Deep Brain Stimulation for Treatment Resistant Depression: Neuropsychological Impact

1. Deep Brain Stimulation for Treatment Resistant Depression:Neuropsychological Impact Heather McNeely, Ph.D., C.Psych. Clinical Neuropsychologist St. Joseph’s Healthcare, Hamilton Associate Professor Department of Psychiatry & Behavioural Neurosciences McMaster University Assistant Professor Department of Psychiatry, University of Toronto

2. Today’s Objectives To become familiar with: • Deep Brain Stimulation (DBS) • Use of DBS for treatment resistant depression (TRD) • Neuropsychological impact of DBS

3. What is DBS? • Chronic, high frequency electrical stimulation targeted to specific brain regions • Micro-electrodes implanted in the brain • Connected to a pulse generator • Individually calibrated to optimal stimulation parameters

4. What is DBS used for? • Approved as a treatment for: • Parkinson’s Disease • Essential Tremor • Dystonia • Investigational use in: • Major Depressive Disorder (MDD) • Obsessive Compulsive Disorder (OCD) • Tourette Syndrome • Phantom Limb Pain • And others

5. Treatment Resistant Depression (TRD) • MDD impacts 10 - 25% of women and 5 - 12% of men • Up to 20% of MDD patients fail to respond to standard interventions • Psychotherapy • Medications • Electroconvulsive Therapy (ECT) • TRD represents a small, but very disabled population Fava, 2003; Keller et al., 1992; Pincus & Petit, 2001

6. Choosing a target for DBS in TRD Evidence from PET studies has shown: • The subgenual anterior cingulate (Cg25) is over-activated in depression • Cg25 activity increases with induced sadness • Cg25 activity down-regulates following standard treatments • Thus directly targeting Cg25 with DBS should elicit similar responses Mayberg, 1997; Mayberg, Liotti et al., 1999; Mayberg, Brannan, et al., 2000

7. Limbic-Frontal Network Mood mb-p Vegetative-Somatic Mayberg, 1997

8. DBS to Cg25 white matter will: Decrease over-active cingulate Increase under-active frontal lobe regions Impact functional pathways linking limbic and frontal regions Leading to: Improved mood ? Improved frontal lobe cognition Hypotheses

9. Why Include Neuropsychology in DBS Treatment Protocol?

10. Neuropsychology of DBS for Parkinson’s Disease Unilateral DBS to subthalamic nucleus (STN) or globus pallidus interna (GPi) leads to: • Improvements in motor symptoms BUT: • Mild frontal cognitive decline • Up to 10% of patients exhibit severe cognitive and psychiatric consequences Funkiewiez et al., 2004, J Neurol Neurosurg; Funkiewiez et al., 2006, Mov Disord Pillon et al., 2000, Neurology; Rodriguez-Oroz, et al., 2005, Brain; Saint-Cyr et al., 2000, Brain ; Vale, 2008, Exp Biol

11. Neuropsychological Assessment • Pre-operative screening • Monitor unexpected events • Evaluate functional outcomes • Ensure cognitive safety • Research purposes

12. Testing Protocol

13. Repeated Testing • Frontal / Executive Functions • Information Processing Speed • Learning and Memory • Manual Motor Skills • Emotional Processing

14. Repeated Measures • Frontal / Executive Skills: • Wisconsin Card Sorting Test (WCST) • Object Alternation (OA) • Iowa Gambling Task (IGT) • Phonemic Verbal Fluency • Stroop Colour Word Test • Emotional Stroop Test

15. Wisconsin Card Sorting Test

16. Object Alternation Task

17. Iowa Gambling Task A B C D WIN $250 LOSE $1000

18. Phonemic Fluency F

19. Stroop Colour Word Tests Standard Emotional RED BLUE GREEN SAD LONELY STUPID

20. Repeated Measures • Emotional Processing: • International Affective Picture System Ratings • Information Processing Speed: • Word reading speed from standard Stroop • Memory: • Hopkins Verbal Learning Test-Revised • Manual Motor Skills: • Finger Tapping Test

21. IAPS “Sad”

22. IAPS “Happy”

23. IAPS “Fear”

24. IAPS “Neutral”

25. IAPS Ratings

26. Participant Requirements • Inclusion Criteria: • Recurrent MDD: current episode > 12 months • Resistant to at least four adequate treatment trials • Hamilton Rating Scale for Depression (HDRS-17) score > 20 • Age 30 to 50 years (later extended to age 75) • Exclusion Criteria: • Other Axis I disorders • Alcohol or substance abuse/dependence within 12 months • Active suicidal ideation • Major medical illness, other implanted stimulator

27. Patient Demographics Kennedy, Rizvi, McNeely, Giacobbe, Mayberg & Lozano (2009)

28. DBS Methods • Surgical Implantation & Stimulation • 4 electrodes per side • Implanted in Cg25 white matter bilaterally • Under local anesthesia • Using MRI guidance Mayberg et al, 2005

29. DBS Methods • Lead placement confirmed by post-op MRI • Optimization of stimulation over 5 days in hospital • 4 week adjustment period • 12 months of chronic DBS Mayberg et al, 2005

30. Treatment Results • Treatment Response • Defined as a 50% reduction in baseline HRSD score • 60 % of patients attained response 6 Months Baseline Kennedy et al; 2009; Lozano et al., 2008; Mayberg et al; 2005

31. Change in Mood

32. Neuropsychology Results • Baseline: • Patients scored in the average to high average range of general intellect (IQ) • Intact functioning on tests of: • Language • Simple attention • Visual spatial skills

33. Changes in Frontal Lobe Function Over 12 Months of Chronic Cg25 DBS

34. Wisconsin Card Sorting Test Perseverative Errors Non-perseverative Errors

35. Object Alternation TRD Patients Frontal Lobe Patients Compared to a sample of patients with orbital-frontal damage (Friedman et al., 1998)

36. Iowa Gambling Task

37. Phonemic Verbal Fluency

38. Stroop Colour Word

39. Emotional Stroop Neutral Negative Positive

40. Information Processing Speed

41. Verbal Memory Learning Delayed Recall Recognition Note: 4 alternate forms of HVLT used

42. Finger Tapping Dominant Hand Nondominant Hand

43. IAPS Valence Ratings Note: TRD group compared to mean control data from Lang et al., 1999

44. IAPS Arousal Ratings Neutral Positive Sad Fear

45. Can baseline emotional reactivity predict DBS response? Over 55% of variance in mood response predicted above chance Significant predictors: IAPS sad valence IAPS sad arousal IAPS happy valence

46. Summary of Findings Following Cg25 DBS in treatment resistant depression: • Cg25 activity went down • Frontal lobe activity went up • 60% of patients achieved clinical response

47. Summary of Findings • No consistent cognitive declines • Subtle cognitive improvements on some measures of frontal lobe function • Not secondary to mood benefits alone • Cg25 DBS appears effective and safe • Emotional reactivity at baseline may be predictive of treatment response

48. Acknowledgements Original TRD Study Investigators • Dr. Helen Mayberg • Dr. Andres Lozano • Dr. Sidney Kennedy Resident / Student / RA Support • Dr. Valerie Voon • Dr. Beverley Bouffard • Ms. Sakina Rizvi • Ms. Kari Fulton • Ms. Jennifer Bryan • Ms. Sarah Uzzaman • Ms. Pushpinder Saini • Ms. Jessica Hurdelbrink • Ms. Christina Velasco National Alliance for Research on Schizophrenia and Affective Disorders

49. Thank you for your attention!