2. Psychophysiological Approach to Assessing Startle Response Conditioning and Extinction Tanja Jovanovic, PhD Grady Trauma Project Dept of Psychiatry & Behavioral Sciences, Emory University University of Southern California Technology and Innovation for the Prevention & Treatment of PTSD October 31, 2012

3. Grady Trauma Project: Risk and Resiliency www.gradytraumaproject.com PIs: Kerry Ressler, MD, PhD and Bekh Bradley, PhD

4. Exposure to multiple types of trauma is the rule rather than the exception Trauma Exposures Often Include Childhood Abuse and Other Types of Family Violence

5. Case example 1 (8622) T.D. is a 33 y/o AA female. From the age of six, she has sustained severe physical and emotional abuse by her father and repeated sexual abuse by her step brother. She was unwilling to talk about any of her traumas, but has significant symptoms of PTSD. She is also drinking about a 6 pack a day and is currently using cocaine. She has no close relationships with any of her family members. She has no friends, no hobbies, nor is she interested in leaving the house. Her current boyfriend has been taking care of her since her last suicide attempt a few weeks ago…this was her 3rd attempt. At that point the interview was discontinued and she was taken to be evaluated by a psychiatrist.

6. Case example (8543) T.I. is a 25 y/o AA female. Until the age of 7, she lived with her mother and father, who were addicted to crack cocaine. She witnessed a number of violent fights between her parents. At age 8 she moved in with her grandmother. But while still living with her parents, she was exposed to a lot of neighborhood violence. As a 7 y/o, she survived a shootout between neighbors and dropped to the floor in the living room, trying to protect herself and her siblings from shots that came through the windows. She met current PTSD for this trauma. She still avoids the apartment complex at which this shooting happened. Today she has a great relationship with her children’s father. She sees her mother weekly (sober for 4 years). She speaks with her father monthly (sober for 2 years), and she is still close with her grandmother. She has no history of substance abuse.

7. PTSD—The Disorder Onset determined by traumatic event, but low rates of illness relative to trauma exposure: gene X environment risk factors Heterogeneous: three major symptom clusters  Re-experiencing symptoms  Avoidance symptoms  Hyper-arousal symptoms High rates of comorbidity with depression, other anxiety disorders, substance abuse

8. GENES ENVIRONMENT TRAUMA PTSD NEUROBIOLOGICAL BIOMARKERS

9. Neurobiological Biomarker: the “Holy Grail” of psychiatry? http://www.youtube.com/watch?v=9V7zbWNznbs

10. Putative Biomarkers HPA axis  Low basal cortisol/CRH  Hyper-suppression by dexamethasone Low NPY Disrupted sleep patterns Elevated heart-rate Reduced hippocampus volume PACAP Exaggerated startle response IMPAIRED INHIBITION OF FEAR-POTENTIATED STARTLE Pubmed search of PTSD and biomarker returned 136 articles Pubmed search of PTSD and biomarker returned 136 articles

11. Neurobiological Biomarker Related to underlying neurobiology of the mental disorder Related to symptoms of the disorder Provide an objective measure of psychopathology Possible to model in preclinical studies— translational approach

12. FEAR-POTENTIATED STARTLE Biomarker:

13. Fear-potentiated startle: a laboratory measure of Fear

14. http://cdmrp.army.mil/pubs/video/prm/norrholm_video.shtml

15. Conditional Discrimination: AX+/BX- Acquisition: 3 blocks of 4 trials

16. Conditional Discrimination: AX+/BX- Acquisition: 3 blocks of 4 trialsTest: 3 trials

17. AX+/BX- in healthy volunteers Jovanovic et al. (2005) Biological Psychiatry

18. AX+/BX- in healthy volunteers * Jovanovic et al. (2005) Biological Psychiatry

19. * * AX+/BX- in healthy volunteers

20. Combat PTSD: Vietnam veterans Jovanovic et al. (2009) Psychiatry Research p<0.05 p<0.01 p<0.05

21. Civilian PTSD: Grady trauma Jovanovic et al. (2010) PNEC p<0.05 p<0.01

22. Combat PTSD vs. Acute Stress in Croatian sample Jovanovic et al. (in press) Depression & Anxiety p=0.001

23. Cognitive inhibition is normal in all groups p<0.001

24. Simple Discrimination: A+/B- Acquisition: 3 blocks of 4 trials CS+ danger signalCS- safety signal

25. p<0.001 Cognitive discrimination between CS+ and CS- CONTROL

26. p<0.001 Cognitive discrimination between CS+ and CS- CONTROLPTSD

27. p<0.001 Startle discrimination between CS+ and CS- CONTROL

28. p<0.001 Startle discrimination between CS+ and CS- p=0.06 CONTROLPTSD p<0.05 p<0.01

29. Correlation between startle to CS+ and CS- and PTSD symptoms Glover et al (2011) Depression & Anxiety DANGER SAFETY

30. CS+ EXPOSURE THERAPY:TRAUMA: LEVEL OF FEAR INTRUSIVE MEMORIES NUMBER OF EXTINCTION TRIALS NUMBER OF THERAPY SESSIONS COMBAT Fear Extinction

31. Extinction: A-/B- 10 min. after Acquisition Extinction: 6 blocks of 4 trials CS- safety signal CS+ danger signal— nonreinforced

32. Extinction in trauma controls

33. p<0.01 Extinction is deficient in PTSD p<0.01 Norrholm et al (2011) Biol Psychiatry

34. Fear inhibition is impaired in PTSD PTSD is associated with impaired fear inhibition using 3 fear-potentiated startle paradigms Impaired fear inhibition is a biomarker of PTSD in different trauma populations

35. Neurobiology of Fear Responses Amygdala involved in expression of fear responses— Fear Acquisition Prefrontal cortex involved in inhibiting amygdala activity— Fear Inhibition

36. MRI Team: GTP Researchers: Ebony Glover, PhD Negar Fani, PhD Sarah Spann Kerry Ressler, MD/PhD Georgia State Collaborators: Erin Tone, PhD Emory Collaborators: Tim Ely, BA David Gutman, MD/PhD

37. PTSD<CONTROL

39. Go/No go fMRI task X

40. O

41. X

42. Contrast: No go > Go Stop>Go CONTROL>PTSD p FDRcorr =0.006 MNI coordinates: x=0, y=44, z=-8 Jovanovic, et al. (in press). Cortex.

43. Correlations with fear inhibition Jovanovic, et al. (in press). Cortex.

44. Potential applications Identify at-risk individuals for early intervention  genes related to fear inhibition (GWAS) Track treatment efficacy Treatment target  Training intervention tasks (e.g. attention bias training)  Stimulation (e.g. DBS, TMS) Developmental approach: emergence of risk phenotypes in traumatized pediatric populations

45. IS IT USEFUL? Fear Inhibition as a Biomarker:

46. Prediction of treatment outcome

47. More inhibition on transfer test Prediction of treatment outcome

48. More inhibition on transfer test 6/7 good inhibitors 9/11 poor inhibitors NON-RESP RESP p=0.005 Prediction of treatment outcome

49. Biomarkers: Neurobiological intermediate phenotypes Related to underlying neurobiology of the mental disorder Related to symptoms of the disorder Objective measure of psychopathology Possible to model in preclinical studies— translational approach

50. Acknowledgements : Emory University : Kerry J. Ressler, M.D., Ph.D. Bekh Bradley, PhD Seth D. Norrholm, Ph.D. Ebony Glover, PhD Negar Fani, PhD Tim Ely Allen Graham Angelo Brown Collaborators: Barbara Rothbaum, Ph.D. Erica Duncan, M.D. Michael Davis, Ph.D. Funding: National Institutes of Mental Health (MH071537, MH092576, MH098212), HHMI, NIH National Centers for Research Resources (M01 RR00039), Burroughs Wellcome Fund, NARSAD, EMCF, Atlanta Clinical and Translational Science Institute which is supported by the National Center for Advancing Translational Sciences of NIH (UL1TR000454).