Safety and tolerability of transcranial magnetic and direct current stimulation in children: Prospective single center evidence from 3.5 million stimulations.

BACKGROUND: Non-invasive brain stimulation is being increasingly used to interrogate neurophysiology and modulate brain function. Despite the high scientific and therapeutic potential of non-invasive brain stimulation, experience in the developing brain has been limited. OBJECTIVE: To determine the safety and tolerability of non-invasive neurostimulation in children across diverse modalities of stimulation and pediatric populations. METHODS: A non-invasive brain stimulation program was established in 2008 at our pediatric, academic institution. Multi-disciplinary neurophysiological studies included single- and paired-pulse Transcranial Magnetic Stimulation (TMS) methods. Motor mapping employed robotic TMS. Interventional trials included repetitive TMS (rTMS) and transcranial direct current stimulation (tDCS). Standardized safety and tolerability measures were completed prospectively by all participants. RESULTS: Over 10 years, 384 children underwent brain stimulation (median 13 years, range 0.8-18.0). Populations included typical development (n = 118), perinatal stroke/cerebral palsy (n = 101), mild traumatic brain injury (n = 121) neuropsychiatric disorders (n = 37), and other (n = 7). No serious adverse events occurred. Drop-outs were rare (<1%). No seizures were reported despite >100 participants having brain injuries and/or epilepsy. Tolerability between single and paired-pulse TMS (542340 stimulations) and rTMS (3.0 million stimulations) was comparable and favourable. TMS-related headache was more common in perinatal stroke (40%) than healthy participants (13%) but was mild and self-limiting. Tolerability improved over time with side-effect frequency decreasing by >50%. Robotic TMS motor mapping was well-tolerated though neck pain was more common than with manual TMS (33% vs 3%). Across 612 tDCS sessions including 92 children, tolerability was favourable with mild itching/tingling reported in 37%. CONCLUSIONS: Standard non-invasive brain stimulation paradigms are safe and well-tolerated in children and should be considered minimal risk. Advancement of applications in the developing brain are warranted. A new and improved pediatric NIBS safety and tolerability form is included.

A Case of Transcranial Direct-Current Stimulation for Childhood Stroke Hemiparesis: A Brief Report.

Purpose: Survivors of childhood stroke incur lifelong physical disability. Treatment options are limited, however, models of motor reorganization after stroke are revealing cortical targets for neuromodulation. Transcranial direct-current stimulation (tDCS) enhances motor learning and may improve motor recovery in adult stroke, but remains uninvestigated in childhood-onset stroke. Here we documented the feasibility and safety of tDCS in an adolescent with chronic stroke-induced hemiparesis.Materials and methods: Over 10 days, the participant underwent occupational therapy paired with contralesional, primary motor cortex-targeting, cathodal tDCS. Clinical motor outcomes, and safety and tolerability measures were completed.Results: tDCS was well-tolerated with no adverse events. Motor outcomes did not regress post-intervention, with clinically significant changes still evident at 6 months.Conclusions: Application of controlled trials of non-invasive neuromodulation are safe and tolerability in childhood-onset stroke.

Robotic TMS mapping of motor cortex in the developing brain.

BACKGROUND: The human motor cortex can be mapped safely and painlessly with transcranial magnetic stimulation (TMS) to explore neurophysiology in health and disease. Human error likely contributes to heterogeneity of such TMS measures. Here, we aimed to use recently pioneered robotic TMS technology to develop an efficient, reproducible protocol to characterize cortical motor maps in a pediatric population. NEW METHOD: Magnetic resonance imaging was performed on 12 typically developing children and brain reconstructions were paired with the robotic TMS system. The system automatically aligned the TMS coil to target sites in 3 dimensions with near-perfect coil orientation and real-time head motion correction. Motor maps of 4 forelimb muscles were derived bilaterally by delivering single-pulse TMS at predefined, uniformly spaced trajectories across a 10 × 10 grid (7 mm spacing) customized to the participant's MRI. RESULTS: Procedures were well tolerated with no adverse events. Two male, eight-year-old participants had high resting motor thresholds that precluded mapping. The mean hotspot coordinate and centre of gravity coordinate were determined in each hemisphere for four forelimb muscles bilaterally. Average mapping time was 14.25 min per hemisphere. COMPARISON WITH EXISTING METHODS: Traditional manual TMS methods of motor mapping are time intensive, technically challenging, prone to human error, and arduous for use in pediatrics. This novel TMS robot approach facilitates improved efficiency, tolerability, and precision in derived, high-fidelity motor maps. CONCLUSIONS: Robotic TMS opens new avenues to explore motor map neurophysiology and its influence on developmental plasticity and therapeutic neuromodulation. Our findings provide evidence that TMS robotic motor mapping is feasible in young participants.

Effects of transcranial direct-current stimulation on laparoscopic surgical skill acquisition.

BACKGROUND: Changes in medical education may limit opportunities for trainees to gain proficiency in surgical skills. Transcranial direct-current stimulation (tDCS) can augment motor skill learning and may enhance surgical procedural skill acquisition. The aim of this study was to determine the effects of tDCS on simulation-based laparoscopic surgical skill acquisition. METHODS: In this double-blind, sham-controlled randomized trial, participants were randomized to receive 20 min of anodal tDCS or sham stimulation over the dominant primary motor cortex, concurrent with Fundamentals of Laparoscopic Surgery simulation-based training. Primary outcomes of laparoscopic pattern-cutting and peg transfer tasks were scored at baseline, during repeated performance over 1 h, and again at 6 weeks. Intent-to-treat analysis examined the effects of treatment group on skill acquisition and retention. RESULTS: Of 40 participants, those receiving tDCS achieved higher mean(s.d.) final pattern-cutting scores than participants in the sham group (207·6(30·0) versus 186·0(32·7) respectively; P = 0·022). Scores were unchanged at 6 weeks. Effects on peg transfer scores were not significantly different (210·2(23·5) in the tDCS group versus 201·7(18·1) in the sham group; P = 0·111); the proportion achieving predetermined proficiency levels was higher for tDCS than for sham stimulation. Procedures were well tolerated with no serious adverse events and no decreases in motor measures. CONCLUSION: The addition of tDCS to laparoscopic surgical training may enhance skill acquisition. Trials of additional skills and translation to non-simulated performance are required to determine the potential value in medical education and impact on patient outcomes. Registration number: NCT02756052 (https://clinicaltrials.gov/).

Methylxanthine reversal of opioid-induced respiratory depression in the neonatal rat: mechanism and location of action.

Methylxanthines like caffeine and theophylline have long been used to treat apnea of prematurity. Despite their success in stimulating neonatal breathing, their mechanism of action remains poorly understood. Methylxanthines can act as both non-specific adenosine receptor antagonists and inhibitors of cAMP-dependent phosphodiesterases, sarcoplasmic/endoplasmic reticulum calcium ATPases or receptor-coupled anion channels, depending on the dose used. Though there is evidence for methylxanthine action at the level of the carotid body, the consensus is that methylxanthines stimulate the respiratory centers of the brainstem. Here we used the in situ neonatal rat working heart-brainstem preparation and the ex vivo neonatal rat carotid body preparation to test the hypothesis that methylxanthines act at the level of the carotid body. We conclude that although the neonatal carotid body has active adenosine receptors, the effects of methylxanthine therapy are likely mediated centrally, predominantly via inhibition of cAMP-dependent phosphodiesterase-4.

Stress peptide PACAP stimulates and stabilizes neonatal breathing through distinct mechanisms.

Pituitary adenylate cyclase-activating peptide (PACAP) is an important mediator of the stress response and is crucial in maintaining breathing in neonates. Here we investigate the role of exogenously applied PACAP in neonatal breathing using the neonatal rat in situ working heart-brainstem preparation. A 1-min bolus of 250 nM PACAP-38 caused an increased in respiratory frequency that was rapid and transient, but had no effect on neural tidal volume or neural minute ventilation. Denervation of the carotid body abolished this effect. PACAP had a persistent effect on breathing stability in both carotid body-intact and -denervated preparations, as shown by decreases in respiratory variability 5 min following application. These data suggest that PACAP released during stress acts via carotid body dependent and independent mechanisms to stimulate and stabilize breathing. These mechanisms may account for PACAP's critical role in defending neonatal breathing against environmental stress.