Deep Brain Stimulation for Treatment Resistant Depression: Neuropsychological Impact

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Deep Brain Stimulation for Treatment Resistant
DepressionNeuropsychological Impact

• Heather McNeely, Ph.D., C.Psych.
• Clinical Neuropsychologist
• St. Josephs Healthcare, Hamilton
• Associate Professor
• Department of Psychiatry Behavioural
  Neurosciences McMaster University
• Assistant Professor
• Department of Psychiatry, University of Toronto

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Todays Objectives

• To become familiar with
• Deep Brain Stimulation (DBS)
• Use of DBS for treatment resistant depression
  (TRD)
• Neuropsychological impact of DBS

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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

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What is DBS used for?

• Approved as a treatment for
• Parkinsons Disease
• Essential Tremor
• Dystonia
• Investigational use in
• Major Depressive Disorder (MDD)
• Obsessive Compulsive Disorder (OCD)
• Tourette Syndrome
• Phantom Limb Pain
• And others

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

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Why Include Neuropsychology in DBS Treatment
Protocol?
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Neuropsychology of DBS for Parkinsons 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
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Neuropsychological Assessment

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

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Testing Protocol
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Repeated Testing

• Frontal / Executive Functions
• Information Processing Speed
• Learning and Memory
• Manual Motor Skills
• Emotional Processing

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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

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Wisconsin Card Sorting Test
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Object Alternation Task
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Iowa Gambling Task
A
B
C
D
WIN 250 LOSE 1000
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Phonemic Fluency
F
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Stroop Colour Word Tests
Standard
Emotional
RED BLUE GREEN
SAD LONELY STUPID
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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

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IAPS Sad
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IAPS Happy
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IAPS Fear
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IAPS Neutral
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IAPS Ratings
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Participant Requirements

• Inclusion Criteria
• Recurrent MDD current episode gt 12 months
• Resistant to at least four adequate treatment
  trials
• Hamilton Rating Scale for Depression (HDRS-17)
  score gt 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

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Patient Demographics
Kennedy, Rizvi, McNeely, Giacobbe, Mayberg
Lozano (2009)
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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
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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
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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
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Change in Mood
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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

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Changes in Frontal Lobe Function

• Over 12 Months of Chronic Cg25 DBS

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Wisconsin Card Sorting Test
Perseverative Errors
Non-perseverative Errors
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Object Alternation
TRD Patients
Frontal Lobe Patients
Compared to a sample of patients with
orbital-frontal damage (Friedman et al., 1998)
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Iowa Gambling Task
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Phonemic Verbal Fluency
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Stroop Colour Word
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Emotional Stroop
Neutral
Negative
Positive
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Information Processing Speed
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Verbal Memory
Learning
Delayed Recall
Recognition
Note 4 alternate forms of HVLT used
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Finger Tapping
Dominant Hand
Nondominant Hand
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IAPS Valence Ratings
Note TRD group compared to mean control data
from Lang et al., 1999
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IAPS Arousal Ratings
Neutral Positive Sad Fear
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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
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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

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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

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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

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Thank you for your attention!