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

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

Aug 18, 2023 113 likes •822 views

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 Childrens Hospital, Boston Y Conflict of

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TMS in Special Populations

Alexander Rotenberg, M.D., Ph.D.

Director, Neuromodulation Program

  • Dept. Neurology, Div. Epilepsy and Clinical Neurophysiology

Children’s Hospital, Boston

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

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Conflict of Interest Disclosure

Alexander Rotenberg

Current:

Neuro’motion Inc. (co-founder, consultant) NeuroRex Inc. (consultant, medical advisory board) Brainsway Inc. (research support) Soterix Medical Inc. (research support) Neuroelectrics Inc. (research support) Sage Therapeutics Inc. (research support)

Wuhan Yirude Medical Equipment New Technology Co., Ltd. (research support)

Assimon Family Fund (research support) NIH NIMH, NIH NINDS, DoD, CIMIT, ERF, TRP, MassLife, Assimon Family, Autism Speaks (research grants)

Past:

Research support from: Neuropace Inc., Neuronetics Inc., Nexstim Inc., Fisher Family Fund, Al Rashedi Family Fund

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

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NBS in Children

Boston Children’s Hospital Neuromodulation Program

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

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Neuronetics Trial N=164; 23 centers; triple blind L DLPF 10 Hz rTMS 120% MT 4 sec trains 26 sec ITI 3000 pulses/day 2-3 weeks

Lisanby et al., 2008

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

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N=6

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

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N=64 (32: 90% RMT; 32: 20% RMT) 0.5 Hz rTMS over seizure focus

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

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Clinical trials: gaps in knowledge

  • Limited TMS data in pediatrics
  • Few clinical trials segmented by

developmental stage

  • Fragmented pediatric data available from

inclusive prospective trials

14yF 15yF

Fregni et al., 2005

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

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...but, conventional TMS does not reach the temporal lobe

Electrical current distribution (phantom model) Roth and Zangen

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

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1 Hz rTMS in temporal lobe epilepsy, trial in progress

Deep TMS H-Coil System

Boston Children’s Hospital Neuromodulation Program

Epilepsy Therapy Project (PI: Rotenberg) Seizure frequency around rTMS block Seizures per day * rTMS

20 40 60 80 100 120 140 160 sham verum

Seizure frequency (% of baseline)

*

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

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2 4 6

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

First treatment block

seizure cluster 1 2 3 4 5 6

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

Second treatment block

1 2 3 4 5 6

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

Third treatment block

A B C Figure 1

10 sessions rTMS 15 sessions rTMS 30 sessions rTMS

Gersner et al., 2016

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

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Stimulation protocols

Frye, Rotenberg, et al. Child Neurol 2007

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

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Presurgical motor mapping by TMS

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

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Motor cortex TMS in children

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

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Motor TMS example

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

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Right hand (APB) map

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

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Right foot (TA) map

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

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

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Motor map relative to lesion (hand; FDI)

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

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Motor map relative to lesion (foot; TA)

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

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Map identifies surgical access

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

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Presurgical motor mapping by TMS

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

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Dashed: contra Solid: ipsi

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

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

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Left hand Right hand

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

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Healthy 12yF

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

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

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Hand Motor Task - fMRI R hand L hand

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

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N=4 boys with hemispheric polymicrogyria fMRI: ipsilesional BOLD signal in 3 / 4 nTMS: 0 / 4 crossed lesional corticospinal connections 4 / 4 with preserved grasp in paretic hand after hemispherectomy

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

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Right (ipsilesional) Hemisphere Stimulation

Right FDI MEP

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

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Left (ipsilesional) Hemisphere APB Stimulation

APB R APB L

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

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Tib L Tib R

Right (ipsilesional) Hemisphere Stimulation

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

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Color Coded Left and right Tibialis Anterior Map

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

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Special considerations in pediatric TMS

  • Head and brain growth
  • Developmental regulation of

neuronal excitability

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

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Developing brain is a moving target

  • Vulnerability (or resistance) to injury likely

varies with age

  • Studies restricted to narrow age windows are

lacking

  • Subdivision of the pediatric age group may be

necessary

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

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Potential mechanisms for injury to the developing brain

  • Enhanced excitabilty and vulnerability to seizure in

early life

– Risk for excitotoxicity

  • Enhanced synaptic plasticity

– Risk for interference with learning and memory

  • Ongoing neurogenesis, synaptogenesis, myelination,

etc.

– Risk of use‐dependent structural change

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

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Physiology is reflected in disease …and maybe in neurostimulation risks

Status epilepticus by age

DeLorenzo et al., 1992

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

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Motor threshold

Smith et al., 2011

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

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Motor Threshold v. Age

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

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Motor threshold and age

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

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P0 P5 P10 P15 P20 P25 P30 Adult

Neuronal Receptor Expression vs Age

Kainate

% Adult Function

Human Rodent

preterm term 1-2y >10y Adult

EXCITATION INHIBITION excitatory glutamate

Silverstein and Jensen, Ann Neurol, 2007 Rakhade and Jensen, Nature Rev., 2010

GABA (excitatory) GABA (inhibitory) AMPA NMDA

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

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Chloride homeostasis in the immature brain

Ben-Ari 2002

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

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NKCC1:KCC2

0.0 1.0 2.0 3.0 4.0 5.0

****

Fold change

*** **

100 200 300 400

* ***

NKCC1

% of Control

**** **** ****

KCC2

% of Control

20 40 60 80 100 120

NKCC1 and KCC2 expression in autism, as compared epilepsy and controls

Autism Frontal Lobe (A-FL) Autism Temporal Lobe (A-TL) Epilepsy Temporal Lobe (E-TL)

Salah and Talos, in preparation

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

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1

Conditioning TMS 2 Test TMS Control SICI; 2 ms ISI ICF; 12 ms ISI

0.5 mV 25 ms

LICI; 200 ms ISI

0.5 mV 50 ms

Rotenberg and Pascual-Leone, 2010

Measures of Cortical Excitability by Paired‐Pulse TMS (ppTMS)

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

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1

Conditioning TMS 2 Test TMS

50 ms

Paired-pulse MEP inhibition

GABAergic cortical inihibition measures by paired‐pulse TMS (ppTMS)

Rotenberg and Pascual-Leone, 2010

GABA-mediated inhibition

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

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

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

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Stagg et al., J Neurophysiol, 2009

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

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Theta burst stimulation and synaptic plasticity

Oberman et al., Eur. J. Neuroscience, 2012

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

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Hyperplasticity in Autism Spectrum Disorders

0.60 0.70 0.80 0.90 1.00 1.10 1.20 1.30 1.40 1.50 1.60 5 10 20 30 40 50 60 75 90 105 120

cTBS iTBS

Time after TBS [ min] MEP amplitude

[ proportion of baseline]

Baseline

Oberman et al. 2009 & in press

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

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Maturation of motor plasticity

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

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

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Paradoxical facilitation in children with ASD

Oberman et al., 2014

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

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Why is this interesting?

Chloride homeostasis may be dysmature in the ASD brain, and NKCC1 block may rescue the ASD phenotype

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

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CARS: childhood autism rating scale

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

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Threshold: TMS safety in pediatrics

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

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  • N = 40
  • Avg age 12y 7mo
  • no serious adverse events
  • Five of 40 children reported mild,

self-limited adverse events:

  • a subjective sensation of

finger twitching (1)

  • neck stiffness (1)
  • mild headache (3)
  • Total adverse event rate was

11.6%. No emotional changes, as rated with the visual analog mood scale, were identified (p > 0.05).

Wu et al., Annual Meeting Child Neurology Society, 2011

…..Though still limited, pediatric data are emerging

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

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more enjoyable than “a long car ride”

J Child Neurol, 2001

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

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Heart Rate Measures

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

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Heart Rate Stability During nTMS

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

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Right deltoid sample

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

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Right Deltoid sample (stim in CSF)

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

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Right deltoid map

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

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

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Left deltoid and tibialis anterior Motor Maps

Left deltoid Left tibialis anterior Kaye et al., Epilepsy & Behav. Case Repor

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

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Diffusion Tractography Imaging

corticospinal connectivity within the tuber tissue

Kaye et al., Epilepsy & Behav. Case Reports 2016

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

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  • No spurious VNS trigger
  • Minimal current (200 nA X 1 ms)

induced between the leads

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

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rTMS safety after cranial surgery

Rotenberg et al., 2007 Rotenberg and Pascual-Leone 2009

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

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Ex vivo stimulation

Rotenberg et al., Clin Neirophysiol 2007

Titanium Skull Plates and Gold EEG Electrode Temperature vs. Time During 1Hz rTMS

Time (s)

200 400 600 800 1000 1200 1400 1600 1800

Temperature (oC)

20 30 40 50 60 70

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

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Ex vivo stimulation (aneurism clip)

Hsieh et al., Clin Neurophys 2011

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

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THANKS!

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