Feasibility study to unveil the potential: considerations of constrained spherical deconvolution tractography with unsedated neonatal diffusion brain MRI data.

Purpose: The study aimed to (1) assess the feasibility constrained spherical deconvolution (CSD) tractography to reconstruct crossing fiber bundles with unsedated neonatal diffusion MRI (dMRI), and (2) demonstrate the impact of spatial and angular resolution and processing settings on tractography and derived quantitative measures. Methods: For the purpose of this study, the term-equivalent dMRIs (single-shell b800, and b2000, both 5 b0, and 45 gradient directions) of two moderate-late preterm infants (with and without motion artifacts) from a local cohort [Brain Imaging in Moderate-late Preterm infants (BIMP) study; Calgary, Canada] and one infant from the developing human connectome project with high-quality dMRI (using the b2600 shell, comprising 20 b0 and 128 gradient directions, from the multi-shell dataset) were selected. Diffusion tensor imaging (DTI) and CSD tractography were compared on b800 and b2000 dMRI. Varying image resolution modifications, (pre-)processing and tractography settings were tested to assess their impact on tractography. Each experiment involved visualizing local modeling and tractography for the corpus callosum and corticospinal tracts, and assessment of morphological and diffusion measures. Results: Contrary to DTI, CSD enabled reconstruction of crossing fibers. Tractography was susceptible to image resolution, (pre-) processing and tractography settings. In addition to visual variations, settings were found to affect streamline count, length, and diffusion measures (fractional anisotropy and mean diffusivity). Diffusion measures exhibited variations of up to 23%. Conclusion: Reconstruction of crossing fiber bundles using CSD tractography with unsedated neonatal dMRI data is feasible. Tractography settings affected streamline reconstruction, warranting careful documentation of methods for reproducibility and comparison of cohorts.

Structural network topology associated with naming improvements following intensive aphasia therapy in post-stroke aphasia.

A stroke can disrupt the finely tuned language network resulting in aphasia, a language impairment. Though many stroke survivors with aphasia recover within the first 6 months, a significant proportion have lasting deficits. The factors contributing to optimal treatment response remain unclear. Some evidence suggests that increased modularity or fragmentation of brain networks may underlie post-stroke aphasia severity and the extent of recovery. We examined associations between network organization and aphasia recovery in sixteen chronic stroke survivors with non-fluent aphasia following 35 h of Multi-Modality Aphasia Therapy over 10 days and 20 healthy controls who underwent imaging at a single timepoint. Using diffusion-weighted scans obtained before and after treatment, we constructed whole-brain structural connectomes representing the number of probabilistic streamlines between brain regions. Graph theory metrics were quantified for each connectome using the Brain Connectivity Toolbox. Correlations were examined between graph metrics and speech performance measured using the Boston Naming Test (BNT) at pre-, post- and 3-months post-intervention. Compared to controls, participants with stroke demonstrated higher whole-brain modularity at pre-treatment. Modularity did not differ between pre- and post-treatment. In individuals who responded to therapy, higher pre-treatment modularity was associated with worse performance on the BNT. Moreover, higher pre-treatment participation coefficients (i.e., how well a region is connected outside its own module) for the left IFG, planum temporale, and posterior temporal gyri were associated with greater improvements at post-treatment. These results suggest that pre-treatment network topology may impact therapeutic gains, highlighting the influence of network organization on post-stroke aphasia recovery.

Executive functioning, ADHD symptoms and resting state functional connectivity in children with perinatal stroke.

Perinatal stroke describes a group of focal, vascular brain injuries that occur early in development, often resulting in lifelong disability. Two types of perinatal stroke predominate, arterial ischemic stroke (AIS) and periventricular venous infarction (PVI). Though perinatal stroke is typically considered a motor disorder, other comorbidities commonly exist including attention-deficit hyperactivity disorder (ADHD) and deficits in executive function. Rates of ADHD symptoms are higher in children with perinatal stroke and deficits in executive function may also occur but underlying mechanisms are not known. We measured resting state functional connectivity in children with perinatal stroke using previously established dorsal attention, frontoparietal, and default mode network seeds. Associations with parental ratings of executive function and ADHD symptoms were examined. A total of 120 participants aged 6-19 years [AIS N = 31; PVI N = 30; Controls N = 59] were recruited. In comparison to typically developing peers, both the AIS and PVI groups showed lower intra- and inter-hemispheric functional connectivity values in the networks investigated. Group differences in between-network connectivity were also demonstrated, showing weaker anticorrelations between task-positive (frontoparietal and dorsal attention) and task-negative (default mode) networks in stroke groups compared to controls. Both within-network and between-network functional connectivity values were highly associated with parental reports of executive function and ADHD symptoms. These results suggest that differences in functional connectivity exist both within and between networks after perinatal stroke, the degree of which is associated with ADHD symptoms and executive function.

Alterations in cortical morphometry of the contralesional hemisphere in children, adolescents, and young adults with perinatal stroke.

Perinatal stroke causes most hemiparetic cerebral palsy and cognitive dysfunction may co-occur. Compensatory developmental changes in the intact contralesional hemisphere may mediate residual function and represent targets for neuromodulation. We used morphometry to explore cortical thickness, grey matter volume, gyrification, and sulcal depth of the contralesional hemisphere in children, adolescents, and young adults after perinatal stroke and explored associations with motor, attention, and executive function. Participants aged 6-20 years (N = 109, 63% male) with unilateral perinatal stroke underwent T1-weighted imaging. Participants had arterial ischemic stroke (AIS; n = 36), periventricular venous infarction (PVI; n = 37) or were controls (n = 36). Morphometry was performed using the Computational Anatomy Toolbox (CAT12). Group differences and associations with motor and executive function (in a smaller subsample) were assessed. Group comparisons revealed areas of lower cortical thickness in contralesional hemispheres in both AIS and PVI and greater gyrification in AIS compared to controls. Areas of greater grey matter volume and sulcal depth were also seen for AIS. The PVI group showed lower grey matter volume in cingulate cortex and less volume in precuneus relative to controls. No associations were found between morphometry metrics, motor, attention, and executive function. Cortical structure of the intact contralesional hemisphere is altered after perinatal stroke. Alterations in contralesional cortical morphometry shown in perinatal stroke may be associated with different mechanisms of damage or timing of early injury. Further investigations with larger samples are required to more thoroughly explore associations with motor and cognitive function.

Electric field simulations of transcranial direct current stimulation in children with perinatal stroke.

Introduction: Perinatal stroke (PS) is a focal vascular brain injury and the leading cause of hemiparetic cerebral palsy. Motor impairments last a lifetime but treatments are limited. Transcranial direct-current stimulation (tDCS) may enhance motor learning in adults but tDCS effects on motor learning are less studied in children. Imaging-based simulations of tDCS-induced electric fields (EF) suggest differences in the developing brain compared to adults but have not been applied to common pediatric disease states. We created estimates of tDCS-induced EF strength using five tDCS montages targeting the motor system in children with PS [arterial ischemic stroke (AIS) or periventricular infarction (PVI)] and typically developing controls (TDC) aged 6-19 years to explore associates between simulation values and underlying anatomy. Methods: Simulations were performed using SimNIBS https://simnibs.github.io/simnibs/build/html/index.html using T1, T2, and diffusion-weighted images. After tissue segmentation and tetrahedral mesh generation, tDCS-induced EF was estimated based on the finite element model (FEM). Five 1mA tDCS montages targeting motor function in the paretic (non-dominant) hand were simulated. Estimates of peak EF strength, EF angle, field focality, and mean EF in motor cortex (M1) were extracted for each montage and compared between groups. Results: Simulations for eighty-three children were successfully completed (21 AIS, 30 PVI, 32 TDC). Conventional tDCS montages utilizing anodes over lesioned cortex had higher peak EF strength values for the AIS group compared to TDC. These montages showed lower mean EF strength within target M1 regions suggesting that peaks were not necessarily localized to motor network-related targets. EF angle was lower for TDC compared to PS groups for a subset of montages. Montages using anodes over lesioned cortex were more sensitive to variations in underlying anatomy (lesion and tissue volumes) than those using cathodes over non-lesioned cortex. Discussion: Individualized patient-centered tDCS EF simulations are prudent for clinical trial planning and may provide insight into the efficacy of tDCS interventions in children with PS.

Structural brain network lateralization across childhood and adolescence.

Developmental lateralization of brain function is imperative for behavioral specialization, yet few studies have investigated differences between hemispheres in structural connectivity patterns, especially over the course of development. The present study compares the lateralization of structural connectivity patterns, or topology, across children, adolescents, and young adults. We applied a graph theory approach to quantify key topological metrics in each hemisphere including efficiency of information transfer between regions (global efficiency), clustering of connections between regions (clustering coefficient [CC]), presence of hub-nodes (betweenness centrality [BC]), and connectivity between nodes of high and low complexity (hierarchical complexity [HC]) and investigated changes in these metrics during development. Further, we investigated BC and CC in seven functionally defined networks. Our cross-sectional study consisted of 211 participants between the ages of 6 and 21 years with 93% being right-handed and 51% female. Global efficiency, HC, and CC demonstrated a leftward lateralization, compared to a rightward lateralization of BC. The sensorimotor, default mode, salience, and language networks showed a leftward asymmetry of CC. BC was only lateralized in the salience (right lateralized) and dorsal attention (left lateralized) networks. Only a small number of metrics were associated with age, suggesting that topological organization may stay relatively constant throughout school-age development, despite known underlying changes in white matter properties. Unlike many other imaging biomarkers of brain development, our study suggests topological lateralization is consistent across age, highlighting potential nonlinear mechanisms underlying developmental specialization.

Repetitive transcranial magnetic stimulation (rTMS) combined with multi-modality aphasia therapy for chronic post-stroke non-fluent aphasia: A pilot randomized sham-controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) shows promise in improving speech production in post-stroke aphasia. Limited evidence suggests pairing rTMS with speech therapy may result in greater improvements. Twenty stroke survivors (>6 months post-stroke) were randomized to receive either sham rTMS plus multi-modality aphasia therapy (M-MAT) or rTMS plus M-MAT. For the first time, we demonstrate that rTMS combined with M-MAT is feasible, with zero adverse events and minimal attrition. Both groups improved significantly over time on all speech and language outcomes. However, improvements did not differ between rTMS or sham. We found that rTMS and sham groups differed in lesion location, which may explain speech and language outcomes as well as unique patterns of BOLD signal change within each group. We offer practical considerations for future studies and conclude that while combination therapy of rTMS plus M-MAT in chronic post-stroke aphasia is safe and feasible, personalized intervention may be necessary.

Robotic mapping of motor cortex in children with perinatal stroke and hemiparesis.

Brain stimulation combined with intensive therapy may improve hand function in children with perinatal stroke-induced unilateral cerebral palsy (UCP). However, response to therapy varies and underlying neuroplasticity mechanisms remain unclear. Here, we aimed to characterize robotic motor mapping outcomes in children with UCP. Twenty-nine children with perinatal stroke and UCP (median age 11 ± 2 years) were compared to 24 typically developing controls (TDC). Robotic, neuronavigated transcranial magnetic stimulation was employed to define bilateral motor maps including area, volume, and peak motor evoked potential (MEP). Map outcomes were compared to the primary clinical outcome of the Jebsen-Taylor Test of Hand Function (JTT). Maps were reliably obtained in the contralesional motor cortex (24/29) but challenging in the lesioned hemisphere (5/29). Within the contralesional M1 of participants with UCP, area and peak MEP amplitude of the unaffected map were larger than the affected map. When comparing bilateral maps within the contralesional M1 in children with UCP to that of TDC, only peak MEP amplitudes were different, being smaller for the affected hand as compared to TDC. We observed correlations between the unaffected map when stimulating the contralesional M1 and function of the unaffected hand. Robotic motor mapping can characterize motor cortex neurophysiology in children with perinatal stroke. Map area and peak MEP amplitude may represent discrete biomarkers of developmental plasticity in the contralesional M1. Correlations between map metrics and hand function suggest clinical relevance and utility in studies of interventional plasticity.

Structural connectivity of the sensorimotor network within the non-lesioned hemisphere of children with perinatal stroke.

Perinatal stroke occurs early in life and often leads to a permanent, disabling weakness to one side of the body. To test the hypothesis that non-lesioned hemisphere sensorimotor network structural connectivity in children with perinatal stroke is different from controls, we used diffusion imaging and graph theory to explore structural topology between these populations. Children underwent diffusion and anatomical 3T MRI. Whole-brain tractography was constrained using a brain atlas creating an adjacency matrix containing connectivity values. Graph theory metrics including betweenness centrality, clustering coefficient, and both neighbourhood and hierarchical complexity of sensorimotor nodes were compared to controls. Relationships between these connectivity metrics and validated sensorimotor assessments were explored. Eighty-five participants included 27 with venous stroke (mean age = 11.5 ± 3.7 years), 26 with arterial stroke (mean age = 12.7 ± 4.0 years), and 32 controls (mean age = 13.3 ± 3.6 years). Non-lesioned primary motor (M1), somatosensory (S1) and supplementary motor (SMA) areas demonstrated lower betweenness centrality and higher clustering coefficient in stroke groups. Clustering coefficient of M1, S1, and SMA were inversely associated with clinical motor function. Hemispheric betweenness centrality and clustering coefficient were higher in stroke groups compared to controls. Hierarchical and average neighbourhood complexity across the hemisphere were lower in stroke groups. Developmental plasticity alters the connectivity of key nodes within the sensorimotor network of the non-lesioned hemisphere following perinatal stroke and contributes to clinical disability.

Frontal interhemispheric structural connectivity, attention, and executive function in children with perinatal stroke.

Perinatal stroke affects ∼1 in 1000 births and concomitant cognitive impairments are common but poorly understood. Rates of Attention Deficit/Hyperactivity Disorder (ADHD) are increased 5-10× and executive dysfunction can be disabling. We used diffusion imaging to investigate whether stroke-related differences in frontal white matter (WM) relate to cognitive impairments. Anterior forceps were isolated using tractography and sampled along the tract. Resulting metrics quantified frontal WM microstructure. Associations between WM metrics and parent ratings of ADHD symptoms (ADHD-5 rating scale) and executive functioning (Behavior Rating Inventory of Executive Function (BRIEF)) were explored. Eighty-three children were recruited (arterial ischemic stroke [AIS] n = 26; periventricular venous infarction [PVI] n = 26; controls n = 31). WM metrics were altered for stroke groups compared to controls. Along-tract analyses showed differences in WM metrics in areas approximating the lesion as well as more remote differences at midline and in the nonlesioned hemisphere. WM metrics correlated with parental ratings of ADHD and executive function such that higher diffusivity values were associated with poorer function. These findings suggest that underlying microstructure of frontal white matter quantified via tractography may provide a relevant biomarker associated with cognition and behavior in children with perinatal stroke.

Effects of Transcranial Direct Current Stimulation and High-Definition Transcranial Direct Current Stimulation Enhanced Motor Learning on Robotic Transcranial Magnetic Stimulation Motor Maps in Children.

Introduction: Conventional transcranial direct current stimulation (tDCS) and high-definition tDCS (HD-tDCS) may improve motor learning in children. Mechanisms are not understood. Neuronavigated robotic transcranial magnetic stimulation (TMS) can produce individualised maps of primary motor cortex (M1) topography. We aimed to determine the effects of tDCS- and HD-tDCS-enhanced motor learning on motor maps. Methods: Typically developing children aged 12-18 years were randomised to right M1 anodal tDCS, HD-tDCS, or Sham during training of their left-hand on the Purdue Pegboard Task (PPT) over 5 days. Bilateral motor mapping was performed at baseline (pre), day 5 (post), and 6-weeks retention time (RT). Primary muscle was the first dorsal interosseous (FDI) with secondary muscles of abductor pollicis brevis (APB) and adductor digiti minimi (ADM). Primary mapping outcomes were volume (mm2/mV) and area (mm2). Secondary outcomes were centre of gravity (COG, mm) and hotspot magnitude (mV). Linear mixed-effects modelling was employed to investigate effects of time and stimulation type (tDCS, HD-tDCS, Sham) on motor map characteristics. Results: Twenty-four right-handed participants (median age 15.5 years, 52% female) completed the study with no serious adverse events or dropouts. Quality maps could not be obtained in two participants. No effect of time or group were observed on map area or volume. LFDI COG (mm) differed in the medial-lateral plane (x-axis) between tDCS and Sham (p = 0.038) from pre-to-post mapping sessions. Shifts in map COG were also observed for secondary left-hand muscles. Map metrics did not correlate with behavioural changes. Conclusion: Robotic TMS mapping can safely assess motor cortex neurophysiology in children undergoing motor learning and neuromodulation interventions. Large effects on map area and volume were not observed while changes in COG may occur. Larger controlled studies are required to understand the role of motor maps in interventional neuroplasticity in children.

Subcortical brain structure in children with developmental coordination disorder: A T1-weighted volumetric study.

Developmental coordination disorder (DCD) is a neurodevelopmental disorder occurring in 5-6% of school-aged children. Converging evidence suggests that dysfunction within cortico-striatal and cortico-cerebellar networks may contribute to motor deficits in DCD, yet limited research has examined the brain morphology of these regions. Using T1-weighted magnetic resonance imaging the current study investigated cortical and subcortical volumes in 37 children with DCD, aged 8 to 12 years, and 48 controls of a similar age. Regional brain volumes of the thalamus, basal ganglia, cerebellum and primary motor and sensory cortices were extracted using the FreeSurfer recon-all pipeline and compared between groups. Reduced volumes within both the left and right pallidum (Left: F = 4.43, p = 0.039; Right: F = 5.24, p = 0.025) were observed in children with DCD; however, these results did not withstand correction for multiple comparisons. These findings provide preliminary evidence of altered subcortical brain structure in DCD. Future studies that examine the morphology of these subcortical regions are highly encouraged in order replicate these findings.

Perinatal stroke: mapping and modulating developmental plasticity.

Most cases of hemiparetic cerebral palsy are caused by perinatal stroke, resulting in lifelong disability for millions of people. However, our understanding of how the motor system develops following such early unilateral brain injury is increasing. Tools such as neuroimaging and brain stimulation are generating informed maps of the unique motor networks that emerge following perinatal stroke. As a focal injury of defined timing in an otherwise healthy brain, perinatal stroke represents an ideal human model of developmental plasticity. Here, we provide an introduction to perinatal stroke epidemiology and outcomes, before reviewing models of developmental plasticity after perinatal stroke. We then examine existing therapeutic approaches, including constraint, bimanual and other occupational therapies, and their potential synergy with non-invasive neurostimulation. We end by discussing the promise of exciting new therapies, including novel neurostimulation, brain-computer interfaces and robotics, all focused on improving outcomes after perinatal stroke.

Robotic transcranial magnetic stimulation motor maps and hand function in adolescents.

INTRODUCTION: Transcranial magnetic stimulation (TMS) motor mapping can characterize the neurophysiology of the motor system. Limitations including human error and the challenges of pediatric populations may be overcome by emerging robotic systems. We aimed to show that neuronavigated robotic motor mapping in adolescents could efficiently produce discrete maps of individual upper extremity muscles, the characteristics of which would correlate with motor behavior. METHODS: Typically developing adolescents (TDA) underwent neuronavigated robotic TMS mapping of bilateral motor cortex. Representative maps of first dorsal interosseous (FDI), abductor pollicis brevis (APB), and abductor digiti minimi (ADM) muscles in each hand were created. Map features including area (primary), volume, and center of gravity were analyzed across different excitability regions (R100%, R75%, R50%, R25%). Correlations between map metrics and validated tests of hand motor function (Purdue Pegboard Test as primary) were explored. RESULTS: Twenty-four right-handed participants (range 12-18 years, median 15.5 years, 52% female) completed bilateral mapping and motor assessments with no serious adverse events or dropouts. Gender and age were associated with hand function and motor map characteristics. Full motor maps (R100%) for FDI did not correlate with motor function in either hand. Smaller excitability subset regions demonstrated reduced variance and dose-dependent correlations between primary map variables and motor function in the dominant hemisphere. CONCLUSIONS: Hand function in TDA correlates with smaller subset excitability regions of robotic TMS motor map outcomes. Refined motor maps may have less variance and greater potential to quantify interventional neuroplasticity. Robotic TMS mapping is safe and feasible in adolescents.

Imaging Developmental and Interventional Plasticity Following Perinatal Stroke.

Perinatal stroke occurs around the time of birth and leads to lifelong neurological disabilities including hemiparetic cerebral palsy. Magnetic resonance imaging (MRI) has revolutionized our understanding of developmental neuroplasticity following early injury, quantifying volumetric, structural, functional, and metabolic compensatory changes after perinatal stroke. Such techniques can also be used to investigate how the brain responds to treatment (interventional neuroplasticity). Here, we review the current state of knowledge of how established and emerging neuroimaging modalities are informing neuroplasticity models in children with perinatal stroke. Specifically, we review structural imaging characterizing lesion characteristics and volumetrics, diffusion tensor imaging investigating white matter tracts and networks, task-based functional MRI for localizing function, resting state functional imaging for characterizing functional connectomes, and spectroscopy examining neurometabolic changes. Key challenges and exciting avenues for future investigations are also considered.

Developmental neuroplasticity of the white matter connectome in children with perinatal stroke.

OBJECTIVE: To employ diffusion imaging connectome methods to explore network development in the contralesional hemisphere of children with perinatal stroke and its relationship to clinical function. We hypothesized alterations in global efficiency of the intact hemisphere would correlate with clinical disability. METHODS: Children with unilateral perinatal arterial (n = 26) or venous (n = 27) stroke and typically developing controls (n = 32) underwent 3T diffusion and T1 anatomical MRI and completed established motor assessments. A validated atlas coregistered to whole-brain tractography for each individual was used to estimate connectivity between 47 regions. Graph theory metrics (assortativity, hierarchical coefficient of regression, global and local efficiency, and small worldness) were calculated for the left hemisphere of controls and the intact contralesioned hemisphere of both stroke groups. Validated clinical motor assessments were then correlated with connectivity outcomes. RESULTS: Global efficiency was higher in arterial strokes compared to venous strokes (p < 0.001) and controls (p < 0.001) and was inversely associated with all motor assessments (all p < 0.012). Additional graph theory metrics including assortativity, hierarchical coefficient of regression, and local efficiency also demonstrated consistent differences in the intact hemisphere associated with clinical function. CONCLUSIONS: The structural connectome of the contralesional hemisphere is altered after perinatal stroke and correlates with clinical function. Connectomics represents a powerful tool to understand whole brain developmental plasticity in children with disease-specific cerebral palsy.

Developmental Remodelling of the Motor Cortex in Hemiparetic Children With Perinatal Stroke.

BACKGROUND: Perinatal stroke often leads to lifelong motor impairment. Two common subtypes differ in timing, location, and mechanism of injury: periventricular venous infarcts (PVI) are fetal white matter lesions while most arterial ischemic strokes (AIS) are cortical injuries acquired near term birth. Both alter motor system development and primary motor cortex (M1) plasticity, often with retained ipsilateral corticospinal fibers from the non-lesioned motor cortex (M1'). METHODS: Task-based functional magnetic resonance imaging was used to define patterns of motor cortex activity during paretic and unaffected hand movement. Peak coordinates of M1, M1', and the supplementary motor area in the lesioned and intact hemispheres were compared to age-matched controls. Correlations between displacements and clinical motor function were explored. RESULTS: Forty-nine participants included 14 PVI (12.59 ± 3.7 years), 13 AIS (14.91 ± 3.9 years), and 22 controls (13.91 ± 3.4 years). AIS displayed the greatest M1 displacement from controls in the lesioned hemisphere while PVI locations approximated controls. Peak M1' activations were displaced from the canonical hand knob in both PVI and AIS. Extent of M1 and M1' displacement were correlated (r = 0.50, P = 0.025) but were not associated with motor function. Supplementary motor area activity elicited by paretic tapping was displaced in AIS compared to controls (P = 0.003). CONCLUSION: Motor network components may be displaced in both hemispheres after perinatal stroke, particularly in AIS and those with ipsilateral control of the affected limb. Modest correlations with clinical function may support that more complex models of developmental plasticity are needed to inform targets for individualized neuromodulatory therapies in children with perinatal stroke.

Transcranial Static Magnetic Field Stimulation of the Motor Cortex in Children.

BACKGROUND: Non-invasive neuromodulation is an emerging therapy for children with early brain injury but is difficult to apply to preschoolers when windows of developmental plasticity are optimal. Transcranial static magnetic field stimulation (tSMS) decreases primary motor cortex (M1) excitability in adults but effects on the developing brain are unstudied. OBJECTIVE/HYPOTHESIS: We aimed to determine the effects of tSMS on cortical excitability and motor learning in healthy children. We hypothesized that tSMS over right M1 would reduce cortical excitability and inhibit contralateral motor learning. METHODS: This randomized, sham-controlled, double-blinded, three-arm, cross-over trial enrolled 24 healthy children aged 10-18 years. Transcranial Magnetic Stimulation (TMS) assessed cortical excitability via motor-evoked potential (MEP) amplitude and paired pulse measures. Motor learning was assessed via the Purdue Pegboard Test (PPT). A tSMS magnet (677 Newtons) or sham was held over left or right M1 for 30 min while participants trained the non-dominant hand. A linear mixed effect model was used to examine intervention effects. RESULTS: All 72 tSMS sessions were well tolerated without serious adverse effects. Neither cortical excitability as measured by MEPs nor paired-pulse intracortical neurophysiology was altered by tSMS. Possible behavioral effects included contralateral tSMS inhibiting early motor learning (p < 0.01) and ipsilateral tSMS facilitating later stages of motor learning (p < 0.01) in the trained non-dominant hand. CONCLUSION: tSMS is feasible in pediatric populations. Unlike adults, tSMS did not produce measurable changes in MEP amplitude. Possible effects of M1 tSMS on motor learning require further study. Our findings support further exploration of tSMS neuromodulation in young children with cerebral palsy.

Microstructure of the Corpus Callosum Long after Pediatric Concussion.

OBJECTIVE: The long-term effects of pediatric concussion on white matter microstructure are poorly understood. This study investigated long-term changes in white matter diffusion properties of the corpus callosum in youth several years after concussion. METHODS: Participants were 8-19 years old with a history of concussion (n = 36) or orthopedic injury (OI) (n = 21). Mean time since injury for the sample was 2.6 years (SD = 1.6). Participants underwent diffusion magnetic resonance imaging, completed cognitive testing, and rated their post-concussion symptoms. Measures of diffusivity (fractional anisotropy, mean, axial, and radial diffusivity) were extracted from white matter tracts in the genu, body, and splenium regions of the corpus callosum. The genu and splenium tracts were further subdivided into 21 equally spaced regions along the tract and diffusion values were extracted from each of these smaller regions. RESULTS: White matter tracts in the genu, body, and splenium did not differ in diffusivity properties between youth with a history of concussion and those with a history of OI. No significant group differences were found in subdivisions of the genu and splenium after correcting for multiple comparisons. Diffusion metrics did not significantly correlate with symptom reports or cognitive performance. CONCLUSIONS: These findings suggest that at approximately 2.5 years post-injury, youth with prior concussion do not have differences in their corpus callosum microstructure compared to youth with OI. Although these results are promising from the perspective of long-term recovery, further research utilizing longitudinal study designs is needed to confirm the long-term effects of pediatric concussion on white matter microstructure.

Effects of Transcranial Direct Current Stimulation on GABA and Glx in Children: A pilot study.

Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation that safely modulates brain excitability and has therapeutic potential for many conditions. Several studies have shown that anodal tDCS of the primary motor cortex (M1) facilitates motor learning and plasticity, but there is little information about the underlying mechanisms. Using magnetic resonance spectroscopy (MRS), it has been shown that tDCS can affect local levels of γ-aminobutyric acid (GABA) and Glx (a measure of glutamate and glutamine combined) in adults, both of which are known to be associated with skill acquisition and plasticity; however this has yet to be studied in children and adolescents. This study examined GABA and Glx in response to conventional anodal tDCS (a-tDCS) and high definition tDCS (HD-tDCS) targeting the M1 in a pediatric population. Twenty-four typically developing, right-handed children ages 12-18 years participated in five consecutive days of tDCS intervention (sham, a-tDCS or HD-tDCS) targeting the right M1 while training in a fine motor task (Purdue Pegboard Task) with their left hand. Glx and GABA were measured before and after the protocol (at day 5 and 6 weeks) using a PRESS and GABA-edited MEGA-PRESS MRS sequence in the sensorimotor cortices. Glx measured in the left sensorimotor cortex was higher in the HD-tDCS group compared to a-tDCS and sham at 6 weeks (p = 0.001). No changes in GABA were observed in either sensorimotor cortex at any time. These results suggest that neither a-tDCS or HD-tDCS locally affect GABA and Glx in the developing brain and therefore it may demonstrate different responses in adults.