Biological Effects of ACEs
Andrea Danese, MD, PhD; Michael D. DeBellis, MD, MPH; and
Martin H. Teicher, MD, PhD
Adverse psychosocial experiences in childhood affect later mental and physical health.1,2 Current evidence suggests that the “biological embedding” of adverse childhood experiences may be attributed to changes in three key systems sensitive to psychological stress: the brain and the endocrine and immune systems.3,4 Experimental research has shown that mice exposed to early life stress undergo biochemical changes in their genetic material that result in abnormal expression of key genes regulating the biological response to stress.5
Through these epigenetic changes, the developing child could modify his or her biological response to stress to maximize adaptation to the current environment. For example, a threatening and unpredictable environment will be associated with hyperactive stress response. Although this might ensure greater adaptation to the immediate environment, the hyperactive stress response may also carry a burden for disease during child development and beyond.
Endocrine and Immune Systems
In conditions of acute psychosocial stress, the secretion of glucocorticoid hormones (e.g., cortisol) and their systemic effects mediated by the glucocorticoid receptor are vital to increase energy provision in the face of adversities. Mice exposed to early life stress exhibit epigenetic changes leading to reduced functioning of the glucocorticoid receptor.6 Consistent with evidence in these animal models, maltreated children show chronic elevation in cortisol levels,7 possibly to compensate for the impaired functioning of the glucocorticoid receptor. Although elevated cortisol elevation might be adaptive in the short-term to support increased bodily demands under conditions of threat, chronic elevation in cortisol levels may become detrimental to health.8
Insufficient glucocorticoid functioning has important implications for the developing immune system. Because glucocorticoid hormones are potent anti-inflammatory compounds, attenuation of their effect may impair regulation of the inflammatory response. Consistent with impaired functioning of the glucocorticoid receptor, children, and adults exposed to early maltreatment show elevated inflammation levels.9,10 Elevated inflammation levels may be adaptive in the short-term to potentiate stress-induced immune response—should the threat be followed by physical injury. However, chronic elevation in inflammation levels contribute to the pathophysiology of several chronic conditions, such as cardiovascular disease or type 2 diabetes.11,12 Abnormal endocrine and immune functioning in children exposed to adverse childhood experiences may affect brain development, with important implications for mental health. Regulation of inflammation and energy balance is also influenced by leptin, which has inhibitory effects acting both as a cytokine and as a hormone. Consistent with the evidence linking child maltreatment to high inflammation and obesity, maltreated children showed blunted elevation in leptin levels in relation to increasing levels of physiological stimuli, inflammation, and adiposity.13
Brain Structure and Function
A growing body of reproducible findings in child victims of maltreatment and adults who were maltreated as children have linked childhood maltreatment to structural and functional brain differences.14 Smaller brain volumes, smaller midsagital areas of the corpus callosum, and functional alterations in the neocortex, visual cortex, and auditory cortex have been observed in maltreatment survivors. Adverse brain development is seen in maltreated children and adolescents with posttraumatic stress disorder (PTSD) and other psychopathology.15,16 However, alterations in the prefrontal cortex of maltreated children are also seen in maltreated children without any DSM-IV Axis I disorders.17 The findings also revealed gender differences; in maltreated girls, neurostructural alterations resided in brain regions involved in emotion regulation, whereas in maltreated boys, the affected brain regions involved impulse control.
In addition to gender differences, timing can also play a role in the degree to which anomalous brain development occurs. During brain maturation, specific windows of vulnerability, called stress-sensitive periods, exist. During these periods, brain regions are are undergoing active maturation and thus are more susceptible to the negative effects of overwhelming stress. To date, the data strongly suggest that child maltreatment is associated with alterations in brain regions that may have profound negative effects on executive function, attention, memory, sequencing, planning, and visual-spatial function.18 These deficits can impair day-to-day function, leading to lower levels of function in victims of maltreatment. However, the neurobiology of child maltreatment in humans is a relatively new field of study, and thus several key questions remain: What changes are adaptive, and what changes will result in long-term disease? Does treatment of stress-related illnesses improves brain structure and function? In order to help victims of child maltreatment, longitudinal studies are needed to address these important issues.
References and Resources
1. Nanni V, Uher R, Danese A. Childhood maltreatment predicts unfavorable course of illness and treatment outcome in depression: a meta-analysis. Am J Psychiatry. 2012;169:141-51.
2. Danese A, Tan M. Childhood maltreatment and obesity: systematic review and meta-analysis. Molecular Psychiatry. 2014;19(5):544-54.
3. Danese A, McEwen BS. Adverse childhood experiences, allostasis, allostatic load, and age-related disease. Physiol Behav. 2012;106:29-39.
4. Shonkoff JP, Boyce WT, McEwen BS. Neuroscience, molecular biology, and the childhood roots of health disparities: building a new framework for health promotion and disease prevention. JAMA. 2009;301:2252-9.
5. Meaney MJ. Epigenetics and the biological definition of gene x environment interactions. Child Dev. 2010;81:41-79.
6. Weaver IC, Cervoni N, Champagne FA, et al. Epigenetic programming by maternal behavior. Nat Neurosci. 2004;7:847-54.
7. Tarullo AR, Gunnar MR. Child maltreatment and the developing HPA axis. Horm Behav. 2006;50:632-9.
8. McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med. 1998;338:171-9.
9. Danese A, Caspi A, Williams B, et al. Biological embedding of stress through inflammation processes in childhood. Molecular Psychiatry. 2011;16:244-6.
10. Danese A, Pariante CM, Caspi A, et al. Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci USA. 2007;104:1319-24.
11. Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868-74.
12. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860-7.
13. Danese A, Dove R, Belsky D, et al Leptin deficiency in maltreated children. Transl Psychiatry. 2014; 4:e446.
14. Teicher MH, Samson JA. Childhood maltreatment and psychopathology: A case for ecophenotypic variants as clinically and neurobiologically distinct subtypes. Am J Psychiatry. 2013;170(10):1114-33.
15. De Bellis MD, Baum A, Birmaher B, et al. Developmental traumatology part I: biological stress systems. Biological Psychiatry. 1999;45:1259-70.
16. De Bellis MD, Keshavan MS, Clark DB, et al. Developmental traumatology part II: brain development. Biological Psychiatry. 1999;45(10):1271-84.
17. Edmiston EE, Wang F, Mazure CM, et al. Corticostriatal-limbic gray matter morphology in adolescents with self-reported exposure to childhood maltreatment. Archives of Pediatrics & Adolescent Medicine. 2011;165(12):1069-77.
18. Burghy CA Stodola DE, Ruttle PL, et al. Developmental pathways to amygdala-prefrontal function and internalizing symptoms in adolescence. Nat Neurosci. 2012;15(12):1736-41.
© 2015 by Academy on Violence and Abuse
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