Post on 01-Feb-2016
description
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
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?
• 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
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
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
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 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
Neuropsychological Assessment
– Pre-operative screening
– Monitor unexpected events
– Evaluate functional outcomes
– Ensure cognitive safety
– Research purposes
Testing Protocol
Baseline:Psychiatric
MedicalFull Neuropsych
MRI
3 MonthsPsychiatric
Part NeuropsychPET
6 MonthsPsychiatric
Part NeuropsychPET
12 MonthsPsychiatric
Full NeuropsychPET
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
RED
BLUE
GREEN
Standard
SAD
LONELY
STUPID
Emotional
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 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)
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
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
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
0
10
20
30
40
50
60
70
Baseline 3 Months 6 Months 12 Months
Test Time
T S
core
Perseverative Errors
Non-perseverativeErrors
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
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
Phonemic Verbal Fluency
44
46
48
50
52
54
56
58
60
Baseline 3 Months 6 Months 12 Months
Test Time
T S
core
Stroop Colour Word
40
42
44
46
48
50
52
Baseline 3 Months 6 Months 12 Months
Test Time
T S
core
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
Information Processing Speed
0
10
20
30
40
50
60
Baseline 3 Months 6 Months 12 Months
Test Time
T S
core
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
Finger Tapping
0
10
20
30
40
50
60
Baseline 3 Months 6 Months 12 Months
Test Time
T S
core
Dominant Hand
NondominantHand
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 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
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
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
Thank you for your attention!