Long Term Effects of Childhood Abuse on the Brain

1. Long Term Effects of Childhood Abuse on the Brain J. Douglas Bremner, MD Emory University, Atlanta, Georgia

2. Disclosures Grant Support NIH: R01 MH56120, T32 MH067547, K24 MH076955 (As co-investigator) R01 AG026255, R01 HL068630, R01 HL703824, R01 MH068791, P50 MH58922 Veterans Administration: Merit Review, VET-HEAL Award National Alliance for Research on Schizophrenia and Depression (NARSAD) Independent Investigator Award American Foundation for Suicide Prevention (AFSP) Georgia Research Alliance GlaxoSmithKline Investigator Initiated Medical Research Consulting Novartis GlaxoSmithKline Speakers Bureaus None Discussion of Off Label Medication Use Phenytoin

3. Childhood Abuse-The Invisible Epidemic 16% of women have a history of childhood sexual abuse (rape or fondling) based on nationwide surveys (McCauley et al., 1997, JAMA) 10% of women (13 million) currently suffer from PTSD (Kessler et al., 1995, AGP), twice as common in women as in men Childhood sexual abuse most common cause of PTSD in women

4. Posttraumatic Stress Disorder Intrusive memories, nightmares, flashbacks, arousal, avoidance, startle, sleep disturbance, gaps in memory and concentration Associated with threat to life or other with fear/horror/helplessness (A) Affects 15% of traumatized individuals 16% of women with sexual abuse 8% lifetime PTSD prevalence (10% women)

5. Lifetime Prevalence Of Trauma

6. 183018401850186018701880189019001910192019301940195019601970198019902000 Description of Railway Injuries-UK Lancet-Railway injury without physical trauma DaCostas Syndrome (US)- Soldiers Heart, nervousness and startle, cardiovascular etiology Erichsen (UK) On Railway and Other Injuries of the Spine and Nervous System – confusion, amnesia, back pain, paralysis (related to unseen cord trauma) Charcot (Fr) “Traumatic hysteria” H. Oppenheim (Ger) “Traumatic neurosis” Freud Studies in Hysteria – developed seduction theory, then quickly abandoned it. Struggles over “pension neurosis” (Ger) Great War – “shell shock” (UK) – mental symptoms from impact of shells (i.e. physical); “war neurosis” “combat hysteria” repressed wish to run from the battlefield (Freud); implied weakness of character; defeat of “traumatic neurosis” in Europe; compensation in US Rise of psychoanalysis in the US, emphasizes fantasy over reality (e.g. trauma) WWII- Gross Stress Reaction in soldiers (US) (similar to hysteria) Rise of biological psychiatry in US lays foundation for viewing a physical role in the development of symptoms whose etiology is emotional trauma DSMIII – PTSD – central role of trauma emphasized (US) – VN veterans only Biological research in PTSD, popular acknowledgement of both VN combat & child sexual trauma (US) Backlash of “false memory” movement

7. Epidemiology of Abuse 17,337 HMO members studied by CDC & Kaiser Permanente (Anda, Giles et al) Adverse Childhood Experiences (ACE) based on 8 categories derived from questionnaire: Emotional, physical and sexual abuse, household dysfunction, substance abuse, mental Illness, mother treated violently, incarcerated household member, parental separation or divorce Number of adverse childhood experiences (ACE Score): 0=36%, 1=26%, 2=15%, 3=9%, = 4=12%

8. Number of Adverse Childhood Events Increases Risk for Other Problems

9. Number of Adverse Childhood Events Increases Risky & Violent Behavior

10. Effects of Stress on Physical Health Neurological and Cognitive: Hippocampal atrophy with associated deficits in verbal declarative memory (new Leaning and memory) Endocrine: Increased cortisol and HPA axis, increased catecholamines (norepinephrine and epinephrine) Metabolic: insulin resistance, ?fat deposition around hips Cardiovascular: ? heart disease, ? lipid levels, ?atherosclerosis Cancer Impaired immunity Psychiatric disorders

11. PTSD: Risk Factors Vietnam combat veterans with childhood abuse had 4-fold increased relative risk of PTSD (Bremner et al 1992) Most significant factor after adjusting for level of combat exposure, months in Vietnam, participation in atrocities Other risk factors: years of education, prior psychiatric illness, young age Twin studies: ~12% genetic

12. What is Borderline Personality Disorder? 80% have early abuse More common in women Sense of emptiness, fears of abandonment Self destructive behavior: cutting, risk taking Destructive relationships

13. “Self Medication” Hypothesis of Anxiety Kosten & Krystal, 1989 Substance abuse reflection of self medication for PTSD symptoms Opiates, benzodiazepines and alcohol decrease activity of the locus coeruleus Decreased NE activity leads to decreased symptoms Opposite: Withdrawal leads to increased LC activity, increased symptoms

14. PTSD and Alcohol Co-Morbidity Women with abuse-related PTSD have a 28% history of past alcohol abuse/dependence versus 14% in non-PTSD women based on nationwide samples (Kessler et al 1995) 65% of patients with combat-related PTSD had lifetime history of alcohol abuse/dependence versus 35% in dizygotic twin brothers (Bremner et al unpublished).

15. Longitudinal Course of Substance Abuse After Trauma Exposure

16. Stress and Psychopathology

17. Functional Neuroanatomy of Traumatic Stress

18. Functional Neuroanatomy of Trauma Spectrum Disorders

20. Stress Results in Decreased Hippocampal Neurogenesis

21. Antidepressant Treatments Promote Hippocampal Neurogenesis

24. Hippocampal Volume Reduction in Childhood Abuse-related PTSD

25. Hippocampal Volume Reduction in PTSD NORMAL PTSD

26. Smaller Hippocampal Volume in Women with Childhood Abuse and Depression

27. Hypothalamic-pituitary-adrenal Axis and Stress

28. Effects of Stress on HPAA and Hippocampus-Preclinical Studies Stress-induced lesions of the hippocampus result in a removal of inhibition of CRF release from the hypothalamus Increased CRF Blunted ACTH response to CRF challenge Increased Cortisol in the periphery Resistance to negative feedback of dexamethasone

29. Study Aims-Abuse-related PTSD Women with sexual abuse before 13 Assess hippocampal structure with MRI Assess hippocampal function with PET in conjunction with paragraph encoding declarative memory task Assess hypothalamic-pituitary-adrenal axis function at baseline and with stressful challenge

30. Early Trauma Inventory: Psychometric Properties High level of inter-rater agreement: ICC=.99; p<.0001 High level of agreement on test-retest: r=.91; p<.001 High level of internal consistency: Cronbach alpha=.95 (items are measuring same construct) High item total correlations for most items (r=.5-.78) in physical, emotional and sexual domains Construct validity shown by correlation with other trauma measure (CLTE): r=.63; p<.05, and PTSD measure (Civilian Mississippi Scale): r=.78; p<.01 Sensitive to discriminate PTSD vs other dx

31. Diurnal Cortisol Levels In Women With Childhood Sexual Abuse-Related PTSD

34. Increased Cortisol Response To Stressors In PTSD

35. Increased Cortisol Response To Trauma-Specific Stress in PTSD

36. Dehydroepiandrosterone (DHEA) and Stress DHEA released during stress DHEA has anti-glucocorticoid effects DHEA has protective effects on the hippocampus Increased diurnal DHEA in depression Decreased DHEA with aging Mixed findings for combat PTSD-single sample

37. Elevated DHEA-S in Women with Childhood Abuse-related PTSD

38. Failure of Extinction in PTSD Pairing of light and shock leads to fear responses to light alone With exposure to light alone there is a gradual decrease in fear responding (“extinction to fear”) Reexposure to light-shock at later time point results in rapid return of fear responding Medial prefrontal cortical inhibition of amygdala represents neural mechanism of extinction to fear responding This brain area mediates emotion (Phineas Gage)

39. Medial Prefrontal Cortical Dysfunction with Traumatic Memories in PTSD

40. Neural Correlates of Traumatic Reminders in Women with Childhood Sexual Abuse-related PTSD 22 med. free women with early childhood sexual abuse with and without PTSD Subjects/ staff prepared personalized script of traumatic childhood sexual abuse event 30 mCi O15 water injected during reading of traumatic scripts followed by positron emission tomography (PET) imaging Brain blood flow during 2 traumatic scripts compared to 2 neutral scripts

41. Decreased Blood Flow during Memories of Abuse in Women with Childhood Sexual Abuse-related PTSD

42. Decreased Blood Flow During Recall of Emotionally Valenced Words in Abuse-related PTSD

43. Decreased Blood Flow with Emotional Stroop in Abused Women with and without PTSD

44. Increased Blood Flow with Fear Acquisition versus Control in Abuse-related PTSD

45. Glucocorticoids

46. Effects of Paroxetine on Hippocampal-based Verbal Declarative Memory in PTSD

47. Increased Hippocampal Volume with Paxil in PTSD

48. Decreased Cortisol Response to Stress Following Paroxetine Treatment in PTSD