Download Deep Brain Stimulation for Treatment Resistant Depression

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!