Y P O C T O N O TMS in Special Populations D E S A E - PowerPoint PPT Presentation

Y P O C T O N O TMS in Special Populations D E S A E Alexander Rotenberg, M.D., Ph.D. L Director, Neuromodulation Program P Dept. Neurology, Div. Epilepsy and Clinical Neurophysiology Children’s Hospital, Boston

Y Conflict of Interest Disclosure P O C T Alexander Rotenberg O Current: N Neuro’motion Inc. (co-founder, consultant) NeuroRex Inc. (consultant, medical advisory board) O Brainsway Inc. (research support) Soterix Medical Inc. (research support) D Neuroelectrics Inc. (research support) Sage Therapeutics Inc. (research support) E Wuhan Yirude Medical Equipment New Technology Co., Ltd. (research support) Assimon Family Fund (research support) S NIH NIMH, NIH NINDS, DoD, CIMIT, ERF, TRP, MassLife, Assimon Family, Autism Speaks (research grants) A E Past: Research support from: Neuropace Inc., Neuronetics Inc., Nexstim Inc., Fisher Family Fund, Al L Rashedi Family Fund P

Y P NBS in Children O C T O N O D E S A E L P Boston Children’s Hospital Neuromodulation Program

Y P Neuronetics Trial O C N=164; 23 centers; triple blind T O L DLPF 10 Hz rTMS 120% MT N 4 sec trains O 26 sec ITI 3000 pulses/day D 2-3 weeks E S Lisanby et al., 2008 A E L P

N=6 Y P O C T O N O D E S A E L P

Y P O C T O N O N=64 (32: 90% RMT; 32: 20% RMT) D 0.5 Hz rTMS over seizure focus E S A E L P

Y P Clinical trials: gaps in knowledge O C • Limited TMS data in pediatrics T O • Few clinical trials segmented by N developmental stage O • Fragmented pediatric data available from D inclusive prospective trials E S A 15yF 14yF E L P Fregni et al., 2005

Y P ...but, conventional TMS does not reach the temporal lobe O C T O N O D E S Electrical current distribution A (phantom model) E L P Roth and Zangen

Y 1 Hz rTMS in temporal lobe epilepsy, P trial in progress O C T O N Boston Children’s Hospital Neuromodulation Program O D 160 Epilepsy Therapy Project (PI: Rotenberg) E Seizure frequency around rTMS block 140 Seizure frequency (% of baseline) 120 S Seizures per day 100 A 80 * E 60 L 40 P 20 * rTMS 0 sham verum Deep TMS H-Coil System

Y Figure 1 P A First treatment block O 6 10 sessions rTMS 4 C 2 T 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 2 4 6 8 10 12 14 16 18 20 22 24 26 28 O seizure cluster N B Second treatment block 6 O 5 15 sessions rTMS 4 D 3 2 1 E 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 2 4 6 8 10 12 14 16 18 20 22 24 26 28 S C A Third treatment block 6 E 5 30 sessions rTMS 4 L 3 P 2 1 0 1 3 5 7 9 11 13 15 17 19 21 23 25 27 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Gersner et al., 2016

Y Stimulation protocols P O C T O N O D E S A E L P Frye, Rotenberg, et al. Child Neurol 2007

Y Presurgical motor mapping by TMS P O C T O N O D E S A E L P

Y P Motor cortex TMS in children O C T O N O D E S A E L P

Y P Motor TMS example O C T O N O D E S A E L P

Y P Right hand (APB) map O C T O N O D E S A E L P

Y P Right foot (TA) map O C T O N O D E S A E L P

Y P O C T O N O D E S A E L P

Y Motor map relative to lesion (hand; FDI) P O C T O N O D E S A E L P

Y Motor map relative to lesion (foot; TA) P O C T O N O D E S A E L P

Y Map identifies surgical access P O C T O N O D E S A E L P

Y Presurgical motor mapping by TMS P O C T O N O D E S A E L P

Y P O C T O N O D E S A E L P Dashed: contra Solid: ipsi

Y P O C T O N O D E S A E L P

Right hand Left hand Y P O C T O N O D E S A E L P

Healthy 12yF Y P O C T O N O D E S A E L P

Y P O C T O N O D E S A E L P

Y P O C T O N O D E S A Hand Motor Task - fMRI E L P R hand L hand

Y P O C T O N O D N=4 boys with hemispheric polymicrogyria E fMRI: ipsilesional BOLD signal in 3 / 4 S nTMS: 0 / 4 crossed lesional corticospinal connections A 4 / 4 with preserved grasp in paretic hand after hemispherectomy E L P

Y Right (ipsilesional) Hemisphere Stimulation P O C T O N O D E Right FDI MEP S A E L P

Y Left (ipsilesional) Hemisphere APB Stimulation P APB O R C T O N O D E S A E APB L L P

Y Right (ipsilesional) Hemisphere Stimulation P O C T O N O Tib L D E S A Tib R E L P

Y Color Coded Left and right Tibialis Anterior P O Map C T O N O D E S A E L P

Y P Special considerations in pediatric TMS O C T O • Head and brain growth N • Developmental regulation of O D neuronal excitability E S A E L P

Y P Developing brain is a moving target O C T O • Vulnerability (or resistance) to injury likely N varies with age O • Studies restricted to narrow age windows are D lacking E S • Subdivision of the pediatric age group may be A necessary E L P

Y P Potential mechanisms for injury to the O developing brain C T • Enhanced excitabilty and vulnerability to seizure in O early life N – Risk for excitotoxicity O • Enhanced synaptic plasticity D – Risk for interference with learning and memory E • Ongoing neurogenesis, synaptogenesis, myelination, S etc. A E – Risk of use ‐ dependent structural change L P

Y Physiology is reflected in disease …and P maybe in neurostimulation risks O C Status epilepticus by age T O N O D E S A E L P DeLorenzo et al., 1992

Smith et al., 2011 Y P O C Motor threshold T O N O D E S A E L P

Y P Motor Threshold v. Age O C T O N O D E S A E L P

Y Motor threshold and age P O C T O N O D E S A E L P

Y Neuronal Receptor Expression vs Age P O C GABA (excitatory) GABA (inhibitory) T EXCITATION NMDA excitatory O AMPA glutamate % Adult Function Kainate N O D E S INHIBITION A E P0 P5 P10 P15 P20 P25 P30 Adult L Rodent P Human preterm term 1-2y >10y Adult Silverstein and Jensen , Ann Neurol, 2007 Rakhade and Jensen, Nature Rev., 2010

Y Chloride homeostasis in the immature brain P O C T O N O D E S A E L P Ben-Ari 2002

Y NKCC1 and KCC2 expression in autism, as compared P epilepsy and controls O C NKCC1 KCC2 120 T 400 **** % of Control % of Control 100 *** O 300 **** 80 **** * N 200 60 40 O 100 20 D 0 0 E NKCC1:KCC2 S 5.0 A **** Fold change 4.0 E *** Autism Frontal Lobe (A-FL) ** 3.0 L Autism Temporal Lobe (A-TL) Epilepsy Temporal Lobe (E-TL) 2.0 P 1.0 0.0 Salah and Talos, in preparation

Measures of Cortical Excitability by Y P Paired ‐ Pulse TMS (ppTMS) O C Conditioning TMS Control T 1 Test TMS O 2 N SICI; 2 ms ISI O D E ICF; 12 ms ISI 0.5 mV S 25 ms A E L P LICI; 200 ms ISI 0.5 mV 50 ms Rotenberg and Pascual-Leone, 2010

GABAergic cortical inihibition measures Y P by paired ‐ pulse TMS (ppTMS) O C Conditioning TMS T Paired-pulse MEP inhibition 1 O Test TMS 2 N GABA-mediated O inhibition D E S A Rotenberg and Pascual-Leone, 2010 50 ms E L P

Y P O C T O N O D E S A E L P

Y P O C T O N O D E S A E L P

Y P O C T O N O D E S A E L P Stagg et al., J Neurophysiol , 2009

Y Theta burst stimulation and synaptic plasticity P O C T O N O D E S A E L P Oberman et al., Eur. J. Neuroscience, 2012

Y Hyperplasticity in Autism Spectrum P O Disorders C T 1.60 O iTBS 1.50 [ proportion of baseline] N 1.40 MEP amplitude O 1.30 D 1.20 1.10 E 1.00 Baseline S 0.90 A 0.80 E 0.70 L cTBS 0.60 P 5 10 20 30 40 50 60 75 90 105 120 Time after TBS [ min] Oberman et al. 2009 & in press

Y P O C T O N O D E S A E Maturation of motor L P plasticity

Y P O C T O N O D E S A E L P

Y Paradoxical facilitation in children with ASD P O C T O N O D E S A E L P Oberman et al., 2014

Y Why is this interesting? P O C T O N O D E S A E L P Chloride homeostasis may be dysmature in the ASD brain, and NKCC1 block may rescue the ASD phenotype

Y P O C T O N O D E S A CARS: childhood autism rating scale E L P

Threshold: TMS safety in pediatrics Y P O C T O N O D E S A E L P

Y …..Though still limited, pediatric data are emerging P O C T O N - N = 40 - Avg age 12y 7mo O - no serious adverse events D - Five of 40 children reported mild, self-limited adverse events: E - a subjective sensation of finger twitching (1) S - neck stiffness (1) A - mild headache (3) E - Total adverse event rate was 11.6%. No emotional changes, as L rated with the visual analog mood P scale, were identified (p > 0.05). Wu et al., Annual Meeting Child Neurology Society, 2011

Y P J Child Neurol, 2001 O C T O N O more enjoyable than “a long car ride” D E S A E L P