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

2. 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.
Effect on brain development is another reason that child abuse is harmful. The last decade has been marked by learning more about the response and how it plays out throughout a person’s life.

3. Developmental Traumatology
Systematic investigation of the neurobiological impact of chronic interpersonal violence on the developing child
A new field that draws from
Developmental psychopathology
Developmental neuroscience
Stress and trauma research
Abuse and neglect are extreme forms of dysfunctional family and interpersonal functioning
They occur in the context of multiple adversities (below) and it is difficult to quantitate the effect of each:
Socioeconomic disadvantage
Parental mental illness
Parental alcohol and substance use disorder
Lack of social support
Individual factors are genetic constitution, neurophysiology, unique psychosocial environment
What is the exact experience-dependent critical period of neurobiological and psychological development?

4. Goals of Developmental Traumatology Research
Improved understanding of risk and resiliency in maltreated children
Improved interventions for maltreatment victims and those at risk
There is a great deal of variability in outcome following child maltreatment.
Research also focuses on what contributes to a victim’s resilience.

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

6. 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
The thalamus also transmits the information to the cortex as illustrated in the second image, so the fear registers cognitively. However, the amygdala route is usually faster and the body has reacted before the cortex thinks through what to do.

7. 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)

8. 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 mPFC
Promote stress response by binding to amygdala receptors
Inhibit release of CRH by the hypothalamus
Inhibit the release of ACTH by the pituitary
medial prefrontal cortex (mPFC)
Corticotropin releasing hormone (CRH)
Adrenocorticotropic hormone (ACTH)
Sternberg (2006)

9. HPA, LC/NA, ANS CRH activates the LC/NA
LC releases increased amounts of norepineprine
Elevated arousal, vigilance, anxiety
HPA: Hypothalamic-pituitary-adrenal axis
LC/NA: locus coeruleus noradrenergic neurotransmitter system
ANS: Autonomic nervous system
CRH: corticotrophin-releasing hormone
HPA and LC/NA sustain and enhance the stress response
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

10. 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

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

12. 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

13. 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

14. 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%
Smaller cerebellar volume
Changes correlate with duration/severity of abuse

15. 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…
Impaired neural integrity
Limbic system: collection of subcortical and cortical brain regions:
Amygdala
Hippocampus
Anterior thalamus
Anterior cingulate gyrus
Image permission: Morris, Charles G., Psychology: An Introduction, 8th Edition, © Reprinted by permission of Pearson Education, Inc., Upper Saddle River, NJ.
Morris, Charles G., Psychology: An Introduction, 8th Edition, © Reprinted by permission of Pearson Education, Inc., Upper Saddle River, NJ.

16. Medial Prefrontal Cortex (mPFC) Changes
Child abuse victims show impaired functioning:
Failure to extinguish fear conditioning
Decreased activity in mPFC correlates with emotional stimuli interfering with simple cognitive tasks
Problem solving
Future planning
Emotional behavioral control
Inhibition of stress response
Prefrontal cortex – green
Anterior cingulate cortex – red
Tost (2012)

17. 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

18. Intervention Addresses Child Maltreatment Psychopathology
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)
*Asterisks single out two groups that deserve more explanation in the next few slides.
Social supports have proven to be very effective, but must be frequent enough to make a difference. Frequency is being studied.
Cognitive behavioral therapy has shown effectiveness in ameliorating symptoms
Psychotropic medications, time limited and followed, also decrease disturbing symptoms.

19. Males Less Resilient than Females
Slide shows enlarged lateral ventricles in an 11 year old maltreated male with chronic PTSD on the right , compared with a healthy, non-maltreated matched control on the left (from DeBellis 1999).
DeBellis 2003: Pediatric posttraumatic stress disorder (PTSD) is associated with adverse brain development. However, sex differences are poorly understood. METHODS: In this study, 61 medically healthy children and adolescents (31 males and 30 females) with chronic PTSD secondary to abuse, who had similar trauma and mental health histories, and 122 healthy controls (62 males and 60 females) underwent comprehensive psychiatric assessments and an anatomical MRI brain scan. RESULTS: When gender groups were analyzed separately, findings of larger prefrontal lobe CSF volumes and smaller midsagittal area of the corpus callosum subregion 7 (splenium) were seen in both boys and girls with maltreatment-related PTSD compared to their gender-matched comparison subjects. Subjects with PTSD did not show the normal age related increases in the area of the total corpus callosum and its region 7 (splenium) compared to non-maltreated subjects; however, this finding was more prominent in males with PTSD. Significant sex by group effects demonstrated smaller cerebral volumes and corpus callosum regions 1 (rostrum) and 6 (isthmus) in PTSD males and greater lateral ventricular volume increases in maltreated males with PTSD than maltreated females with PTSD. CONCLUSIONS: These data suggest that there are sex differences in the brain maturation of boys and girls with maltreatment-related PTSD. Longitudinal MRI brain investigations of childhood PTSD and the relationship of gender to psychosocial outcomes are warranted.
De Bellis, MD, Keshavan, MS (2003): Sex differences in brain maturation in Maltreatment-Related Pediatric Posttraumatic Stress Disorder.

20. Genetic Component Increases Vulnerability in Some
Two genes have been studied
Monoamine oxidase gene (MAOA)
Serotonin transporter gene (5-HTT)
Children homozygous for short allele of either gene, were more vulnerable to mental health problems
But only when exposed to child abuse /neglect
Depression less severe if have social support
This lists a second category of children with increased vulnerability. More on next slide.

21. 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:
McGloin, Widom (2001): Resilience among abused and neglected children grown up
Kaufman (2004): Social supports and serotonin transporter gene moderate depression in maltreated children
McGloin and Widom (2001): Although an extensive literature has accumulated documenting the maladaptive outcomes associated with childhood victimization, a limited body of knowledge addresses resilience. This paper sought to operationalize the construct of resilience across a number of domains of functioning and time periods and to determine the extent to which abused and neglected children grown up demonstrate resilience. Substantiated cases of child abuse and neglect from 1967 to 1971 were matched on gender, age, race, and approximate family social class with nonabused and nonneglected children and followed prospectively into young adulthood. Between 1989 and ,196 participants (676 abused and neglected and 520 controls) were administered a 2-hr in-person interview, including a psychiatric assessment. Resilience requires meeting the criteria for success across six of eight domains of functioning: employment, homelessness, education, social activity, psychiatric disorder, substance abuse, and two domains assessing criminal behavior (official arrest and self-reports of violence). Results indicate that 22% of abused and neglected individuals meet the criteria for resilience. More females met the criteria for resilience and females were successful across a greater number of domains than males. We speculate on the meaning of these findings and discuss implications for the child maltreatment field. Limitations of the study are also acknowledged.
Kaufman (2004): In this study, measures of the quality and availability of social supports were found to moderate risk for depression associated with a history of maltreatment and the presence of the short (s) allele of the serotonin transporter gene promoter polymorphism (5-HTTLPR). The present investigation (i) replicates research in adults showing that 5-HTTLPR variation moderates the development of depression after stress, (ii) extends the finding to children, and (iii) demonstrates the ability of social supports to further moderate risk for depression. Maltreated children with the s/s genotype and no positive supports had the highest depression ratings, scores that were twice as high as the non-maltreated comparison children with the same genotype. However, the presence of positive supports reduced risk associated with maltreatment and the s/s genotype, such that maltreated children with this profile had only minimal increases in their depression scores. These findings are consistent with emerging preclinical and clinical data suggesting that the negative sequelae associated with early stress are not inevitable. Risk for negative outcomes may be modified by both genetic and environmental factors, with the quality and availability of social supports among the most important environmental factors in promoting resiliency in maltreated children, even in the presence of a genotype expected to confer vulnerability for psychiatric disorder.

22. Questions?
“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.”
Kaufman 2004

23. 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:
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):
De Bellis, M. (2001): “Developmental traumatology: the psychobiological development of maltreated children and its implications for research, treatment, and policy.“ Development and Psychopathology 13:

24. De Bellis, M. D. and M. S. Keshavan (2003)
De Bellis, M. D. and M. S. Keshavan (2003). "Sex differences in brain maturation in maltreatment- related pediatric posttraumatic stress disorder." Neurosci Biobehav Rev 27(1-2):
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):
McGloin, J. M. and C. S. Widom (2001). "Resilience among abused and neglected children grown up." Dev Psychopathol 13(4):

25. Permissions for Use of Illustrations
Slide 7: Heulens, I. and F. Kooy (2011). "Fragile X syndrome: from gene discovery to therapy." Front Biosci 16: 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):
Slide 15: Morris, Charles G., Psychology: An Introduction, 8th Edition, © 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):