Miriam H. Beauchamp

SOCIAL: An Integrative Framework for the Development of Social Skills.

Despite significant advances in the field of social neuroscience, much remains to be understood regarding the development and maintenance of social skills across the life span. Few comprehensive models exist that integrate multidisciplinary perspectives and explain the multitude of factors that influence the emergence and expression of social skills. Here, a developmental biopsychosocial model (SOCIAL) is offered that incorporates the biological underpinnings and socio-cognitive skills that underlie social function (attention/executive function, communication, socio-emotional skills), as well as the internal and external (environmental) factors that mediate these skills. The components of the model are discussed in the context of the social brain network and are supported by evidence from 3 conditions known to affect social functioning (autism spectrum disorders, schizophrenia, and traumatic brain injury). This integrative model is intended to provide a theoretical structure for understanding the origins of social dysfunction and the factors that influence the emergence of social skills through childhood and adolescence in both healthy and clinical populations.

De Novo Mutations in FOXP1 in Cases with Intellectual Disability, Autism, and Language Impairment

Heterozygous mutations in FOXP2, which encodes a forkhead transcription factor, have been shown to cause developmental verbal dyspraxia and language impairment. FOXP2 and its closest homolog, FOXP1, are coexpressed in brain regions that are important for language and cooperatively regulate developmental processes, raising the possibility that FOXP1 may also be involved in developmental conditions that are associated with language impairment. In order to explore this possibility, we searched for mutations in FOXP1 in patients with intellectual disability (ID; mental retardation) and/or autism spectrum disorders (ASD). We first performed array-based genomic hybridization on sporadic nonsyndromic ID (NSID) (n = 30) or ASD (n = 80) cases. We identified a de novo intragenic deletion encompassing exons 4-14 of FOXP1 in a patient with NSID and autistic features. In addition, sequencing of all coding exons of FOXP1 in sporadic NSID (n = 110) or ASD (n = 135) cases, as well as in 570 controls, revealed the presence of a de novo nonsense mutation (c.1573C>T [p.R525X]) in the conserved forkhead DNA-binding domain in a patient with NSID and autism. Luciferase reporter assays showed that the p.R525X alteration disrupts the activity of the protein. Formal assessments revealed that both patients with de novo mutations in FOXP1 also show severe language impairment, mood lability with physical aggressiveness, and specific obsessions and compulsions. In conclusion, both FOXP1 and FOXP2 are associated with language impairment, but decrease of the former has a more global impact on brain development than that of the latter.

Preterm infant hippocampal volumes correlate with later working memory deficits

Children born preterm exhibit working memory deficits. These deficits may be associated with structural brain changes observed in the neonatal period. In this study, the relationship between neonatal regional brain volumes and working memory deficits at age 2 years were investigated, with a particular interest in the dorsolateral prefrontal cortex, parietal cortex and the hippocampus. While the eligible sample consisted of 227 very preterm children who were born at the Royal Womens Hospital, Melbourne prior to 30 weeks gestation or weighing <1250 g, 156 children had complete data sets. Neonatal magnetic resonance images of the brain were obtained at term equivalent age and subsequently parcellated into eight sub-regions, while the hippocampus was manually segmented. The relationship between brain volumes for these regions and performance on a working memory task (delayed alternation) at 2 years of age was examined. Very preterm children who perseverated on the working memory task had significantly smaller hippocampal volumes than very preterm children who exhibited intact working memory, even after adjusting for relevant perinatal, sociodemographic and developmental factors. Preterm children appear to have altered hippocampal volumes by discharge from hospital which may have a lasting impact on working memory function.

Clinical Risk Score for Persistent Postconcussion Symptoms Among Children With Acute Concussion in the ED

IMPORTANCE Approximately one-third of children experiencing acute concussion experience ongoing somatic, cognitive, and psychological or behavioral symptoms, referred to as persistent postconcussion symptoms (PPCS). However, validated and pragmatic tools enabling clinicians to identify patients at risk for PPCS do not exist. OBJECTIVE To derive and validate a clinical risk score for PPCS among children presenting to the emergency department. DESIGN, SETTING, AND PARTICIPANTS Prospective, multicenter cohort study (Predicting and Preventing Postconcussive Problems in Pediatrics [5P]) enrolled young patients (aged 5-<18 years) who presented within 48 hours of an acute head injury at 1 of 9 pediatric emergency departments within the Pediatric Emergency Research Canada (PERC) network from August 2013 through September 2014 (derivation cohort) and from October 2014 through June 2015 (validation cohort). Participants completed follow-up 28 days after the injury. EXPOSURES All eligible patients had concussions consistent with the Zurich consensus diagnostic criteria. MAIN OUTCOMES AND MEASURES The primary outcome was PPCS risk score at 28 days, which was defined as 3 or more new or worsening symptoms using the patient-reported Postconcussion Symptom Inventory compared with recalled state of being prior to the injury. RESULTS In total, 3063 patients (median age, 12.0 years [interquartile range, 9.2-14.6 years]; 1205 [39.3%] girls) were enrolled (n = 2006 in the derivation cohort; n = 1057 in the validation cohort) and 2584 of whom (n = 1701 [85%] in the derivation cohort; n = 883 [84%] in the validation cohort) completed follow-up at 28 days after the injury. Persistent postconcussion symptoms were present in 801 patients (31.0%) (n = 510 [30.0%] in the derivation cohort and n = 291 [33.0%] in the validation cohort). The 12-point PPCS risk score model for the derivation cohort included the variables of female sex, age of 13 years or older, physician-diagnosed migraine history, prior concussion with symptoms lasting longer than 1 week, headache, sensitivity to noise, fatigue, answering questions slowly, and 4 or more errors on the Balance Error Scoring System tandem stance. The area under the curve was 0.71 (95% CI, 0.69-0.74) for the derivation cohort and 0.68 (95% CI, 0.65-0.72) for the validation cohort. CONCLUSIONS AND RELEVANCE A clinical risk score developed among children presenting to the emergency department with concussion and head injury within the previous 48 hours had modest discrimination to stratify PPCS risk at 28 days. Before this score is adopted in clinical practice, further research is needed for external validation, assessment of accuracy in an office setting, and determination of clinical utility.

De Novo SYNGAP1 Mutations in Nonsyndromic Intellectual Disability and Autism

BACKGROUND Little is known about the genetics of nonsyndromic intellectual disability (NSID). Recently, we reported de novo truncating mutations in the SYNGAP1 gene of 3 of 94 NSID cases, suggesting that its disruption represents a common cause of autosomal dominant NSID. METHODS To further explore the involvement of SYNGAP1 in NSID, we sequenced its exons and intronic boundaries in 60 additional sporadic cases of NSID, including 30 patients with autism spectrum disorders (ASD) and 9 with epilepsy, and in 380 control individuals. RESULTS We identified de novo out-of-frame deletions in two patients with NSID and mild generalized epilepsy (c.2677delC/p.Q893RfsX184 and c.321_324delGAAG/p. K108VfsX25) and a de novo splicing mutation (c.2294 + 1G>A), which results in the creation of a premature stop codon, in a patient with NSID and autism. No splicing or truncating mutations were found in control subjects. CONCLUSIONS We provide evidence that truncating mutations in SYNGAP1 are common in NSID and can be also associated with autism.

Detecting Traumatic Brain Lesions in Children: CT versus MRI versus Susceptibility Weighted Imaging (SWI)

Cranial CT scans are at the center of decision making in brain injuries in children because of their speed and ability to detect surgically relevant lesions. However, alternative techniques, such as conventional MRI may have advantages in terms of radiation exposure and sensitivity to detect brain injury. Susceptibility-weighted imaging (SWI), a relatively novel MRI sequence, shows promise in terms of its sensitivity in detecting hemorrhagic lesions; however, its clinical potential remains uncertain. In this observational study of children (5-16 years of age) with traumatic brain injury (TBI) at a tertiary pediatric emergency department (ED) we compared the ability of detecting traumatic brain lesions on acute CT and MRI/SWI ∼ 5 weeks post-injury based on detecting the presence or absence, extent, and type of traumatic brain lesions. We analyzed the results of 76 patients (53 male) after TBI (mean age 10.24 ± 2.50 years, range 5.75-14.67 years). Glasgow Coma Score was 13-15 in 54 patients (71%), 9-12 in 13 patients (17%) and <8 in 9 patients (12%). CTs were completed in the ED; MRI and SWI were completed at a mean of 36.11 ± 15.75 days post-injury. Detection of any lesions occurred on CT scan in 68%, on MRI in 54%, and on SWI in 86% of cases, and SWI detected additional lesions 30% of the time compared to CT and MRI. SWI may be more sensitive in detecting traumatic lesions than CT or MRI. This may be important for the ongoing management of TBIs and their prognosis.

Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency.

De novo mutations in SYNGAP1, which codes for a RAS/RAP GTP‐activating protein, cause nonsyndromic intellectual disability (NSID). All disease‐causing point mutations identified until now in SYNGAP1 are truncating, raising the possibility of an association between this type of mutations and NSID. Here, we report the identification of the first pathogenic missense mutations (c.1084T>C [p.W362R], c.1685C>T [p.P562L]) and three novel truncating mutations (c.283dupC [p.H95PfsX5], c.2212_2213del [p.S738X], and (c.2184del [p.N729TfsX31]) in SYNGAP1 in patients with NSID. A subset of these patients also showed ataxia, autism, and a specific form of generalized epilepsy that can be refractory to treatment. All of these mutations occurred de novo, except c.283dupC, which was inherited from a father who is a mosaic. Biolistic transfection of wild‐type SYNGAP1 in pyramidal cells from cortical organotypic cultures significantly reduced activity‐dependent phosphorylated extracellular signal‐regulated kinase (pERK) levels. In contrast, constructs expressing p.W362R, p.P562L, or the previously described p.R579X had no significant effect on pERK levels. These experiments suggest that the de novo missense mutations, p.R579X, and possibly all the other truncating mutations in SYNGAP1 result in a loss of its function. Moreover, our study confirms the involvement of SYNGAP1 in autism while providing novel insight into the epileptic manifestations associated with its disruption.

Hippocampus, amygdala and global brain changes 10 years after childhood traumatic brain injury.

Traumatic brain injury (TBI) in children results in damage to the developing brain, particularly in severely injured individuals. Little is known, however, of the long‐term structural aspects of the brain following childhood TBI. This study investigated the integrity of the brain 10 years post‐TBI using magnetic resonance imaging volumetrics in a sample of 49 participants with mild, moderate and severe TBI, evaluated against a normative sample of 20 individuals from a pediatric database with comparable age and gender distribution. Structural integrity was investigated in gray and white matter, and by manually segmenting two regions of interest (hippocampus, amygdala), potentially vulnerable to the effects of childhood TBI. The results indicate that more severe injuries caused a reduction in gray and white brain matter, while all TBI severity levels resulted in increased volumes of cerebrospinal fluid and smaller hippocampal volumes. In addition, enlarged amygdala volumes were detected in severely injured patients compared to their mild and moderate counterparts, suggesting that childhood TBI may disrupt the development of certain brain regions through diffuse pathological changes. The findings highlight the lasting impact of childhood TBI on the brain and the importance of monitoring brain structure in the long‐term after early injury.

Selective Changes in Executive Functioning Ten Years After Severe Childhood Traumatic Brain Injury

Pediatric traumatic brain injury (TBI) impacts on childrens executive functions, but little is known of how such deficits evolve in the long term. Forty adolescents with TBI were assessed ten years post-injury and compared to 19 typically developing participants on a range of executive measures (attentional control, cognitive flexibility, goal setting, information processing). Children with mild or moderate TBI performed within age expectations on all tests; however, those with severe injuries had poorer performance on goal setting and processing speed tasks. Childhood TBI may result in subtle lasting changes in complex executive skills, which could require ongoing support into adulthood.

Social function assessment tools for children and adolescents: A systematic review from 1988 to 2010

Advances in neuroscience have added to the understanding of social functioning which has become an increasing area of focus in the psychology and neuropsychology literature. Given importance of appropriate social functioning to everyday interactions, as well as psychological well-being, accurately identifying and documenting such functions constitute a critical undertaking for both researchers and clinicians in psychology and related health professions. This review aimed to identify available social function assessment tools for children and adolescents using a comprehensive search method. Eighty-six measures were identified. Information on the assessment tools including the theoretical model they are based on, age range, sample used in development, and psychometric information are described. Results will aid researchers, psychologists and other health professionals in the selection of an appropriate tool to assess social function.