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 Today’s Objectives To become familiar with: • Deep Brain Stimulation (DBS) • Use of DBS for treatment resistant depression (TRD) • Neuropsychological impact of DBS 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 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 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 Choosing a target for DBS in TRD Evidence from PET studies has shown: • The subgenual anterior cingulate (Cg25) is overactivated 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 Limbic-Frontal Network Mood mb-p Vegetative-Somatic Mayberg, 1997 Hypotheses • 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 Why Include Neuropsychology in DBS Treatment Protocol? 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 Neuropsychological Assessment – Pre-operative screening – Monitor unexpected events – Evaluate functional outcomes – Ensure cognitive safety – Research purposes Testing Protocol Baseline: Psychiatric Medical Full Neuropsych MRI 3 Months Psychiatric Part Neuropsych PET 6 Months Psychiatric Part Neuropsych PET 12 Months Psychiatric Full Neuropsych PET Repeated Testing • • • • • Frontal / Executive Functions Information Processing Speed Learning and Memory Manual Motor Skills Emotional Processing 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 Wisconsin Card Sorting Test Object Alternation Task Iowa Gambling Task A B C D WIN $250 LOSE $1000 Phonemic Fluency F Stroop Colour Word Tests Standard Emotional RED SAD BLUE LONELY GREEN STUPID 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 IAPS “Sad” IAPS “Happy” IAPS “Fear” IAPS “Neutral” IAPS Ratings 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 Patient Demographics Gender Current Age (yrs) Age at MDD onset (yrs) Current Episode (yrs) #Lifetime Episodes Received ECT Received Psychotherapy Family History MDD +ve Melancholic subtype Atypical subtype Baseline HDRS Baseline SF36 Years of Education NART Estimated IQ All 20 47.4 27.1 6.9 3.9 17 20 14 13 7 24.3 27.4 15.4 110.9 Male 9 49.6 24.4 6.8 3.6 8 9 6 7 2 24.3 25.3 15.2 111 Female 11 45.3 29.2 7 4.1 9 11 8 6 5 24.3 28.4 15.5 110.7 Kennedy, Rizvi, McNeely, Giacobbe, Mayberg & Lozano (2009) 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 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 Treatment Results • Treatment Response • Defined as a 50% reduction in baseline HRSD score • 60 % of patients attained response Baseline 6 Months Kennedy et al; 2009; Lozano et al., 2008; Mayberg et al; 2005 Change in Mood 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 Changes in Frontal Lobe Function Over 12 Months of Chronic Cg25 DBS Wisconsin Card Sorting Test 70 60 T Score 50 40 Perseverative Errors 30 20 Non-perseverative Errors 10 0 Baseline 3 Months 6 Months Test Time 12 Months Object Alternation 50 45 40 Total Errors 35 30 25 20 15 10 TRD Patients 5 0 Baseline 3 Months 6 Months Test Time 12 Months Frontal Lobe Patients Compared to a sample of patients with orbital-frontal damage (Friedman et al., 1998) Iowa Gambling Task 54 Total "Risky" Choices 52 50 48 46 44 42 40 38 Baseline 3 months 6 months Test Time 12 months Phonemic Verbal Fluency 60 58 56 T Score 54 52 50 48 46 44 Baseline 3 Months 6 Months Test Time 12 Months Stroop Colour Word 52 50 T Score 48 46 44 42 40 Baseline 3 Months 6 Months Test Time 12 Months Emotional Stroop 70 Number Items Read 60 50 40 30 Neutral 20 Negative 10 Positive 0 Baseline 3 Months 6 Months Test Time 12 Months Information Processing Speed 60 50 T Score 40 30 20 10 0 Baseline 3 Months 6 Months Test Time 12 Months Verbal Memory 60 50 T Score 40 30 Learning 20 Delayed Recall Recognition 10 0 Baseline 3 Months 6 Months 12 Months Test Time Note: 4 alternate forms of HVLT used Finger Tapping 60 50 T Score 40 30 20 Dominant Hand 10 Nondominant Hand 0 Baseline 3 Months 6 Months Test Time 12 Months IAPS Valence Ratings Note: TRD group compared to mean control data from Lang et al., 1999 IAPS Arousal Ratings Neutral Positive Sad Fear Can baseline emotional reactivity predict DBS response? Model Summary Model R 1 .844 R Square a Adjusted R Std. Error of the Square Estimate .712 .552 Over 55% of variance in mood response predicted above chance 4.30767 a. Predictors: (Constant), baseline; positive; mean valence, baseline; sad; mean arousal, Negative interference: neutral-negative, baseline; positive; mean arousal, baseline; sad; mean valence a ANOVA Model Sum of Squares df Mean Square Regression 412.996 5 82.599 Residual 167.004 9 18.556 Total 580.000 14 F 4.451 Sig. .026 1 a. Dependent Variable: HRSD 2-1 b. Predictors: (Constant), baseline; positive; mean valence, baseline; sad; mean arousal, Negative interference: neutral-negative, baseline; positive; mean arousal, baseline; sad; mean valence b Significant predictors: IAPS sad valence IAPS sad arousal IAPS happy valence 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 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 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 Thank you for your attention!