Y P Overview of Talk O Potential Neurological Diagnosis / - PDF document

Y P Overview of Talk O Potential Neurological • Diagnosis / Prognosis Applications of – Presurgical Motor & Language Mapping C – Motor outcome after stroke Transcranial Magnetic Stimulation • Therapeutics across neurologic indications – Migraine (FDA-Cleared) T – Neuropathic Pain Daniel Press, M.D., Clinical Director Berenson-Allen Center for Non-invasive Brain Stimulation, – Stroke (Motor, Aphasia, Neglect) Beth Israel Deaconess Medical Center – Alzheimer’s Disease Associate Professor of Neurology, O – Epilepsy Harvard Medical School – Tinnitus – Parkinson’s disease N O D E Noninvasive Brain Stimulation (eg rTMS or S tDCS) Neuronetics Brainsway Magstim Neuronix • Diagnostic Applications • TMS A • Characterization of underlying neurobiology • Physiologic Biomarker E • Predictor of Treatment Response • Therapeutic Applications L • TMS & tDCS • Stimulation alone or in FDA cleared for the FDA cleared for treatment of medication- P combination with other cortical brain mapping resistant depression. interventions

Y P O Motor / Language Mapping Motor Cortical Output Mapping Umer Najib C • FDA approval of Nexst im NBS device for: – Mapping of the primary motor cortex – Localization of cortical T areas that do NOT contain essential speech function – For pre-procedural planning O Picht 2011 Nagib et al. Neurosurg Clin 2011 N Neurosurgery O D E Motor mapping S Motor Cortical Output Mapping • Comparing nTMS to Direct Cortical Stimulation (DCS): Comparing Noninvasive and Invasive Mapping – Mean distance between nTMS & DCS hotspots was 7.83 +/- A 1.18 mm for APB (95% CI 5.36 to 10.36 cm) – nTMS and DCS hotspots were in same gyrus for all patients E L P Najib et al. Neurosurg Clin 2011 Picht 2011 Neurosurgery

Y P nTMS vs fMRI Motor mapping w/ nTMS improves outcome? O • Krieg 2014 Neurosurgery : Compared outcomes in 100 • Several studies have evaluated accuracy of motor consecutive patients bw 2010-2013 vs 100 historical mapping with nTMS vs fMRI (with DCS as gold standard) controls without nTMS from immediately prior period C – Forster 2011, Neurosurgery : 10 pts, mean distance to DCS hotspot 10.5 +/- 5. 7 mm for nTMS vs 15.0 +/- 7.6 mm for fMRI – All patients underwent intraoperative MEP monitoring as well – Mangraviti 2013, Neurol Sci : 7 patients, mean distance to DCS – Craniotomy size significantly smaller in nTMS group hotspot 8.5 +/- 4.6 mm for nTMS vs 12.9 +/- 5.7 mm for fMRI – 12 pts in nTMS group improved, vs only 1 in control group – Residual tumor in 22% of nTMS group vs 42% of controls Coburger 2013, Neurosurg Rev : 30 T patients; all 30 completed nTMS, whereas only 23 completed fMRI. Authors binned results into 4 O levels, where 1 is most accurate, 4 is least accurate N O D E Language mapping Language mapping … S • Picht 2013, Neurosurgery : Evaluated nTMS and DCS responses during language mapping in 20 patients with A tumors close to left-sided language areas • A subsequent study (T arapore 2013, NeuroImage ) also E demonstrated high negative predictive value, with improved specificity L P

Y P MEPs predict functional recovery after stroke Overview of Talk O • Diagnosis / Prognosis – Presurgical Motor & Language Mapping C – Motor outcome after stroke • Therapeutics across neurologic indications – Migraine (FDA-Cleared) T – Neuropathic Pain – Stroke (Motor, Aphasia, Neglect) – Alzheimer’s Disease O – Epilepsy – Tinnitus Brain 2012 – Parkinson’s disease N O D E Theraputic effects? Overview of Talk S • rTMS has been studied as a therapeutic modality in • Diagnosis / Prognosis different neurologic conditions including – Presurgical Motor & Language Mapping A – Epilepsy – Motor outcome after stroke – Migraine prevention – Motor rehabilitation after stroke • Therapeutics across neurologic indications – Cognitive rehabilitation in post-stroke aphasia, post- E stroke neglect and Alzheimer’s Disease – Migraine (FDA-Cleared) – Movement Disorders (primarily Parkinson’s) – Neuropathic Pain – Chronic Pain L – Stroke (Motor, Aphasia, Neglect) – Tinnitus – Alzheimer’s Disease • However, FDA indication has not been yet obtained – Epilepsy for any of these (multi-center trials currently P underway in several disease conditions) – Tinnitus – Parkinson’s disease

Y P TMS and tDCS for Neurological indications O Principles for successful 0 10 20 30 40 50 60 intervention with TMS/tDCS Percent Improvement (NIBS – Sham) C • Known brain region or network • Known goal to enhance or decrease activity of that network • Target can be engaged by T stimulation intervention O N O D E Key References Blinding in TMS studies is difficult S • TMS produces • Handbook of Clinical Neurology – An auditory clicking sound w/ bone conduction – Volume 116, Pages 2-763, 2013; Edited by Andres A – A tapping sensation (trigeminal afferents) Lozano and Mark Hallett – Contraction of the temporalis and frontalis muscles – Overview of Deep Brain Stimulation and Noninvasive • Particularly problematic in trials in which “real” Brain Stimulation across spectrum of neurologic E diseases stimulation is used to determine motor threshold for titration of stimulation intensity à crossover trials • Lefaucheur et al, Clinical Neurophysiology 2014 L compromised, parallel-group studies are needed! – Recent evidence-based review/guidelines on • Recently, placebo coils that can be preprogrammed therapeutic use of rTMS in neurologic and psychiatric diseases and that use electrical stimulation to produce scalp P sensations have become commercially available

Y P As a result study quality is often poor Abortive therapy migraine O • FDA approval for the SpringTMS single-pulse portable TMS system obtained for abortive therapy C of migraine with aura – 2 pulses of TMS administered approximately 30s apart to occipital region T • Primarily due to lack of allocation concealment and O inadequate blinding of participants (e.g. coil tilted away as sham stimulation group). Random sequence generation also often not specified in reports Shafiet al, in preparation Image from www.medgadget.com N O D E Efficacy in acute migraine Migraine (chronic treatment) S • Randomized 201 patients with migraine with aura, 1-8 • A total of 4 studies evaluating efficacy of rTMS episodes per month, aura for at least 30% of episodes for prophylactic treatment of migraine A – 201 randomized, 164 had migraines and treated • In largest (class III) study of 95 patients, 10 Hz • Higher pain-free response rates after 2 hours (39% in stimulation to L M1 resulted in more than 50% verum vs 22% in sham), sustained at 24 and 48 hours E reduction in headache frequency in 79% of HOWEVER, a number of patients receiving real TMS, vs only 33.3% of pts secondary endpoints (patients receiving sham (Misra 2013 J Neurol ) who achieved no or mild pain 2h L after treatment, use of rescue • Small studies evaluated HF stimulation of LDPFC drugs, consistency of pain relief, with mixed results; LF stimulation of vertex with global assessment of relief) P showed no significant differences no benefit. Lipton, Lancet Neurology 2010

Y P Chronic pain All pain trials O • Trials have attempted to normalize dysregulated corticothalamic pain networks in conditions as diverse as post-stroke pain, complex regional pain C syndrome, fibromyalgia, chronic neuropathic pain, visceral pain, and post-operative pain • Largest crossover study in 60 patients showed rTMS reduced pain by 22% on a VAS scale (vs 8% in sham). T • Studies suggest improvement from HF but not LF stimulation, targeting of M1 but not other regions. • Beneficial response to rTMS may correlate with O subsequent positive outcome of implanted epidural stimulator over M1 Lefaucheur 2014 Clin Neurophys N O D E Motor Rehab after stroke Most studies show a beneficial effect S A E L • High-frequency (“excitatory”) stimulation of ipsilesional hemisphere • Low-frequency (“inhibitory”) stimulation of P contralesional motor cortex Hsu 2012 Stroke Mean effect size of 0.55 in one recent meta-analysis Edwardson 2013 Exp Brain Res

Y P Open questions Effects of parameters? O • Does benefit actually exist? – Multi-center study of “inhibitory” contralesional C navigated rTMS currently underway (NICHE trial) • Optimal type of stimulation – High-frequency ipsilesional vs low-frequency contralesional vs both? T – Acute, subacute or chronic? • Combining brain stimulation with physical O therapy beneficial? Timing? • Current multi-center RCT underway Hsu 2012, Stroke N O D E Task Oriented Rehabilitation S Repetitive T ranscranial Magnetic Stimulation (rTMS) Patient Goals: • Cut food with knife & fork • Cook A • Reach for items above shoulder height • Fasten clothing (buttons, Aiming tool: centering, rotation, tilting zippers, laces) E • Hold grandchild • Hold tools in affected hand • Driving Electrical field display • Golf Parameters: L • 900 pulses Person • 1 Hz rTMS (inhibitory) to M1 of non-lesioned hemisphere • 110% of motor threshold for P Environment Occupation Extensor Digitorum Communis Patient set up Collaborative process (m.EDC) between therapist and patient