Disclosures 10/19/2016. Modulating Brain Networks to Promote Recovery from Brain Injury November 12, Modulating Brain Networks

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1 Modulating Brain Networks to Promote Recovery from Brain Injury November 12, 2016 Alvaro Pascual-Leone, MD, PhD Berenson-Allen Center for Noninvasive Brain Stimulation Harvard Catalyst Beth Israel Deaconess Medical Center Harvard Medical School Alvaro Pascual-Leone, MD, PhD Disclosures Scientific Advisory Board Member for Neuronix, Nexstim, Neosync, J&J, Codman, Starlab, Neuroelectrics, Magstim, Axilum Robotics Serve on Device Expert Panel at FDA Funding from National Institutes of Health, National Science Foundation, Michael J Fox Foundation, Sidney- Baer Foundation I will talk about off-label applications of noninvasive brain stimulation Listed inventor on various patents on combination of noninvasive brain stimulation with EEG and fmri Modulating Brain Networks 1. The proximal cause of the symptoms/disabilities caused by disorders of the nervous system is a dysfunction of specific, plastic neural networks/circuits (circuitopathies) 2. (Noninvasive) Brain Stimulation enables targeted, personalized modulation of specific brain circuits 3. Characterization of the dynamics of such circuits can provide novel insights into the neurobiology of neuropsychiatric diseases and offer new individualized therapeutic opportunities 1

2 Translational Science Research The N of 1 Approach Clinic-guided Reverse Engineering Improved Diagnostic and Therapeutic Approaches Fundamental knowledge Help the patient Constantin Von Monakow Lesion localization Functional localization Symptom (disability) localization 2

3 A. vivid, well-formed and elaborate colorful visual hallucinations of moving people and animals in well defined, non-stereotypic environments Peduncular Hallucinosis Jean Lhermitte, Rev Neurol (Paris) 1922 A. Peduncular Hallucinosis Aaron Boes Brain 2015 Mike Fox Peduncular Hallucinosis Aaron Boes Brain 2015 Mike Fox 3

4 A. Peduncular Hallucinosis Aaron Boes Brain 2015 Mike Fox Lesion Network Overlap A. Lesion Network Mapping Peduncular Hallucinosis Central Post-Stroke Pain Auditory Hallucinosis Subcortical Aphasia Boes et al. Brain 2015 Simon Laganiere Mike Fox Lesion Localization N=15 1 Lesion Network Mapping of Freezing of Gait Network Overlap Functional Connectivity 15.. n= 11 n= 15 Laganiere et al. Neurology

5 Symptoms Localization NIBS Target Frameless Navigation Systems Infrared camera Coil with trackers 5

6 Diagnostic Applications of TMS FDA approved for presurgical mapping (motor & speech) Nagib et al. Neurosurg Clin 2011 Umer Nagib Shahid Bashir Motor Cortical Output Mapping Comparing Noninvasive and Invasive Mapping Alex Golby Nagib et al. Neurosurg Clin 2011 Characterizing Brain Cortical Reactivity 6

7 Robot-guided TMS Target different network nodes in specific order and timing Adaptive close loop system A. Valero-Cabré Sham TMS Modulating Cortical Activity by rtms Differential local impact depending on stimulation frequency 1 Hz TMS or ctbs 20 Hz TMS or itbs Valero-Cabré et al Exp Brain Res 07 A. Valero-Cabré 1 Hz rtms SVA = Splenial visual area Cg = Cingulate Valero-Cabré et al Exp Brain Res 05 7

8 Network impact is defined by the anatomical connections A. Valero-Cabré Valero-Cabré et al Exp Brain Res 05 Merging TMS with fmri: Characterize Neural Networks Amir Amedi Joan Camprodon Mike Fox Need to measure! Modulating Functional Connectivity Eldaief et al PNAS,

9 Modulating Functional Connectivity Mark Halko Eldaief, Halko et al PNAS 2013 Halko et al J Neurosci 2014 Marney Naeser Induction of speech arrest 9

10 Paraphasic Errors Speech Arrest Marney Naeser R R Anterior Pars Triangularis Posterior Pars Triangularis Pars Opercularis Ventral Premotor Cortex Arcuate Fasciculus Seed for Arcuate Fasciculus 10

11 Marney Naeser Modulation of Neural Networks as Therapeutic Strategy Aphasia: Language Circuit - Rt. Pars Triangularis After rtms Pars Triangularis Martin et al Naeser et al. 2006, 07 Modulation of Neural Networks as Therapeutic Strategy Aphasia: Language Circuit - Rt. Pars Triangularis Before After rtms Precision is Important Central Sulcus Diagonal Sulcus Inferior Frontal Sulcus Vertical Ascending Ramus Triangular Sulcus S&V Pictures Named Correctly, post-rtms [Max.=20] PTr post. POp PTr middle M1, mouth PTr ant. 14, , Horizontal Ramus Sylvian Fissure Martin et al Semin Speech Lang. 2004; Curr Neurol Neurosci Rep. 2009; Brain Lang Naeser et al. Neurocase. 2005; Brain Lang. 2005; Cogn Behav Neurol. 2010; Restor Neurol Neurosci Kaplan et al. Neuroimage

12 Named Items 10 day TMS + Speech Rx 10 day TMS Course Naeser et al. Brain Lang 2011; Arch PMR 2012 Adaptive Plasticity Aphasia Maladaptive Plasticity NINDS; NICH Promoting Motor Recovery After Stroke Before After rtms 12

13 Predicted CLinical Efficacy 10/19/2016 Combine NIBS with Other Therapy Edwards D.J., Krebs H.I., Volpe B. Mechanical Engineering, MIT Burke Rehab Institute, Cornell Univ. NY NINDS, NICHD Proof-of-Principle Non-fluent aphasia Hand motor function following stroke FDA premarket [Nexstim] Depression 4 FDA approved systems, insurance covered Pain / Migraine FDA approved system Cognitive dysfunction Dementia / AD - FDA premarket [Neuronix] Empathy Social Behavior Autism [NIH] Akinesia & Bradykinesia PD [MJFF] Gait, Posture, Ataxia SCA [NIH] Cognitive Control Addictive Behavior [NIH] Focal E/I imbalance focal epilepsy [NIH; CURE] etc Mike Fox Defining Cortical Target to Enhance Efficacy rs-fcmri for TMS in Depression Clinical Efficacy versus SG AntiCorrelation 0.8 R² = Correlation with Subgenual Fox et al Biological Psych 2012; Neuroimage

14 BOLD Signal (% change) 10/19/2016 FDA approved Treatment for Medication-Resistant Depression Lancet 1996 Pascual-Leone et al Lancet 1996 O Reardon et al Biol Psych 2007 Janicak et al J Clin Psych 2008 TMS for Medication-Resistant Depression Changing Lives! >500 systems in clinical use in the US 250 days/year & 5 patients/day = 625,000 treatments per year avg. 25 treatment sessions/patient = 25,000 patients per year 30% remission rate = 7,500 remitters per year 20 remitters per day Individualized TMS targets for depression X = X 2 = 2 X = X -4 = -4 Subgenual Seed Time (sec) X = X -4 = Group Map Subject 1 Subject 2 Fox et al Neuroimage 14

15 Stimweaver: Multifocal tcs & EEG-modulated tacs Rs-fcMRI with Subgenual Simulated E field Ruffini et al. Neuroimage 2015 Distributed cortical field Mike Fox Neuroelectrics EEG-guided stimulation frequency Multifocal tcs & Concurrent EEG Multifocal targeting may translate in greater behavioral/therapeutic impact M. Fox et al. PNAS

16 Combine Brain Stimulation with Other Interventions e.g. VRT, PT with Robotic Support Plow E, Merabet L Monitor for VRT presentation Eye Tracking Camera Cathode Electrode Eye Tracking System Visual Stimulus Fixation Target Anode Electrode Response Button tdcs Device Home Use? Medina J, Vidal J, Tormos JM, et al Institut Guttmann Edwards D.J., Krebs H.I., Volpe B. Mechanical Engineering, MIT Burke Rehab Institute, Cornell Univ. NY Conclusions 1. Noninvasive brain stimulation - combined with EEG, fmri, etc - can serve to examine and characterize human neural network dynamics 2. Individually-tailored (spatial and temporal), neuronavigated noninvasive stimulation enables targeted, specific brain circuit modulation and offers novel therapeutic approaches in neurorehabilitation An essential first step is the precise characterization of the clinical phenotype Reverse engineering from symptoms to functional localization 16