Deep Brain Stimulation and Depression: A Decade of Progress Kevin - PowerPoint PPT Presentation

Deep Brain Stimulation and Depression: A Decade of Progress Kevin Warren Helen S. Mayberg, MD Emory University Brain & Behavior Research Foundation Webinar January 14, 2014

Disclosures Grant Support: NARSAD, Dana Foundation, Woodruff Fund, Stanley Medical Research Institute, Hope for Depression Research Foundation Off-Label Use of Devices: DBS electrodes/pulse generators 1. Medtronic Inc. (UT, Emory) 2. St. Jude Medical, Inc (Emory) Emory DBS study: FDA IDE: G060028 (PI: HM), G130107 (PI: HM) Clinicaltrials.gov ID#: NCT00367003 research devices donated by SJM and Medtronic Patent: US2005/0033379A1 (Andres Lozano, co-inventor) issued March 2008, St. Jude Medical Inc, assignee Consultant: St Jude Medical Inc / Neuromodulation Division

DBS Team University of Toronto Neurosurgery Psychiatry and Psychophysiology R Gross P Holtzheimer A Lozano S. Kennedy C. Hamani S Garlow P Riva Posse A Crowell Imaging: DTI, PET, fMRI, Modeling Electrophysiology Animal Models K Choi C McGrath J Rajendra O Smart V Tiruvadi C McIntyre D Rainnie T Madsen Biostats Psychotherapy Patient Coordination Affective/Cog NS/Psychology S Hamann C Inman L Ritschel C Ramirez M Kelley M Woody S Quinn

Context: Proof-of-Principle Pilot Study 2005 6 month open-label, chronic, continuous DBS in 6 patients severe TRD, HDRS17>20, GAF<50 chronic: Illness duration avg 5.6 yrs failed multiple meds, CBT, ECT 6 months open label DBS 4/6 Resp; 3/6 remission hypothesis supported by PET Δ Toronto: Pilot Proof of principle Pre- op PET ∆ 6 months DBS Pre-op MRI Post-op MRI  mF9 dACC dACC cc g vst F10 ac vst sgC25 sn oF11 oF11 SCC25 hth  C25 C25 hth Electrode Confirm electrode Pts vs Controls Responders Targeting placement Funded by NARSAD, Toronto Western hospital

DBS for Depression: Motivation  Status Quo: treatments available; not always effective < 40% achieve remission with first treatment no reliable biomarkers to guide treatment selection relapse, recurrence common ~ 10% become treatment resistant over time only experimental options if fail ECT (ablation, VNS, ketamine)  Thinking 2001: Neuromodulation as a Potential Strategy 1. Advances in stereotaxic neurosurgery Scientific 2. Experience in other neurological disorders Facilitators 3. Knowledge from structural/functional imaging

Prototype Neurological Disorder DBS for Parkinson’s Disease tremor stooped posture Diagnosis Treatment Syndrome → Pathology Pathology→ Chemistry masked facies rigidity Rx L-dopa St SN tremor 1963 18F-Dopa PET healthy PD short shuffling steps Circuit Define Lesions Circuits Circuit Tuning Hi freq 130Hz STN DBS. Courtesy Andres Lozano U Toronto DBS FDA approved 1997 ET, PD 2002 Benabid et al. Appl Neurophysiol 1987 Delong, Alexander, Strick 1986 >100,000 pts implanted. No Δ basic technology in 25 yrs

Can we Treat Depression Like PD? Critical Questions: • Is there an “illness” circuit • What changes are necessary/sufficient? • Where should we stimulate? • Which patients?

Defining Depression Circuits Deconstruct syndrome into component dimensions Frontal/Cingulate Cortex mood cognition vegetative motor circadian Motor Premotor Prefrontal Adapted from Limbic Alexander, Delong, Strick 1986 Approach: Symptoms map to distinct pathways. Treatment impacts some or all subcircuits

Step 1: Define candidate regions in circuit Imaging studies of structure and function  MRI volume  MRI volume, Glia Focal Strokes Variability PF  dPF hc Drevets 97; Ongur 98 Sheline, 1999 Robinson 1983 Baxter AmJP 1985 Parkinson’s Unipolar Bipolar  VPF  aCg aCg  Thal F9 F9 F9 F9 F9 F9  Amg P40 P40 P40 P40  Drevets JNS 1992 Early clues to possible Mayberg et al. AJP 1988 J Nuc Med 1994 Baxter et al. 1985 Starkstein Brain 1989 NeurReport 1997 Kruger et al. 2003 subtypes? Ann Neurol 1990 J NPCNS 1997 Neurol 1992 Am J Psych 1999

Step 2: What regions change with treatment? treatment specific effects Cognition attention-appraisal-action CBT hc PM6 Par40 PF9/46 vPF PCC MCC Cg25 ↓ ruminative thought ↑emotional awareness thal mF9/10 na-vst Mood Emotion Regulation state pACC24 Self-awareness amg oF11 mb-sn Insight Salience Is one node, Motivation compartment, sACC25 MEDS or behavior most critical? a-ins hth bstem Meds dPF PCC Mayberg J Neuropsych Clin NS 1997 Cg25 Interoception Mayberg, Br Med Bul 2003, Psych Annals 2006 ins Cg25 drive-autonomic-circadian p Goldapple et al Arch GP 2004, Kennedy et al AJP 2007 McGrath et al JAMA Psych 2013 ∆ limbic tone, emotion reactivity

Step 3: What are core clinical features are key? “ It is a positive and active anguish, a sort of William James 1902 psychical neuralgia wholly unknown to normal life. ” “ Psychic energy throttled back close to zero. William Styron 1991 Nearly immobilized, a trance of supreme discomfort .” “ A gnawing agony; a painful self-loathing that Toronto DBS #7 consumes all your energy and attention… ” Map Negative Mood Directly Hypothesis Pre-frontal pCg cognitive Vegetative changes symptoms Negative insula Hth SCC25 SCC25 mood Motor slowing Personal sad memory CBF PET

Step 4: Isolate necessary and sufficient regions Converging findings in the subcallosal cingulate SCC25  volume;  glia Sad Memory Tryptophan Deplete Increased sCg25 with induced  SCC25 depressed mood activity Drevets, Ongur, Rajkowska Mayberg Talbot SSRI SNRI Placebo Decreased SCC25 with diverse successful treatments  SCC25 activity Kennedy Mayberg Mayberg ECT rTMS VNS Hypothesis: TRD=dysregulated SCC25. Target this critical hub Pardo George Nobler

Back to the Beginning: Area 25 DBS for TRD Pt #1 May 13, 2003 Toronto Depression Circuit Model CBF PET Path Connections FDG PET Attention-cognition-Action pm F6 dFr 9/46/10 inf Par 40 dCg 24b pCg 23/31 Cg 24a St Th Cg25 Cg25 Cg 25 a-Hc pons hth a-p Ins JNP 1997 Impacted fibers based Transient Sadness Dep Recovery w/ meds Vegetative-circadian On tract tracing studies Activation of SCC25 reduced SCC25 activity Eligible Patients MDD only GAF<50 cc Episode >1 yr, Ham17>20 Failed 4 meds, ECT, PsyTx genu No medical/psych ac comorbidity mid-SCC Anatomical Target Bilateral Leads+ IPG Surgical Implantation Stereotactic MRI Parameters 130Hz/90usec/ ~ 6mA While Awake

Toronto: Continued Proof-of-Principle Testing Unblinded, safety and efficacy testing of chronic stimulation 2008 2011 Long Term f/u: 3-6 yrs, n=14 20 patients: 1 Year Follow-up 25 Total HAM-D 17 Score 20 All time points Resp 62.5% 46.2% 75% 64% p < 0.001 Rem 18.8% 15.4% 50% 42% 15 IT 10 OC 5 avg=42 mo Resp=60%; Resp=55% 0 Base 1 2 3 4 5 6 7 8 9 10 11 12 Months Post - DBS months after implant years after implant

Emerging Questions • Predictors  Who are the right Patients?  Can surgery, parameters be further optimized? • What does DBS do?   negative mood or  positive mood?  Mood PLUS motivation, vegetative features, cognition?  Do different brain target differentially affect different symptoms?  Can rehabilitation enhance DBS effects; facilitate plasticity? • Basic Mechanisms  What regions/pathways/cell types are most critical  reverse-engineering to animal models  Real-time readouts (brain radio, actigraphy)  platform for non-invasive alternatives?

Other Brain Targets Under Study Same/different: circuit? 1 ° target symptoms? best pts? Biological Psychiatry Feb 2009 15 MDD (1BP1), 3 sites; 6 months open; 40% Resp Final H24=17.5; 53% R last f/u Biological Psychiatry (2010) epub Dec 2009 10 MDD; 1 year open; 50% Resp; Final H28=15 Biological Psychiatry (2013) epub Apr 2013 7 MDD, 12 wk-33 wks open; 6/7 Responders at 12 wks MADRAS=14.6; 4 of 6 in remission

Emory Studies: Replication, Extension Response Remission HDRS 6 mo 42% 18% ALL pts 24 1 yr 36% 36% 2 yr 65% 58% 18 Entry Criteria 12 6 No change in meds for Last f/u: 12/14 (80%R) T 0 =Jan07 6 months 10UP/7BP2; 10W/7M; age 42+9, MDE 5.3+4y 0 3 explanted, 11 new cohort Meds stable, 1 mo placebo, 6 mo open DBS BL sh 1m 2 3 4 5 6 7 8 9 10 11 12 2y First patient Jan 12, 2007 Subgroups • time course, remission rate, similar to Toronto BP2 24 • modest sham effect; carryover from OR? • Continued improvement over time MDD 18 H D R S • if Remitter, no spont relapses, more resilient? 12 Spain n=8 62% 1 yr BP=MDD at all time point SJM pilot n=21 48% 6 mo (3 centers) 6 No induced mania/hypomania case reports (Argentina, GR, Calgary) 0 Funding: Dana, Stanley, Woodruff Found’n , Emory Hosp baseline sham 4 weeks 24 weeks 1 year 2 years Baseline sham 4 wks 24 wks 1 yr 2 yrs Devices donated by St. Jude Medical , IDE: G060028/S002

Is Recovery Stable Without Continued DBS? Is relapse the same As original TRD state? Reproducible loss of effect over 2 wks; further confirmed with battery depletion No evidence of ‘plasticity’ although not tested to see if rescued with other Tx Rate of deterioration may vary for different DBS targets. Opportunity: time course of relapse suggests cycling of stimulation possible Holtzheimer et al. Arch Gen Psych 2012