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Helen S. Mayberg, MD Emory University School of Medicine ASENT meeting 2012 Washington DC

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. Grant Support: NIMH, CIHR, NARSAD, Dana Foundation,

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Helen S. Mayberg, MD Emory University School of Medicine ASENT meeting 2012 Washington DC

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  1. 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

  2. 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

  3. 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

  4. 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)

  5. Hypothesis: Depression and the Brain post-natal insults early abuse life events medical illness Biological Vulnerability Exogenous Stressors gender family history temperament genetics pre-natal insults homeostasis Regions Connections Chemistry Mood Regulatory Circuits endophenotypes recovery stress Rx Effects CBT/PT Medication ECT, rTMS, VNS DBS Subphenotypes MDD, BP Melancholic Atypical Recurrent TRD Depressive episode Phenotypes

  6. hc Parkinson’s Unipolar Bipolar  aCg aCg F9 F9 F9 F9 F9 F9 P40  P40 P40 P40 Defining Depression Circuits 1 Identify circuit constituents Focal Strokes  MRI volume  MRI volume, Glia PF Structure CT, MRI, pathology PF Frontal Cingulate hippocampus Drevets 97; Ongur 98 Robinson 1983 Sheline, 1999 Frontal Cingulate Parietal Also Amygdala Basal ganglia Function PET, fMRI EEG Mayberg 19990 Mayberg 1994, 1997 Kruger 2003

  7. pCg Fr hc hc vst p vst p Cg25 Fr Fr pCg hc hc p cg25 ins vst Cg25 p Defining Depression Circuits 2 Changes with well characterized treatments 1 week fluoxetine Subcortical Brainstem Limbic early Limbic switch + Cortex late 6 weeks fluoxetine Similar time course to neurogenesis, BDNF ∆ Mayberg et al. Biol Psychiatry 2000

  8. Defining Depression Circuits 2b responder-nonresponder differences Cg25 F9 pCg31 Fluoxetine Responders hc hc Cg25 Cg25 p Non- Responders pCg31 F9 F9 hc hc Failure to Switch = Non-Response

  9. Common Changes Placebo and SSRI Drug = Placebo Plus Cg25 Common Cg25 PCg Fr9 pCg Placebo fluoxetine Fr9 cg25 Cg25 Also Hc BS Cg25 Fr9/46 pCg Active Fluxotine hc hc cd p cg25 Cg25 p distinguish Placebo R from Active Drug response with scans? Am J Psych 159: 728-37, 2002

  10.  Defining Depression Circuits 3 Drug Resp vs Nonresponders Baseline Pre-genual Anterior Cingulate 24 pACC24 F9 → F9 pACC (r24) pACC (r24) Non-responders Drug responders Common Frontal change Multiple interactive Nodes More than 1 area of Cg involved First clue to potential subtypes rACC Mayberg et al NeuroReport 1997 Baseline EEG Theta R>NR to TCA Pizzagalli AJP 01

  11. Scan Type A B C recovery D Hypothesis Scan =“insult”+ongoing compensation baseline heterogeneity defines clinical subtypes illness is failure to self-correct over- correction Trigger CBT network activity partial meds Bad day symptoms Hypothesis: recovery is optimized by matching treatment to state of network dysregulation under ECT failed Depression diagnosis DBS? absent adaptive brain response Mayberg, J Clin Invest 119:717, 2009

  12. Baseline Pretreatment Pts vs Controls comparable severity dPF dPF dPF dPF Cg24 vPF vPF vPF vPF  UPD Group 2 UPD Group 1 Proof of Principle Comparison drug to CBT mF10/9 Change with clinical response PF9 MCC PF9 mF9/10 oF11  thal P40 SCC SSRI (paroxetine) HamD 20+3  6.7+4 Cognitive Behavior Therapy HamD 22+3  6+4 Suggests Baseline differences Impacting ultimate Response to a specific Treatment Need to know if it also Predicts non-response to The alternative Kennedy et al. Am J Psych 2001 Goldapple et al. Arch Gen Psych2004

  13. PCC MCC Evolution of Depression Circuit Model Template to consider different treatments, common effectts Cognition (attention-appraisal-action) PF hc Par40 PM6 PF9/46 Cg25 CBT thal Mood state mF9/10 na-vst Emotion Regulation Self-awareness insight pACC24 amg mb-sn oF11 Salience Motivation Is any one mode Or clinical feature Most critical? MEDS sACC25 a-ins hth bstem PF P Meds PCC Cg25 Interoception (drive-autonomic-circadian) Mayberg, Br Med Bul 65:193-207, 2003 BS Mayberg, J Clin Invest 119:717, 2009

  14. Isolating Key Components focus on negative mood R Recovery w/SSRI FDG PET Transient Sadness CBF PET F9 F9 ins ins Cg25 Cg25 +4z Cg31  Cg31 Limbic + Cortex Reciprocal Cingulate-Frontal changes Cg25 Cg25 Cg25 Cg25 - 4z  Depressed Patients Healthy Volunteers Mayberg et al. Am J Psych 156:675-82 1999

  15. volume; glia Drevets, Ongur, Rajkowska ECT rTMS VNS Pardo Nobler George pre-Cingulotomy Med NR Dougherty Greicius Critical Role of the Subcallosal Cingulate ∆ Spines/Dendrites Sad Memory Tryptophan Deplete Cortisol Correlate SCC activity McEwen 1994 etc Kalin Mayberg Talbot SSRI SNRI Placebo SCC activity Mayberg Mayberg Kennedy Pre-DBS Hypothesis: TRD=dysregulated Cg25 connectivity. Target the problem at its origin Ketamine SCC Deakin 2009 Mayberg

  16. rACC mF10 Hth 4 nAc 3 2 Am/hc sCg25 oF11 1 PET target Likely remote effects Cortex Cognitive control, action mF9 mACC PF9 F11 F10 PCC Cg24 MCC sCg25 bs sn vst Thal Striatal-thalamic drive, motivation am hth ins hippocampus Limbic circadian, stress responses Direct ‘Circuit’ Modulation using DBS block aberrant sCg25 activity with 2° effect on connections MRI: target localization Focus: Treatment Resistant Depression

  17. Pre-op PET ∆ 6 months DBS mF9 dACC dACC cc vst F10 g vst ac sn oF11 oF11 hth SCC25 C25 sgCg C25 hth Pts vs Controls Responders 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 Toronto: Pilot Proof of principle Post-op MRI Pre-op MRI   Electrode Targeting Confirm electrode placement First patient May 13, 2003 Funded by NARSAD, Toronto Western hosp

  18. Toronto Long-term Followup Emory Sham Controlled Trial Remission Response 6 mo 18% 41% 1 yr 36% 36% 2 yr 58% 65% 3-6 yrs, n=14 BP-D/MDD N=17 24 18 12 6 0 Resp 62.5% 46.2% 75% 64.3% Rem 18.8% 15.4% 50% 42% HDRS-17 score IT OC avg=42 mo No change in meds for 6 months years after implant BL sham 1m 2 3 4 5 6 7 8 9 10 11 12 2y Kennedy S, et al. Am J Psych in Adv Feb 1, 2011 Holtzheimer et al. Arch Gen Psych Feb 2012 Lozano A, et al. Biol Psych 64:461-67, 2008

  19. 4 MCC Map Remote Effects mF10 nA 25 mF10 Hth 3 nAc Am/hc oF11 nA putative tracts 25 oF mF10 mACC both Clues from PET changes? 25 nA mF9 dACC DTI/DSI 4 Probablistic Tractography Variable impact on remote ROI F10 3 vst 2 oF11 oF11 C25 C25 hth 1 hth Non-Resp Local PLUS remote effects Responders Responder/Nonresponder Differences surgical precision vs remote effects Active Contact Planned Target cc g Non-R ac sCg Resp Hamani et al J Neurosurg 2009 Simple localization uninformative. Hitting the ‘target’ is not the problem Can this be linked back to patient behavior?

  20. Presurgical Response Predictors towards optimal patient selection: resting fMRI Independent Component Analysis (ICA) Resting State BOLD fMRI Correlation: baseline fMRI DFM with 6 mo outcome ICA - Zscore  worse IDI-D* better  Difference DBS pts Controls SCC FC Similar to PET Can potentially be done in individuals ICA default mode component mF10 - = SCC25 Alex Franco, 2011 Holtzheimer et al SOBP 2011 abstract

  21. EEG, 32 sites, Bio-Semi System 4min rest, eyes open     0 5 10 15 20 25 30 40 45 50 Hz Presurgical Response Predictors towards optimal patient selection Baseline resting EEG Similar location to PET and fMRI Confirms findings, could be a more practical alternative Broadway, Hilimire , Corballis. GA Tech unpublished

  22. Hi NMDA Lo GABA-b Towards Novel Drug Development Chemical Specificity within the Cingulate sad induction Trypt depletion DBS effects Ketamine acute     Deakin AGP 2009 Talbot BP 2004 Human Post Mortem Human Whole Brain Autoradiography sACC Hi SERT, 5HT1a Arango et al Prog Br Res 2002 Palomero-Gallagher Human Br Mapping 2009

  23. Future: Imaging Biomarkers Guide DBS patient selection and parameter optimization DTI tractography Define optimal contact Micro-electrode Lead localization Resting BOLD fMRI to confirm DBS type mF mF mF10 mF10 Cg24 4 3 2 1 nA sCg Cg32 sCG BA10 nAc SCC25 25 Amg Intraoperative LFP Tune critical  Voltage Steering: Volume of tissue activated Realtime Readouts: Closed loop adjustments post Ipsilat Fr Bilat Fr Pole Contral Fr Vertex collaborations at Emory, Yerkes, GA Tech, Cleveland Clinic

  24. Depression DBS Collaborators Emory Clinical DBS 2005-Paul Holtzheimer MD Steven Garlow, MD PhD Patricio 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 Johns Hopkins 1985-91 UTHSCSA 1991-98 Neurosurgery/Neurology Robert Gross, MD, PhD Klaus Mewes, PhD Kevin Gotay, MS Donald Bliwise, PhD Kathryn Rahimzadeh, RN Mahlon DeLong, MD Thomas Wichmann, MD Psychology/Physiology Stephan Hamann PhD Cory Inman Otis Smart, PhD Mike Jutras, PhD Beth Buffalo, PhD Paul Corballis, PhD (GTech) Matt Hilimire BA (GT) Jim Broadway PhD (GT) Amy Alderson, PhD (NPsy) Toronto 1999-2004 Andres Lozano MD PhD Sidney Kennedy MD Clement Hamani MD Zindel Segal PhD (CBT) Emory Depression Biomarkers Ed Craighead Boadie Dunlop Tanja Mletzko CB Nemeroff Imaging Lab Alex Franco, PhD Callie McGrath, BS KiSueng Choi, MS Mary Kelley, PhD David Gutman, MD C Craddock, PhD Jared Moreines, BS Yerkes/Animal Models Donald Rainnie PhD Teresa Madsen BS Leonard Howell PhD Mar Sanchez PhD Sue Tye, PhD (AUST) Clement Hamani MD (TO) S Pannu PhD (Berkeley) M Ghovanloo PhD (GTech) External Collaborators H Johansenberg PhD (UK) N. P-Gallagher PhD (GR) C McIntyre PhD (Ohio) Grants: NARSAD, Woodruff Fund, Emory Healthcare, Stanley Medical Research Institute, Dana Foundation, NSF CBN Venture, K23 MH077869,R01MH073719, P50MH077083, RO1MH080880

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