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How Functional Brain Imaging Can Help Speed Drug Development and Clinical Trials Depression Helen S. Mayberg, MD Emory University School of Medicine ASENT meeting 2012 Washington DC Disclosures 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 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 Context: Current State of Treatment Options 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) Hypothesis: Depression and the Brain gender family history temperament genetics pre-natal insults endophenotypes Subphenotypes MDD, BP Melancholic Atypical Recurrent TRD Biological Vulnerability Exogenous Stressors homeostasis Mood Regulatory Circuits stress recovery Depressive episode Phenotypes post-natal insults early abuse life events medical illness Regions Connections Chemistry Rx Effects CBT/PT Medication ECT, rTMS, VNS DBS P F Defining Depression Circuits 1 Identify circuit constituents Focal Strokes MRI volume, Glia MRI volume PF Structure CT, MRI, pathology hc Robinson 1983 Parkinson’s aCg Function PET, fMRI EEG Frontal Cingulate hippocampus F9 Drevets 97; Ongur 98 Unipolar aCg F9 Mayberg 19990 Bipolar F9 F9 P40 Sheline, 1999 P40 Mayberg 1994, 1997 F9 P40 F9 P40 Kruger 2003 Frontal Cingulate Parietal Also Amygdala Basal ganglia Defining Depression Circuits 2 Changes with well characterized treatments 1 week fluoxetine pCg hc hc vst Fr p vst p Cg25 6 weeks fluoxetine Fr pCg hc cg25 vst p Fr hc ins p Mayberg et al. Biol Psychiatry 2000 Similar time course to neurogenesis, BDNF ∆ Cg25 Subcortical Brainstem Limbic early Limbic switch + Cortex late Defining Depression Circuits 2b responder-nonresponder differences Cg25 Fluoxetine Responders F9 pCg31 hc hc Cg25 Cg25 NonResponders p F9 F9 hc hc Failure to Switch = Non-Response pCg31 Common Changes Placebo and SSRI Drug = Placebo Plus Cg25 Placebo fluoxetine Common Cg25 PCg Fr9 pCg Fr9 cg25 Cg25 Cg25 Fr9/46 Active Fluxotine pCg hc cd Cg25 cg25 p hc p distinguish Placebo R from Active Drug response with scans? Am J Psych 159: 728-37, 2002 Also Hc BS Defining Depression Circuits 3 Drug Resp vs Nonresponders Baseline Pre-genual Anterior Cingulate 24 F9 pACC24 F9 → pACC (r24) pACC (r24) Drug responders Non-responders Common Frontal change Mayberg et al NeuroReport 1997 Multiple interactive Nodes More than 1 area of Cg involved First clue to potential subtypes rACC Baseline EEG Theta R>NR to TCA Pizzagalli AJP 01 Hypothesis Scan =“insult”+ongoing compensation baseline heterogeneity defines clinical subtypes Scan Type Trigger overcorrection A CBT illness is failure to self-correct network activity B partial meds recovery Bad day symptoms C under failed Depression diagnosis absent D adaptive brain response Mayberg, J Clin Invest 119:717, 2009 ECT DBS? Hypothesis: recovery is optimized by matching treatment to state of network dysregulation Proof of Principle Comparison drug to CBT mF10/9 Change with clinical response PF9 MCC PF9 mF9/10 P40 SCC SSRI (paroxetine) dPF dPF HamD 22+3 6+4 dPF dPF Cg24 vPF vPF UPD Group 1 Kennedy et al. Am J Psych 2001 Cognitive Behavior Therapy HamD 20+3 6.7+4 Baseline Pretreatment Pts vs Controls comparable severity oF11 thal vPF vPF UPD Group 2 Suggests Baseline differences Impacting ultimate Response to a specific Treatment Need to know if it also Predicts non-response to The alternative Goldapple et al. Arch Gen Psych 2004 Evolution of Depression Circuit Model Template to consider different treatments, common effectts Cognition (attention-appraisal-action) PF PF9/46 Cg25 PM6 Par40 hc PCC MCC CBT Emotion Regulation Self-awareness insight mF9/10 thal amg mb-sn pACC24 oF11 Is any one mode Or clinical feature Most critical? Mayberg, Br Med Bul 65:193-207, 2003 Mayberg, J Clin Invest 119:717, 2009 na-vst Mood state Salience Motivation sACC25 a-ins hth bstem Interoception (drive-autonomic-circadian) MEDS PF Meds PCC Cg25 P BS Isolating Key Components focus on negative mood R Recovery w/SSRI FDG PET Transient Sadness CBF PET F9 F9 ins ins Cg25 Cg25 + Cg3 4 1 z Cg31 Cg25 Depressed Patients 4 z Cg25 Cg25 Cg25 Limbic + Cortex Reciprocal Cingulate-Frontal changes Healthy Volunteers Mayberg et al. Am J Psych 156:675-82 1999 Critical Role of the Subcallosal Cingulate Sad Memory Tryptophan Deplete volume; glia Cortisol Correlate ∆ Spines/Dendrites SCC activity Mayberg SSRI SNRI Drevets, Ongur, Rajkowska Kalin Talbot Placebo rTMS ECT McEwen 1994 etc VNS SCC activity Mayberg pre-Cingulotomy Mayberg Kennedy Med NR Pre-DBS George Ketamine SCC Dougherty Greicius Mayberg Deakin 2009 Nobler Hypothesis: TRD=dysregulated Cg25 connectivity. Target the problem at its origin Pardo Direct ‘Circuit’ Modulation using DBS block aberrant sCg25 activity with 2° effect on connections mF9 mACC rACC mF10 sCg25 4 3 2 1 oF11 PET target Hth nAc Am/hc Likely remote effects Cortex Cognitive control, action F11 PF9 F10 Cg24 MCC PCC sCg25 sn vst Thal bs Striatal-thalamic drive, motivation am hth ins hippocampus Limbic circadian, stress responses MRI: target localization Focus: Treatment Resistant Depression Toronto: Pilot Proof of principle Pre-op MRI Post-op MRI Toronto Proof of Principle Pilot: 6 severe TRD, GAF<50 Illness duration avg 5.6 yrs Failed mult meds, CBT, ECT 6 mo open DBS 4/6 Resp; 3/6 remission Pre-op PET ∆ 6 months DBS mF9 dACC dACC cc g sgCg vst ac SCC25 hth Electrode Targeting Confirm electrode placement First patient May 13, 2003 F10 sn Pts vs Controls vst oF11 C25 hth oF11 C25 Responders Funded by NARSAD, Toronto Western hosp Toronto Long-term Followup Emory Sham Controlled Trial 3-6 yrs, n=14 Resp Rem 62.5% 18.8% 46.2% 75% 15.4% 50% 64.3% 42% IT OC avg=42 mo years after implant Kennedy S, et al. Am J Psych in Adv Feb 1, 2011 Lozano A, et al. Biol Psych 64:461-67, 2008 HDRS-17 score 24 Remission Response 6 mo 18% 41% 1 yr 36% 36% 2 yr 58% 65% BP-D/MDD N=17 18 12 6 No change in meds for 6 months 0 BL sham 1m 2 3 4 5 6 7 8 9 10 11 12 Holtzheimer et al. Arch Gen Psych Feb 2012 2y Responder/Nonresponder Differences surgical precision vs remote effects Planned Target Active Contact Map Remote Effects cc g mF10 mACC 25 mF10 Resp Hamani et al localization J Neurosurg 2009 Simple uninformative. Hitting the ‘target’ is not the problem 4 nA Non-R ac sCg mF10 MCC oF11 4 3 2 1 Hth nAc Am/hc 3 putative tracts oF nA 25 Clues from PET changes? both mF9 F10 dACC vst oF11 C25 hth Responders oF11 DTI/DSI C25 hth Non-Resp Local PLUS remote effects 25 nA Probablistic Tractography Variable impact on remote ROI Can this be linked back to patient behavior? Presurgical Response Predictors towards optimal patient selection: resting fMRI Independent Component Analysis (ICA) Resting State BOLD fMRI DBS pts Difference Controls Similar to PET Can potentially be done in individuals mF10 ICA default mode component - = SCC25 4 3 ICA - Zscore Correlation: baseline fMRI DFM with 6 mo outcome 2 1 SCC FC R² = 0.6133 worse IDI-D* better 0 0.0 0.5 1.0 Alex Franco, 2011 Holtzheimer et al SOBP 2011 abstract Presurgical Response Predictors towards optimal patient selection Baseline resting EEG 1.4 1.2 EEG, 32 sites, Bio-Semi System 4min rest, eyes open 1 0.8 6m Resp 0.6 6m Non-Resp 0.4 0.2 0 0 5 10 15 20 25 30 40 45 50 Hz Similar location to PET and fMRI Confirms findings, could be a more practical alternative 6 mo HDRS Change Baseline 1 mo DBS 6 mo DBS 100 R² = 0.576 80 60 40 20 0 -100 0 -20 Broadway, Hilimire , Corballis. GA Tech unpublished 100 200 300 Theta%Chng at 4 weeks 400 Towards Novel Drug Development Chemical Specificity within the Cingulate DBS effects Ketamine acute sad induction Trypt depletion Deakin AGP 2009 Human Post Mortem Talbot BP 2004 Human Whole Brain Autoradiography sACC Hi SERT, 5HT1a Arango et al Prog Br Res 2002 Hi NMDA Lo GABA-b Palomero-Gallagher Human Br Mapping 2009 Future: Imaging Biomarkers Guide DBS patient selection and parameter optimization Resting BOLD fMRI to confirm DBS type Micro-electrode Lead localization DTI tractography Define optimal contact mF mF10 mF mF10 Cg24 Cg32 BA10 25 sCg SCC25 sCG nA nAc Amg Intraoperative LFP Tune critical Voltage Steering: Volume of tissue activated Realtime Readouts: Closed loop adjustments post Ipsilat Fr Bilat Fr Pole Contral Fr collaborations at Emory, Yerkes, GA Tech, Cleveland Clinic Vertex Depression DBS Collaborators Emory Clinical DBS 2005Neurosurgery/Neurology Robert Gross, MD, PhD Paul Holtzheimer MD Klaus Mewes, PhD Steven Garlow, MD PhD Kevin Gotay, MS Patricio Riva Posse MD Donald Bliwise, PhD Dylan Wint, MD Kathryn Rahimzadeh, RN Lori Ritschel PhD (CBT) Mahlon DeLong, MD C Ramirez PhD (CBT) Thomas Wichmann, MD Sinead Quinn Psychology/Physiology Kelsey Hagan Stephan Hamann PhD Megan Filkowski Cory Inman Andrea Barrocas Emory Depression Biomarkers Otis Smart, PhD Margaret Craighead Ed Craighead Mike Jutras, PhD Andrea Crowell MD Boadie Dunlop Beth Buffalo, PhD Tanja Mletzko Paul Corballis, PhD (GTech) Imaging Lab CB Nemeroff Matt Hilimire BA (GT) Alex Franco, PhD Jim Broadway PhD (GT) Callie McGrath, BS Yerkes/Animal Models Amy Alderson, PhD (NPsy) KiSueng Choi, MS Donald Rainnie PhD External Collaborators Mary Kelley, PhD Teresa Madsen BS H Johansenberg PhD (UK) David Gutman, MD Leonard Howell PhD N. P-Gallagher PhD (GR) C Craddock, PhD Mar Sanchez PhD C McIntyre PhD (Ohio) Jared Moreines, BS Sue Tye, PhD (AUST) Clement Hamani MD (TO) Grants: NARSAD, Woodruff Fund, Emory Healthcare, Stanley Medical S Pannu PhD (Berkeley) Research Institute, Dana Foundation, NSF CBN Venture, K23 MH077869,R01MH073719, P50MH077083, RO1MH080880 M Ghovanloo PhD (GTech) Johns Hopkins 1985-91 UTHSCSA 1991-98 Toronto 1999-2004 Andres Lozano MD PhD Sidney Kennedy MD Clement Hamani MD Zindel Segal PhD (CBT)