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.

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.

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.

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.

Functional magnetic resonance imaging study of working memory several years after pediatric concussion.

PRIMARY OBJECTIVE: The neurophysiological effects of pediatric concussion several years after injury remain inadequately characterized. The objective of this study was to determine if a history of concussion was associated with BOLD response differences during an n-back working memory task in youth. RESEARCH DESIGN: Observational, cross-sectional. METHODS AND PROCEDURES: Participants include 52 children and adolescents (M = 15.1 years, 95%CI = 14.4-15.8, range = 9-19) with past concussion (n = 33) or orthopedic injury (OI; n = 19). Mean time since injury was 2.5 years (95%CI = 2.0-3.0). Measures included postconcussion symptom ratings, neuropsychological testing, and blood-oxygen-dependent-level (BOLD) functional magnetic resonance imaging (fMRI) during an n-back working memory task. MAIN OUTCOMES AND RESULTS: Groups did not differ on accuracy or speed during the three n-back conditions. They also did not differ in BOLD signal change for the 1- vs. 0-back or 2- vs. 0-back contrasts (controlling for task performance). CONCLUSIONS: This study does not support group differences in BOLD response during an n-back working memory task in youth who are on average 2.5 years post-concussion. The findings are encouraging from the perspective of understanding recovery after pediatric concussion.

Crossed Cerebellar Atrophy in Perinatal Stroke.

Background and Purpose- Perinatal stroke causes most hemiparetic cerebral palsy and lifelong disability. Crossed cerebellar atrophy (CCA) is chronic cerebellar volume loss following contralateral motor pathway injury. We hypothesized that CCA is quantifiable in perinatal stroke and associated with poor motor outcome. Methods- Term-born children with perinatal stroke, magnetic resonance imaging beyond 6 months of age, and no additional neurological disorders were recruited. Blinded scorers measured cerebellar volumes expressed as ratios (contralesional/ipsilesional), with values <1 suggesting CCA. Motor outcomes including perinatal stroke outcome measure (PSOM) motor and cognitive scores (good/poor), Assisting Hand Assessment, and Melbourne Assessment were compared with cerebellar volume measures. Results- Seventy-three children met criteria (53% male). Mean cerebellar ratios were <1.0 (0.975±0.04; range, 0.885-1.079; P<0.001) suggesting occurrence of CCA. Cerebellar ratios did not differ between stroke types or across PSOM motor outcomes. Larger ipsilesional cerebellar volume was associated with poor PSOM cognitive outcome (P=0.042), possibly with poor PSOM motor outcome (P=0.063), and overall PSOM score (P=0.034). Conclusions- CCA occurs in perinatal stroke but is not strongly associated with motor outcome. However, ipsilesional cerebellar volume is associated with poor cognitive and overall outcomes.

Imaging functional motor connectivity in hemiparetic children with perinatal stroke.

Perinatal stroke causes lifelong disability, particularly hemiparetic cerebral palsy. Arterial ischemic strokes (AIS) are large, cortical, and subcortical injuries acquired near birth due to acute occlusion of the middle cerebral artery. Periventricular venous infarctions (PVI) are smaller, subcortical strokes acquired prior to 34 weeks gestation involving injury to the periventricular white matter. Both stroke types can damage motor pathways, thus, we investigated resulting alterations in functional motor networks and probed function. We measured blood oxygen level dependent (BOLD) fluctuations at rest in 38 participants [10 arterial patients (age = 14.7 ± 4.1 years), 10 venous patients (age = 13.5 ± 3.7 years), and 18 typically developing controls (TDCs) (age = 15.3 ± 5.1 years)] and explored strength and laterality of functional connectivity in the motor network. Inclusion criteria included MRI-confirmed, unilateral perinatal stroke, symptomatic hemiparetic cerebral palsy, and 6-19 years old at time of imaging. Seed-based functional connectivity analyses measured temporal correlations in BOLD response over the whole brain using primary motor cortices as seeds. Laterality indices based on mean z-scores in lesioned and nonlesioned hemispheres explored laterality. In AIS patients, significant differences in both strength and laterality of motor network connections were observed compared with TDCs. In PVI patients, motor networks largely resembled those of healthy controls, albeit slightly weaker and asymmetric, despite subcortical damage and hemiparesis. Functional connectivity strengths were not related to motor outcome scores for either stroke group. This study serves as a foundation to better understand how resting-state fMRI can assess motor functional connectivity and potentially be applied to explore mechanisms of interventional therapies after perinatal stroke.

Corticospinal tract diffusion properties and robotic visually guided reaching in children with hemiparetic cerebral palsy.

Perinatal stroke is the leading cause of hemiparetic cerebral palsy (CP), resulting in life-long disability. In this study, we examined the relationship between robotic upper extremity motor impairment and corticospinal tract (CST) diffusion properties. Thirty-three children with unilateral perinatal ischemic stroke (17 arterial, 16 venous) and hemiparesis were recruited from a population-based research cohort. Bilateral CSTs were defined using diffusion tensor imaging (DTI) and four diffusion metrics were quantified: fractional anisotropy (FA), mean (MD), radial (RD), and axial (AD) diffusivities. Participants completed a visually guided reaching task using the KINARM robot to define 10 movement parameters including movement time and maximum speed. Twenty-six typically developing children underwent the same evaluations. Partial correlations assessed the relationship between robotic reaching and CST diffusion parameters. All diffusion properties of the lesioned CST differed from controls in the arterial group, whereas only FA was reduced in the venous group. Non-lesioned CST diffusion measures were similar between stroke groups and controls. Both stroke groups demonstrated impaired reaching performance. Multiple reaching parameters of the affected limb correlated with lesioned CST diffusion properties. Lower FA and higher MD were associated with greater movement time. Few correlations were observed between non-lesioned CST diffusion and unaffected limb function though FA was associated with reaction time (R = -0.39, p < .01). Diffusion properties of the lesioned CST are altered after perinatal stroke, the degree of which correlates with specific elements of visually guided reaching performance, suggesting specific relevance of CST structural connectivity to clinical motor function in hemiparetic children.

Spectroscopic biomarkers of motor cortex developmental plasticity in hemiparetic children after perinatal stroke.

Perinatal stroke causes hemiparetic cerebral palsy and lifelong motor disability. Bilateral motor cortices are key hubs within the motor network and their neurophysiology determines clinical function. Establishing biomarkers of motor cortex function is imperative for developing and evaluating restorative interventional strategies. Proton magnetic resonance spectroscopy (MRS) quantifies metabolite concentrations indicative of underlying neuronal health and metabolism in vivo. We used functional magnetic resonance imaging (MRI)-guided MRS to investigate motor cortex metabolism in children with perinatal stroke. Children aged 6-18 years with MRI-confirmed perinatal stroke and hemiparetic cerebral palsy were recruited from a population-based cohort. Metabolite concentrations were assessed using a PRESS sequence (3T, TE = 30 ms, voxel = 4 cc). Voxel location was guided by functional MRI activations during finger tapping tasks. Spectra were analysed using LCModel. Metabolites were quantified, cerebral spinal fluid corrected and compared between groups (ANCOVA) controlling for age. Associations with clinical motor performance (Assisting Hand, Melbourne, Box-and-Blocks) were assessed. Fifty-two participants were studied (19 arterial, 14 venous, 19 control). Stroke participants demonstrated differences between lesioned and nonlesioned motor cortex N-acetyl-aspartate [NAA mean concentration = 10.8 ± 1.9 vs. 12.0 ± 1.2, P < 0.01], creatine [Cre 8.0 ± 0.9 vs. 7.4 ± 0.9, P < 0.05] and myo-Inositol [Ins 6.5 ± 0.84 vs. 5.8 ± 1.1, P < 0.01]. Lesioned motor cortex NAA and creatine were strongly correlated with motor performance in children with arterial but not venous strokes. Interrogation of motor cortex by fMRI-guided MRS is feasible in children with perinatal stroke. Metabolite differences between hemispheres, stroke types and correlations with motor performance support functional relevance. MRS may be valuable in understanding the neurophysiology of developmental neuroplasticity in cerebral palsy. Hum Brain Mapp 38:1574-1587, 2017. © 2016 Wiley Periodicals, Inc.

Sensory tractography and robot-quantified proprioception in hemiparetic children with perinatal stroke.

Perinatal stroke causes most hemiparetic cerebral palsy, resulting in lifelong disability. We have demonstrated the ability of robots to quantify sensory dysfunction in hemiparetic children but the relationship between such deficits and sensory tract structural connectivity has not been explored. It was aimed to characterize the relationship between the dorsal column medial lemniscus (DCML) pathway connectivity and proprioceptive dysfunction in children with perinatal stroke. Twenty-nine participants (6-19 years old) with MRI-classified, unilateral perinatal ischemic stroke (14 arterial, 15 venous), and upper extremity deficits were recruited from a population-based cohort and compared with 21 healthy controls. Diffusion tensor imaging (DTI) defined DCML tracts and five diffusion properties were quantified: fractional anisotropy (FA), mean, radial, and axial diffusivities (MD, RD, AD), and fiber count. A robotic exoskeleton (KINARM) tested upper limb proprioception in an augmented reality environment. Correlations between robotic measures and sensory tract diffusion parameters were evaluated. Lesioned hemisphere sensory tracts demonstrated lower FA and higher MD, RD, and AD compared with the non-dominant hemisphere of controls. Dominant (contralesional) hemisphere tracts were not different from controls. Both arterial and venous stroke groups demonstrated impairments in proprioception that correlated with lesioned hemisphere DCML tract diffusion properties. Sensory tract connectivity is altered in the lesioned hemisphere of hemiparetic children with perinatal stroke. A correlation between lesioned DCML tract diffusion properties and robotic proprioceptive measures suggests clinical relevance and a possible target for therapeutic intervention. Hum Brain Mapp 38:2424-2440, 2017. © 2017 Wiley Periodicals, Inc.

Neuropsychological Outcome in Perinatal Stroke Associated With Epileptiform Discharges in Sleep.

BACKGROUND: Patients with arterial perinatal stroke often suffer long-term motor sequelae, difficulties in language, social development, and behaviour as well as epilepsy. Despite homogeneous lesions, long-term behavioural and cognitive outcomes are variable and unpredictable. Sleep-related epileptic encephalopathies can occur after early brain injury and are associated with global developmental delays. We hypothesized that sleep-potentiated epileptiform abnormalities are associated with worse developmental outcomes after perinatal stroke. METHODS: Participants were identified from a population-based cohort (Alberta Perinatal Stroke Project). Inclusion criteria were magnetic resonance imaging-confirmed arterial perinatal stroke, age 4 to 18 years, electroencephalogram (EEG) including sleep, and comprehensive neuropsychological evaluation. Sleep-related EEG abnormalities were categorized by an epileptologist blinded to the cognitive outcome. Associations between EEG classification and neuropsychological outcomes were explored (t tests, Bonferroni correction for multiple comparisons). RESULTS: Of 128 potentially eligible participants, 34 (53% female) had complete EEG (mean age, 8.1 years; range, 0.2-16.4) and neuropsychology testing (mean age, 9.8 years; range 4.4-16.7). Twelve (35%) were classified as having electrical status epilepticus in sleep. Patients with abnormal EEGs were more likely to have statistically worse scores when corrected for multiple comparisons, in receptive language (median, 1st percentile; IQR 1-7th percentile; p<0.05), and externalizing behaviours (median, 82nd percentile; IQR, 79-97th percentile; p<0.05). CONCLUSIONS: Developmental outcome in language and behaviour in children with arterial perinatal stroke is associated with electrical status epilepticus in sleep. Increased screening with sleep EEG is suggested, whereas further studies are necessary to determine if treatment of EEG abnormalities can improve outcome.

Cognition in the Emergency Department as a Predictor of Recovery after Pediatric Mild Traumatic Brain Injury.

Cognitive abilities can be acutely disrupted in children and adolescents who sustain a mild traumatic brain injury (mTBI), with the potential that these disruptions may be predictive of recovery. The objective of this study was to determine if cognitive abilities in the emergency department (ED) can differentiate and predict poor symptom recovery following a pediatric mTBI. Participants included 77 male and female youth with a mTBI (mean age=13.6; SD=2.6). All participants completed computerized cognitive testing (four subtests from the CNS Vital Signs) when they presented to the ED. Symptom measurement occurred in the ED (for pre-injury), at 7-10 days, 1 month, 2 months, and 3 months post-mTBI using the post-concussion symptom inventory (PCSI). Recovery was determined using reliable change scores for symptom ratings from 28 orthopedic injury controls (mean age=13.9 years; SD=2.1). Significantly worse Reaction Time scores (i.e., rapid information processing) in the ED were found in those who remained symptomatic at 1 month. Performances on the Reaction Time and Cognitive Flexibility domain scores were predictive of symptom outcome at 1 month for youth (above and beyond sex and baseline symptom burden). Youth with low scores on Reaction Time and/or Cognitive Flexibility were nearly 15 times (95% CI=1.8-323.5) more likely to remain symptomatic at 1 month post-mTBI. No significant group differences were found at 7-10 days, 2 months, or 3 months post-injury. Rapid computerized cognitive testing in the ED following a mTBI may help clinicians predict which youth may or may not remain symptomatic at follow-up.

Effectiveness of cognitive rehabilitation following epilepsy surgery: Current state of knowledge.

OBJECTIVE: Cognitive rehabilitation (CR) is a well-researched therapeutic option for a variety of neurocognitive problems. Recently, CR has been proposed as an option for patients who experience cognitive difficulties following epilepsy surgery (ES). However, there is inconsistency in reporting the efficacy of CR in this population. We appraise existing evidence regarding CR approaches in patients undergoing resective ES and review effectiveness of specific CR strategies. METHODS: A comprehensive literature search using MEDLINE, Embase, CINAHL, PsycINFO, and EBM Reviews (including the Cochrane database) identified studies in English published before September 2014, without age restriction, related to CR in patients who underwent resective ES. We included studies focused on patients who underwent ES and who received at least one type of cognitive rehabilitation. RESULTS: Of 2,059 citations identified, four fulfilled eligibility criteria (n = 577), and all investigated the effectiveness of specific CR strategies in patients with either left or right temporal lobe resections. CR strategies used included internal compensatory strategies, external memory aids, psychoeducation, verbal and visual memory training, and exercises of attention and executive functions. None were randomized trials, and only one study involved standardized methods or described the procedures in detail. Evidence suggests that CR may contribute to improvements in aspects of verbal memory, with particular benefit of visual imagery techniques; CR aimed at verbal memory functions may be less effective for patients with hemispheric-dominant resections, and figural memory may not be improved by CR. Furthermore, CR may improve functional and life outcomes, but its timing does not appear to influence its effectiveness. SIGNIFICANCE: We demonstrate that CR interventions are overwhelmingly under researched or underreported, and there is a need for a systematic evaluation of CR in this patient population. CR should be given greater attention after ES to determine its efficacy and role in the management of these patients.

Reliability and variability of diffusion tensor imaging (DTI) tractography in pediatric epilepsy.

BACKGROUND: Diffusion tensor imaging (DTI) tractography is useful for isolating white matter (WM) trajectories and exploring microstructural integrity. Tractography can be performed on atypical brain anatomy when landmarks are malformed or displaced but has been criticized for its subjectivity even when investigators have advanced anatomical knowledge. Also, little is known about the variability and reliability of tractography as a tool for assessing white matter damage in clinical populations such as children with pediatric epilepsy. METHODS: Children diagnosed with epilepsy [N=43, mean age=11.7 years, standard deviation=3.7 years, 53% male] underwent a DTI sequence (6 directions, 2×2×3 mm voxels). Tractography for six white matter tracts (anterior forceps, fornices, bilateral arcuate fasciculi, and bilateral anterior cingula) was conducted twice by two experienced tractographers. Percent coefficient of variation (CV; for measuring variability) and intraclass correlation coefficients (ICCs; for measuring reliability) were calculated for tract volume and diffusion variables (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD] and radial diffusivity [RD]). RESULTS: Diffusion variables showed low variability (CV=2.7-8.8%) and very high reliability (ICC=.97-.99) except for limbic tracts [fornix (ICC=.75-.94); cingulum (ICC=.71-.98)]. Tract volume measurements showed high variability (CV=21.9-62.0%) and moderate reliability (ICC=.54-.99). Overall, tract volume measurements were much more variable and less reliable than diffusion characteristics. Limbic structures showed more variability compared with others. CONCLUSIONS: This suggests that DTI tractography and resulting diffusivity variables can reliably inform on the integrity of WM structures in a clinical sample with pediatric epilepsy and highlights the importance of reporting reliability information in studies that aim to answer clinical questions about WM integrity.

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.

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.

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.

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.

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.

Relationship Between Neonatal Brain Injury and Objective Measures of Head Trauma: A Case-Control Study.

BACKGROUND AND OBJECTIVES: Neonatal brain injury is a common and devastating diagnosis conferring lifelong challenges for children and families. The role of mechanical forces applied to the head, often referred to as "birth trauma," are often considered although evidence for this association is lacking. The objective of this study was to investigate the association between common types of neonatal brain injury and scalp swelling using a novel method to quantify scalp swelling as an unbiased proxy for mechanical forces applied to the head. METHODS: Case-control study using population-based, prospectively collected tertiary care center databases and healthy controls from the Human Connectome Development Project. Included were infants born 32-42 weeks gestational age and MRI in the first 9 days. Outcomes categories included healthy neonates, hypoxic ischemic encephalopathy (HIE) with or without brain injury, or stroke (ischemic or hemorrhagic). Volume of scalp swelling was objectively quantified by a novel imaging method blinded to brain injury. Variables included mode of delivery and use of instrumentation. Statistical tests included Kruskal-Wallis test, chi square, and multivariable and multinomial logistic regression. RESULTS: There were 309 infants included (55% male): 72 healthy controls, 77 HIE without brain injury on MRI, 78 HIE with brain injury, and 82 with stroke (60 ischemic, 22 hemorrhagic). Scalp swelling was present in 126 (40.8%, 95% confidence interval [CI] 35.2%-46.5%) with no difference in proportions between outcome groups. Compared to healthy controls, median volume was higher in those with HIE without brain injury (17.5 mL, 95% CI 6.8-28.2), HIE with brain injury (12.1 mL, 95% CI 5.5-18.6), but not ischemic stroke (4.7 mL, 95% CI -1.2-10.6) nor hemorrhagic stroke (8.3 mL, 95% CI -2.2-18.8). Scalp swelling was associated with instrumented delivery (OR 2.1, 95% CI 1.0-4.1), but not associated with increased odds of brain injury in those with HIE (OR 1.5, 95% CI 0.76-3.30). Scalp swelling measures were highly reliable (ICC = 0.97). DISCUSSION: "Birth trauma" quantified by scalp swelling volume was more common in infants with difficult deliveries, but not associated with greater odds of brain injury due to hypoxia or stroke. These results may help parents and practitioners to dissociate the appearance of trauma with the risk of brain injury.