Helen S. Mayberg, MDEmory University School of Medicine

ASENT meeting 2012

Washington DC

How Functional Brain Imaging Can Help Speed Drug Development and Clinical Trials

Depression

Grant Support: NIMH, CIHR, NARSAD, Dana Foundation, Stanley Medical Research Fund, Woodruff Fund

Off-Label Use of Devices: DBS electrodes/pulse generators 1. Medtronics Inc. (U Toronto) 2. St. Jude Medical, Inc (Emory)

Patent: US2005/0033379A1 (Andres Lozano, co-inventor) issued March 2008, St. Jude Medical Inc, assignee

Consultant: St Jude Medical Inc / Neuromodulation Division

Emory DBS study: FDA IDE: G060028 (PI: HM) Clinicaltrials.gov ID#: NCT00367003 devices for research donated by SJM

Disclosures

Imaging Wish-List: Science, Trials, Care, Dev’t

Diagnostic Markers illness subtypes (heterogeneity for clinical trials) risk identification (pre-symptomatic intervention?) response predictors (placebo, responders, nonresp, resistant) relapse, recurrence potential (Tx continuation, ID hi risk pts?)

Evidence Based Treatment Algorithms• Triage pateints for different trials• Identify placebo responders in advance of trials• tailor treatment to what the brain needs• know in advance what treatments won’t work

Needed studies circuit characterization; variability; genetic, clinical correlates define treatment specific response pathways (psychotx, drug, somatic) determine what changes are critical; early surrogates reliability, practicality of such biomarkers in individual patients

Treatments available but one size does not fit all• < 40% achieve remission (drug, CBT, other)• placebo response common in trials• > 10% become treatment resistant over time • ECT > 50-70% Remit but > 50% relapse in 6 months• rTMS 18-24% Resp in 6wks, limited efficacy in pt > 1 failed AD Tx• VNS 30% Resp at 1yr but <20% long-term Resp• ketamine (rapid effects, but unsustained)

Limits to progress, Innovation • no pathology, clinical heterogeneity, no clear biomarkers• 50 year focus on monoamines, few new leads• animal models: none capture recurrence, relapse, resistance• overinclusive, nonspecific outcome measures,

w/ all symptoms treated equally (COMPARE TO PD)

Context: Current State of Treatment Options

Biological Vulnerability

Exogenous Stressors

Mood RegulatoryCircuits

Depressiveepisode

stress

homeostasis

Phenotypes

post-natal insults early abuse life events

medical illness

genderfamily history temperament

geneticspre-natal insults

Hypothesis: Depression and the Brain

Rx EffectsCBT/PT

MedicationECT, rTMS, VNS

DBS

SubphenotypesMDD, BP

MelancholicAtypical

RecurrentTRD

RegionsConnectionsChemistry

recovery

endophenotypes

MRI volume, Glia

Drevets 97; Ongur 98 Robinson 1983

Focal Strokes

hc

Sheline, 1999

MRI volume

PF

UnipolarParkinson’s Bipolar

F9 F9F9 F9

F9 F9

P40 P40 P40 P40

aCg aCg

StructureCT, MRI,pathology

FunctionPET, fMRI

EEG

FrontalCingulateParietal

AlsoAmygdala

Basal ganglia

Mayberg 19990 Mayberg 1994, 1997 Kruger 2003

FrontalCingulate

hippocampus

PF

Defining Depression Circuits 1Identify circuit constituents

1 week fluoxetine

6 weeksfluoxetine

Similar time course to neurogenesis, BDNF ∆

Defining Depression Circuits 2Changes with well characterized treatments

p

hchc

pCg

p

Fr

vst

cg25

pCg

p

vst

hc

Cg25

p hc

ins

Fr

Cg25

Fr

vst

Mayberg et al. Biol Psychiatry 2000

Subcortical Brainstem

Limbicearly

Limbic switch

+Cortex late

Non-Responders

FluoxetineResponders

F9

Cg25

F9

hc

Cg25

hc

hchc

Cg25

pCg31F9

p

pCg31

Failure to Switch = Non-Response

Defining Depression Circuits 2bresponder-nonresponder differences

Common Changes Placebo and SSRIDrug = Placebo Plus

Placebofluoxetine

Am J Psych 159: 728-37, 2002

ActiveFluxotine

cg25

pCgCg25

Cg25

Fr9

hc

Cg25

hc

cg25p

pCg

Cg25

Fr9/46

cd p

distinguish Placebo R from Active Drug response with scans?

CommonCg25PCgFr9

AlsoHcBS

Non-responders

F9 pACC24F9

pACC(r24)

pACC(r24)

Drug responders

→

Pre-genual Anterior Cingulate 24

Common Frontal change

Baseline

Mayberg et alNeuroReport 1997

Multiple interactive Nodes More than 1 area of Cg involvedFirst clue to potential subtypes

Baseline EEG Theta R>NR to TCAPizzagalli AJP 01

rACC

Defining Depression Circuits 3Drug Resp vs Nonresponders

over-correction

absent

adaptive brainresponse

partial

underfailed

network

Trigger

activity

Depressiondiagnosis

recovery

symptomsHypothesis: recovery is optimized by matching treatment to state of

network dysregulation

meds

CBT

DBS?

ECT

A

B

D

C

Scan Type

HypothesisScan =“insult”+ongoing compensation

baseline heterogeneity defines clinical subtypes

Bad day

Mayberg, J Clin Invest 119:717, 2009

illness is failure to self-correct

Proof of PrincipleComparison drug to CBT

SSRI (paroxetine) HamD 20+3 6.7+4

Goldapple et al. Arch Gen Psych 2004

mF10/9

Cognitive Behavior TherapyHamD 22+3 6+4

mF9/10

oF11

MCCPF9PF9

P40 SCC thal

SuggestsBaseline differencesImpacting ultimate

Response to a specific Treatment

Need to know if it alsoPredicts non-response to

The alternative

Changewith

clinical response

UPD Group 1

dPF

Cg24vPF

dPF

vPF

UPD Group 2

dPF

vPF

dPF

vPF

BaselinePretreatment

Pts vs Controlscomparable

severity

Kennedy et al. Am J Psych 2001

oF11pACC24

mF9/10

PCCMCC

PF9/46 Par40PM6

sACC25

hth bstema-ins

amg mb-sn

hc

na-vst thal

SalienceMotivation

MoodstateEmotion Regulation

Self-awarenessinsight

Cognition(attention-appraisal-action)

Interoception(drive-autonomic-circadian)Mayberg, Br Med Bul 65:193-207, 2003

Is any one modeOr clinical feature

Most critical?

Mayberg, J Clin Invest 119:717, 2009

Evolution of Depression Circuit ModelTemplate to consider different treatments, common effectts

MedsPF

P

Cg25

PCC

BS

MEDS

CBT

Cg25

PF

+4z

- 4z

Depressed Patients

F9

Cg25

Cg25

Recovery w/SSRI FDG PET

R

Cg31

ins

Mayberg et al. Am J Psych 156:675-82 1999

Cg25

Transient SadnessCBF PET

Cg25Cg25

Healthy Volunteers

F9

Cg25ins

Cg31

Isolating Key Components focus on negative mood

Limbic + Cortex

Reciprocal Cingulate-Frontal

changes

SSRI SNRI

SCCactivity

Placebo

Mayberg

Critical Role of the Subcallosal Cingulate

SCCactivity

Sad Memory Tryptophan Deplete

Mayberg Talbot

Mayberg Kennedy

volume; glia

Drevets, Ongur, Rajkowska

Cortisol Correlate

Kalin

Hypothesis:TRD=dysregulated Cg25 connectivity.

Target the problem at its origin

McEwen 1994 etc

∆ Spines/Dendrites

Pardo

ECT

Nobler

rTMS

George

VNS

Pre-DBS

MaybergDougherty

pre-Cingulotomy Med NR

Greicius

SCC

Ketamine

Deakin 2009

ThalvstsCg25

hth

bs

am

Cortex

Limbic

sn

Striatal-thalamic

ins

hippocampus

F11 F10

Cg24 MCC

PF9

circadian, stress responses

drive, motivation

Cognitive control, action

PCC

sCg25

PET target

4321

mACCmF9

oF11

mF10

nAcAm/hc

Hth

rACC

Likely remote effects

Direct ‘Circuit’ Modulation using DBSblock aberrant sCg25 activity with 2° effect on connections

Focus: Treatment Resistant Depression

MRI: target localization

Toronto Proof of PrinciplePilot: 6 severe TRD, GAF<50Illness duration avg 5.6 yrsFailed mult meds, CBT, ECT6 mo open DBS4/6 Resp; 3/6 remission

Pre-op MRI

Electrode Targeting

dACC

vst

snSCC25 hth

Pre-op PET ∆ 6 months DBS

C25oF11

F10

oF11

dACC

hth

vst

C25

mF9

RespondersPts vs ControlsConfirm electrodeplacement

Post-op MRI

cc

acg

sgCg

First patient May 13, 2003 Funded by NARSAD, Toronto Western hosp

Toronto: Pilot Proof of principle

Toronto Long-term FollowupEmory Sham Controlled Trial

avg=42 mo

3-6 yrs, n=14

ITOC

Resp 62.5% 46.2% 75% 64.3% Rem 18.8% 15.4% 50% 42%

Kennedy S, et al. Am J Psych in Adv Feb 1, 2011

Lozano A, et al. Biol Psych 64:461-67, 2008

years after implantBL sham 1m 2 3 4 5 6 7 8 9 10 11 12 2y

24

18

12

6

0

BP-D/MDDN=17

HD

RS

-17

sc

ore

No changein meds for 6 months

Remission Response 6 mo 18% 41% 1 yr 36% 36% 2 yr 58% 65%

Holtzheimer et al. Arch Gen Psych Feb 2012

Resp

Non-R

cc

acg

Planned Target

Responder/Nonresponder Differencessurgical precision vs remote effects

sCg

Hamani et al J Neurosurg 2009

Active Contact

Can this be linked back to patient behavior?

C25oF11hth

F10

oF11

dACC

hth

vst

C25

mF9

Responders Non-Resp

Clues from PET changes?

Simple localization uninformative.Hitting the ‘target’ is not the problem

Local PLUS remote effects

25

both

4mF10 MCC

nA25

3

oF

nA25

nA

Probablistic TractographyVariable impact on remote ROI

4321

mACCmF10

oF11

mF10nAc

Hth

putative tracts

DTI/DSI

Am/hc

Map Remote Effects

Presurgical Response Predictorstowards optimal patient selection: resting fMRI

worse IDI-D* better ICA

- Zsc

oreCorrelation:

baseline fMRI DFMwith 6 mo outcome SCC FC

DBS pts Controls Difference

ICAdefault modecomponent

- =mF10

SCC25

Alex Franco, 2011Holtzheimer et al SOBP 2011 abstract

Resting StateBOLD fMRI

Independent Component Analysis (ICA)

Similar to PETCan

potentially be done in

individuals

EEG, 32 sites, Bio-Semi System4min rest, eyes open

0 5 10 15 20 25 30 40 45 50 Hz

Broadway, Hilimire , Corballis. GA Tech unpublished

Similar location to PET and fMRIConfirms findings, could be a

more practical alternative

Presurgical Response Predictorstowards optimal patient selection

Baseline resting EEG

Towards Novel Drug DevelopmentChemical Specificity within the Cingulate

Palomero-Gallagher Human Br Mapping 2009

Hi NMDA Lo GABA-bHi SERT, 5HT1a

sACC

Arango et al Prog Br Res 2002

Ketamine acuteDBS effects

Talbot BP 2004

sad induction Trypt depletion

Deakin AGP 2009

HumanWholeBrain

Autoradiography

HumanPost

Mortem

Resting BOLD fMRIto confirm DBS type

Future: Imaging Biomarkers Guide DBS patient selection and parameter optimization

mF10

SCC25

mF

sCG

mF

sCg

mF10

nA25

Cg24

BA10Cg32

nAc

Amg

DTI tractographyDefine optimal contact

43

21

Micro-electrodeLead localization

Intraoperative LFPTune critical

Ipsilat Fr

Bilat Fr Pole Contral Fr Vertex

post

Voltage Steering:Volume of tissue activated

Realtime Readouts:Closed loop adjustments

collaborations at Emory, Yerkes, GA Tech, Cleveland Clinic

Depression DBS Collaborators

Emory Clinical DBS 2005- Paul Holtzheimer MD

Steven Garlow, MD PhDPatricio Riva Posse MD Dylan Wint, MD

Lori Ritschel PhD (CBT)C Ramirez PhD (CBT)

Sinead Quinn Kelsey Hagan Megan Filkowski Andrea Barrocas Margaret Craighead

Andrea Crowell MD

Neurosurgery/NeurologyRobert Gross, MD, PhDKlaus Mewes, PhDKevin Gotay, MSDonald Bliwise, PhDKathryn Rahimzadeh, RNMahlon DeLong, MDThomas Wichmann, MD

Psychology/PhysiologyStephan Hamann PhDCory InmanOtis Smart, PhDMike Jutras, PhDBeth Buffalo, PhDPaul Corballis, PhD (GTech)Matt Hilimire BA (GT)Jim Broadway PhD (GT)Amy Alderson, PhD (NPsy)

External CollaboratorsH Johansenberg PhD (UK)N. P-Gallagher PhD (GR)C McIntyre PhD (Ohio)

Yerkes/Animal ModelsDonald Rainnie PhDTeresa Madsen BSLeonard Howell PhDMar Sanchez PhDSue Tye, PhD (AUST)Clement Hamani MD (TO)S Pannu PhD (Berkeley)M Ghovanloo PhD (GTech)

Grants: NARSAD, Woodruff Fund, Emory Healthcare, Stanley Medical Research Institute, Dana Foundation, NSF CBN Venture, K23 MH077869,R01MH073719, P50MH077083, RO1MH080880

Imaging Lab Alex Franco, PhD Callie McGrath, BS KiSueng Choi, MS Mary Kelley, PhD David Gutman, MD

C Craddock, PhD Jared Moreines, BS

Toronto 1999-2004Andres Lozano MD PhDSidney Kennedy MDClement Hamani MDZindel Segal PhD (CBT)

Johns Hopkins 1985-91UTHSCSA 1991-98

Emory Depression BiomarkersEd Craighead Boadie DunlopTanja MletzkoCB Nemeroff