Deep Brain Stimulation for Treatment Resistant Depression: Neuropsychological Impact
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Transcript of Deep Brain Stimulation for Treatment Resistant Depression: Neuropsychological Impact
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Deep Brain Stimulation for
Treatment Resistant Depression:
Neuropsychological ImpactHeather McNeely, Ph.D., C.Psych.Clinical Neuropsychologist
St. Joseph’s Healthcare, Hamilton
Associate ProfessorDepartment of Psychiatry & Behavioural Neurosciences
McMaster University
Assistant ProfessorDepartment of Psychiatry, University of Toronto
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Today’s 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?
• Micro-electrodes implanted in the brain
• Connected to a pulse generator
• Individually calibrated to optimal stimulation parameters
• Chronic, high frequency electrical stimulation targeted to specific brain regions
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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
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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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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
Choosing a target for DBS in TRD
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Limbic-Frontal Network
Mood
Vegetative-Somatic
mb-p
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 Parkinson’s Disease
Unilateral DBS to subthalamic nucleus (STN) or
globus pallidus interna (GPi) leads to:Improvements in motor symptoms
BUT:Mild frontal cognitive declineUp to 10% of patients exhibit severe cognitive
and psychiatric consequences
Funkiewiez et al., 2004, J Neurol Neurosurg; Funkiewiez et al., 2006, Mov DisordPillon 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
Baseline:Psychiatric
MedicalFull Neuropsych
MRI
3 MonthsPsychiatric
Part NeuropsychPET
6 MonthsPsychiatric
Part NeuropsychPET
12 MonthsPsychiatric
Full NeuropsychPET
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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
RED
BLUE
GREEN
Standard
SAD
LONELY
STUPID
Emotional
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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 > 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
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Patient DemographicsAll Male Female
Gender 20 9 11Current Age (yrs) 47.4 49.6 45.3Age at MDD onset (yrs) 27.1 24.4 29.2Current Episode (yrs) 6.9 6.8 7#Lifetime Episodes 3.9 3.6 4.1Received ECT 17 8 9Received Psychotherapy 20 9 11Family History MDD +ve 14 6 8Melancholic subtype 13 7 6Atypical subtype 7 2 5Baseline HDRS 24.3 24.3 24.3Baseline SF36 27.4 25.3 28.4Years of Education 15.4 15.2 15.5NART Estimated IQ 110.9 111 110.7
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
Mayberg et al, 2005
- Lead placement confirmed by post-op MRI
- Optimization of stimulation over 5 days in hospital
- 4 week adjustment period
- 12 months of chronic DBS
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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
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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
0
10
20
30
40
50
60
70
Baseline 3 Months 6 Months 12 Months
Test Time
T S
core
Perseverative Errors
Non-perseverativeErrors
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Object Alternation
0
5
10
15
20
25
30
35
40
45
50
Baseline 3 Months 6 Months 12 Months
Test Time
To
tal
Err
ors
Compared to a sample of patients with orbital-frontal damage (Friedman et al., 1998)
Frontal LobePatients
TRD Patients
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Iowa Gambling Task
38
40
42
44
46
48
50
52
54
Baseline 3 months 6 months 12 months
Test Time
To
tal
"Ris
ky"
Ch
oic
es
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Phonemic Verbal Fluency
44
46
48
50
52
54
56
58
60
Baseline 3 Months 6 Months 12 Months
Test Time
T S
core
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Stroop Colour Word
40
42
44
46
48
50
52
Baseline 3 Months 6 Months 12 Months
Test Time
T S
core
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Emotional Stroop
0
10
20
30
40
50
60
70
Baseline 3 Months 6 Months 12 Months
Test Time
Nu
mb
er I
tem
s R
ead
Neutral
Negative
Positive
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Information Processing Speed
0
10
20
30
40
50
60
Baseline 3 Months 6 Months 12 Months
Test Time
T S
core
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Verbal Memory
0
10
20
30
40
50
60
Baseline 3 Months 6 Months 12 Months
Test Time
T S
core
Learning
Delayed Recall
Recognition
Note: 4 alternate forms of HVLT used
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Finger Tapping
0
10
20
30
40
50
60
Baseline 3 Months 6 Months 12 Months
Test Time
T S
core
Dominant Hand
NondominantHand
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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?
Model Summary
Model R R Square Adjusted R
Square
Std. Error of the
Estimate
1 .844a .712 .552 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
ANOVAa
Model Sum of Squares df Mean Square F Sig.
1
Regression 412.996 5 82.599 4.451 .026b
Residual 167.004 9 18.556
Total 580.000 14
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 arousalIAPS happy valence
Over 55% of variance in mood response predicted above chance
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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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AcknowledgementsOriginal 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!