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Y P O C T O Neurological Applications of N Transcranial Magnetic Stimulation O D Mouhsin Shafi, MD/PhD E Berenson-Allen Center for Noninvasive S Brain Stimulation A BIDMC, Harvard Medical School E L P Y P Overview of Talk O

  1. Y P O C T O Neurological Applications of N Transcranial Magnetic Stimulation O D Mouhsin Shafi, MD/PhD E Berenson-Allen Center for Noninvasive S Brain Stimulation A BIDMC, Harvard Medical School E L P

  2. Y P Overview of Talk O C • FDA-Approved Indications T – Presurgical Motor & Language Mapping O – Migraine N • Diagnosis / Prognosis O D – Motor outcome after stroke, Epilepsy, Vegetative state E • Therapeutics S A – Review of results across neurologic indications E L P

  3. Y P Overview of Talk O C • FDA-Approved Indications T – Presurgical Motor & Language Mapping O – Migraine N • Diagnosis / Prognosis O D – Motor outcome after stroke, Epilepsy, Vegetative state E • Therapeutics S A – Review of results across neurologic indications E L P

  4. Y P Motor / Language Mapping O C T O • FDA approval of Nexstim N NBS device for: – Mapping of the primary O motor cortex D – Localization of cortical areas E that do NOT contain S essential speech function A – For pre-procedural planning E L P Picht 2011 Neurosurgery

  5. Y P O Motor Cortical Output Mapping C T O N O D E S A E L P Nagib et al. Neurosurg Clin 2011

  6. Y P O Motor Cortical Output Mapping C Comparing Noninvasive and Invasive Mapping T O N O D E S A E L P Najib et al. Neurosurg Clin 2011

  7. Y Motor mapping P O • Comparing nTMS to Direct C Cortical Stimulation (DCS): – Mean distance between nTMS T & DCS hotspots was 7.83 +/- O 1.18 mm for APB (95% CI 5.36 to 10.36 cm) N – nTMS and DCS hotspots were in same gyrus for all patients O D E S A E L P Picht 2011 Neurosurgery

  8. Y P nTMS vs fMRI O C • Several studies have evaluated accuracy of motor mapping with nTMS vs fMRI (with DCS as gold standard) T O – 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 N – Mangraviti 2013, Neurol Sci : 7 patients, mean distance to DCS O hotspot 8.5 +/- 4.6 mm for nTMS vs 12.9 +/- 5.7 mm for fMRI D Coburger 2013, Neurosurg Rev : 30 E patients; all 30 completed nTMS, S whereas only 23 completed fMRI. A Authors binned results into 4 E levels, where 1 is most accurate, 4 L is least accurate P

  9. Y P Motor mapping w/ nTMS improves outcome? O C • Krieg 2014 Neuro-Oncology : Compared outcomes in 100 consecutive patients bw 2010-2013 vs 100 historical T controls without nTMS from immediately prior period O – All patients underwent intraoperative MEP monitoring as well N – Craniotomy size significantly smaller in nTMS group O – 12 pts in nTMS group improved, vs only 1 in control group D – Residual tumor in 22% of nTMS group vs 42% of controls E S A E L P

  10. Y P Motor mapping w/ nTMS improves outcome? O C • Frey 2014 Neurosurgery : Compared outcomes in 250 consecutive pts from 2007 – 2012 with 115 controls T from 2005-2007 O – 165 cases with intraoperative stimulation mapping, nTMS N location of primary motor cortex confirmed in all cases. O – In 82 cases with navigated intraop stim, mean distance bw D nTMS and DCS hotspot was 6.2 mm (range 0.4 – 14.8 mm) – Gross total resection achieved in 59% of nTMS group vs only E 42% of historical control, with no change in post-op deficits S A Progression-free survival E significantly higher in nTMS group than in control group L P (15.5 vs 12.4 months), although no change in overall survival

  11. Y P Motor mapping w/ nTMS improves outcome? O C • Krieg 2015 BMC Cancer : Compared nTMS outcomes in 70 patients with high-grade (grade III or grade IV) glioma T vs 70 historical controls O – Trend towards decreased permanent weakness in nTMS group N – Greater survival in grade III tumor patients in nTMS group due O to greater percentage achieving gross total resection (but not D present across all patients) – Higher survival rate at 3, 6, 9 and 12 months in nTMS group E S A E L P

  12. Y P And resecting nTMS motor areas is bad O C • Moser 2017 Neurosurgery : Evaluated motor outcomes in 43 patients with Rolandic or T O prerolandic gliomas undergoing nTMS N – 31 patients had nTMS motor points in prerolandic O regions - 13/43 underwent resection D of nTMS-positive points; E 8/13 suffered permanent S paresis A - 30/43 did not undergo any E resection of nTMS-positive L points; only 1/30 suffered P permanent paresis

  13. Y P Language mapping O C • Picht 2013, Neurosurgery : Evaluated nTMS and DCS responses during language mapping in 20 patients with T O tumors close to left-sided language areas N O D E S A E L P

  14. Y P Language mapping … O C T O • A subsequent study (Tarapore 2013, N NeuroImage ) also O demonstrated high D negative predictive value, with E improved specificity S A E L P

  15. Y Compared with fMRI and DCS P O C Ille 2015a, b: T Compared language O mapping results from N rTMS (C) and fMRI (D) O with those from DCS D (B) E S A E L P

  16. Y P And may have beneficial effects O C T O N O D E S A E L P Early language deficits decreased Craniotomy size smaller w/ TMS Sollman 2015

  17. Y P Preoperative mapping using nTMS O C • Review paper: Clinical Neurophysiology 2016 T O N O D E • Operationalization and workflow: World Neurosurgery S A 2017 E L P

  18. Y P Abortive therapy migraine O C • FDA approval for the SpringTMS single-pulse T portable TMS system obtained for abortive therapy O of migraine with aura N – 2 pulses of TMS administered approximately 30s apart to occipital region O D E S A E L P Image from www.medgadget.com

  19. Y P Efficacy in acute migraine O C • Randomized 201 patients with migraine with aura, 1-8 episodes per month, aura for at least 30% of episodes T O – 201 randomized, 164 had migraines and treated N • Higher pain-free response rates after 2 hours (39% in verum vs 22% in sham), sustained at 24 and 48 hours O D HOWEVER, a number of secondary endpoints (patients E who achieved no or mild pain 2h S after treatment, use of rescue A drugs, consistency of pain relief, E global assessment of relief) L showed no significant differences P Lipton, Lancet Neurology 2010

  20. Y P Overview of Talk O C • FDA-Approved Indications T – Presurgical Motor & Language Mapping O – Migraine N • Diagnosis / Prognosis O D – Motor outcome after stroke, Epilepsy, Vegetative state E • Therapeutics S A – Review of results across neurologic indications E L P

  21. Y MEPs predict functional recovery after P acute stroke O C T O N O D E S A E L P Stinear 2012, Brain

  22. Y Paired-pulse measures identify cortical P O hyperexcitability in Epilepsy C T O N O D E S A Paired-pulse measures suggest altered excitation E / inhibition balance in patients with newly- L diagnosed epilepsy compared to healthy controls P Badawy 2007 Ann Neurol

  23. Y P And predict response to medications O C TMS-EMG paired-pulse measures normalize in T patients who respond to O meds; no such changes seen N those with ongoing seizures O D E S A E L P Epilepsy patients, before meds Badawy 2010, Ann Neurol Epilepsy patients, after meds Normal controls

  24. Y P Diagnosis of Persistent Vegetative vs O Minimally Conscious State Casali 2013, Science Trans Med C T O N O D E S A E L Decreased complexity of evoked response in subjects with loss of P consciousness due to any etiology, and in patients with vegetative versus minimally conscious versus locked-in states M /F

  25. Y P Overview of Talk O C • FDA-Approved Indications T – Presurgical Motor & Language Mapping O – Migraine N • Diagnosis / Prognosis O D – Motor outcome after stroke, Epilepsy, Vegetative state E • Therapeutics S A – Review of results across neurologic indications E L P

  26. Y P Theraputic effects? O C • rTMS has been studied as a therapeutic modality in different neurologic conditions including T – Epilepsy O – Migraine prevention N – Motor rehabilitation after stroke O – Cognitive rehabilitation in post-stroke aphasia, post- stroke neglect and Alzheimer’s Disease D – Movement Disorders (primarily Parkinson’s) E – Chronic Pain S – Tinnitus A • However, FDA indication has not been yet obtained E for any of these (multi-center trials currently L underway in several disease conditions) P

  27. Y P Key References O C • Handbook of Clinical Neurology T – Volume 116, Pages 2-763, 2013; Edited by Andres O Lozano and Mark Hallett N – Overview of Deep Brain Stimulation and Noninvasive O Brain Stimulation across spectrum of neurologic D diseases • Lefaucheur et al, Clinical Neurophysiology 2014 E S – Recent evidence-based review/guidelines on A therapeutic use of rTMS in neurologic and psychiatric E diseases L P

  28. Y Principles for successful intervention P O with TMS/tDCS C T • Known brain region or network O • Known goal to enhance or decrease activity of N that network O • Target can be engaged by stimulation D intervention E S A E L P

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