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September 15 – 17, 2016 | The Biltmore Hotel | Miami, FL
#CHAIR2016
Wayne K. Goodman, MDBaylor College of MedicineHouston, TX
Brain Stimulation Therapies for Neuropsychiatric Disorders
Evaluate role of brain stimulation therapies for neuropsychiatric disorders
Learning Objective 1
#CHAIR2016
Wayne K. Goodman, MD
●Research/Grants: NIMH; Brainsway; Medtronic (donated devices); Simons Foundation
Disclosures
Types of Neuromodulation Devices for Neuropsychiatric Disorders ● Surgical– Deep Brain Stimulation (DBS)✓– Epidural Cortical Stimulation– Vagus Nerve Stimulation (VNS)
● Non-surgical– Electroconvulsive Therapy (ECT)– Focused Ultrasound (FUS)– Transcranial Magnetic Stimulation (rTMS and Deep TMS)✓– Transcranial Direct Current Stimulation (tDCS)– Near-infrared Irradiation Therapy (NIR)
Deep Transcranial Magnetic Stimulation for Depression● Response rates at week 5
and week 16 were significantly higher in the active vs. sham groups
● Well-tolerated● One seizure in subject
who had been consuming EtOH
Levkovitz Y, et al. World Psychiatry. 2015;14(1):64-73.
FDA Approval Status for Deep Brain Stimulation (DBS)● Full FDA approval
– Essential tremor-1997– Refractory Parkinson’s Disease-1997– Refractory epilepsy-2013
● Humanitarian Device Exemption (HDE)* approval– Dystonia (2003)– Obsessive compulsive disorder (2009)
● *About HDEs: 1. Intended for fewer than 4,000 people in the US every year2. Demonstrate the product's safety and probable benefit3. IRB approval is required at each center.
HDE = humanitarian device exemption For more about HDE, please visit http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/ PremarketSubmissions/HumanitarianDeviceExemption/default.htm.
Applications of DBS for intractable Neuropsychiatric disorders● Obsessive Compulsive Disorder✓● Depression✓● Tourette’s Disorder● Substance Use Disorders● Alzheimer’s Disease● Anorexia Nervosa● Autism
DBS in OCD: 1999
●Bilateral stimulation of Anterior Limb of Internal Capsule (ALIC) in severe, chronic OCD
●3 of 4 cases showed improvement●Follow-up in 3 cases showed:–ON/OFF blinded testing confirmed superiority of
stimulation condition– lasting improvement for 6-12 months
Nuttin B, et al. Lancet. 1999;354(9189):1526.
DBS Electrode Placement
AcM = accumbens
ac = anterior commissure
aic = anterior limb of internal capsule
BSTC = bed nucleus of the striatum terminalis
Eligibility for DBS
● Neurosurgical procedure for adults with severe, chronic, and treatment-resistant OCD
● Must have failed multiple medication treatments including SSRIs, clomipramine, and SSRI plus antipsychotic
● Must have failed CBT● Robust informed consent procedures that include spelling
out alternative treatments, detailing risks and acknowledging limited evidence for efficacy
Hamani C, et al. Neurosurgery. 2014;75(4):327-333.
DBS in OCD Study Design
● Subjects: 6 adults with severe, chronic symptoms, failed multiple prior treatments
● Alternatives explained; appropriateness of patients for study evaluated by internal and external review panels
● Bilateral implantation in anterior limb internal capsule● Double-blind, randomized, sham-controlled staggered onset● Funded by NIMH● Devices provided by manufacturer
Goodman WK, et al. Biol Psychiatry. 2010;67(6):535-542.
Change in OCD Severity During DBS
Goodman WK, et al. Biol Psychiatry. 2010;67:535-542.
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OCD-DBS Pilot Study Results
● After 12 months of stimulation, 4/6 (66.7%) of patients met stringent criteria for response
● Patients did not improve during sham● Depressive symptoms improved significantly as a whole as did global
functioning● Adverse events were generally mild and modifiable● Stimulation interruption led to rapid but reversible induction of depressive
symptoms in two cases● Energizing and motivational effects of VC/VS stimulation warrant follow-up
Goodman WK, et al. Biol Psychiatry. 2010;67(6):535-542.
Published*Studies*of*DBS*for*OCD*! !! ALIC* VC/VS* NAc* STN* ITP* BNST* VCN*#*Studies*(32)* 9! 6! 7! 5! 1! 1! 2!#*Patients*(122)* 14! 34! 35! 27! 6! 6! 2!! N=83! N=27! ! ! !ALIC=Anterior!Limb!Internal!Capsule;!VC/VS=Ventral!Capsule/Ventral!Striatum;!STN=Subthalamic!Nucleus;!ITP=Inferior!Thalamic!Peduncle;!BNST=Bed!Nucleus!Stria!Terminalis;!VCN=ventral!caudate!nucleus;!!!
Anatomical Targets for DBS in OCD
● Effects of DBS have been reported in ∼120 cases of OCD for 5 anatomic targets● Overall response rate appears to exceed 50% during bilateral electrical stimulation.● DBS was generally well tolerated, but some unique, target- and stimulation-specific
adverse effects were observed (e.g., hypomania).
Goodman WK, Alterman RL. Annu Rev Med. 2012;63:511-524.
Deep Brain StimulationSafety● Surgical (all indications)
– Intracranial Hemorrhage (1-3%)– Infection (2-5%)– Intraoperative seizure (1.2%)
● Device (all indications)– (1-3%) component malfunction
● Programming in OCD (reversible, can require rapid intervention)– Mood elevation/hypomania/impulsivity (2/26, 8%)– Other DBS-induced AEs
● OFF effects in OCD– Symptom return (3/26, 12%) depression & anxiety > OCD, (possibly stimulation-induced)
Greenberg BD, et al. Mol Psychiatry. 2010;15(1):64-79.
Published Reports on DBS for TRD
TRD = treatment resistant depression, Nac = Nucleus Accumbens; VC/VS = Ventral Capsule/Ventral Striatum; SCG = Subgenual Cingulate Gyrus; ITP = Inferior Thalamic Peduncle; MFB = Medial Forebrain Bundle; LHb = Lateral Habenula
N = 170NAc (N = 14) 11
3Bewernick, Neuropsychopharm, 2012Schlaepfer, Neuropsychopharm, 2008
VC/VS (N = 56)111530
Kubo, Stereo Funct Neurosurg, 2013Malone, Biol Psych, 2009
Dougherty et al, Biol Psych 2015
SCG (N = 90)
7841621172015
Neumann, Mol Psych, 2014Perez-Caballero, Mol Psych, 2014
Ramasubbu, J Psychiatry Neurosci, 2013Lujan, Brain Stim, 2013
Merkl, Exper Neurol, 2013Lozano, J Neurosurg, 2012
Holtzheimer, Arch Gen Psych, 2012Kennedy, Am J Psych, 2011Neimat, Am J Psych, 2008
Puigdemont, J Psych Neurosci, 2015
ITP (N = 1) 1 Jimenez, Neurosurg, 2005
MFB (N = 7) 7 Schlaepfer, Biol Psych, 2013
LHb (N = 2) 11
Kiening, EMBO Mol Med, 2013Sartorius, Biol Psych, 2010
Rationale for DBS Target Selection in Depression● Ventral Capsule/Ventral Striatum (VC/VS)1*– Observation of mood elevation in patients with OCD during DBS– Proximity to NAc and possible stimulation of reward circuitry
● Subcallosal Cingulate Gyrus White Matter (SCGwm)2
– Functional brain imaging studies showing BA25 is metabolically overactive in TRD (Helen Mayberg)
– BA25 activation at baseline is normalized by antidepressant therapy– DBS applied to modulate BA25
*Names of related targets: Anterior Limb of Internal Capsule (ALIC); Nucleus Accumbens (NAc)
Chang WS, Restor Neurol Neurosci. 2013;31(6):723-732. Hilimire MR, et al., Brain Stimul. 2015;8(2):185-191.
VC/VS DBS in DepressionEfficacy
● Malone et al, 2009; N = 15; open-label results– Stringent inclusion criteria, including failed ECT– 40% response rate after 6 months
● Bewernick et al, 2012; N = 11; open-label results– 5/11 (45%) responders at 12 months – sustained at 4 yr follow up– One non-responder committed suicide
● Dougherty et al, 2015; N = 30; double-blind results– Randomized to 4 months active versus sham then open-label– 3/15 (20%) responded to active; 2/14 (14%) responded to sham– Some additional patients improved during open-label continuation phase
Malone DA Jr, et al. Biol Psychiatry. 2009;65(4):267-75. Bewernick BH, et al. Neuropsychopharmacology. 2012;37(9):1975-1985.Dougherty DD, et al. Biol Psychiatry. 2015;78(4):240-248.2
DBS and Sustained Remission in Patients with Depression
Mayberg H, et al. Neuron. 2005;45(5):651-660.
● 4 of 6 patients showed sustained remission after 6 months of DBS
SCG DBS in DepressionEfficacy● Mayberg et al, 2005; N = 6; open-label results
– 4/6 patients in remission after 6 months of DBS
● Kennedy et al, N = 20; open-label results; long-term follow up– Follow up range=3-6 years; at last visit, average response rate=64%– 2 patients died by suicide during depressive relapses
● Lozano et al, 2012; N = 21; 3-center open-label results– 6-month response = 48%; 12-month response = 29% -- increased to 62% when HAM-D responder definition
change to 40% decrease
● Holtzheimer et al, 2012; N = 17; single-blind sham for 4 weeks, then open-label for 24 weeks– Seven with bipolar depression– 10 of 17 (59%) were responders after 24 weeks– Comparable response in bipolar depression
● BROADEN double-blind, sham-controlled study halted because of futility
Mayberg H, et al. Neuron. 2005;45:651-660;;McNeely HE, et al. J Nerv Ment Dis. 2008;196(5):405-10; Lozano AM, et al. Society of Biological Psychiatry 67th annual scientific convention; 2012 May 3–5; Philadelphia, Pa.; Holtzheimer PE, et al. Arch Gen Psychiatry. 2012;69(2):150-158.
Defining Critical White Matter Pathways Mediating Successful Subcallosal Cingulate DBS for Treatment Resistant Depression
● Tractography maps define 3 fiber bundles associated with response to SCC DBS
● Defining this map pre-op can be used for optimizing electrode placement and programming
Riva-Posse P, et al. Biol Psychiatry. 2014;15:76(12):963-969.
Rationale for DBS Target Selection in Depression●Medial Forebrain Bundle (MFB)– Innervation of reward pathways1
– “Hedonic Highway” from VTA to Nucleus Accumbens2
1. Gálvez JF, et al., Prog Neuropsychopharmacol Biol Psychiatry. 2015;58:59-70. 2. Clark D, et al., Chapter 8: Diencephalon: hypothalamus and epithalamus. In: The brain and behavior: an
introduction to behavioral neuroanatomy. 3rd ed., 2010.
Rapid Effects of DBS for Treatment-Resistant Depression
Schlaepfer TW, et al. Biol Psychiatry. 2013;73(12):1204-1212.
● Bilateral DBS Medial Forebrain Bundle (MFB) associated with response in 6 of 7 patients within weeks
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Why Study Other DBS Targets for TRD?● Effects of DBS have been reported in ∼135 cases of TRD for six anatomic
targets● Initial encouraging results with VC/VS, but negative RCT● Most evidence in favor of SCG DBS, but pivotal trial (sponsored by St. Jude;
n∼125) was aborted● Now two negative (or failed?) RCTs● Unclear whether failure to separate groups is attributable to patient selection,
targeting (unlikely in case of VC/VS) or inadequate optimization● Considerable initial enthusiasm for MFB and certainly worth further study● Scientifically strong rationale for Lateral Habenula DBS in TRD and possibly
in other psychiatric conditions involving impaired reward circuit processing
Possible Role of Lateral Habenula in Depression● The LHb is activated when animal fails to receive expected reward
(“disappointment”) or expects an aversive outcome● Output of LHb is inhibitory to major monoaminergic nuclei (VTA [dopamine])
and (DRN [serotonin]) that regulate neurotransmitter systems implicated in depression
● Henn and Sartorius first hypothesized in 2007 that high-frequency DBS would inhibit LHb activity, releasing inhibition of dopamine-containing neurons in the VTA and restoring normal reward circuit function in depressed patients2*
Matsumoto M, Hikosaka O. PLoS One. 2011;6(10):e26701.Ilango A, et al. PLoS One. 2013;8(6):e65684.Proulx C, et al. Nat Neurosci. 2014;17(9):1146–1152.
Pilot Study of LH DBS in TRDOverview ● Aim: To test safety, feasibility and potential efficacy of applying
bilateral DBS to the lateral habenulae in 6 adults with TRD● Investigators: Goodman (PI), Kopell, Henn● Received FDA approval of Investigational Device Exemption (IDE)
and IRB approval● Funding:– Simons Foundation– Devices donated by Medtronic, Inc
Goodman WK. Unpublished data. Clinical trials.gov. Website. A Pilot Study of Deep Brain Stimulation to the Lateral Habenulae in TRD https://clinicaltrials.gov/ct2/show/NCT01798407. Accessed September 11, 2016
SUMMARY Lateral Habenula DBS in TRD●Our preliminary experience with 3 cases of LHb
DBS suggests that this approach is feasible and generally well-tolerated, i.e., stimulation induced side effects were rapidly reversible.
●One case met a priori criteria for response; two were non-responders.
●Dose-limiting side effects of stimulation, especially oculomotor effects, may have interfered with optimal benefits.
DBS in TRD: Challenges & Opportunities● Which target: SCG? MFB? NAc? LHb? Others?● Optimize DBS parameters – difficult to do under double-
blind conditions● Patient selection? Use of biomarkers, including imaging
data● Develop closed loop/demand responsive system● Investigate mechanism of action: may lead to new
treatments, including less invasive approaches
Call to Action
●Consider brain stimulation therapy in your patients with neuropsychiatric disorders and develop referral system
AcknowledgementsBaylor College of Medicine● Aswin Viswanathan, MD, Neurosurgery● Ramiro Salas, PhD, PsychiatryMount Sinai● Fritz Henn, MD, PhD, Psychiatry● Tom Naidich, MD, Radiology● Charles Kellner, MD, Psychiatry● Gordon Xu, PhD, Radiology● Rafael O’Halloran, PhD, Radiology● Kate Burdick, PhD, PsychiatryFunding and Support● Simons Foundation● Medtronic donated devices
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