D O N TMS in Special Populations: O Part 1 T C O P Y - - PowerPoint PPT Presentation

TMS in Special Populations: Part 1

Alexander Rotenberg, M.D., Ph.D. Director, Neuromodulaion Program

• Dept. Neurology, Div. Epilepsy and Clinical Neurophysiology

Children’s Hospital, Boston

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Conflict of Interest Disclosure

Current:

Neuro’motion Inc. (technology for improving emotional control; co-founder) NeuroRex (medical advisor) Brainsway Inc. (research support [equipment and personnel]) Soterix Medical Inc. (research support [equipment]) Neuroelectrics Inc. (research support [equipment]) Journal of Central Nervous System Diseases (EIC) NIH NIMH, DoD, CIMIT, ERF, TRP (research grants)

Past:

Neuropace Inc. (research grant and equipment) Nexstim Inc. (consultant) Sage Therapeutics Inc. (consultant) Fisher Family Fund and Fisher-Wallace Inc. (research support [unrestricted gift and equipment])

Alexander Rotenberg

D O N O T C O P Y

Why Stimulate in Pediatric Neurology?

• Therapeutic

– Pharmacoresistance is prevalent in many disorders

• Epilepsy: ~1/3
• Major Depression: ~1/3
• Tourette syndrome: ~1/4
• Dystonia: most

– Some patients do not tolerate pharmacotherapy

• Diagnostic

– Localize function – Measure cortical excitability – Track a biomarker

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Special considerations in pediatric brain stimulation

• Head and brain growth
• Developmental regulation of

neuronal excitability

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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

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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

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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

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Chloride homeostasis in the immature brain

Ben-Ari 2002

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Physiology is reflected in disease …and maybe in neurostimulation risks

Status epilepticus by age

DeLorenzo et al., 1992

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Maturation of motor plasticity

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Paradoxical facilitation in children with ASD

Oberman et al., 2014

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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

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CARS: childhood autism rating scale

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Ethical Concerns

• Children are a “vulnerable” population
• Consent / assent in healthy volunteers is

difficult

• Better in disease state where potential benefit

to patient, or to field is more apparent

• Strict local guidelines limit investigations

D O N O T C O P Y

Gaps in knowledge

• Limited neurostimulation data in pediatrics
• Few clinical trials segmented by developmetal

stage

• Fragmented pediatric data available from

inclusive prospective trials

14yF 15yF

Fregni et al., 2005

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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

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Dashed: contra Solid: ipsi

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Clinical motor mapping in pediatrics: Sample case

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right FDI map

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left FDI map

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right TA map

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left TA map

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nTMS for motor mapping: Spatial resolution approximates fMRI (and DCS)

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Verification by subdural electrodes

from Rotenberg, 2012

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Motor lateralization in pediatric epilepsy: test of preserved ipsilateral corticospinal connectivity

Lesional and contra-lesional mapping (Rotenberg, unpublished)

Left hand map Right hand map Left hand map

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Patient with hemispheric malformation, referred for motor mapping

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Bilateral hand MEPs with contralesional stimulation of the POSTcentral gyrus

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Healthy 12yF

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Absent MEP with lesional stimulation

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Same patient as previsly: Hand Motor Task - fMRI R hand L hand

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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

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….other special populations

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

induced between the leads

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rTMS safety after cranial surgery

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

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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

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Ex vivo stimulation (aneurism clip)

Hsieh et al., Clin Neurophys 2011

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Threshold: TMS safety in pediatrics

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more enjoyable than “a long car ride”

J Child Neurol, 2001

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Now on to clinical TMS applications in pediatrics…

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