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.

Pituitary volume in schizophrenia spectrum disorders.

INTRODUCTION: There is converging evidence supporting hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in schizophrenia spectrum disorders (SSD), such as schizotypal personality disorder (SPD), first-episode schizophrenia (FESZ) and chronic schizophrenia (CHSZ). Such an aberrant HPA activity might have volumetric consequences on the pituitary gland. However, previous magnetic resonance imaging (MRI) studies assessing pituitary volume (PV) in SSD are conflicting. The main objective of this study was to examine further PV in SSD. METHODS: PV were manually traced on structural MRIs in 137 subjects, including subjects with SPD (n = 40), FESZ (n = 15), CHSZ (n = 15), and HC (n = 67). We used an ANCOVA to test PV between groups and gender while controlling for inter-subject variability in age, years of education, socioeconomic status, and whole brain volume. RESULTS: Overall, women had larger PV than men, and within the male sample all SSD subjects had smaller PV than HC, statistically significant only for the SPD group. In addition, dose of medication, illness duration and age of onset were not associated with PV. CONCLUSION: Chronic untreated HPA hyperactivity might account for smaller PV in SPD subjects, whereas the absence of PV changes in FESZ and CHSZ patients might be related to the normalizing effects of antipsychotics on PV. SPD studies offer a way to examine HPA related alterations in SSD without the potential confounds of medication effects.

Left medial temporal cytosolic choline in early onset depression.

OBJECTIVE: Previous studies have linked the choline (Cho) resonance seen in proton magnetic resonance spectroscopy (1H-MRS) to major depressive disorder (MDD). We endeavoured to clarify the possible involvement of cytosolic choline in the amygdala (anterior medial temporal region) of juvenile subjects with MDD. METHOD: A total of 11 age- and sex-matched MDD and control pairs aged 14 to 18 years participated in long-echo proton magnetic resonance spectroscopic imaging (1H-MRSI) of the amygdala. Compounds available include N-acetyl-aspartate (NAA), creatine-phosphocreatine (Cr) and choline-containing compounds. RESULTS: Subjects with depression demonstrated lower left amygdala Cho-Cr ratios, compared with control subjects (paired t = 2.624, df 10, P = 0.025). Left amygdala NAA-Cr and right amygdala Cho-Cr and NAA-Cr did not differ significantly between subjects with depression and control subjects. In subjects with depression, simple regression revealed a negative trend between left amygdala Cho-Cr and Beck Depression Inventory (BDI) score (F = 3.509, P = 0.098). Right amygdala NAA-Cr and Cho-Cr did not differ significantly. CONCLUSION: Cytosolic choline appears to be involved in the pathophysiology of early-onset MDD, likely secondary to corticosteroid-neuroendocrine-driven changes.

Decrease in caudate glutamatergic concentrations in pediatric obsessive-compulsive disorder patients taking paroxetine.

OBJECTIVE: To measure in vivo neurochemical changes in the caudate nucleus in pediatric obsessive-compulsive disorder (OCD) before and after treatment. METHOD: Single-voxel proton magnetic resonance spectroscopic (1H-MRS) examinations of the left caudate were conducted in 11 psychotropic drug-naive children, aged 8 to 17 years, with OCD before and after 12 weeks of monotherapy with the selective serotonin reuptake inhibitor paroxetine (10-60 mg/day) and 11 healthy children aged 8 to 17 years. A different sample of 8 pediatric OCD patients and 8 healthy children had a 1H-MRS examination of occipital cortex. RESULTS: Caudate glutamatergic concentrations (Glx) were significantly greater in treatment-naive OCD patients than in controls but declined significantly after paroxetine treatment to levels comparable with those of controls. Decrease in caudate Glx was associated with decrease in OCD symptom severity. Occipital Glx did not differ between OCD patients and controls. CONCLUSIONS: These preliminary findings provide new evidence of Glx abnormalities in the caudate nucleus in pediatric OCD and suggest that paroxetine treatment may be mediated by a serotonergically modulated reduction in caudate Glx.

Neurobiology of childhood obsessive-compulsive disorder.

Despite the observation that obsessive-compulsive disorder (OCD) frequently has its onset during childhood or adolescence, most studies have examined OCD in adults. Because pediatric OCD patients are near illness onset with limited or no medication exposure, this population represents a unique window through which to view the neurobiology of OCD. In this article, the authors summarize data from existing studies of pediatric OCD and attempt to interpret the data within the context of a neurobiologic discourse based largely on research in adults. The authors review current neuroanatomic models of OCD and examine neuroimaging and neuropsychologic studies designed to test those models. In addition, the authors examine irregularities of neurotransmitter systems though to be involved in OCD.

Case study: caudate glutamatergic changes with paroxetine therapy for pediatric obsessive-compulsive disorder.

Neurobiological models for obsessive-compulsive disorder (OCD) have consistently implicated the caudate nucleus in the pathophysiology of this disorder. OCD symptoms improved markedly in a 9-year-old boy treated with paroxetine, a selective serotonin reuptake inhibitor, for whom pre/posttreatment proton magnetic resonance spectroscopic examinations were acquired to assess the relationship between neurochemical profile in the caudate nucleus, symptom severity, and treatment with paroxetine. Striking changes of the glutamate resonance in the caudate were observed after 12 weeks of paroxetine treatment. These data provide further support for glutamatergic-serotonin pathway involvement in the caudate nucleus of OCD patients.

Corpus callosal morphology in treatment-naive pediatric obsessive compulsive disorder.

1. Abnormalities in association circuits have been described in Obsessive Compulsive Disorder (OCD) and may reflect neurodevelopmental abnormalities. Primary and association cortices are topographically mapped in the corpus callosum (CC). The authors hypothesized alterations in CC subdivisions that connect association, but not primary cortices in pediatric OCD. The authors predicted that normal age-related increases in CC area would be absent in OCD. 2. The authors compared the midsagittal magnetic resonance images of 21 psychotropic-naive, nondepressed OCD patients, 7.2-17.7 years, and 21 case-matched healthy controls. Total CC area as well as that of the anterior, middle and posterior genu, anterior and posterior bodies, isthmus, and the anterior, middle and the posterior splenii were measured. 3. All of the CC regions except the isthmus were significantly larger in OCD patients than in controls. CC area correlated significantly with OCD symptom severity but not illness duration. The age-related increase in CC size seen in normal subjects was absent in OCD patients. 4. These findings support theories of abnormal association cortex development in OCD but also suggest possible abnormalities of other primary cortical regions as well.