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!