Effect of Abuse and Neglect on Brain Development

Effect of Abuse and Neglect on Brain Development Michael D De Bellis, MD, MPH Marilyn Kaufhold, MD, FAAP

Learning Objectives The participant will be able to: • Define the term developmental traumatology. • Summarize evidence that shows the effect of early life stress on the biologic stress response system in maltreated children. • Compare and contrast brain development in healthy versus maltreated children. • List circumstances capable of attenuating or accentuating the effects of maltreatment.

Developmental Traumatology Systematic investigation of the neurobiological impact of chronic interpersonal violence on the developing child A new field that draws from • Developmental psychopatholog y • Developmental neuroscience • Stress and trauma research

Goals of Developmental Traumatology Research Improved understanding of risk and resiliency in maltreated children Improved interventions for maltreatment victims and those at risk

Review: The Normal Biological Stress Response System Mediated by four interacting systems • HPA: Hypothalamic-pituitaryadrenal axis • LC/NA: locus coeruleus noradrenergic neurotransmitter system • ANS: Autonomic nervous system • Immune system

Child abuse activates the biologic stress response system • Threatening external stimuli are processed through the thalamus which • Activates the amygdala fear detection circuit • Amygdala transmits signals to the basal forebrain, paraventricular nucleus of the hypothalamus and brainstem

HPA Axis • Hypothalamus secretes corticotrophin-releasing hormone (CRH) • CRH binds to receptors in the anterior pituitary gland, stimulating release of adrenocorticotropic hormone (ACTH) • ACTH binds to receptors in the adrenal cortex • Adrenal cortex secretes cortisol Heulens (2011)

Cortisol binds to receptors throughout the body to… • Suppress the immune system • Stimulate gluconeogenesis • Regulate the stress response system: • Attenuate stress response by binding to receptors in the m. PFC • Promote stress response by binding to amygdala receptors • Inhibit release of CRH by the hypothalamus • Inhibit the release of ACTH by the pituitary Sternberg (2006)

HPA, LC/NA, ANS • CRH activates the LC/NA • LC releases increased amounts of norepineprine • Elevated arousal, vigilance, anxiety • LC/NA activates the sympathetic nervous system • Increases heart rate/BP/sweating/muscle tone • Redistributes blood away from the skin, intestines, and kidney to the heart, brain, and skeletal muscle

The Biological Stress Response System in Maltreated Children Research in child abuse victims shows: • Baseline cortisol levels are higher in maltreated children • With PTSD as manifested by symptoms of anxiety and depression • In sexually abused girls • With significant internalizing symptoms • Plasma ACTH responses to cortisol are attenuated • HPA axis hyper-responds

LC/NA, ANS and Immune System in Maltreated Children Produce… Immune system suppressio n Impaired growth Metabolic syndrome Elevated heart rate Decreased alpha 2 – adrenergic receptors Elevated 24 hour excretion of catecholeamine metabolites Hypertension

Review: Healthy Brain Development Steady increase in intracranial volume until age 10 • Overproduction of neurons in utero • Increases in neuron size and synapses during childhood • Apoptosis: selective pruning of many neurons • Increase in myelination during adolescence and young adulthood

Brain Development in Maltreated Children Increased levels of catecholamines and cortisol lead to adverse brain development through… Accelerated loss of neurons (premature aging) Delay in myelination Abnormalities in normal pruning Neurogenesis inhibition

Cerebral Cortex, Corpus Callosum and Cerebellum MRI Studies of healthy brains vs. those of maltreated children show… • Size reduction in portions of the corpus callosum • Decrease in white, not grey, matter in the brain (depending on area and age of child may see decrease in both) • Increased size of ventricles (males only) • Decreased intracranial volume by 7% • Decreased total brain volume by 8% • Smallercorrelate cerebellar volume Changes with duration/severity of abuse

The Limbic System: Emotion and Memory Changes • Amygdala activates the stress response – CA victims show… • Exaggerated startle response • Enhanced fear conditioning • Hippocampus is responsible for biological stress system, especially contextual memory – CA victims show… Morris, Charles G. , Psychology: An Introduction, 8 th Edition, © 1996. • Impaired neural integrity Reprinted by permission of Pearson Education, Inc. , Upper Saddle River, NJ.

Medial Prefrontal Cortex (m. PFC) Changes • Child abuse victims show impaired functioning: • Failure to extinguish fear conditioning • Decreased activity in m. PFC correlates with emotional stimuli interfering with simple cognitive tasks • Problem solving • Future planning • Emotional behavioral control • Inhibition of stress response Tost (2012)

Cognitive Function of Maltreated Children Multiple studies document impaired functioning • • Decreased intellectual measurement Verbal deficiencies Lower reading ability Deficits in attention, abstract reasoning and executive functioning • Higher rates of impulsivity Important to determine specific deficits to design effective interventions

Intervention Addresses Child Maltreatment Psychopathology results from exposure that depends on: Duration Severity Age-of-onset Gender* Genetics* Social supports and evidence-based interventions promote recovery from effects of maltreatment (*specific needs)

Males Less Resilient than Females De Bellis, MD, Keshavan, MS (2003): Sex differences in brain maturation in Maltreatment-Related Pediatric Posttraumatic Stress Disorder.

Genetic Component Increases Vulnerability in Some Two genes have been studied Children homozygous for short allele of either gene, were more vulnerable to mental health problems • Monoamine oxidase gene (MAOA) • Serotonin transporter gene (5 -HTT) • But only when exposed to child abuse /neglect • Depression less severe if have social support

Specific Interventions Offer a Positive Outcome Even for those children with a genetic predisposition to be severely affected if abused, social supports were able to ameliorate the PTSD and depression Two studies: • Mc. Gloin, Widom (2001): Resilience among abused and neglected children grown up • Kaufman (2004): Social supports and serotonin transporter gene moderate depression in maltreated children

Questions? Kaufman 2004 “We believe the life course trajectory of maltreated children can be improved through ongoing research efforts that span from neurobiology to social policy, identifying mechanisms responsible for the etiology of depression and other stress-related psychiatric disorders and systematically testing interventions to improve the system of care for these children. ”

References • Crozier, J. , E. Van Voorhees, et al. (2011). Effects of Abuse and Neglect on Brain Development. Child Abuse and Neglect: Diagnosis, Treatment, and Evidence. C. Jenny. St. Louis, Elsevier/Saunders: 516 -525. • De Bellis, M. D. , M. S. Keshavan, et al. (1999). "A. E. Bennett Research Award. Developmental traumatology. Part II: Brain development. " Biol Psychiatry 45(10): 12711284. • De Bellis, M. (2001): “Developmental traumatology: the psychobiological development of maltreated children and its implications for research, treatment, and policy. “ Development and Psychopathology 13: 537 -561.

• De Bellis, M. D. and M. S. Keshavan (2003). "Sex differences in brain maturation in maltreatmentrelated pediatric posttraumatic stress disorder. " Neurosci Biobehav Rev 27(1 -2): 103 -117. • Kaufman, J. , B. Z. Yang, et al. (2004). "Social supports and serotonin transporter gene moderate depression in maltreated children. " Proc Natl Acad Sci U S A 101(49): 17316 -17321. • Mc. Gloin, J. M. and C. S. Widom (2001). "Resilience among abused and neglected children grown up. " Dev Psychopathol 13(4): 1021 -1038.

• Permissions for Use of Illustrations • Slide 7: Heulens, I. and F. Kooy (2011). "Fragile X syndrome: from gene discovery to therapy. " Front Biosci 16: 1211 -1232. DOI: 3785 [pii] • Slice 8: Sternberg, E. M. (2006). "Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. " Nat Rev Immunol 6(4): 318328. • Slide 15: Morris, Charles G. , Psychology: An Introduction, 8 th Edition, © 1996. Reprinted by permission of Pearson Education, Inc. , Upper Saddle River, NJ. • Slide 16: Tost, H. and A. Meyer-Lindenberg (2010). "I fear for you: a role for serotonin in moral behavior. " Proc Natl Acad Sci U S A 107(40): 17071 -17072.