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 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

Limbic-Frontal Network

Mood Vegetative-Somatic mb-p

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 C D A B

WIN $250 LOSE $1000

Phonemic Fluency

F

Stroop Colour Word Tests Standard RED Emotional SAD BLUE GREEN LONELY 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 50 40 30 20 10 0 Perseverative Errors Non-perseverative Errors Baseline 3 Months

Test Time

6 Months 12 Months

25 20 15 10 5 0 50 45 40 35 30 Baseline Object Alternation 3 Months 6 Months

Test Time

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

46 44 42 40 38 54 52 50 48 Iowa Gambling Task Baseline 3 months

Test Time

6 months 12 months

Phonemic Verbal Fluency 60 58 56 54 52 50 48 46 44 Baseline 3 Months

Test Time

6 Months 12 Months

Stroop Colour Word 52 50 48 46 44 42 40 Baseline 3 Months

Test Time

6 Months 12 Months

30 20 10 0 70 60 50 40 Baseline Emotional Stroop 3 Months

Test Time

6 Months 12 Months Neutral Negative Positive

Information Processing Speed 60 50 40 30 20 10 0 Baseline 3 Months

Test Time

6 Months 12 Months

60 50 40 30 20 10 0 Baseline Verbal Memory 3 Months 6 Months

Test Time

12 Months Learning Delayed Recall Recognition Note: 4 alternate forms of HVLT used

30 20 10 0 60 50 40 Baseline Finger Tapping 3 Months

Test Time

6 Months 12 Months Dominant Hand Nondominant Hand

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 R .844

a

Model Summary

R Square .712 Adjusted R Square .552 Std. Error of the Estimate 4.30767 1 a. Predictors: (Constant), baseline; positive; mean valence, baseline; sad; mean arousal, Negative interference: neutral-negative, baseline; positive; mean arousal, baseline; sad; mean valence Over 55% of variance in mood response predicted above chance Model 1 Regression Residual Total Sum of Squares

ANOVA a

df 412.996 167.004 5 9 580.000 14 Mean Square 82.599 18.556 F 4.451 Sig. .026

b 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

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!