D O N TMS in Special Populations: O Part 1 T C O P Y Alexander Rotenberg, M.D., Ph.D. Director, Neuromodulaion Program Dept. Neurology, Div. Epilepsy and Clinical Neurophysiology Children’s Hospital, Boston
Conflict of Interest Disclosure D O Alexander Rotenberg N O Current: T Neuro’motion Inc. (technology for improving emotional control; co-founder) NeuroRex (medical advisor) Brainsway Inc. (research support [equipment and personnel]) C Soterix Medical Inc. (research support [equipment]) Neuroelectrics Inc. (research support [equipment]) O Journal of Central Nervous System Diseases (EIC) NIH NIMH, DoD, CIMIT, ERF, TRP (research grants) P Past: Y 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])
Why Stimulate in Pediatric Neurology? D O • Therapeutic N – Pharmacoresistance is prevalent in many disorders • Epilepsy: ~1/3 O • Major Depression: ~1/3 T • Tourette syndrome: ~1/4 • Dystonia: most C – Some patients do not tolerate pharmacotherapy O • Diagnostic P – Localize function Y – Measure cortical excitability – Track a biomarker
Special considerations in pediatric D brain stimulation O N O • Head and brain growth T • Developmental regulation of C neuronal excitability O P Y
Developing brain is a moving target D O N • Vulnerability (or resistance) to injury likely O varies with age T • Studies restricted to narrow age windows are C lacking O • Subdivision of the pediatric age group may be P Y necessary
Potential mechanisms for injury to the D developing brain O N • Enhanced excitabilty and vulnerability to seizure in early life O – Risk for excitotoxicity T • Enhanced synaptic plasticity C – Risk for interference with learning and memory O • Ongoing neurogenesis, synaptogenesis, myelination, P etc. Y – Risk of use-dependent structural change
Neuronal Receptor Expression vs Age D O GABA (excitatory) GABA (inhibitory) EXCITATION N NMDA excitatory AMPA % Adult Function glutamate O Kainate T C O P INHIBITION Y P0 P5 P10 P15 P20 P25 P30 Adult Rodent Human preterm term 1-2y >10y Adult Silverstein and Jensen , Ann Neurol, 2007 Rakhade and Jensen, Nature Rev., 2010
Chloride homeostasis in the immature brain D O N O T C O P Y Ben-Ari 2002
Physiology is reflected in disease …and maybe in neurostimulation risks D O Status epilepticus by age N O T C O P Y DeLorenzo et al., 1992
D O N O T Maturation of motor C plasticity O P Y
Paradoxical facilitation in children with ASD D O N O T C O P Y Oberman et al., 2014
Why is this interesting? D O N O T C O P Y Chloride homeostasis may be dysmature in the ASD brain, and NKCC1 block may rescue the ASD phenotype
D O N CARS: childhood autism rating scale O T C O P Y
Ethical Concerns D O • Children are a “vulnerable” population N • Consent / assent in healthy volunteers is O difficult T • Better in disease state where potential benefit C to patient, or to field is more apparent O • Strict local guidelines limit investigations P Y
Gaps in knowledge D O • Limited neurostimulation data in pediatrics N • Few clinical trials segmented by developmetal O stage T • Fragmented pediatric data available from C inclusive prospective trials O P Y 15yF 14yF Fregni et al., 2005
…..Though still limited, pediatric data are emerging D O N O - N = 40 T - Avg age 12y 7mo - no serious adverse events C - Five of 40 children reported mild, self-limited adverse events: O - a subjective sensation of finger twitching (1) P - neck stiffness (1) Y - 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
D O N O T C O P Y Dashed: contra Solid: ipsi
Clinical motor mapping in pediatrics: Sample case D O N O T C O P Y
right FDI map D O N O T C O P Y
left FDI map D O N O T C O P Y
right TA map D O N O T C O P Y
left TA map D O N O T C O P Y
nTMS for motor mapping: D Spatial resolution approximates fMRI (and DCS) O N O T C O P Y
Verification D by subdural O electrodes N O T C O P Y from Rotenberg, 2012
Motor lateralization in pediatric epilepsy: test of preserved ipsilateral corticospinal connectivity D O N O T C O Left hand map Right hand map Left hand map P Y Lesional and contra-lesional mapping (Rotenberg, unpublished)
Patient with hemispheric malformation, referred for motor mapping D O N O T C O P Y
Bilateral hand MEPs with contralesional stimulation of the POSTcentral gyrus D O N O T C O P Y
D O N O T C O Healthy 12yF P Y
Absent MEP with lesional stimulation D O N O T C O P Y
Same patient as previsly: Hand Motor Task - fMRI D O R hand N O T C O P L hand Y
D O N O T C N=4 boys with hemispheric polymicrogyria O fMRI: ipsilesional BOLD signal in 3 / 4 P nTMS: 0 / 4 crossed lesional corticospinal connections Y 4 / 4 with preserved grasp in paretic hand after hemispherectomy
….other special populations D O N O T C O P Y
D O N O T C O - No spurious VNS trigger - Minimal current (200 nA X 1 ms) P induced between the leads Y
rTMS safety after cranial surgery D O N O T C O P Y Rotenberg et al., 2007 Rotenberg and Pascual-Leone 2009
Ex vivo stimulation D Titanium Skull Plates and Gold EEG Electrode O Temperature vs. Time During 1Hz rTMS N 70 O 60 T Temperature ( o C) C 50 O 40 P Y 30 20 0 200 400 600 800 1000 1200 1400 1600 1800 Time (s) Rotenberg et al., Clin Neirophysiol 2007
Ex vivo stimulation (aneurism clip) D O N O T C O P Y Hsieh et al., Clin Neurophys 2011
Threshold: TMS safety in pediatrics D O N O T C O P Y
J Child Neurol, 2001 D O N O T more enjoyable than “a long car ride” C O P Y
D Now on to clinical TMS applications in pediatrics… O N O T C O P Y
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