Longitudinal Functional Connectome in Pediatric Concussion: An Advancing Concussion Assessment in Pediatrics Study.

Advanced magnetic resonance imaging (MRI) techniques indicate that concussion (i.e., mild traumatic brain injury) disrupts brain structure and function in children. However, the functional connectivity of brain regions within global and local networks (i.e., functional connectome) is poorly understood in pediatric concussion. This prospective, longitudinal study addressed this gap using data from the largest neuroimaging study of pediatric concussion to date to study the functional connectome longitudinally after concussion as compared with mild orthopedic injury (OI). Children and adolescents (n = 967) 8-16.99 years with concussion or mild OI were recruited from pediatric emergency departments within 48 h post-injury. Pre-injury and 1-month post-injury symptom ratings were used to classify concussion with or without persistent symptoms based on reliable change. Subjects completed a post-acute (2-33 days) and chronic (3 or 6 months via random assignment) MRI scan. Graph theory metrics were derived from 918 resting-state functional MRI scans in 585 children (386 concussion/199 OI). Linear mixed-effects modeling was performed to assess group differences over time, correcting for multiple comparisons. Relative to OI, the global clustering coefficient was reduced at 3 months post-injury in older children with concussion and in females with concussion and persistent symptoms. Time post-injury and sex moderated group differences in local (regional) network metrics of several brain regions, including degree centrality, efficiency, and clustering coefficient of the angular gyrus, calcarine fissure, cuneus, and inferior occipital, lingual, middle occipital, post-central, and superior occipital gyrus. Relative to OI, degree centrality and nodal efficiency were reduced post-acutely, and nodal efficiency and clustering coefficient were reduced chronically after concussion (i.e., at 3 and 6 months post-injury in females; at 6 months post-injury in males). Functional network alterations were more robust and widespread chronically as opposed to post-acutely after concussion, and varied by sex, age, and symptom recovery at 1-month post-injury. Local network segregation reductions emerged globally (across the whole brain network) in older children and in females with poor recovery chronically after concussion. Reduced functioning between neighboring regions could negatively disrupt specialized information processing. Local network metric alterations were demonstrated in several posterior regions that are involved in vision and attention after concussion relative to OI. This indicates that functioning of superior parietal and occipital regions could be particularly susceptibile to the effects of concussion. Moreover, those regional alterations were especially apparent at later time periods post-injury, emerging after post-concussive symptoms resolved in most and persisted up to 6 months post-injury, and differed by biological sex. This indicates that neurobiological changes continue to occur up to 6 months after pediatric concussion, although changes emerge earlier in females than in males. Changes could reflect neural compensation mechanisms.

IQ After Pediatric Concussion.

OBJECTIVES: This study investigated IQ scores in pediatric concussion (ie, mild traumatic brain injury) versus orthopedic injury. METHODS: Children (N = 866; aged 8-16.99 years) were recruited for 2 prospective cohort studies from emergency departments at children's hospitals (2 sites in the United States and 5 in Canada) ≤48 hours after sustaining a concussion or orthopedic injury. They completed IQ and performance validity testing postacutely (3-18 days postinjury; United States) or 3 months postinjury (Canada). Group differences in IQ scores were examined using 3 complementary statistical approaches (linear modeling, Bayesian, and multigroup factor analysis) in children performing above cutoffs on validity testing. RESULTS: Linear models showed small group differences in full-scale IQ (d [95% confidence interval] = 0.13 [0.00-0.26]) and matrix reasoning (0.16 [0.03-0.30]), but not in vocabulary scores. IQ scores were not related to previous concussion, acute clinical features, injury mechanism, a validated clinical risk score, pre- or postinjury symptom ratings, litigation, or symptomatic status at 1 month postinjury. Bayesian models provided moderate to very strong evidence against group differences in IQ scores (Bayes factor 0.02-0.23). Multigroup factor analysis further demonstrated strict measurement invariance, indicating group equivalence in factor structure of the IQ test and latent variable means. CONCLUSIONS: Across multisite, prospective study cohorts, 3 complementary statistical models provided no evidence of clinically meaningful differences in IQ scores after pediatric concussion. Instead, overall results provided strong evidence against reduced intelligence in the first few weeks to months after pediatric concussion.

Altered longitudinal structural connectome in paediatric mild traumatic brain injury: an Advancing Concussion Assessment in Paediatrics study.

Advanced diffusion-weighted imaging techniques have increased understanding of the neuropathology of paediatric mild traumatic brain injury (i.e. concussion). Most studies have examined discrete white-matter pathways, which may not capture the characteristically subtle, diffuse and heterogenous effects of paediatric concussion on brain microstructure. This study compared the structural connectome of children with concussion to those with mild orthopaedic injury to determine whether network metrics and their trajectories across time post-injury differentiate paediatric concussion from mild traumatic injury more generally. Data were drawn from of a large study of outcomes in paediatric concussion. Children aged 8-16.99 years were recruited from five paediatric emergency departments within 48 h of sustaining a concussion (n = 360; 56% male) or mild orthopaedic injury (n = 196; 62% male). A reliable change score was used to classify children with concussion into two groups: concussion with or without persistent symptoms. Children completed 3 T MRI at post-acute (2-33 days) and/or chronic (3 or 6 months, via random assignment) post-injury follow-ups. Diffusion-weighted images were used to calculate the diffusion tensor, conduct deterministic whole-brain fibre tractography and compute connectivity matrices in native (diffusion) space for 90 supratentorial regions. Weighted adjacency matrices were constructed using average fractional anisotropy and used to calculate global and local (regional) graph theory metrics. Linear mixed effects modelling was performed to compare groups, correcting for multiple comparisons. Groups did not differ in global network metrics. However, the clustering coefficient, betweenness centrality and efficiency of the insula, cingulate, parietal, occipital and subcortical regions differed among groups, with differences moderated by time (days) post-injury, biological sex and age at time of injury. Post-acute differences were minimal, whereas more robust alterations emerged at 3 and especially 6 months in children with concussion with persistent symptoms, albeit differently by sex and age. In the largest neuroimaging study to date, post-acute regional network metrics distinguished concussion from mild orthopaedic injury and predicted symptom recovery 1-month post-injury. Regional network parameters alterations were more robust and widespread at chronic timepoints than post-acutely after concussion. Results suggest that increased regional and local subnetwork segregation (modularity) and inefficiency occurs across time after concussion, emerging after post-concussive symptom resolve in most children. These differences persist up to 6 months after concussion, especially in children who showed persistent symptoms. While prognostic, the small to modest effect size of group differences and the moderating effects of sex likely would preclude effective clinical application in individual patients.

Longitudinal Gray Matter Trajectories in Pediatric Mild Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: This prospective, longitudinal cohort study examined trajectories of brain gray matter macrostructure after pediatric mild traumatic brain injury (mTBI). METHODS: Children aged 8-16.99 years with mTBI or mild orthopedic injury (OI) were recruited from 5 pediatric emergency departments. Reliable change between preinjury and 1 month postinjury symptom ratings was used to classify mTBI with or without persistent symptoms. Children completed postacute (2-33 days) and/or chronic (3 or 6 months) postinjury T1-weighted MRI, from which macrostructural metrics were derived using automated segmentation. Linear mixed-effects models were used, with multiple comparisons correction. RESULTS: Groups (N = 623; 407 mTBI/216 OI; 59% male; age mean = 12.03, SD = 2.38 years) did not differ in total brain, white, or gray matter volumes or regional subcortical gray matter volumes. However, time postinjury, age at injury, and biological sex-moderated differences among symptom groups in cortical thickness of the angular gyrus, basal forebrain, calcarine cortex, gyrus rectus, medial and posterior orbital gyrus, and the subcallosal area all corrected p < 0.05. Gray matter macrostructural metrics did not differ between groups postacutely. However, cortical thinning emerged chronically after mTBI relative to OI in the angular gyrus in older children (d [95% confidence interval] = -0.61 [-1.15 to -0.08]); and in the basal forebrain (-0.47 [-0.94 to -0.01]), subcallosal area (-0.55 [-1.01 to -0.08]), and the posterior orbital gyrus (-0.55 [-1.02 to -0.08]) in females. Cortical thinning was demonstrated for frontal and occipital regions 3 months postinjury in males with mTBI with persistent symptoms vs without persistent symptoms (-0.80 [-1.55 to -0.05] to -0.83 [-1.56 to -0.10]) and 6 months postinjury in females and younger children with mTBI with persistent symptoms relative to mTBI without persistent symptoms and OI (-1.42 [-2.29 to -0.45] to -0.91 [-1.81 to -0.01]). DISCUSSION: These findings signal little diagnostic and prognostic utility of postacute gray matter macrostructure in pediatric mTBI. However, mTBI altered the typical course of cortical gray matter thinning up to 6 months postinjury, even after symptoms typically abate in most children. Collapsing across symptom status obscured the neurobiological heterogeneity of discrete clinical outcomes after pediatric mTBI. The results illustrate the need to examine neurobiology in relation to clinical outcomes and within a neurodevelopmental framework.

The development of the pediatric stroke neuroimaging platform (PEDSNIP).

Childhood stroke occurs from birth to 18 years of age, ranks among the top ten childhood causes of death, and leaves lifelong neurological impairments. Arterial ischemic stroke in infancy and childhood occurs due to arterial occlusion in the brain, resulting in a focal lesion. Our understanding of mechanisms of injury and repair associated with focal injury in the developing brain remains rudimentary. Neuroimaging can reveal important insights into these mechanisms. In adult stroke population, multi-center neuroimaging studies are common and have accelerated the translation process leading to improvements in treatment and outcome. These studies are centered on the growing evidence that neuroimaging measures and other biomarkers (e.g., from blood and cerebrospinal fluid) can enhance our understanding of mechanisms of risk and injury and be used as complementary outcome markers. These factors have yet to be studied in pediatric stroke because most neuroimaging studies in this population have been conducted in single-centred, small cohorts. By pooling neuroimaging data across multiple sites, larger cohorts of patients can significantly boost study feasibility and power in elucidating mechanisms of brain injury, repair and outcomes. These aims are particularly relevant in pediatric stroke because of the decreased incidence rates and the lack of mechanism-targeted trials. Toward these aims, we developed the Pediatric Stroke Neuroimaging Platform (PEDSNIP) in 2015, funded by The Brain Canada Platform Support Grant, to focus on three identified neuroimaging priorities. These were: developing and harmonizing multisite clinical protocols, creating the infrastructure and methods to import, store and organize the large clinical neuroimaging dataset from multiple sites through the International Pediatric Stroke Study (IPSS), and enabling central searchability. To do this, developed a two-pronged approach that included building 1) A Clinical-MRI Data Repository (standard of care imaging) linked to clinical data and longitudinal outcomes and 2) A Research-MRI neuroimaging data set acquired through our extensive collaborative, multi-center, multidisciplinary network. This dataset was collected prospectively in eight North American centers to test the feasibility and implementation of harmonized advanced Research-MRI, with the addition of clinical information, genetic and proteomic studies, in a cohort of children presenting with acute ischemic stroke. Here we describe the process that enabled the development of PEDSNIP built to provide the infrastructure to support neuroimaging research priorities in pediatric stroke. Having built this Platform, we are now able to utilize the largest neuroimaging and clinical data pool on pediatric stroke data worldwide to conduct hypothesis-driven research. We are actively working on a bioinformatics approach to develop predictive models of risk, injury and repair and accelerate breakthrough discoveries leading to mechanism-targeted treatments that improve outcomes and minimize the burden following childhood stroke. This unique transformational resource for scientists and researchers has the potential to result in a paradigm shift in the management, outcomes and quality of life in children with stroke and their families, with far-reaching benefits for other brain conditions of people across the lifespan.

Longitudinal white matter microstructural changes in pediatric mild traumatic brain injury: An A-CAP study.

In the largest sample studied to date, white matter microstructural trajectories and their relation to persistent symptoms were examined after pediatric mild traumatic brain injury (mTBI). This prospective, longitudinal cohort study recruited children aged 8-16.99 years with mTBI or mild orthopedic injury (OI) from five pediatric emergency departments. Children's pre-injury and 1-month post-injury symptom ratings were used to classify mTBI with or without persistent symptoms. Children completed diffusion-weighted imaging at post-acute (2-33 days post-injury) and chronic (3 or 6 months via random assignment) post-injury assessments. Mean diffusivity (MD) and fractional anisotropy (FA) were derived for 18 white matter tracts in 560 children (362 mTBI/198 OI), 407 with longitudinal data. Superior longitudinal fasciculus FA was higher in mTBI without persistent symptoms relative to OI, d (95% confidence interval) = 0.31 to 0.37 (0.02, 0.68), across time. In younger children, MD of the anterior thalamic radiations was higher in mTBI with persistent symptoms relative to both mTBI without persistent symptoms, 1.43 (0.59, 2.27), and OI, 1.94 (1.07, 2.81). MD of the arcuate fasciculus, -0.58 (-1.04, -0.11), and superior longitudinal fasciculus, -0.49 (-0.90, -0.09) was lower in mTBI without persistent symptoms relative to OI at 6 months post-injury. White matter microstructural changes suggesting neuroinflammation and axonal swelling occurred chronically and continued 6 months post injury in children with mTBI, especially in younger children with persistent symptoms, relative to OI. White matter microstructure appears more organized in children without persistent symptoms, consistent with their better clinical outcomes.

Comparison of CPU and GPU bayesian estimates of fibre orientations from diffusion MRI.

BACKGROUND: The correct estimation of fibre orientations is a crucial step for reconstructing human brain tracts. Bayesian Estimation of Diffusion Parameters Obtained using Sampling Techniques (bedpostx) is able to estimate several fibre orientations and their diffusion parameters per voxel using Markov Chain Monte Carlo (MCMC) in a whole brain diffusion MRI data, and it is capable of running on GPUs, achieving speed-up of over 100 times compared to CPUs. However, few studies have looked at whether the results from the CPU and GPU algorithms differ. In this study, we compared CPU and GPU bedpostx outputs by running multiple trials of both algorithms on the same whole brain diffusion data and compared each distribution of output using Kolmogorov-Smirnov tests. RESULTS: We show that distributions of fibre fraction parameters and principal diffusion direction angles from bedpostx and bedpostx_gpu display few statistically significant differences in shape and are localized sparsely throughout the whole brain. Average output differences are small in magnitude compared to underlying uncertainty. CONCLUSIONS: Despite small amount of differences in output between CPU and GPU bedpostx algorithms, results are comparable given the difference in operation order and library usage between CPU and GPU bedpostx.

Functional Magnetic Resonance Imaging Findings in Children and Adolescents With Chronic Kidney Disease: Preliminary Findings.

This cross-sectional study provides preliminary findings from one of the first functional brain imaging studies in children with chronic kidney disease (CKD). The sample included 21 children with CKD (ages, 14.4 ± 3.0 y) and 11 healthy controls (ages, 14.5 ± 3.4 y). Using functional magnetic resonance imaging during a visual-spatial working memory task, findings showed that the CKD group and healthy controls invoked similar brain regions for encoding and retrieval phases of the task, but significant group differences were noted in the activation patterns for both components of the task. For the encoding phase, the CKD group showed lower activation in the posterior cingulate, anterior cingulate, precuneus, and middle occipital gyrus than the control group, but more activation in the superior temporal gyrus, middle frontal gyrus, middle temporal gyrus, and the insula. For the retrieval phase, the CKD group showed underactivation for brain systems involving the posterior cingulate, medial frontal gyrus, occipital lobe, and middle temporal gyrus, and greater activation than the healthy controls in the postcentral gyrus. Few group differences were noted with respect to disease severity. These preliminary findings support evidence showing a neurologic basis to the cognitive difficulties evident in pediatric CKD, and lay the foundation for future studies to explore the neural underpinnings for neurocognitive (dys)function in this population.

Prenatal antidepressant exposure and sex differences in neonatal corpus callosum microstructure.

Prenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants may influence white matter (WM) development, as previous studies report widespread microstructural alterations and reduced interhemispheric connectivity in SSRI-exposed infants. In rodents, perinatal SSRIs had sex-specific disruptions in corpus callosum (CC) axon architecture and connectivity; yet it is unknown whether SSRI-related brain outcomes in humans are sex specific. In this study, the neonate CC was selected as a region-of-interest to investigate whether prenatal SSRI exposure has sex-specific effects on early WM microstructure. On postnatal day 7, diffusion tensor imaging was used to assess WM microstructure in SSRI-exposed (n = 24; 12 male) and nonexposed (n = 48; 28 male) term-born neonates. Fractional anisotropy was extracted from CC voxels and a multivariate discriminant analysis was used to identify latent patterns differing between neonates grouped by SSRI-exposure and sex. Analysis revealed localized variations in CC fractional anisotropy that significantly discriminated neonate groups and correctly predicted group membership with an 82% accuracy. Such effects were identified across three dimensions, representing sex differences in SSRI-exposed neonates (genu, splenium), SSRI-related effects independent of sex (genu-to-rostral body), and sex differences in nonexposed neonates (isthmus-splenium, posterior midbody). Our findings suggest that CC microstructure may have a sex-specific, localized, developmental sensitivity to prenatal SSRI exposure.

Diagnostic Yield and Treatment Impact of Targeted Exome Sequencing in Early-Onset Epilepsy.

Targeted whole-exome sequencing (WES) is a powerful diagnostic tool for a broad spectrum of heterogeneous neurological disorders. Here, we aim to examine the impact on diagnosis, treatment and cost with early use of targeted WES in early-onset epilepsy. WES was performed on 180 patients with early-onset epilepsy (≤5 years) of unknown cause. Patients were classified as Retrospective (epilepsy diagnosis >6 months) or Prospective (epilepsy diagnosis <6 months). WES was performed on an Ion Proton™ and variant reporting was restricted to the sequences of 620 known epilepsy genes. Diagnostic yield and time to diagnosis were calculated. An analysis of cost and impact on treatment was also performed. A molecular diagnoses (pathogenic/likely pathogenic variants) was achieved in 59/180 patients (33%). Clinical management changed following WES findings in 23 of 59 diagnosed patients (39%) or 13% of all patients. A possible diagnosis was identified in 21 additional patients (12%) for whom supporting evidence is pending. Time from epilepsy onset to a genetic diagnosis was faster when WES was performed early in the diagnostic process (mean: 145 days Prospective vs. 2,882 days Retrospective). Costs of prior negative tests averaged $8,344 per patient in the Retrospective group, suggesting savings of $5,110 per patient using WES. These results highlight the diagnostic yield, clinical utility and potential cost-effectiveness of using targeted WES early in the diagnostic workup of patients with unexplained early-onset epilepsy. The costs and clinical benefits are likely to continue to improve. Advances in precision medicine and further studies regarding impact on long-term clinical outcome will be important.

Hub distribution of the brain functional networks of newborns prenatally exposed to maternal depression and SSRI antidepressants.

BACKGROUND: Prenatal maternal depression (PMD) and selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with increased developmental risk in infants. Reports suggest that PMD is associated with hyperconnectivity of the insula and the amygdala, while SSRI exposure is associated with hyperconnectivity of the auditory network in the infant brain. However, associations between functional brain organization and PMD and/or SSRI exposure are not well understood. METHODS: We examined the relation between PMD or SSRI exposure and neonatal brain functional organization. Infants of control (n = 17), depressed SSRI-treated (n = 20) and depressed-only (HAM-D ≥ 8) (n = 16) women, underwent resting-state functional magnetic resonance imaging at postnatal Day 6. At 6 months, temperament was assessed using Infant Behavioral Questionnaire (IBQ). We applied GTA and partial least square regression (PLSR) to the resting-state time series to assess group differences in modularity, and connector and provincial hubs. RESULTS: Modularity was similar across all groups. The depressed-only group showed higher connector hub values in the left anterior cingulate, insula, and caudate as well as higher provincial hub values in the amygdala compared to the control group. The SSRI group showed higher provincial hub values in Heschl's gyrus relative to the depressed-only group. PLSR showed that newborns' hub values predicted 10% of the variability in infant temperament at 6 months, suggesting different developmental patterns between groups. CONCLUSIONS: Prenatal exposures to maternal depression and SSRIs have differential impacts on neonatal functional brain organization. Hub values at 6 days predict variance in temperament between infant groups at 6 months of age.

Alterations in Resting-State Networks Following In Utero Selective Serotonin Reuptake Inhibitor Exposure in the Neonatal Brain.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat depression during pregnancy. SSRIs cross the placenta, inhibit serotonin reuptake, and thereby are thought to alter central fetal serotonin signaling. Both prenatal maternal mood disturbances and in utero SSRI exposure have been associated with altered fetal and infant behavior. Resting-state functional magnetic resonance imaging has identified resting-state networks (RSNs) in newborns, reflecting functional capacity of auditory and visual networks and providing opportunities to examine early experiences effects on neurodevelopment. We sought to examine the effect of in utero SSRI exposure on neonatal RSN functional organization. We hypothesized that prenatal SSRI exposure would be associated with alterations in neonatal RSNs compared with healthy control infants and infants exposed to mothers with depression. METHODS: Clinician-rated Hamilton Depression Rating Scale and self-reported Pregnancy Experiences Scale were completed during the third trimester. Control (n = 17), maternal depression-exposed (Hamilton Depression Rating Scale ≥8 without SSRI exposure, n = 16), and SSRI-exposed (n = 20) 6-day-old neonates underwent resting-state functional magnetic resonance imaging. Independent component analysis was used as a data-driven approach to extract 22 RSNs. RESULTS: SSRI-exposed neonates had higher connectivity in a putative auditory RSN compared with depressed-only (p = .01) and control (p = .02) infants (corrected for multiple comparisons), controlling for sex, age at the magnetic resonance imaging, and Pregnancy Experiences Scale score. CONCLUSIONS: Hyperconnectivity in auditory RSN in neonates with in utero SSRI exposure relative to neonates of depressed but not pharmacologically treated mothers and control infants may offer an insight into the functional organization origins of shifts in language perception and altered language development, previously reported in infants and children with prenatal SSRI exposure.

Brain abnormalities in children and adolescents with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a risk factor for vascular disease and stroke. The spectrum of brain injury and microstructural white matter abnormalities in children with CKD is largely unknown. METHODS: Cross sectional study at two North American pediatric hospitals. A cohort of 49 children, 29 with CKD, including renal transplant (mean age 14.4 ± 2.9 years; range 9-18), and 20 healthy controls (mean age 13.7 ± 3.1 years; range 9-18) had their conventional brain magnetic resonance images (MRIs) reviewed by one neuroradiologist to determine the prevalence of brain injury. Fractional anisotropy (FA) maps calculated from diffusion tensor imaging (DTI) were generated to compare white matter microstructure in CKD compared to controls, using tract-based spatial statistics (TBSS). RESULTS: Focal and multifocal white matter injury was seen on brain MRI in 6 children with CKD (21%). Relative to controls, CKD subjects showed reduced white matter fractional anisotropy and increased mean diffusivity and radial diffusivity in the anterior limb of the internal capsule, suggestive of abnormal myelination. CONCLUSION: Cerebral white matter abnormalities, including white matter injury, are under-recognized in pediatric CKD patients. Brain imaging studies through progression of CKD are needed to determine the timing of white matter injury and any potentially modifiable risk factors.

Advancing Concussion Assessment in Pediatrics (A-CAP): a prospective, concurrent cohort, longitudinal study of mild traumatic brain injury in children: protocol study.

INTRODUCTION: Paediatric mild traumatic brain injury (mTBI) is a public health burden. Clinicians urgently need evidence-based guidance to manage mTBI, but gold standards for diagnosing and predicting the outcomes of mTBI are lacking. The objective of the Advancing Concussion Assessment in Pediatrics (A-CAP) study is to assess a broad pool of neurobiological and psychosocial markers to examine associations with postinjury outcomes in a large sample of children with either mTBI or orthopaedic injury (OI), with the goal of improving the diagnosis and prognostication of outcomes of paediatric mTBI. METHODS AND ANALYSIS: A-CAP is a prospective, longitudinal cohort study of children aged 8.00-16.99 years with either mTBI or OI, recruited during acute emergency department (ED) visits at five sites from the Pediatric Emergency Research Canada network. Injury information is collected in the ED; follow-up assessments at 10 days and 3 and 6 months postinjury measure a variety of neurobiological and psychosocial markers, covariates/confounders and outcomes. Weekly postconcussive symptom ratings are obtained electronically. Recruitment began in September 2016 and will occur for approximately 24 months. Analyses will test the major hypotheses that neurobiological and psychosocial markers can: (1) differentiate mTBI from OI and (2) predict outcomes of mTBI. Models initially will focus within domains (eg, genes, imaging biomarkers, psychosocial markers), followed by multivariable modelling across domains. The planned sample size (700 mTBI, 300 OI) provides adequate statistical power and allows for internal cross-validation of some analyses. ETHICS AND DISSEMINATION: The ethics boards at all participating institutions have approved the study and all participants and their parents will provide informed consent or assent. Dissemination will follow an integrated knowledge translation plan, with study findings presented at scientific conferences and in multiple manuscripts in peer-reviewed journals.

Epidemiology and Outcomes of Arterial Ischemic Stroke in Children: The Canadian Pediatric Ischemic Stroke Registry.

BACKGROUND: Pediatric arterial ischemic stroke remains incompletely understood. Population-based epidemiological data inform clinical trial design but are scant in this condition. We aimed to determine age-specific epidemiological characteristics of arterial ischemic stroke in neonates (birth to 28 days) and older children (29 days to 18 years). METHODS: We conducted a 16-year, prospective, national population-based study, the Canadian Pediatric Ischemic Stroke Registry, across all 16 Canadian acute care children's hospitals. We prospectively enrolled children with arterial ischemic stroke from January 1992 to December 2001 and documented disease incidence, presentations, risk factors, and treatments. Study outcomes were assessed throughout 2008, including abnormal clinical outcomes (stroke-related death or neurological deficit) and recurrent arterial ischemic stroke or transient ischemic attack. RESULTS: Among 1129 children enrolled with arterial ischemic stroke, stroke incidence was 1.72/100,000/year, (neonates 10.2/100,000 live births). Detailed clinical and radiological information were available for 933 children (232 neonates and 701 older children, 55% male). The predominant clinical presentations were seizures in neonates (88%), focal deficits in older children (77%), and diffuse neurological signs (54%) in both. Among neonates, 44% had no discernible risk factors. In older children, arteriopathy (49% of patients with vascular imaging), cardiac disorders (28%), and prothrombotic disorders (35% of patients tested) predominated. Antithrombotic treatment increased during the study period (P < 0.001). Stroke-specific mortality was 5%. Outcomes included neurological deficits in 60% of neonates and 70% of older children. Among neonates, deficits emerged during follow-up in 39%. Overall, an initially decreased level of consciousness, a nonspecific systemic presentation, and the presence of stroke risk factors predicted abnormal outcomes. For neonates, predictors were decreased level of consciousness, nonspecific systemic presentation, and basal ganglia infarcts. For older children, predictors were initial seizures, nonspecific systemic presentation, risk factors, and lack of antithrombotic treatment. Recurrent arterial ischemic stroke or transient ischemic attack developed in 12% of older children and was predicted by arteriopathy, presentation without seizures, and lack of antithrombotic treatment. Emerging deficit was predicted by neonatal age at stroke and by cardiac disease. CONCLUSIONS: This national data set provides a population-based disease incidence rate and demonstrates the protective effect of antithrombotic treatment in older children, and frequent long-term emerging deficits in neonates and in children with cardiac disorders. Further clinical trials are required to develop effective age-appropriate treatments for children with acute arterial ischemic stroke.

Harnessing Neuroimaging Capability in Pediatric Stroke: Proceedings of the Stroke Imaging Laboratory for Children Workshop.

On June 5, 2015 the International Pediatric Stroke Study and the Stroke Imaging Laboratory for Children cohosted a unique workshop focused on developing neuroimaging research in pediatric stroke. Pediatric neurologists, neuroradiologists, interventional neuroradiologists, physicists, nurse practitioners, neuropsychologists, and imaging research scientists from around the world attended this one-day meeting. Our objectives were to (1) establish a group of experts to collaborate in advancing pediatric neuroimaging for stroke, (2) develop consensus clinical and research magnetic resonance imaging protocols for pediatric stroke patients, and (3) develop imaging-based research strategies in pediatric ischemic stroke. This article provides a summary of the meeting proceedings focusing on identified challenges and solutions and outcomes from the meeting. Further details on the workshop contents and outcomes are provided in three additional articles in the current issue of Pediatric Neurology.

Further Validation of the SIGMAR1 c.151+1G>T Mutation as Cause of Distal Hereditary Motor Neuropathy.

Distal hereditary motor neuropathies represent a group of rare genetic disorders characterized by progressive distal motor weakness without sensory loss. Their genetic heterogeneity is high and thus eligible for diagnostic whole exome sequencing. The authors report successful application of whole exome sequencing in diagnosing a second consanguineous family with distal hereditary motor neuropathy due to a homozygous c.151+1G>T variant in SIGMAR1. This variant was recently proposed as causal for the same condition in a consanguineous Chinese family. Compared to this family, the Afghan ethnic origin of our patient is distinct, yet the features are identical, validating the SIGMAR1 deficiency phenotype: progressive muscle wasting/weakness in lower and upper limbs without sensory loss. Rapid disease progression during adolescent growth is similar and may be due to SIGMAR1's role in regulating axon elongation and tau phosphorylation. Finally, the authors conclude that SIGMAR1 deficiency should be added to the differential diagnosis of distal hereditary motor neuropathies.

Neonatal Pain and Infection Relate to Smaller Cerebellum in Very Preterm Children at School Age.

OBJECTIVE: To examine whether specific neonatal factors differentially influence cerebellar subregional volumes and to investigate relationships between subregional volumes and outcomes in very preterm children at 7 years of age. STUDY DESIGN: Fifty-six children born very preterm (24-32 weeks gestational age) followed longitudinally from birth underwent 3-dimensional T(1)-weighted neuroimaging at median age 7.6 years. Children with severe brain injury were excluded. Cerebellar subregions were automatically segmented using the multiple automatically generated templates algorithm. The relation between cerebellum subregional volumes (adjusted for total brain volume and sex) and neonatal clinical factors were examined using constrained principal component analysis. Cognitive and visual-motor integration functions in relation to cerebellar volumes were also investigated. RESULTS: Higher neonatal procedural pain and infection, as well as other clinical factors, were differentially associated with reduced cerebellar volumes in specific subregions. After adjusting for clinical risk factors, neonatal procedural pain was distinctively associated with smaller volumes bilaterally in the posterior VIIIA and VIIIB lobules. Specific smaller cerebellar subregional volumes were related to poorer cognition and motor/visual integration. CONCLUSIONS: In very preterm children, exposure to painful procedures, as well as additional neonatal risk factors such as infection, were associated with reduced cerebellar volumes in specific subregions and poorer outcomes at school age.

Cerebellar language mapping and cerebral language dominance in pediatric epilepsy surgery patients.

OBJECTIVE: Children with epilepsy often have reorganization of language networks and abnormal brain anatomy, making determination of language lateralization difficult. We characterized the proportion and distribution of language task activation in the cerebellum to determine the relationship to cerebral language lateralization. METHODS: Forty-six pediatric epilepsy surgery candidates (aged 7-19 years) completed an fMRI auditory semantic decision language task. Distribution of activated voxels and language laterality indices were computed using: (a) Broca's and Wernicke's areas and their right cerebral homologues; and (b) left and right cerebellar hemispheres. Language task activation was anatomically localized in the cerebellum. RESULTS: Lateralized language task activation in either cerebral hemisphere was highly correlated with lateralized language task activation in the contralateral cerebellar hemisphere (Broca vs. cerebellar: ρ = -0.54, p < 0.01). Cerebellar language activation was located within Crus I/II, areas previously implicated in non-motor functional networks. CONCLUSIONS: Cerebellar language activation occurs in homologous regions of Crus I/II contralateral to cerebral language activation in patients with both right and left cerebral language dominance. Cerebellar language laterality could contribute to comprehensive pre-operative evaluation of language lateralization in pediatric epilepsy surgery patients. Our data suggest that patients with atypical cerebellar language activation are at risk for having atypical cerebral language organization.

The effects of pediatric epilepsy on a language connectome.

This study introduces a new approach for assessing the effects of pediatric epilepsy on a language connectome. Two novel data-driven network construction approaches are presented. These methods rely on connecting different brain regions using either extent or intensity of language related activations as identified by independent component analysis of fMRI. An auditory word definition decision task paradigm was used to activate the language network for 29 patients and 30 controls. Evaluations illustrated that pediatric epilepsy is associated with a network efficiency reduction. Patients showed a propensity to inefficiently use the whole brain network to perform the language task; whereas, controls seemed to efficiently use smaller segregated network components to achieve the same task. To explain the causes of the decreased efficiency, graph theoretical analysis was performed. The analysis revealed substantial global network feature differences between the patients and controls for the extent of activation network. It also showed that for both subject groups the language network exhibited small-world characteristics; however, the patient's extent of activation network showed a tendency toward randomness. It was also shown that the intensity of activation network displayed ipsilateral hub reorganization on the local level. We finally showed that a clustering scheme was able to fairly separate the subjects into their respective patient or control groups. The clustering was initiated using local and global nodal measurements. Compared to the intensity of activation network, the extent of activation network clustering demonstrated better precision. This ascertained that the network differences presented by the networks were associated with pediatric epilepsy.