Purpose: The purpose of this study was to examine the effects of a medically centered, interdisciplinary treatment model on adaptive behavior in children with Autism Spectrum Disorder (ASD). The Cortica model involves a comprehensive program including behavioral and developmental therapies, overseen by a neurodevelopmental physician. Here, we investigated how adaptive behaviors change over time during care at Cortica. Methods: We analyzed changes in the Vineland Adaptive Behavior Scales over the course of Cortica care compared to a community sample comprising longitudinal data from the National Database for Autism Research (NDAR). Results: Using propensity score weights to match cohorts based on baseline functioning, multilevel growth curve models showed significant Cohort × Time interactions for the Adaptive Behavior Composite (ABC) score and all subscale scores, indicating increased growth in adaptive behavior skills for children in the Cortica cohort relative to NDAR. Conclusions: Results of this study highlight the importance of using adaptive behaviors as a primary outcome in clinical research studies and suggest that a personalized, multidisciplinary approach to intervention can result in improved adaptive behavior skills over time.

Research aimed at understanding how baseline clinical and demographic characteristics influence outcomes over time is critically important to inform individualized therapeutic programs for children with neurodevelopmental differences. This study characterizes adaptive behavior trajectories in children receiving medical and behavioral therapy within a network of care centers with a shared data-gathering mechanism for intake and longitudinal assessments. We then take the further step of utilizing intake data to develop machine-learning models which predict differences in those trajectories. Specifically, we evaluated data from 1225 autistic children, aged 20-90 months, using latent class growth mixture modeling (LCGMM) with scores on the Vineland Adaptive Behavior Scales, 3rd Edition, as the primary outcome measure. The LCGMM analysis revealed two distinct clusters of adaptive behavior trajectories. The “Less Impairment/Improving Trajectory” group (≥66% of the sample) exhibited greater developmental change in adaptive behavior, while the “Higher Impairment/Stable Trajectory” group (≤33% of the sample) showed little change over time relative to age-matched normative data. For a subset of 729 children, we used machine learning algorithms to forecast adaptive behavior trajectories using clinical and sociodemographic data collected at the initial assessment, comparing elastic net GLM, support vector machine, and random forest. The best-performing random forest model predicted adaptive behavior trajectory with an accuracy rate of 77%. The strongest predictors in our model were socioeconomic status, history of developmental regression, child temperament, paternal age at the time of the child’s birth, baseline autism symptom severity, parent concerns about development, presence of ADHD symptoms, and parent concerns about mood. Notably, the inclusion of cumulative hours of applied behavioral analysis and developmental therapies in the machine learning models did not yield significant changes in performance metrics, indicating that increased therapy hours did not predict greater improvement. These findings extend our understanding of adaptive behavior development in autistic children and underscore the value of gathering comprehensive patient information at intake to tailor clinical care.

Background: Nonacog beta pegol (N9-GP) is an extended half-life PEGylated factor (F)IX product with established efficacy and short-term safety in persons with hemophilia B (HB). Long-term safety has been evaluated for polyethylene glycol exposure but not N9-GP. Objectives: To assess safety, neurodevelopmental, and efficacy outcomes of children with HB receiving N9-GP prophylaxis across 2 open-label, single-arm, phase 3 studies: paradigm5 (previously treated patients [PTPs]) and paradigm6 (previously untreated patients [PUPs]) in this interim analysis. Methods: PTPs (aged <= 12 years) and PUPs (aged <6 years) with severe/moderate (<= 2% FIX level) HB were recruited to N9-GP prophylaxis (40 IU/kg once weekly) in paradigm5 and paradigm6, respectively. Safety assessments included FIX inhibitor incidence, adverse events, neurocognitive and neurologic outcomes, polyethylene glycol concentration in plasma, and medical events of special interest. Efficacy endpoints included bleeds, N9-GP hemostatic effect, and FIX consumption. Results: Overall, 25 patients in paradigm5 and 50 patients in paradigm6 received N9-GP and were followed for up to 8 and 6 years, respectively. No inhibitory antibodies were reported in PTPs; 4 of the 50 PUPs developed inhibitors. Extensive evaluation revealed no neurocognitive or neurologic concerns with N9-GP use in children during the study period. Across both studies, few adverse events were reported as possibly related to N9-GP. High hemostatic response rate, high treatment adherence, low annualized bleeding rates, and no new target joints were reported. Conclusion: These data provide the longest follow-up for an extended half-life FIX and confirm the long-term efficacy of N9-GP prophylaxis in children with HB with no observed neurocognitive or neurologic safety concerns.

ObjectiveTo assess cognitive, behavioral, and adaptive functions in children and young adults with hemophilia treated according to contemporary standards of care.Study designeTHINK was a US-based, prospective, cross-sectional, observational study (September 2018 through October 2019). Males (aged 1-21 years) with hemophilia A or B of any severity, with or without inhibitors, were eligible. Participants underwent neurological examinations and age-appropriate neuropsychological assessments, including standardized tests/ratings scales of early development, cognition, emotional/behavioral adjustment, and adaptive skills.Results551 males with hemophilia A (n=433) or B (n=101) were enrolled. Performance on cognitive tests was largely comparable with that of age-matched US population norms, although participants in certain age groups (4-5 and 10-21 years) performed worse on measures of attention and processing speed. Furthermore, adolescents and young adults and those with comorbid attention-deficit/hyperactivity disorder (ADHD; n=64) reported more adaptive and executive function problems in daily life. Incidence of ADHD in adolescents (21%) was higher than expected in the general population.ConclusionsIn general, males with hemophilia demonstrated age-appropriate intellectual, behavioral, and adaptive development. However, specific patient/age groups showed poorer attention performance and concerns for executive and adaptive development. This study established a normative data set for monitoring neurodevelopment in individuals with hemophilia and highlights the importance of screening and intervention for challenges with cognitive and adaptive skills in this population.

Children with autism and other neurodevelopmental concerns (NDC) frequently exhibit an array of sensory processing dysfunction phenotypes, posing a significant challenge their adaptive development. Additionally, these children often encounter difficulties with self-regulation, including emotion dysregulation, anxiety, and symptoms associated with attention and hyperactivity. However, further research is required to comprehend how patterns of sensory processing differences across neurodevelopmental conditions may contribute to regulatory control problems. Adopting a transdiagnostic perspective within the Research Domain Criteria (RDoC) framework, this study examined the relationship between clusters of sensory processing phenotypes and differential patterns of self-regulation behaviors. We recruited a sample of 117 participants (8-12 years) with a diverse range of neurodevelopmental concerns including autism, ADHD, anxiety, and sensory processing differences. This study aimed to (1) establish the prevalence of self-regulation problems in a community-recruited cohort of children with diverse NDCs; (2) construct data-driven sensory processing latent subtypes; (3) investigate group differences in emotion dysregulation, anxiety, and ADHD symptoms. Results showed that 39% of NDC children met clinically concerning thresholds for emotion dysregulation, 19% for anxiety, and 62% for ADHD. Second, latent profile analysis identified five sensory processing subtypes categorized by modality: Typical Processing, Intermediate/Mixed, Sensory Over-Responsive, Sensory Seeking, and Sensory Under-Responsive. Notably, the Sensory Over-Responsive group exhibited distinctively elevated anxiety scores, while the Sensory Seeking and Sensory Under-Responsive groups showed heightened ADHD scores. Intriguingly, the Sensory Over-Responsive, Sensory Under-Responsive, and Sensory Seeking subgroups all demonstrated elevated emotion dysregulation scores, suggesting a potential shared mechanism of emotion dysregulation that might elucidate the connection between sensory processing differences and increased anxiety and ADHD behaviors in children with autism and other NDCs.

The short pre-M1 helix within the S1-M1 linker (also referred to as the pre-M1 linker) between the agonist-binding domain (ABD, S1) and the M1 transmembrane helix of the NMDA receptor (NMDAR) is devoid of missense variants within the healthy population but is a locus for de novo pathogenic variants associated with neurological disorders. Several de novo variants within this helix have been identified in patients presenting early in life with intellectual disability, developmental delay, and/or epilepsy. In this study, we evaluated functional properties for twenty variants within the pre-M1 linker in GRIN1, GRIN2A, and GRIN2B genes, including six novel missense variants. The effects of pre-M1 variants on agonist potency, sensitivity to endogenous allosteric modulators, response time course, channel open probability, and surface expression were assessed. Our data indicated that virtually all of the variants evaluated altered channel function, and multiple variants had profound functional consequences, which may contribute to the neurological conditions in the patients harboring the variants in this region. These data strongly suggest that the residues within the pre-M1 helix play a key role in channel gating and are highly intolerant to genetic variation.

Children with autism and other neurodevelopmental concerns (NDC) present an array of sensory processing patterns and frequently encounter challenges with self-regulation, including emotion dysregulation, anxiety, and ADHD symptoms. Adopting a transdiagnostic perspective within the Research Domain Criteria (RDoC) framework, this study examined the relationship between clusters of sensory processing phenotypes and differential patterns of self-regulation behaviors. In a sample of 117 participants (8–12 years), this study aimed to: 1) establish the prevalence of self-regulation problems in a community-recruited cohort of children with diverse NDCs; 2) construct data-driven sensory processing latent subtypes; 3) investigate group differences in emotion dysregulation, anxiety, and ADHD symptoms. Results indicated that 40, 20, and 62% of NDC children met clinically concerning thresholds for emotion dysregulation, anxiety, and ADHD, respectively. Second, latent profile analysis identified five sensory processing subtypes categorized by modality: Typical Processing, Intermediate/Mixed, Sensory Seeking (SS), Sensory Under-responsive (SUR), and Sensory Over-Responsive (SOR). Notably, the SOR group exhibited distinctively elevated anxiety scores, while the SS and SUR groups showed heightened ADHD scores. Intriguingly, the SOR, SUR, SS, and Intermediate/Mixed subgroups all demonstrated elevated emotion dysregulation scores, suggesting a potential shared mechanism of emotion dysregulation that might elucidate the connection between sensory processing differences and increased anxiety and ADHD behaviors in children with autism and other NDCs.

Neurological morbidity is common after pediatric stroke, with moderate to severe deficits that can significantly impact education and social function. Care and recovery occur in phases distinguished by the time interval after stroke onset. These phases include the hyperacute and acute periods in which the focus is on cerebral reperfusion and prevention of neurological deterioration, followed by the subacute and chronic phases in which the focus is on secondary stroke prevention and mitigation of disability through rehabilitation, adaptation, and reintegration into the community. In this article, a multidisciplinary group of pediatric stroke experts review the stages of recovery after pediatric stroke with an emphasis on critical assessment time points. Our goal is to encourage increased standardization of outcome assessment to facilitate future clinical trials comparing various treatment and intervention options and advance optimized care for children with stroke.

Objective: Individuals with neurodevelopmental disorders often report disturbances in the autonomic nervous system (ANS)-related behavioral regulation, such as sensory sensitivity, anxiety, and emotion dysregulation. Cranial electrotherapy stimulation (CES) is a method of non-invasive neuromodulation presumed to modify behavioral regulation abilities via ANS modulation. Here we examined the feasibility and preliminary effects of a 4-week CES intervention on behavioral regulation in a mixed neurodevelopmental cohort of children, adolescents, and young adults. Methods: In this single-arm open-label study, 263 individuals aged 4–24 who were receiving clinical care were recruited. Participants received at-home CES treatment using an Alpha-Stim® AID CES device for 20 minutes per day, 5–7 days per week, for four weeks. Before and after the intervention, a parent-report assessment of sensory sensitivities, emotion dysregulation, and anxiety was administered. Adherence, side effects, and tolerance of the CES device were also evaluated at follow-up. Results: Results showed a 75% completion rate, an average tolerance score of 68.2 (out of 100), and an average perceived satisfaction score of 58.8 (out of 100). Additionally, a comparison between pre- and post-CES treatment effects showed a significant reduction in sensory sensitivity, anxiety, and emotion dysregulation in participants following CES treatment. Conclusions: Results provide justification for future randomized control trials using CES in children and adolescents with behavioral dysregulation. Significance: CES may be a useful therapeutic tool for alleviating behavioral dysregulation symptoms in children and adolescents with neurodevelopmental differences.

Pediatric stroke is associated with a range of maladaptive cognitive and behavioral outcomes that often require targeted intervention. Despite increasing research on neuropsychological outcomes over the past decade, evidence for effective therapies and interventions for the most commonly reported cognitive and behavioral challenges is still limited. The most widely prescribed interventions address more overt deficits in sensorimotor and speech/language functions, yet interventions for higher-order cognitive, linguistic and behavioral deficits are notably less defined. Moreover, concepts of rehabilitation in adult stroke cannot be easily translated directly to pediatric populations because the effect of stroke and recovery in the developing brain takes a very different course than in the mature brain. In pediatric stroke, neuropsychological deficits often emerge gradually over time necessitating a long-term approach to intervention. Furthermore, family and school context often play a much larger role. The goal of this review is to describe cognitive and behavioral interventions for perinatal and childhood stroke, as motor rehabilitation is covered elsewhere in this issue. We also discuss cognitive aspects of current rehabilitative therapies and technology. Acknowledging the current limited state of stroke-specific rehabilitation research in children, findings from pediatric acquired brain injury intervention and use of transdiagnostic approaches lend important insights. Because there is limited support for single domain (cognitive) trainings and translation of research rehabilitation programs to clinical practice can be challenging, the value of holistic multidisciplinary approaches to improve everyday function in children and adolescents following stroke is emphasized.

Dyslexia is a neurodevelopmental disorder mainly defined by reading difficulties. During reading, individuals with dyslexia exhibit hypoactivity in left-lateralized language systems. Lower activity in one brain circuit can be accompanied by greater activity in another, and, here, we examined whether right-hemisphere-based emotional reactivity may be elevated in dyslexia. We measured emotional reactivity (i.e., facial behavior, physiological activity, and subjective experience) in 54 children ages 7-12 with (n = 32) and without (n = 22) dyslexia while they viewed emotion-inducing film clips. Participants also underwent task-free functional magnetic resonance imaging. Parents of children with dyslexia completed the Behavior Assessment System for Children, which assesses real-world behavior. During film viewing, children with dyslexia exhibited significantly greater reactivity in emotional facial behavior, skin conductance level, and respiration rate than those without dyslexia. Across the sample, greater emotional facial behavior correlated with stronger connectivity between right ventral anterior insula and right pregenual anterior cingulate cortex (p(FwE)<.05), key salience network hubs. In children with dyslexia, greater emotional facial behavior related to better real-world social skills and higher anxiety and depression. Our findings suggest there is heightened visceromotor emotional reactivity in dyslexia, which may lead to interpersonal strengths as well as affective vulnerabilities. (C) 2020 Elsevier Ltd. All rights reserved.

OBJECTIVE:To characterize predictors of recovery and outcome following pediatric arterial ischemic stroke, hypothesizing that age influences recovery after stroke.METHODS:We studied children enrolled in the International Pediatric Stroke Study between January 1, 2003 and July 31, 2014 with 2-year follow-up after arterial ischemic stroke. Outcomes were defined at discharge by clinician grading and at 2 years by the Pediatric Stroke Outcome Measure. Demographic, clinical, and radiologic outcome predictors were examined. We defined changes in outcome from discharge to 2 years as recovery (improved outcome), emerging deficit (worse outcome), or no change.RESULTS:Our population consisted of 587 patients, including 174 with neonatal stroke and 413 with childhood stroke, with recurrent stroke in 8.2% of childhood patients. Moderate to severe neurological impairment was present in 9.4% of neonates versus 48.8% of children at discharge compared to 8.0% versus 24.7% after 2 years. Predictors of poor outcome included age between 28 days and 1 year (compared to neonates, odds ratio [OR] = 3.58, p < 0.05), underlying chronic disorder (OR = 2.23, p < 0.05), and involvement of both small and large vascular territories (OR = 2.84, p < 0.05). Recovery patterns differed, with emerging deficits more common in children <1 year of age (p < 0.05).INTERPRETATION:Outcomes after pediatric stroke are generally favorable, but moderate to severe neurological impairments are still common. Age between 28 days and 1 year appears to be a particularly vulnerable period. Understanding the timing and predictors of recovery will allow us to better counsel families and target therapies to improve outcomes after pediatric stroke. ANN NEUROL 2020;87:840-852.

PURPOSE:Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts.METHODS:We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts.RESULTS:We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts.CONCLUSION:We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.

OBJECTIVE:To determine that children with arterial ischemic stroke (AIS) due to an identifiable arteriopathy are distinct from those without arteriopathy and that each arteriopathy subtype has unique and recognizable clinical features. METHODS:We report a large, observational, multicenter cohort of children with AIS, age 1 month to 18 years, enrolled in the International Pediatric Stroke Study from 2003 to 2014. Clinical and demographic differences were compared by use of the Fisher exact test, with linear step-up permutation min-p adjustment for multiple comparisons. Exploratory analyses were conducted to evaluate differences between cases of AIS with and without arteriopathy and between arteriopathy subtypes. RESULTS:Of 2,127 children with AIS, 725 (34%) had arteriopathy (median age 7.45 years). Arteriopathy subtypes included dissection (27%), moyamoya (24.5%), focal cerebral arteriopathy-inflammatory subtype (FCA-i; 15%), diffuse cerebral vasculitis (15%), and nonspecific arteriopathy (18.5%). Children with arteriopathic AIS were more likely to present between 6 and 9 years of age (odds ratio [OR] 1.93, p = 0.029) with headache (OR 1.55, p = 0.023), multiple infarctions (OR 2.05, p < 0.001), sickle cell anemia (OR 2.9, p = 0.007), and head/neck trauma (OR 1.93, p = 0.018). Antithrombotic use and stroke recurrence were higher in children with arteriopathy. Among arteriopathy subtypes, dissection was associated with male sex, older age, headache, and anticoagulant use; FCA-i was associated with hemiparesis and single infarcts; moyamoya was associated with seizures and recurrent strokes; and vasculitis was associated with bilateral infarctions. CONCLUSION:Specific clinical profiles are associated with cerebral arteriopathies in children with AIS. These observations may be helpful indicators in guiding early diagnosis and defining subgroups who may benefit most from future therapeutic trials.

Almost all of what is known about neurologic and cognitive development in hemophilia derives from the Hemophilia Growth and Development Study, conducted during an era when treatment regimens and comorbidities differed significantly from the current environment. Results suggested hemophilia and human immunodeficiency virus had independent effects, and hemophilia negatively impacts academic achievement, attention, and behavior. The introduction of prophylaxis treatment in hemophilia has created the need for re-evaluation of the effects of hemophilia on neurodevelopment and cognition. We outline the Evolving Treatment of Hemophilia's Impact on Neurodevelopment, Intelligence, and Other Cognitive Functions (NCT03660774) study, which aims to meet this need.

Background: Patients with nonfluent/agrammatic variant primary progressive aphasia (nfvPPA) have more difficulty producing verbs than nouns, but the reason for this discrepancy remains unclear. One possibility is that it results from impaired access to motor programs integral to semantic representations of actions. Another is that the disruption affects specific lexical or grammatical features of verbs. Aims: To use an oral picture naming task to examine the effects of motor associations on verb production in patients with nfvPPA. Methods & Procedures: We administered noun and verb naming tasks to 12 nfvPPA patients and 9 controls. We varied the manipulability of target items across categories as a proxy for the degree to which lexical access depends on motor knowledge. Outcomes & Results: Nonfluent PPA patients were significantly more impaired in both noun and verb naming compared to control participants. However, the nfvPPA patients were significantly more impaired in naming verbs than nouns, but there was no effect of manipulability. Conclusions: The results suggest that the verb naming deficit in nfvPPA is not directly related to impaired motor knowledge and is more likely to be related to other properties that distinguish verbs from nouns.

There is increasing recognition of a relationship between regional variability in cerebral gyrification and neurodevelopment. Recent work in morphometric MRI has shown that the local gyrification index (lGI), a measure of regional brain folding, may be altered in certain neurodevelopmental disorders. Other studies report that the lGI generally decreases with age in adolescence and young adulthood; however, little is known about how these age-dependent differences in brain maturation occur in atypical neurodevelopment and mechanisms underlying gyrification, such as synaptic pruning. Organization and optimization of dendrites and axons connections across the brain might be driving gyrification and folding processes. In this study, we first assessed lGI differences in the left hemisphere in a cohort of 39 children with developmental dyslexia (DD) between the ages of 7 and 15 years in comparison to 56 typically developing controls (TDC). To better understand the microstructural basis of these changes, we next explored the relationship between lGI differences and cortical thickness and neurite morphology by applying neurite orientation dispersion and density imaging (NODDI). We identified significant differences in lGI between children with DD and TDC in left lateral temporal and middle frontal regions. Further, DD failed to show the expected age-related decreases in lGI in the same regions. Age-related differences in lGI in DD were not explained by differences in cortical thickness, but did correlate with NODDI neurite density and orientation dispersion index. Our findings suggest that gyrification changes in DD are related to abnormal neurite morphology, and are possibly an expression of differences in synaptic pruning.

We aimed to characterize the timing of recovery and predictors of outcome following pediatric stroke, with the hypothesis that the recovery pattern after stroke is influenced by age. While the immature brain is often presumed to have an increased capacity for neuroplasticity, there is little direct data examining how recovery differs in children of different ages. We reviewed data for children with arterial ischemic stroke (AIS) who were enrolled in the International Pediatric Stroke Study, a prospective registry of children with stroke. Inclusion criteria included a diagnosis of AIS and the availability of outcome at two years after the index stroke event. A subset of these patients who had multiple assessments over time were used to study longitudinal patterns of recovery. We investigated demographic, clinical, and radiologic associations with both early outcome at discharge and long term outcome at two years using multinomial logistic regression. Categorical outcomes at each timepoint were defined by Pediatric Stroke Outcome Measure (PSOM). We studied longitudinal recovery using time-to-event (survival) analysis. 614 out of 4,294 patients met our inclusion criteria. 202 patients had perinatal AIS while 412 had childhood AIS. Perinatal AIS was associated with significant worsening between discharge and two years, as neurologic impairment became more apparent, but with better outcomes at both timepoints compared with childhood AIS (moderate/severe: 14% vs 49% at discharge, 47% vs 54% at 2 years). Predictors of severe deficits in univariate analyses included age at stroke (perinatal vs. childhood), hemiparesis or decreased consciousness at presentation, anterior circulation, and large vessel involvement. In longitudinal analysis, improvement in PSOM occurred for a longer time after stroke onset in younger children compared to older children. Although age has a strong influence on recovery after pediatric stroke, all children had the capacity to demonstrate recovery over extended periods of time. Understanding the timing and predictors of recovery will allow us to better target therapies to the appropriate windows of opportunity, thereby improving outcomes after pediatric stroke.