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 0.8e18.0). Populations included typical development (n ¼ 118), perinatal stroke/cerebral palsy (n ¼ 101), mild traumatic brain injury (n ¼ 121) neuropsychiatric disorders (n ¼ 37), and other (n ¼ 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.

Neurophysiology of nonlesioned M1 and its relationship to motor function is measureable in children with perinatal stroke. Correlation of excitability and intracortical circuitry measures between contralateral and ipsilateral sides suggests common control mechanisms.

Posttraumatic headache is one of the most common and disabling symptoms after traumatic brain injury. However, evidence for treating posttraumatic headache is sparse, especially in the pediatric literature. This retrospective chart review evaluated the use of occipital nerve blocks in adolescents treated for posttraumatic headache following mild traumatic brain injury, presenting to the Complex Concussion and Traumatic Brain Injury clinic. Fifteen patients (mean age 15.47; range: 13-17) received occipital nerve block for posttraumatic headache. Follow-up was obtained in 14 patients at 5.57 (standard deviation = 3.52) months postinjury. The headache burden was high, with all except one having headaches 15 or more days per month (median 30, range 10-30). Sixty-four percent reported long-term response to the occipital nerve blocks, with associated improved quality of life and decreased postconcussion symptom scores (P < .05). One patient reported transient allopecia. Occipital nerve blocks are well tolerated and can be helpful in posttraumatic headache.

TMS measures of cortical excitability are altered at one month in children with mTBI. Long interval cortical inhibition is decreased in children who remain symptomatic at one month post-injury.

BackgroundBy the age of sixteen, one in five children will sustain a mild traumatic brain injury also known as concussion. Our research found that one in seven school children with mild traumatic brain injury suffer post-concussion syndrome symptoms for three months or longer. Post-concussion syndrome is associated with significant disability in the child and his/her family and yet there are no evidence-based medical treatments available. Melatonin has several potential mechanisms of action that could be useful following mild traumatic brain injury, including neuroprotective effects. The aim of this study is to determine if treatment with melatonin improves post-concussion syndrome in youths following mild traumatic brain injury. Our hypothesis is that treatment of post-concussion syndrome following mild traumatic brain injury with 3 or 10 mg of sublingual melatonin for 28 days will result in a decrease in post-concussion syndrome symptoms compared with placebo.Methods/DesignNinety-nine youths with mild traumatic brain injury, aged between 13 and 18 years, who are symptomatic at 30 days post-injury will be recruited. This study will be conducted as a randomized, double blind, placebo-controlled superiority trial of melatonin. Three parallel treatment groups will be examined with a 1:1:1 allocation: sublingual melatonin 3 mg, sublingual melatonin 10 mg, and sublingual placebo. Participants will receive treatment for 28 days. The primary outcome is a change on the Post-Concussion Symptom Inventory (Parent and Youth). The secondary outcomes will include neurobehavioral function, health-related quality of life and sleep. Neurophysiological and structural markers of change, using magnetic resonance imaging techniques and transcranial magnetic stimulation, will also be investigated.DiscussionMelatonin is a safe and well-tolerated agent that has many biological properties that may be useful following a traumatic brain injury. This study will determine whether it is a useful treatment for children with post-concussion syndrome. Recruitment commenced on 4 December 2014.Trial registrationThis trial was registered on 6 June 2013 at ClinicalTrials.gov. Registration number: NCT01874847.

Objectives: This study aimed to explore cytokine alterations following pediatric sports-related concussion (SRC) and whether a specific cytokine profile could predict symptom burden and time to return to sports (RTS). Setting: Sports Medicine Clinic. Participants: Youth ice hockey participants (aged 12-17 years) were recruited prior to the 2013-2016 hockey season. Design: Prospective exploratory cohort study. Main Measure: Following SRC, saliva samples were collected and a Sport Concussion Assessment Tool version 3 (SCAT3) was administered within 72 hours of injury and analyzed for cytokines. Additive regression of decision stumps was used to model symptom burden and length to RTS based on cytokine and clinical features. RRelieFF feature selection was used to determine the predictive value of each cytokine and clinical feature, as well as to identify the optimal cytokine profile for the symptom burden and RTS. Results: Thirty-six participants provided samples post-SRC (81% male; age 14.4 ± 1.3 years). Of these, 10 features, sex, number of previous concussions, and 8 cytokines, were identified to lead to the best prediction of symptom severity (r = 0.505, P = .002), while 12 cytokines, age, and history of previous concussions predicted the number of symptoms best (r = 0.637, P < .001). The prediction of RTS led to the worst results, requiring 21 cytokines, age, sex, and number of previous concussions as features (r = −0.320, P = .076). Conclusions: In pediatric ice hockey participants following SRC, there is evidence of saliva cytokine profiles that are associated with increased symptom burden. However, further studies are needed.

Introduction: Early Supported Discharge (ESD) is a clinical flow management service offering interdisciplinary rehabilitation, wherein patients are provided supported in-home rehabilitation treatment; in comparison to conventional hospital-based rehabilitation model of service delivery. There has been little research into the functional outcomes for other types of acquired brain injury (ABI).Methods: In this prospective cohort study, ABI patients presenting at a level I trauma center in Calgary, Canada were placed in either an ESD program or conventional inpatient rehabilitation (IPR) program based on their medical history and presentation. A small number of patients completed both programs (ESD+IPR group). ESD therapies were designed to emulate IPR. Participants completed professionally-rated Mayo-Portland Adaptability Index-4 (MPAI), Quality of Life after Brain Injury (QOLIBRI), Generalized Anxiety Questionnaire-7 (GAD7), Montreal Cognitive Assessment (MoCA), and Patient Health Questionnaire-9 (PHQ9) surveys at 1, 3, and 6 months following initial assessment pre-rehabilitation. Caregivers completed the Zarit Burden Interview (ZBI) at the same time points. The Supervision Rating Scale (SRS) and Disability Rating Scale (DRS) were completed at admission to rehabilitation and all follow-ups. Generalized estimate equations models were used to describe the three groups over time, including age as a covariate.Results: Significant effects of time were reported in the MPAI participant sub-score in the ESD and IPR groups (χ(2)2 = 42.429, p &lt; 0.000; χ(2)2 = 9.773, p = 0.008), showing significantly higher scores between 1 and 3 month timepoints for both groups. ZBI scores were significantly lower in the ESD group at 1 month compared to 3 and 6 months (χ(2)2 = 31.252, p &lt; 0.001). The proportion of patients with medical complications during rehabilitation was 25.3% in ESD compared to 74.7% patients in IPR.Conclusions: Improvements in functional outcomes were evident in patients participating in ESD and IPR, with more medical complications reported in the IPR group. Caregiver burden lessened over time in the ESD group but not in the IPR group. Both ESD and ESD+IPR groups can be considered viable alternatives to traditional inpatient rehabilitation. A randomized control trial would be required to properly compare rehabilitation streams. Further investigation into affective and lifestyle elements of ABI recovery would also improve our understanding of targeted neurorehabilitation in this population.

Introduction: Symptoms following a mild traumatic brain injury (mTBI) usually resolve quickly but may persist past 3 months in up to 15% of children. Mechanisms of mTBI recovery are poorly understood, but may involve alterations in cortical neurophysiology. Transcranial Magnetic Stimulation (TMS) can non-invasively investigate such mechanisms, but the time course of neurophysiological changes in mTBI are unknown. Objective/Hypothesis: To determine the relationship between persistent post-concussive symptoms (PPCS) and altered motor cortex neurophysiology over time. Methods: This was a prospective, longitudinal, controlled cohort study comparing children (8–18 years) with mTBI (symptomatic vs. asymptomatic) groups to controls. Cortical excitability was measured using TMS paradigms at 1 and 2 months post injury. The primary outcome was the cortical silent period (cSP). Secondary outcomes included short interval intracortical inhibition (SICI) and facilitation (SICF), and long-interval cortical inhibition (LICI). Generalized linear mixed model analyses were used to evaluate the effect of group and time on neurophysiological parameters. Results: One hundred seven participants (median age 15.1, 57% female) including 78 (73%) with symptomatic PPCS and 29 with asymptomatic mTBI, were compared to 26 controls. Cortical inhibition (cSP and SICI) was reduced in the symptomatic group compared to asymptomatic group and tended to increase over time. Measures of cortical facilitation (SICF and ICF) were increased in the asymptomatic group and decreased over time. TMS was well tolerated with no serious adverse events. Conclusions: TMS-assessed cortical excitability is altered in children following mild TBI and is dependent on recovery trajectory. Our findings support delayed return to contact sports in children even where clinical symptoms have resolved.