Background: Transcranial direct current stimulation (tDCS) is a safe, tolerable, and acceptable technique in adults. However, there is limited evidence for its safety in youth. Although limited, there are a handful of important empirical articles that have evaluated safety and tolerability outcomes in youth. However, a synthesis of pediatric safety studies is not currently available. Objective: To synthesize objective evidence regarding the safety and tolerability of pediatric tDCS based on the current state of the literature. Methods: Our search and report used PRISMA guidelines. Our method systematically examined investigations purposefully designed to evaluate the safety, tolerability, and acceptability of tDCS in healthy and atypical youth that were submitted to three databases, from the beginning of the database to November 2019. Safety considerations were evaluated by studies utilizing neuroimaging, physiological changes, performance on tasks, and by analyzing reported and objective side effects; tolerability via rate of adverse events; and acceptability via rate of dropouts. Results: We report on 203 sham sessions, 864 active sessions up to 2 mA, and 303 active hours of stimulation in 156 children. A total of 4.4% of the active sessions were in neurotypical controls, with the other 95.6% in clinical subjects. Conclusion: In spite of the fact that the current evidence is sporadic and scarce, the presently reviewed literature provides support for the safety, tolerability, and acceptability, of tDCS in youth for 1–20 sessions of 20 min up to 2 mA. Future pediatric tDCS research is encouraged.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique with substantial evidence for its safety and tolerability in adults. However, less than 5% of published tDCS research is in pediatrics. Our primary objective was to investigate tDCS safety, tolerability, and acceptability in a sample of children and adults. We hypothesized that children and adults would be equal with regard to tDCS safety, tolerability, and acceptability. We tested this hypothesis using a Bayesian approach. Sixty participants aged 6–45 (balanced for sex) participated in a randomized double-blind controlled trial. They were randomly assigned to two ten-minute tDCS sessions with varying amperages and electrode locations. The primary outcome measure of this study was the intensity of 13 potential side effects evaluated at six different time points spanning two weeks. Independent sample Bayes factor tests were conducted between children/adults, males/females, clinical/healthy, and low/high amperage groups. As predicted, there was moderate support for the null hypothesis in all between-group analyses. There were no serious adverse events or dropouts, and the number needed to treat for an additional harmful outcome was 23. This study provided evidence supporting the overall short-term safety, tolerability, and acceptability of tDCS including amperages up to 2 mA and different electrode placements.

The effect of levodopa in alleviating the symptoms of Parkinson’s disease is altered in a highly nonlinear manner as the disease progresses. This can be attributed to different compensation mechanisms taking place in the basal ganglia where the dopaminergic neurons are progressively lost. This alteration in the effect of levodopa complicates the optimization of a drug regimen. The present work aims at investigating the nonlinear dynamics of Parkinson’s disease and its therapy through mechanistic mathematical modeling. Using a holistic approach, a pharmacokinetic model of levodopa was combined to a dopamine dynamics and a neurocomputational model of basal ganglia. The influence of neuronal death on these different mechanisms was also integrated. Using this model, we were able to investigate the nonlinear relationships between the levodopa plasma concentration, the dopamine brain concentration, and a response to a motor task. Variations in dopamine concentrations in the brain for different levodopa doses were also studied. Finally, we investigated the narrowing of a levodopa therapeutic index with the progression of the disease as a result of these nonlinearities. In conclusion, various consequences of nonlinear dynamics in Parkinson’s disease treatment were studied by developing an integrative model. This model paves the way toward individualization of a dosing regimen. Using sensor based information, the parameters of the model could be fitted to individual data to propose optimal individual regimens.

Background: Some pediatric patients with attention-deficit/hyperactivity disorder (ADHD) use natural health products (NHPs) such as herbal remedies. Although herbal remedies are generally considered to be safe when they are used appropriately, they may contain active components that can interact with medications being used concurrently, with potential for NHP-drug interactions leading to adverse events. Objectives: The objectives of this study were (1) to identify adverse event reports (AERs) involving commonly used herbal remedies and ADHD prescription medicines in children and adolescents; (2) to evaluate the quality of collected AERs; and (3) to assess whether NHP-drug interactions can be causally linked to reported adverse events. Methods: We systematically searched the FDAble database (FDAble.com) for herbal remedies commonly used by patients (4–18 years old) also taking ADHD drugs from 1997 to 2015. We assessed the completeness of the AERs and used three causality assessment tools modified for NHPs (Naranjo Adverse Drug Reaction Probability Scale, HORN Drug Interaction Probability Scale, and World Health Organization Uppsala Monitoring Centre Scale). Results: Of the 23 identified AERs involving both an herbal remedy and an ADHD prescription medication, most involved multiple (>3) substances with inadequate detail to assess multiple potential interactions. Following data extraction and evaluation of completeness, five AERs involving only one herbal remedy and one ADHD medication were evaluated for causality. An NHP-drug interaction was assessed to be probable in one case and to be possible in another. Both these reports involved a methylphenidate formulation and St. John's wort. Conclusions: Eighteen of the 23 identified AERs involving both an herbal remedy and an ADHD drug also involved other multiple ingredient products. The reporting quality was poor for the five AERs examined. Further research is needed to study the interaction between St. John's wort and methylphenidate.

The interest in using non-invasive brain stimulation (NIBS) for the treatment of major depression (MD), including treatment resistant depression, is growing rapidly. The paper by Bennabi and Haffen (Brain Sci. 2018, 8) was an important step towards the formal acceptance of transcranial direct current stimulation (tDCS) as a possible form of therapy. Their review demonstrated favourable support for the beneficial effects of tDCS for MD, coupled with necessary practical considerations, such as its relatively low cost, portability/ease of use in clinical settings, non-invasiveness, and good tolerability. Here, we provide a follow-up to their review and sketch a current update. Means for optimizing tDCS efficacy and potential limitations of current studies are discussed.