1. Richard K. Nakamura, Ph.D. Deputy Director National Institute of Mental Health The Future of Behavioral Science: One Perspective Merrill Phoenix March 2007

2. Who moved the cheese??

3. Why do we have such a hard time convincing the public, Congress and other scientists about the need for behavioral science?

4. Everyone has a theory of behavior…..

5. The science of behavior is the new “rocket science”. It is moving very quickly and is very exciting but disciplines such as psychology and psychiatry must change or they are in danger of becoming obsolete.

6. Plasticity One Word

7. The changing science of behavior The modern integration of : Brain/Behavior Mind/Brain Nature/Nurture Genes/Environment

8. We now understand that our genes specify a general plan with many options. Our brain changes its physical structure through behavior and interactions with the environment. The brain is the substrate of our thoughts and behavior. We now understand that our genes specify a general plan with many options. Our brain changes its physical structure through behavior and interactions with the environment. The brain is the substrate of our thoughts and behavior. Genes, the Brain, and Behavior and Behavior

9. Genes: multiple susceptibility alleles each of small effect Cells: subtle molecular abnormalities Systems: abnormal information processing Behavior: complex functional interactions and emergent phenomena Schizophrenia Autism Mood Disorders Anxiety Disorders ADHD temperament Cognition, emotion, behavior

10. The brain is the substrate of our thoughts and behavior.

11. Genes guide the general structure of the brain throughout our lives

12. The physical structure of our brain changes under the influence of our behavior and the environment.

13. Neurogenesis in the Adult Human I II Source: Eriksson et al., 1999

14. Source: van Praag et al., 1999 Physical Activity & Neurogenesis

15. Stress Impairs Neurogenesis Gould 2000 400 300 200 100 0 BrdU Labeled Cells/mm 3 ControlStress Dentate Gyrus, Marmoset Monkey 4000 3000 2000 1000 0 BrdU Labeled Cells DominantSubordinate p<.05 * * Gould 1998 Dentate Gyrus, Adult Rat p<.05

16. Voluntary Exercise leads to increase in the number of BrdU- positive cells 24 hours post-BrdU injection and environmental enrichment leads to no change at this time point Olson, AK et al. Hippocampus. 2006;16(3):250-60

17. The percentage of BrdU-positive cells remaining at 4 weeks Olson, AK et al. Hippocampus. 2006;16(3):250-60

18. Prairie Vole (Microtus ochrogaster) Highly socialAsocial Montane Vole (Microtus montanus) Biparental Minimally Parental Pair bondsPromiscuous Sep. Distress- HighSep. Distress - Low

19. Prairie (and Pine) vole microsatellite insert in the V1a receptor promoter. Prairie Montane +1 Prairie Meadow Pine Montane 600 170.......(GACA) 8.......(AC) 4....(AC) 4.....(AG) 5....(CATA) 9.....(GA) 13.....

20. But the environment and behavior changes gene activity

22. Maternal licking and grooming changes the brain permanently Source: Meaney and Szyf, Trends in Neuroscience, September 2005

23. By changing gene activity permanently Source: Meaney and Szyf, Trends in Neuroscience, September 2005

24. Environmental enrichment changes the brain also Source: Bredy et al. European Journal of Neuroscience, July 2004

25. Understanding Mental Illness

26. Weissman, M. M. et al. JAMA 2006;295:1389-1398. Relation Between Maternal Remission Status and Change in Child's Specific Diagnoses (Baseline to 3 Months)

28. Disaster

30. Medial Prefrontal cortex can modulate fear expression via projections to the amygdala LA B Ce Amygdala Fear mPFC

31. Shin et al., Biological Psychiatry, 2001 Evidence in Humans: PTSD Patients Fail to Show mPFC Activation When Exposed to Traumatic Reminders

32. Non-PTSD

33. PTSD

34. Depression

35. Science, 302: 386-388, 2003

36. Among those who had 4+ episodes of life stress; 33% of “s” genotype developed MDD vs. 17% of those with “l” type genotype Genotype Interacts with Stress to Increase Risk of Depression

39. SSRI  Cg25 Placebo TMS ECT NoblerGeorge Mayberg Critical Role of Cg25 in Depression: Converging Evidence hc Am Cg25 nl: SERT s/s< l/l Pezawas Structural Changes Dep:  volume;  glia Drevets, Ongur, Rajkowska

40. X X Microelectrode mapping Insertion bilateral electrodes (Medtronic 3387) Turn on the devices/program (acute, chronic stimulation) Local anaesthesia Leksell frame MRI Targeting Cg25WM DBS Procedure

41. Acute Intra-operative Stimulation Effects Contact and voltage specific Spontaneous Self-Reports Sense of intense calm, quiet, relief Dissipation of visceral symptoms resolution of the ‘pain,’ dread, void, mental heaviness Followed within 15-20 seconds by  interest, energy, personal connectedness  attention, motor speed, spontaneous speech  visual perception; colors, clarity, brightness, details  PANAS:  positive;  negative scores Adverse Effects No autonomic, motor, overt mood changes Mental slowness at top contacts near cc. Awareness of a sudden shift from an all-consuming internal focus to the realization there are other things around to do… Cg25, Insula, Hth? nAcc, mF, PF? Not am, bs, ins

42. Wk 0Wk 1Wk 2Wk 12Wk 26 Mean HAMD17 Scores* 24.9 +2.9 14.2 +5.416.5 +7.013.6 +5.211.9 +4.1 Men (n=8) 24.0 +2.8 14.0 +4.216.0 +6.9513.5 +2.112.6 +3.96 Women (n=4) 26.8 +2.6 14.5 +7.817.7 +8.513.8 +9.411.8 +5.1 No significant differences between Men and Women *All time points significant different from Wk 0; p<0.05; 8/12 R (66%) 7 pts at 1 yr: 5/7 R (71%) 3/7 Remitters (42%) Change in Depression Scores

43. Patient 5: 2 months of Stimulation “ the most fundamental change that I can see, is that it isn’t like something has been added—no, something has been taken away. That heavy sinking vortex feelings was always there in some form or another. And now it is gone. (acute primary change at target?) It is as if instead of being in the grand canyon, you are now up on a ledge, no longer in a pit. You look around, and you know it is still 800 feet to where I want to be, but you are not in a hole anymore. Now it comes down to you. (new learning, plasticity, rehabilitation?) Patient’s Perception of DBS Effects

44. Ketamine Non-barbiturate, rapid- acting disassociate anesthetic Non-competitive NMDA receptor antagonist –Slow blocking kinetics of open channel Psychotomimetic properties (5-20%) Abused as “ club drug ” Studied in: schizophrenia, cognition, alcoholism, chronic pain syndrome, and neuroprotection

45. Response Rates to Ketamine in a Double-Blind Placebo Crossover Trial in Patients with Treatment-Resistant Major Depression (N=18) 40 m 80 m 110 m 230 m 1 d 2 d 3 d 13 % 35 % 53 % 56 % 71 % 58 % 53 % Venlafaxin e SSRI Ketamine Bupropion Response: 50% decrease in HAMD from baseline 35 % Placebo 7 d **Thase et al. J Clin Psychiatry 2005;66:974-81 8 Wk ***62- 65% Historical Control Zarate et al. Arch Gen Psychiatry 2006;63:856-64.

46. PF9 thal bg Cg25 P40 hippocampus hth bs a-ins am Summary: Modulation of Common ‘System’ Treatment-Specific Effects drug - - pCg CBT attention-cognition vegetative-circadian mood state mF9/10 oF11 aCg24 SRI only CBT SRI inverse CBT only Emotion- cognition integration

47. Aaron T. Beck, MD

48. We need a science of behavior which is an integrative and inclusive science

49. Change happens Change is happening faster Change creates opportunity

50. www.nimh.nih.gov Research = Hope