube SR, Felitti VJ, Dong M, Chapman DP, Giles WH, Anda RF. Childhood abuse, neglect, and household dysfunction and the risk of illicit drug use: the adverse childhood experiences study. Pediatrics (2003) 111:564–72. doi: 10.1542/peds.111.3.564

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Kim J, Cicchetti D. Longitudinal pathways linking child maltreatment, emotion regulation, peer relations, and psychopathology. J Child Psychol Psychiatr. (2010) 51:706–16. doi: 10.1111/j.1469-7610.2009.02202.x

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Dannlowski U, Stuhrmann A, Beutelmann V, Zwanzger P, Lenzen T, Grotegerd D, et al. Limbic scars: long-term consequences of childhood maltreatment revealed by functional and structural magnetic resonance imaging. Biol Psychiatr. (2012) 71:286–93. doi: 10.1016/j.biopsych.2011.10.021

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Dalgleish T, Moradi AR, Taghavi MR, Neshat-Doost HT, Yule W. An experimental investigation of hypervigilance for threat in children and adolescents with post-traumatic stress disorder. Psychol Med. (2001) 31:541–7. doi: 10.1017/S0033291701003567

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Dillon DG, Holmes AJ, Birk JL, Brooks N, Lyons-Ruth K, Pizzagalli DA. Childhood adversity is associated with left basal ganglia dysfunction during reward anticipation in adulthood. Biol Psychiatr. (2009) 66:206–13. doi: 10.1016/j.biopsych.2009.02.019

PubMed Abstract | CrossRef Full Text | Google Scholar

12. McNally RJ, Kaspi SP, Riemann BC, Zeitlin SB. Selective processing of threat cues in posttraumatic stress disorder. J Abnorm Psychol. (1990) 99:398–402. doi: 10.1037/0021-843X.99.4.398

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Mehta MA, Gore-Langton E, Golembo N, Colvert E, Williams SC, Sonuga-Barke E. Hyporesponsive reward anticipation in the basal ganglia following severe institutional deprivation early in life. J Cogn Neurosci. (2010) 22:2316–25. doi: 10.1162/jocn.2009.21394

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Pine DS, Mogg K, Bradley BP, Montgomery L, Monk CS, McClure E, et al. Attention bias to threat in maltreated children: implications for vulnerability to stress-related psychopathology. Am J Psychiatr. (2005) 162:291–6. doi: 10.1176/appi.ajp.162.2.291

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Pollak SD, Cicchetti D, Hornung K, Reed A. Recognizing emotion in faces: developmental effects of child abuse and neglect. Dev Psychol. (2000) 36:679–88. doi: 10.1037/0012-1649.36.5.679

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Pollak SD, Vardi S, Putzer Bechner AM, Curtin JJ. Physically abused children's regulation of attention in response to hostility. Child Dev. (2005) 76:968–977. doi: 10.1111/j.1467-8624.2005.00890.x

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Takiguchi S, Fujisawa TX, Mizushima S, Saito DN, Okamoto Y, Shimada K, et al. Ventral striatum dysfunction in children and adolescents with reactive attachment disorder: functional MRI study. BJPsych Open (2015) 1:121–128. doi: 10.1192/bjpo.bp.115.001586

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Hart H, Rubia K. Neuroimaging of child abuse: a critical review. Front Hum Neurosci. (2012) 6:52. doi: 10.3389/fnhum.2012.00052

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Pechtel P, Pizzagalli DA. Effects of early life stress on cognitive and affective function: an integrated review of human literature. Psychopharmacology (2011) 214:55–70. doi: 10.1007/s00213-010-2009-2

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Yehuda R, Hoge CW, McFarlane AC, Vermetten E, Lanius RA, Nievergelt CM, et al. Post-traumatic stress disorder. Nat Rev Dis Primers (2015) 1:15057. doi: 10.1038/nrdp.2015.57

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Baker LM, Williams LM, Korgaonkar MS, Cohen RA., Heaps JM., Paul RH. Impact of early vs. late childhood early life stress on brain morphometrics. Brain Imaging Behav. (2013) 7:196–203. doi: 10.1007/s11682-012-9215-y

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Cohen RA, Grieve S, Hoth KF, Paul RH, Sweet L, Tate D, et al. Early life stress and morphometry of the adult anterior cingulate cortex and caudate nuclei. Biol Psychiatr. (2006) 59:975–82. doi: 10.1016/j.biopsych.2005.12.016

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Grabe HJ, Wittfeld K, Van der Auwera S, Janowitz D, Hegenscheid K, Habes M, et al. 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. (2016) 37:1602–13. doi: 10.1002/hbm.23123

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Korgaonkar MS, Antees C, Williams LM, Gatt JM, Bryant RA, Cohen R, et al. Early exposure to traumatic stressors impairs emotional brain circuitry. PLoS ONE (2013) 8:e75524. doi: 10.1371/journal.pone.0075524

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Kuhn M, Scharfenort R, Schumann D, Schiele MA, Munsterkotter AL, Deckert J, et al. Mismatch or allostatic load? Timing of life adversity differentially shapes gray matter volume and anxious temperament. Soc Cogn Affect Neurosci. (2016) 11:537–47. doi: 10.1093/scan/nsv137

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Pechtel P, Lyons-Ruth K, Anderson CM, Teicher MH. Sensitive periods of amygdala development: the role of maltreatment in preadolescence. Neuroimage (2014) 97:236–44. doi: 10.1016/j.neuroimage.2014.04.025

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Teicher MH, Anderson CM, Polcari A. Childhood maltreatment is associated with reduced volume in the hippocampal subfields CA3, dentate gyrus, and subiculum. Proc Natl Acad Sci USA. (2012) 109:E563–72. doi: 10.1073/pnas.1115396109

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Neuner F, Schauer M, Karunakara U, Klaschik C, Robert C, Elbert T. Psychological trauma and evidence for enhanced vulnerability for posttraumatic stress disorder through previous trauma among West Nile refugees. BMC Psychiatr. (2004) 4:34. doi: 10.1186/1471-244X-4-34

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Pietrek C, Elbert T, Weierstall R, Muller O, Rockstroh B. Childhood adversities in relation to psychiatric disorders. Psychiatry Res. (2013) 206:103–10. doi: 10.1016/j.psychres.2012.11.003

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Schalinski I, Teicher MH, Nischk D, Hinderer E, Müller O, Rockstroh B. Type and timing of adverse childhood experiences differentially affect severity of PTSD, dissociative and depressive symptoms in adult inpatients. BMC Psychiatry (2016) 16:295. doi: 10.1186/s12888-016-1004-5

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Weber K, Rockstroh B, Borgelt J, Awiszus B, Popov T, Hoffmann K, et al. Stress load during childhood affects psychopathology in psychiatric patients. BMC Psychiatry (2008) 8:63. doi: 10.1186/1471-244X-8-63

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Wilker S, Pfeiffer A, Kolassa S, Koslowski D, Elbert T, Kolassa I.-T. How to quantify exposure to traumatic stress? Reliability and predictive validity of measures for cumulative trauma exposure in a post-conflict population. Eur J Psychotraumatol. (2015) 6. doi: 10.3402%2Fejpt.v6.28306

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Bernstein DP, Ahluvalia T, Pogge D, Handelsman L. Validity of the childhood trauma questionnaire in an adolescent psychiatric population. J Am Acad Child Adolesc. Psychiatry (1997). 36:340–8. doi: 10.1097/00004583-199703000-00012

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Andersen SL, Tomada A, Vincow ES, Valente E, Polcari A, Teicher MH. Preliminary evidence for sensitive periods in the effect of childhood sexual abuse on regional brain development. J Neuropsychiatry Clin Neurosci. (2008) 20:292–301. doi: 10.1176/jnp.2008.20.3.292

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Teicher MH, Samson JA. Childhood maltreatment and psychopathology: a case for ecophenotypic variants as clinically and neurobiologically distinct subtypes. Am J Psychiatry (2013) 170:1114–33. doi: 10.1176/appi.ajp.2013.12070957

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Teicher MH, Samson JA. Annual research review: enduring neurobiological effects of childhood abuse and neglect. J Child Psychol Psychiatr. (2016) 57:241–66. doi: 10.1111/jcpp.12507

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Calem M, Bromis K, McGuire P, Morgan C, Kempton MJ. Meta-analysis of associations between childhood adversity and hippocampus and amygdala volume in non-clinical and general population samples. Neuroimage Clin. (2017) 14:471–9. doi: 10.1016/j.nicl.2017.02.016

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Sapolsky RM. Stress and plasticity in the limbic system. Neurochem Res. (2003) 28:1735–42. doi: 10.1023/A:1026021307833

PubMed Abstract | CrossRef Full Text | Google Scholar

39. Brambilla P, Soloff PH, Sala M, Nicoletti MA, Keshavan MS, Soares J. C. Anatomical MRI study of borderline personality disorder patients. Psychiatry Res. (2004) 131:125–33. doi: 10.1016/j.pscychresns.2004.04.003

CrossRef Full Text | Google Scholar

40. Bremner JD, Randall P, Vermetten E, Staib L, Bronen RA, Mazure C, et al. Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse–a preliminary report. Biol Psychiatry (1997) 41:23–32. doi: 10.1016/S0006-3223(96)00162-X

PubMed Abstract | CrossRef Full Text | Google Scholar

41. Driessen M, Herrmann J, Stahl K, Zwaan M, Meier S, Hill A, et al. Magnetic resonance imaging volumes of the hippocampus and the amygdala in women with borderline personality disorder and early traumatization. Arch Gen Psychiatry (2000) 57:1115–22. doi: 10.1001/archpsyc.57.12.1115

PubMed Abstract | CrossRef Full Text | Google Scholar

42. Everaerd D, Gerritsen L, Rijpkema M, Frodl T, van Oostrom I, Franke B, et al. Sex modulates the interactive effect of the serotonin transporter gene polymorphism and childhood adversity on hippocampal volume. Neuropsychopharmacology (2012) 37:1848–55. doi: 10.1038/npp.2012.32

PubMed Abstract | CrossRef Full Text | Google Scholar

43. Schmahl CG, Vermetten E, Elzinga BM, Douglas Bremner J. Magnetic resonance imaging of hippocampal and amygdala volume in women with childhood abuse and borderline personality disorder. Psychiatry Res. (2003) 122:193–8. doi: 10.1016/S0925-4927(03)00023-4

PubMed Abstract | CrossRef Full Text | Google Scholar

44. Vythilingam M, Heim C, Newport J, Miller AH, Anderson E, Bronen R, et al. Childhood trauma associated with smaller hippocampal volume in women with major depression. Am. J. Psychiatry (2002) 159:2072–80. doi: 10.1176/appi.ajp.159.12.2072

PubMed Abstract | CrossRef Full Text | Google Scholar

45. Woon FL, Sood S, Hedges DW. Hippocampal volume deficits associated with exposure to psychological trauma and posttraumatic stress disorder in adults: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry (2010) 34:1181–8. doi: 10.1016/j.pnpbp.2010.06.016

PubMed Abstract | CrossRef Full Text | Google Scholar

46. Frodl T, Reinhold E, Koutsouleris N, Reiser M, Meisenzahl EM. Interaction of childhood stress with hippocampus and prefrontal cortex volume reduction in major depression. J Psychiatr Res. (2010) 44:799–807. doi: 10.1016/j.jpsychires.2010.01.006

PubMed Abstract | CrossRef Full Text | Google Scholar

47. Karl A, Schaefer M, Malta LS, Dorfel D, Rohleder N, Werner A. A meta-analysis of structural brain abnormalities in PTSD. Neurosci Biobehav Rev. (2006) 30:1004–31. doi: 10.1016/j.neubiorev.2006.03.004

PubMed Abstract | CrossRef Full Text | Google Scholar

48. Samplin E, Ikuta T, Malhotra AK., Szeszko PR, Derosse P. Sex differences in resilience to childhood maltreatment: effects of trauma history on hippocampal volume, general cognition and subclinical psychosis in healthy adults. J Psychiatr Res. (2013) 47:1174–9. doi: 10.1016/j.jpsychires.2013.05.008

PubMed Abstract | CrossRef Full Text | Google Scholar

49. Helpman L, Zhu X, Suarez-Jimenez B, Lazarov A, Monk C, Neria Y. Sex differences in trauma-related psychopathology: a critical review of neuroimaging literature (2014-2017). Curr Psychiatry Rep. (2017) 19:104. doi: 10.1007/s11920-017-0854-y

PubMed Abstract | CrossRef Full Text | Google Scholar

50. Teicher MH, Anderson CM, Ohashi K, Khan A, McGreenery CE, Bolger EA, et al. Differential effects of childhood neglect and abuse during sensitive exposure periods on male and female hippocampus. Neuroimage (2018) 169:443–52. doi: 10.1016/j.neuroimage.2017.12.055

PubMed Abstract | CrossRef Full Text | Google Scholar

51. Mitra R, Jadhav S, McEwen BS, Vyas A, Chattarji S. Stress duration modulates the spatiotemporal patterns of spine formation in the basolateral amygdala. Proc Natl Acad Sci USA. (2005) 102:9371–6. doi: 10.1073/pnas.0504011102

PubMed Abstract | CrossRef Full Text | Google Scholar

52. Tottenham N, Hare T. A, Quinn BT, McCarry TW, Nurse M, Gilhooly T, et al. Prolonged institutional rearing is associated with atypically larger amygdala volume and difficulties in emotion regulation. Dev Sci. (2010) 13:46. doi: 10.1111/j.1467-7687.2009.00852.x

CrossRef Full Text | Google Scholar

53. Lupien SJ, Parent S, Evans AC, Tremblay RE, Zelazo PD, Corbo V, et al. Larger amygdala but no change in hippocampal volume in 10-year-old children exposed to maternal depressive symptomatology since birth. Proc Natl Acad Sci USA. (2011) 108:14324–9. doi: 10.1073/pnas.1105371108

PubMed Abstract | CrossRef Full Text | Google Scholar

54. Schulze L, Schmahl C, Niedtfeld I. Neural correlates of disturbed emotion processing in borderline personality disorder: a multimodal meta-analysis. Biol Psychiatr. (2016) 79:97–106. doi: 10.1016/j.biopsych.2015.03.027

PubMed Abstract | CrossRef Full Text | Google Scholar

55. Vermetten E, Schmahl C, Lindne S, Loewenstein RJ, Bremner JD. Hippocampal and amygdalar volumes in dissociative identity disorder. Am J Psychiatr. (2006) 163:630–6. doi: 10.1176/ajp.2006.163.4.630

PubMed Abstract | CrossRef Full Text | Google Scholar

56. Van Dam NT, Rando K, Potenza MN, Tuit K, Sinha R. Childhood maltreatment, altered limbic neurobiology, and substance use relapse severity via trauma-specific reductions in limbic gray matter volume. JAMA Psychiatr. (2014) 71:917–25. doi: 10.1001/jamapsychiatry.2014.680

CrossRef Full Text | Google Scholar

57. Thomaes K, Dorrepaal E, Draijer N, de Ruiter MB, van Balkom AJ, Smit JH, et al. Reduced anterior cingulate and orbitofrontal volumes in child abuse-related complex PTSD. J Clin Psychiatr. (2010) 71:1636–44. doi: 10.4088/JCP.08m04754blu

PubMed Abstract | CrossRef Full Text | Google Scholar

58. Heim CM, Mayberg HS, Mletzko T, Nemeroff CB, Pruessner JC. Decreased cortical representation of genital somatosensory field after childhood sexual abuse. Am. J. Psychiatr. (2013) 170:616–23. doi: 10.1176/appi.ajp.2013.12070950

PubMed Abstract | CrossRef Full Text | Google Scholar

59. Choi J, Jeong B, Rohan ML, Polcari AM, Teicher MH. Preliminary evidence for white matter tract abnormalities in young adults exposed to parental verbal abuse. Biol Psychiatry (2009) 65:227–34. doi: 10.1016/j.biopsych.2008.06.022

PubMed Abstract | CrossRef Full Text | Google Scholar

60. Choi J, Jeong B, Polcari A, Rohan ML, Teicher MH. Reduced fractional anisotropy in the visual limbic pathway of young adults witnessing domestic violence in childhood. Neuroimage (2012) 59:1071–9. doi: 10.1016/j.neuroimage.2011.09.033

PubMed Abstract | CrossRef Full Text | Google Scholar

61. Tomoda A, Polcari A, Anderson CM, Teicher MH. Reduced visual cortex gray matter volume and thickness in young adults who witnessed domestic violence during childhood. PLoS ONE (2012) 7:e52528. doi: 10.1371/journal.pone.0052528

PubMed Abstract | CrossRef Full Text | Google Scholar

62. Teicher MH, Parigger A. The ‘Maltreatment and Abuse Chronology of Exposure' (MACE) scale for the retrospective assessment of abuse and neglect during development. PLoS ONE (2015) 10:e0117423. doi: 10.1371/journal.pone.0117423

PubMed Abstract | CrossRef Full Text | Google Scholar

63. Whittle S, Dennison M, Vijayakumar N, Simmons JG, Yucel M, Lubman DI, et al. Childhood maltreatment and psychopathology affect brain development during adolescence. J Am Acad Child Adolesc Psychiatr. (2013) 52:940–52.e941. doi: 10.1016/j.jaac.2013.06.007

PubMed Abstract | CrossRef Full Text | Google Scholar

64. Phelps EA, LeDoux JE. Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron (2005) 48:175–87. doi: 10.1016/j.neuron.2005.09.025

PubMed Abstract | CrossRef Full Text | Google Scholar

65. Bogdan R, Williamson DE, Hariri AR. Mineralocorticoid receptor Iso/Val (rs5522) genotype moderates the association between previous childhood emotional neglect and amygdala reactivity. Am J Psychiatr. (2012) 169:515–22. doi: 10.1176/appi.ajp.2011.11060855

PubMed Abstract | CrossRef Full Text | Google Scholar

66. McCrory EJ, De Brito SA, Sebastian CL, Mechelli A, Bird G, Kelly PA, et al. (2011). Heightened neural reactivity to threat in child victims of family violence. Curr Biol. 21:R947–8. doi: 10.1016/j.cub.2011.10.015

CrossRef Full Text

67. McCrory EJ, Gerin MI, Viding E. Annual research review: childhood maltreatment, latent vulnerability and the shift to preventative psychiatry - the contribution of functional brain imaging. J Child Psychol. Psychiatr. (2017) 58:338–57. doi: 10.1111/jcpp.12713

PubMed Abstract | CrossRef Full Text | Google Scholar

68. Suzuki H, Luby JL, Botteron KN, Dietrich R, McAvoy MP, Barch DM. Early life stress and trauma and enhanced limbic activation to emotionally valenced faces in depressed and healthy children. J Am Acad Child Adolesc Psychiatry (2014) 53:800–813.e810. doi: 10.1016/j.jaac.2014.04.013

PubMed Abstract | CrossRef Full Text | Google Scholar

69. Tottenham N, Hare TA, Millner A, Gilhooly T, Zevin JD, Casey BJ. Elevated amygdala response to faces following early deprivation. Dev Sci. (2011) 14:190–204. doi: 10.1111/j.1467-7687.2010.00971.x

PubMed Abstract | CrossRef Full Text | Google Scholar

70. Hein TC, Monk CS. Research review: neural response to threat in children, adolescents, and adults after child maltreatment – a quantitative meta-analysis. J Child Psychol Psychiatr. (2017) 58:222–30. doi: 10.1111/jcpp.12651

PubMed Abstract | CrossRef Full Text | Google Scholar

71. Rauch SL, Shin LM, Phelps EA. Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research—past, present, and future. Biol Psychiatr. (2006) 60:376–82. doi: 10.1016/j.biopsych.2006.06.004

PubMed Abstract | CrossRef Full Text | Google Scholar

72. Etkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatr. (2007) 164:1476–88. doi: 10.1176/appi.ajp.2007.07030504

PubMed Abstract | CrossRef Full Text | Google Scholar

73. Admon R, Lubin G, Stern O, Rosenberg K, Sela L, Ben-Ami H, et al. Human vulnerability to stress depends on amygdala's predisposition and hippocampal plasticity. Proc Natl Acad Sci USA. (2009) 106:14120–5. doi: 10.1073/pnas.0903183106

PubMed Abstract | CrossRef Full Text | Google Scholar

74. Swartz JR, Knodt AR, Radtke SR., Hariri AR. A neural biomarker of psychological vulnerability to future life stress. Neuron (2015) 85:505–11. doi: 10.1016/j.neuron.2014.12.055

PubMed Abstract | CrossRef Full Text | Google Scholar

75. Herzog JI, Niedtfeld I, Rausch S, Thome J, Mueller-Engelmann M, Steil R, et al. Increased recruitment of cognitive control in the presence of traumatic stimuli in complex PTSD. Eur Arch Psychiatr Clin Neurosci. (2017). doi: 10.1007/s00406-017-0822-x [Epub ahead of print].

PubMed Abstract | CrossRef Full Text | Google Scholar

76. Puetz VB, Viding E, Palmer A, Kelly PA, Lickley R, Koutoufa I, et al. Altered neural response to rejection-related words in children exposed to maltreatment. J Child Psychol Psychiatr. (2016) 57:1165–73. doi: 10.1111/jcpp.12595

PubMed Abstract | CrossRef Full Text | Google Scholar

77. Thomaes K, Dorrepaal E, Draijer N, de Ruiter MB, Elzinga BM, van Balkom AJ, et al. Treatment effects on insular and anterior cingulate cortex activation during classic and emotional Stroop interference in child abuse-related complex post-traumatic stress disorder. Psychol Med. (2012) 42:2337–49. doi: 10.1017/S0033291712000499

PubMed Abstract | CrossRef Full Text | Google Scholar

78. Lanius RA, Vermetten E, Loewenstein RJ, Brand B, Schmahl C, Bremner JD, et al. Emotion modulation in PTSD: clinical and neurobiological evidence for a dissociative subtype. Am J Psychiatr. (2010) 167:640–7. doi: 10.1176/appi.ajp.2009.09081168

PubMed Abstract | CrossRef Full Text | Google Scholar

79. Smith AR, Steinberg L, Chein J. The role of the anterior insula in adolescent decision making. Dev Neurosci. (2014) 36:196–209. doi: 10.1159/000358918

PubMed Abstract | CrossRef Full Text | Google Scholar

80. Francati V, Vermetten E Bremner JD. Functional neuroimaging studies in posttraumatic stress disorder: review of current methods and findings. Depress Anxiety (2007) 24:202–18. doi: 10.1002/da.20208

PubMed Abstract | CrossRef Full Text | Google Scholar

81. Boyda D, McFeeters D, Shevlin M. Intimate partner violence, sexual abuse, and the mediating role of loneliness on psychosis. Psychosis (2015) 7:1–13. doi: 10.1080/17522439.2014.917433

CrossRef Full Text | Google Scholar

82. Tost H, Champagne FA, Meyer-Lindenberg A. Environmental influence in the brain, human welfare and mental health. Nat. Neurosci. (2015) 18:1421–31. doi: 10.1038/nn.4108

PubMed Abstract | CrossRef Full Text | Google Scholar

83. Ferguson CJ. Video games and youth violence: a prospective analysis in adolescents. J Youth Adolesc. (2011) 40:377–91. doi: 10.1007/s10964-010-9610-x

PubMed Abstract | CrossRef Full Text | Google Scholar

84. Danese A, Moffitt TE, Harrington H, Milne BJ, Polanczyk G, Pariante CM, et al. Adverse childhood experiences and adult risk factors for age-related disease: depression, inflammation, and clustering of metabolic risk markers. Arch Pediatr Adolesc Med. (2009) 163:1135–43. doi: 10.1001/archpediatrics.2009.214

PubMed Abstract | CrossRef Full Text | Google Scholar

85. Widom CS, DuMont K, Czaja SJ. A prospective investigation of major depressive disorder and comorbidity in abused and neglected children grown up. Arch Gen Psychiatr. (2007) 64:49–56. doi: 10.1001/archpsyc.64.1.49

PubMed Abstract | CrossRef Full Text | Google Scholar

86. Green JG, McLaughlin KA, Berglund PA, Gruber MJ, Sampson NA Zaslavsky AM., et al. Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication I: associations with first onset of DSM-IV disorders. Arch Gen Psychiatr. (2010) 67:113–23. doi: 10.1001/archgenpsychiatry.2009.186

PubMed Abstract | CrossRef Full Text | Google Scholar

87. Scott KM, Hwang I, Chiu WT, Kessler RC, Sampson NA, Angermeyer M, et al. Chronic physical conditions and their association with first onset of suicidal behavior in the world mental health surveys. Psychosom Med. (2010) 72:712–19. doi: 10.1097/PSY.0b013e3181e3333d

PubMed Abstract | CrossRef Full Text | Google Scholar

88. Widom CS, Czaja SJ, Paris J. A prospective investigation of borderline personality disorder in abused and neglected children followed up into adulthood. J Pers Disorders (2009) 23:433–46. doi: 10.1521/pedi.2009.23.5.433

PubMed Abstract | CrossRef Full Text | Google Scholar

89. Kendler KS, Bulik CM, Silberg J, Hettema JM, Myers J, Prescott CA. Childhood sexual abuse and adult psychiatric and substance use disorders in women: an epidemiological and cotwin control analysis. Arch Gen Psychiatr. (2000) 57:953–59. doi: 10.1001/archpsyc.57.10.953

PubMed Abstract | CrossRef Full Text | Google Scholar

90. Hovens JG, Giltay EJ, Wiersma JE, Spinhoven P, Penninx BW, Zitman FG. Impact of childhood life events and trauma on the course of depressive and anxiety disorders. Acta Psychiatr Scand. (2012) 126:198–207. doi: 10.1111/j.1600-0447.2011.01828.x

PubMed Abstract | CrossRef Full Text | Google Scholar

91. Harkness KL, Wildes JE. Childhood adversity and anxiety versus dysthymia co-morbidity in major depression. Psychol Med. (2002) 32:1239–49. doi: 10.1017/S0033291702006177

PubMed Abstract | CrossRef Full Text | Google Scholar

92. Agnew-Blais J, Danese A. Childhood maltreatment and unfavourable clinical outcomes in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatr. (2016) 3:342–9. doi: 10.1016/S2215-0366(15)00544-1

PubMed Abstract | CrossRef Full Text | Google Scholar

93. Norman RE, Byambaa M, De R, Butchart A, Scott J, Vos T. The long-term health consequences of child physical abuse, emotional abuse, and neglect: a systematic review and meta-analysis. PLoS Med. (2012) 9:e1001349. doi: 10.1371/journal.pmed.1001349

PubMed Abstract | CrossRef Full Text | Google Scholar

94. Schoedl AF, Costa MC, Mari JJ, Mello MF, Tyrka AR, Carpenter LL, et al. The clinical correlates of reported childhood sexual abuse: an association between age at trauma onset and severity of depression and PTSD in adults. J Child Sex Abus. (2010) 19:156–170. doi: 10.1080/10538711003615038

PubMed Abstract | CrossRef Full Text | Google Scholar

95. Glod CA, Teicher MH. Relationship between early abuse, posttraumatic stress disorder, and activity levels in prepubertal children. J Am Acad Child Adolesc Psychiatr. (1996) 35:1384–93. doi: 10.1097/00004583-199610000-00026

PubMed Abstract | CrossRef Full Text | Google Scholar

96. Khan A, McCormack HC, Bolger EA, McGreenery CE, Vitaliano G, Polcari A, et al. Childhood maltreatment, depression, and suicidal ideation: critical importance of parental and peer emotional abuse during developmental sensitive periods in males and females. Front Psychiatr. (2015) 6:42. doi: 10.3389/fpsyt.2015.00042

PubMed Abstract | CrossRef Full Text | Google Scholar

97. Kaplow JB, Widom CS. Age of onset of child maltreatment predicts long-term mental health outcomes. J Abnorm Psychol. (2007) 116:176–187. doi: 10.1037/0021-843X.116.1.176

PubMed Abstract | CrossRef Full Text | Google Scholar

98. Dunn EC, McLaughlin KA, Slopen N, Rosand J, Smoller JW. Developmental timing of child maltreatment and symptoms of depression and suicidal ideation in young adulthood: results from the National Longitudinal Study of Adolescent Health. Depress Anxiety (2013) 30:955–64. doi: 10.1002/da.22102

PubMed Abstract | CrossRef Full Text | Google Scholar

99. Turecki G, Ota VK, Belangero SI, Jackowski A, Kaufman J. Early life adversity, genomic plasticity, and psychopathology. Lancet Psychiatr. (2014) 1:461–6. doi: 10.1016/S2215-0366(14)00022-4

PubMed Abstract | CrossRef Full Text | Google Scholar

100. Nieratschker V, Massart R, Gilles M, Luoni A, Suderman MJ, Krumm B, et al. Morc1 exhibits cross-species differential methylation in association with early life stress as well as genome-wide association with mdd. Transl Psychiatr. (2014) 4:e429. doi: 10.1038/tp.2014.75

PubMed Abstract | CrossRef Full Text | Google Scholar

101. Luoni A, Massart R, Nieratschker V, Nemoda Z, Blasi G, Gilles M, et al. Ankyrin-3 as a molecular marker of early-life stress and vulnerability to psychiatric disorders. Transl Psychiatr. (2016) 6:e943. doi: 10.1038/tp.2016.211

PubMed Abstract | CrossRef Full Text | Google Scholar

102. Watkins LE, Han S, Harpaz-Rotem I, Mota NP, Southwick SM, Krystal JH, et al. FKBP5 polymorphisms, childhood abuse, and PTSD symptoms: results from the National Health and Resilience in Veterans Study. Psychoneuroendocrinology (2016) 69:98–105. doi: 10.1016/j.psyneuen.2016.04.001

PubMed Abstract | CrossRef Full Text | Google Scholar

103. McCrory E, De Brito SA, Viding E. The link between child abuse and psychopathology: a review of neurobiological and genetic research. J R Soc Med. (2012) 105:151–6. doi: 10.1258/jrsm.2011.110222

PubMed Abstract | CrossRef Full Text | Google Scholar

104. Zannas AS, West AE. Epigenetics and the regulation of stress vulnerability and resilience. Neuroscience (2014) 264:157–70. doi: 10.1016/j.neuroscience.2013.12.003

PubMed Abstract | CrossRef Full Text | Google Scholar

105. Alastalo H, Raikkonen K, Pesonen AK, Osmond C, Barker DJ, Heinonen K, et al. (2013). Early life stress and blood pressure levels in late adulthood. J Hum Hypertens. 27:90–94. doi: 10.1038/jhh.2012.6

PubMed Abstract | CrossRef Full Text | Google Scholar

106. Fuller-Thomson E West KJ, Sulman J, Baird SL. Childhood maltreatment is associated with ulcerative colitis but not Crohn's disease: findings from a population-based study. Inflamm Bowel Dis. (2015) 21:2640–48. doi: 10.1097/MIB.0000000000000551

CrossRef Full Text | Google Scholar

107. Tamayo T, Christian H, Rathmann W. 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 (2010) 10:525. doi: 10.1186/1471-2458-10-525

PubMed Abstract | CrossRef Full Text | Google Scholar

108. Leeners B, Gorres G, Block E, Hengartner MP. Birth experiences in adult women with a history of childhood sexual abuse. J Psychosom Res. (2016) 83:27–32. doi: 10.1016/j.jpsychores.2016.02.006

PubMed Abstract | CrossRef Full Text | Google Scholar

109. Tesarz J Eich W, Treede RD, Gerhardt A. Altered pressure pain thresholds and increased wind-up in adult patients with chronic back pain with a history of childhood maltreatment: a quantitative sensory testing study. Pain (2016) 157:1799–1809. doi: 10.1097/j.pain.0000000000000586

PubMed Abstract | CrossRef Full Text | Google Scholar

110. Coelho R, Viola TW, Walss-Bass C, Brietzke E, Grassi-Oliveira R. Childhood maltreatment and inflammatory markers: a systematic review. Acta Psychiatr Scand. (2014) 129:180–192. doi: 10.1111/acps.12217

PubMed Abstract | CrossRef Full Text | Google Scholar

111. Baumeister D, Akhtar R, Ciufolini S, Pariante CM, Mondelli V. Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α. Mol Psychiatr. (2016) 21:642–9. doi: 10.1038/mp.2015.67

PubMed Abstract | CrossRef Full Text | Google Scholar

112. Tesarz J, Gerhardt A, Leisner S, Janke S, Treede RD, Eich W. Distinct quantitative sensory testing profiles in nonspecific chronic back pain subjects with and without psychological trauma. Pain (2015) 156:577–86. doi: 10.1097/01.j.pain.0000460350.30707.8d

PubMed Abstract | CrossRef Full Text | Google Scholar

113. Hoheisel U, Vogt MA, Palme R, Gass P, Mense S. Immobilization stress sensitizes rat dorsal horn neurons having input from the low back. Eur J Pain (2015) 19:861–70. doi: 10.1002/ejp.682

PubMed Abstract | CrossRef Full Text | Google Scholar

114. Lomazzo E, Bindila L, Remmers F, Lerner R, Schwitter C, Hoheisel U, et al. Therapeutic potential of inhibitors of endocannabinoid degradation for the treatment of stress-related hyperalgesia in an animal model of chronic pain. Neuropsychopharmacology (2015) 40:488–501. doi: 10.1038/npp.2014.198.E

PubMed Abstract | CrossRef Full Text | Google Scholar

115. Schneider P, Patz M, Spanagel R, Schneider M. Adolescent social rejection alters pain processing in a CB1 receptor dependent manner. Eur Neuropsychopharmacol. (2016b) 26:1201–12. doi: 10.1016/j.euroneuro.2016.04.007

PubMed Abstract | CrossRef Full Text | Google Scholar

116. Schneider P, Bindila L, Schmahl C, Bohus M, Meyer-Lindenberg A, Lutz B, et al. Adverse social experiences in adolescent rats result in enduring effects on social competence, pain sensitivity and endocannabinoid signaling. Front Behav Neurosci. (2016a) 10:203. doi: 10.3389/fnbeh.2016.00203

PubMed Abstract | CrossRef Full Text | Google Scholar

117. Harville EW, Do M. Reproductive and birth outcomes in haiti before and after the 2010 earthquake. Disaster Med Public Health Prep. (2016) 10:59–66. doi: 10.1017/dmp.2015.69

PubMed Abstract | CrossRef Full Text | Google Scholar

118. Pesonen AK, Raikkonen K, Heinonen K, Kajantie E, Forsen T, Eriksson JG. Reproductive traits following a parent-child separation trauma during childhood: a natural experiment during World War II. Am. J. Hum. Biol. (2008) 20:345–51. doi: 10.1002/ajhb.20735

PubMed Abstract | CrossRef Full Text | Google Scholar

119. Smith MV, Gotman N, Yonker KA. Early childhood adversity and pregnancy outcomes. Matern Child Health J. (2016) 20:790–8. doi: 10.1007/s10995-015-1909-5

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: adverse childhood experiences, childhood maltreatment, neuroimaging, psychopathology, somatic disorders, type and timing

Citation: Herzog JI and Schmahl C (2018) Adverse Childhood Experiences and the Consequences on Neurobiological, Psychosocial, and Somatic Conditions Across the Lifespan. Front. Psychiatry 9:420. doi: 10.3389/fpsyt.2018.00420

Received: 13 February 2018; Accepted: 15 August 2018;
Published: 04 September 2018.

Edited by:

Jutta Lindert, University of Applied Sciences Emden Leer, Germany

Reviewed by:

Arash Javanbakht, Wayne State University School of Medicine, United States
Leandro Da Costa Lane Valiengo, Universidade de São Paulo, Brazil

Copyright © 2018 Herzog and Schmahl. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Julia I. Herzog, julia.herzog@zi-mannheim.de

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.