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
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