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Background and Purpose: Childhood and adolescence coincide with rapid maturation of distributed brain networks supporting social cognition; however, little is known about the impact of early ischemic brain insult on the acquisition of these skills. This study aimed to examine the influence of arterial ischemic stroke (AIS) on facial emotion recognition and theory of mind (ToM) abilities of children and adolescents initially recruited to a single-center, prospective longitudinal study of recovery following AIS. Methods: The study involved 67 participants, including 30 children with AIS (mean time since stroke=5 years) and 37 age-matched typically developing controls who were assessed on measures of cognitive ToM, facial emotion recognition, and affective ToM. Acute clinical magnetic resonance imaging, including diffusion-weighted imaging sequences, were used to evaluate prospective structure-function relationships between acute lesion characteristics (size, location, and arterial territories affected) and long-term social cognitive abilities. Results: Relative to age-matched typically developing controls, children with AIS showed significantly worse performance on measures of basic facial emotion processing, cognitive ToM, and affective ToM. In univariate models, poorer ToM was associated with larger infarcts, combined cortical-subcortical pathology, and involvement of multiple arterial territories. In multivariate analyses, larger lesions and multiterritory infants were predictive of ToM processing but not facial emotion recognition. Poorer cognitive ToM predicted less frequent prosocial behavior and increased peer problems. Conclusions: Social cognitive skills appear vulnerable to disruption from early ischemic brain insult. In the first study to examine social cognition in a prospective cohort of children with AIS, our findings suggest that acute magnetic resonance imaging-based lesion characteristics may have predictive value for long-term social cognitive outcomes and may assist to identify children at elevated risk for social cognitive dysfunction.

Recent evidence suggests social cognitive deficits may be among the most profound and disabling consequences of childhood traumatic brain injury (TBI); however, it is only over the last decade that this area has received increasing research attention. This study aims to systematically review all studies reporting on the effects of childhood TBI on social cognition. Meta-analytic techniques were employed to determine the magnitude of social cognitive deficits in childhood TBI. Literature searches were conducted in electronic databases (Medline/PubMed, Scopus, Cochrane, EMBASE, PsycINFO and CINAHL) to retrieve relevant articles on social cognitive outcomes of paediatric TBI published from 2007-2019. The systematic review identified fourteen eligible studies, which examined the effect of paediatric TBI on five dimensions of social cognition, including emotion recognition or perception, theory of Mind (ToM), pragmatic language, moral reasoning, and social problem solving. Of these studies, eleven articles were included in subsequent meta-analyses, which included 482 children with TBI. Meta-analysis using a random-effects model revealed non-significant differences between TBI and typically developing (TD) control groups on measures of emotion perception or recognition. In contrast, children and adolescents with TBI performed significantly worse than control groups on ToM and pragmatic language tasks, with small and medium effect sizes, respectively (Hedge's g = -0.46; -0.73). Meta-regression indicated that post-injury social cognitive deficits were not moderated by child age. While the effect of time since injury was not statistically significant, poorer social cognitive outcomes are documented soon after injury. Despite relatively intact basic social cognitive skills (i.e. emotion perception or recognition) children and adolescents with TBI are vulnerable to deficits in higher-order aspects of social cognition, including ToM and pragmatic language. These findings underscore the importance of further research, using well-validated, standardised outcome instruments, in larger paediatric TBI samples. Furthermore, longitudinal prospective studies are needed to evaluate the respective contribution of injury and non-injury factors to individual variation in outcome and recovery of social cognition after paediatric TBI.

Traumatic brain injury (TBI) is a major cause of death and disability in children in both developed and developing nations. Children and adolescents suffer from TBI at a higher rate than the general population, and specific developmental issues require a unique context since findings from adult research do not necessarily directly translate to children. Findings in pediatric cohorts tend to lag behind those in adult samples. This may be due, in part, both to the smaller number of investigators engaged in research with this population and may also be related to changes in safety laws and clinical practice that have altered length of hospital stays, treatment, and access to this population. The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Pediatric Moderate/Severe TBI (msTBI) group aims to advance research in this area through global collaborative meta-analysis of neuroimaging data. In this paper, we discuss important challenges in pediatric TBI research and opportunities that we believe the ENIGMA Pediatric msTBI group can provide to address them. With the paucity of research studies examining neuroimaging biomarkers in pediatric patients with TBI and the challenges of recruiting large numbers of participants, collaborating to improve statistical power and to address technical challenges like lesions will significantly advance the field. We conclude with recommendations for future research in this field of study.

Traumatic brain injury (TBI) during critical periods of early-life brain development can affect the normal formation of brain networks responsible for a range of complex social behaviors. Because of the protracted nature of brain and behavioral development, deficits in cognitive and socioaffective behaviors may not become evident until late adolescence and early adulthood, when such skills are expected to reach maturity. In addition, multiple pre- and post-injury factors can interact with the effects of early brain insult to influence long-term outcomes. In recent years, with advancements in magnetic-resonance-based neuroimaging techniques and analysis, studies of the pediatric population have revealed a link between neurobehavioral deficits, such as social dysfunction, with white matter damage. In this review, in which we focus on contributions from Australian researchers to the field, we have highlighted pioneering longitudinal studies in pediatric TBI, in relation to social deficits specifically. We also discuss the use of advanced neuroimaging and novel behavioral assays in animal models of TBI in the immature brain. Together, this research aims to understand the relationship between injury consequences and ongoing brain development after pediatric TBI, which promises to improve prediction of the behavioral deficits that emerge in the years subsequent to early-life injury.

BACKGROUND . Demographic and environmental factors can affect child recovery after traumatic brain injury (TBI); however, little is known about their role in predicting child perceptions of competence (i.e., subjective judgments of ability or a sense of adequacy). OBJECTIVES . This prospective, cohort study examined the contribution of participant sex, age at assessment, socioeconomic status, parent-reported change in academic performance post-injury, and the quality of a child's relationship with their family (i.e., family affective involvement, intimacy, integration, and the nature of family roles) to child perceptions of global and academic competence 12 months after pediatric TBI. METHODS . Participants included 127 children, 84 with a TBI (53 mild, 31 moderate-severe TBI; injury age: 5-15 years) and 43 age-matched typically developing (TD) controls. Children rated their perceptions of global and academic competence and degree of family intimacy and integration. Parents completed questionnaires measuring socioeconomic status, family affective involvement, and the nature of family roles. Parents also indicated whether they perceived a change in their child's post-injury academic performance. RESULTS . Child perceptions of academic competence were significantly lower for children with moderate-severe TBI relative to TD children. In contrast, child perceptions of global competence were comparable between TBI and TD control groups. Socioeconomic status, age at assessment, parent-reported relative change in academic performance post-TBI, and family roles were associated with child perceptions of academic competence. Degree of family integration was the sole predictor of child perceptions of global competence. CONCLUSIONS . Child perceptions of academic competence are vulnerable to the effects of moderate-severe TBI, particularly among older children and those from low socioeconomic backgrounds. Well-defined family roles for handling family functions and greater integration of family units might enhance perceptions of global and academic competence in children with TBI.

Background Despite increasing evidence of a link between early life brain injury and anti-social behavior, very few studies have assessed factors that explain this association in children with traumatic brain injury (TBI). One hypothesis suggests that childhood TBI elevates risk for anti-social behavior via disruption to anatomically distributed neural networks implicated in executive functioning (EF). In this longitudinal prospective study, we employed high-resolution structural neuroimaging to (a) evaluate the impact of childhood TBI on regional morphometry of the central executive network (CEN) and (b) evaluate the prediction that lower EF mediates the prospective relationship between structural differences within the CEN and postinjury anti-social behaviors. Methods This study involved 155 children, including 112 consecutively recruited, hospital-confirmed cases of mild-severe TBI and 43 typically developing control (TDC) children. T1-weighted brain magnetic resonance imaging (MRI) sequences were acquired sub-acutely in a subset of 137 children [TBI: n = 103; TDC: n = 34]. All participants were evaluated using direct assessment of EF 6 months postinjury, and parents provided ratings of anti-social behavior 12 months postinjury. Results Severe TBI was associated with postinjury volumetric differences within the CEN and its putative hub regions. When compared with TD controls, the TBI group had significantly worse EF, which was associated with more frequent anti-social behaviors and abnormal CEN morphometry. Mediation analysis indicated that reduced EF mediated the prospective association between postinjury volumetric differences within the CEN and more frequent anti-social behavior. Conclusions Our longitudinal prospective findings suggest that detection of neurostructural abnormalities within the CEN may aid in the early identification of children at elevated risk for postinjury executive dysfunction, which may in turn contribute to chronic anti-social behaviors after early life brain injury. Findings underscore the potential value of early surveillance and preventive measures for children presenting with neurostructural and/or neurocognitive risk factors.

This study assessed the consequences of childhood traumatic brain injury (TBI) on sleep, fatigue, depression, and quality of life (QoL) outcomes and explored the relationships between these variables at 20 years following childhood TBI.We followed up 54 young adults with mild, moderate, and severe TBI, and 13 typically developing control (TDC) participants, recruited at the time of TBI.Sleep was assessed with the Pittsburgh Sleep Quality Index and actigraphy.At 20 years postinjury, results showed no significant difference between whole TBI group and TDC participants on subjective sleep quality; however, the moderate TBI group reported significantly poorer subjective sleep quality compared to those with severe TBI. Poorer subjective sleep was associated with increased symptoms of fatigue, depression, and poorer perceptions of General Health in the TBI group. Actigraphic sleep efficiency, fatigue, depression, and QoL outcomes were not significantly different between TBI and TDC or among TBI severity groups.These preliminary findings underscore associations between subjective sleep disturbance, fatigue, depression, and QoL in this TBI sample, and mostly comparable outcomes in sleep, fatigue, depression, and QoL between the TBI and TDC groups. Further research is required to clarify these findings.

Although childhood traumatic brain injury (TBI) has been linked to heightened risk of impaired social skills and behavior, current evidence is weakened by small studies of variable methodological quality. To address these weaknesses, this international multi-cohort study involved synthesis of data from two large observational cohort studies of complicated mild-severe child TBI in Australia and North America. Both studies adopted a unified approach to data collection and coding procedures, providing the opportunity to merge datasets from multiple, well-characterized cohorts for which gold standard measures of social outcomes were collected during the chronic recovery phase. The study involved 218 children, including 33 children with severe TBI, 83 children with complicated mild-moderate TBI, 59 children with orthopedic injury, and 43 age- and sex-matched typically developing control children. All injured children were recruited from academic children's hospitals and underwent direct cognitive assessments including measures of theory of mind (ToM) at least 1-year post- injury. Parents rated their child's social adjustment using standardized measures of social skills, communication and behavior. Results showed a brain-injury specific effect on ToM abilities, such that children with both complicated mild to moderate and severe TBI displayed significantly poorer ToM than children without TBI. In mediator models, poorer ToM predicted poorer parent-rated self-direction and social skills, as well as more frequent behavioral symptoms. The ToM mediated the effect of severe TBI on parent ratings of communication and social skills, as well as on overall behavior symptoms. The findings suggest that deficits in ToM are evident across the spectrum of TBI severity and represent one mechanism linking severe child TBI to long-term social adjustment difficulties. The findings underscore the value of large-scale data harmonization projects to increase the quality of evidence regarding the outcomes of TBI. Clinical and scientific implications are discussed.

ObjectiveOur study addressed aims (1) to test the hypothesis that moderate-severe traumatic brain injury (TBI) in pediatric patients is associated with widespread white matter (WM) disruption, (2) to test the hypothesis that age and sex affect WM organization after injury, and (3) to examine associations between WM organization and neurobehavioral outcomes.MethodsData from 10 previously enrolled, existing cohorts recruited from local hospitals and clinics were shared with the Enhancing NeuroImaging Genetics Through Meta-Analysis (ENIGMA) Pediatric Moderate/Severe TBI (msTBI) working group. We conducted a coordinated analysis of diffusion MRI (dMRI) data using the ENIGMA dMRI processing pipeline.ResultsFive hundred seven children and adolescents (244 with complicated msTBI and 263 controls) were included. Patients were clustered into 3 postinjury intervals: acute/subacute, ConclusionsWM disruption after msTBI is widespread, persistent, and influenced by demographic and clinical variables. Future work will test techniques for harmonizing neurocognitive data, enabling more advanced analyses to identify symptom clusters and clinically meaningful patient subtypes.

Annually, approximately 3 million children around the world experience traumatic brain injuries (TBIs), of which up to 20% are characterized as moderate to severe (msTBI) and/or have abnormal imaging findings. Affected children are vulnerable to long-term cognitive and behavioral dysfunction, as injury can disrupt or alter ongoing brain maturation. Post-injury outcomes are highly variable, and there is only limited understanding of how inter-individual differences in outcomes arise. Small sample sizes have also complicated efforts to better understand factors influencing the impact of TBI on the developing brain. White matter (WM) disruption is a critical aspect of TBI neuropathology and diffusion MRI (dMRI) is particularly sensitive to microstructural abnormalities. Here we present the results of a coordinated analysis of dMRI data across ten cohorts from three countries. We had three primary aims: (1) to characterize the nature and extent of WM disruption across key post-injury intervals (acute/subacute - within 2 months, post-acute - 2-6 months, chronic - 6+ months); (2) evaluate the impact of age and sex on WM in the context of injury; and (3) to examine associations between WM and neurobehavioral outcomes. Based on data from 507 children and adolescents (244 with complicated mild to severe TBI and 263 control children), we report widespread WM disruption across all post-injury intervals. As expected, injury severity was a significant contributor to the pattern and extent of WM degradation, but explained less variance in dMRI measures with increasing time since injury, supporting other research indicating that other factors contribute increasingly to outcomes over time. The corpus callosum appears to be particularly vulnerable to injury, an effect that persists years post-TBI. We also report sex differences in the effect of TBI on the uncinate fasciculus (UNC), a structure with a key role in emotion regulation. Females with a TBI had significantly lower fractional anisotropy (FA) in the UNC than those with no TBI, and this phenomenon was further associated with more frequent parent-reported behavioral problems as measured by the Child Behavior Checklist (CBCL). These effects were not detected in males. With future harmonization of imaging and neurocognitive data, more complex modeling of factors influencing outcomes will be possible and help to identify clinically-meaningful patient subtypes.

Childhood and adolescence represent sensitive developmental periods for brain networks implicated in a range of complex skills, including executive functions (EF; inhibitory control, working memory, and cognitive flexibility). As a consequence, these skills may be particularly vulnerable to injuries sustained during these sensitive developmental periods. The present study investigated 1) whether age at injury differentially affects EF 6 months and 2 years after TBI in children aged 5-15 years, and 2) whether the association between brain lesions and EF depend on age at injury. Children with TBI (n = 105) were categorized into four age-at-injury groups based on previous studies and proposed timing of cerebral maturational spurts: early childhood (5-6 years, n = 14), middle childhood (7-9 years, n = 24), late childhood (10-12 years, n = 52), and adolescence (13-15 years, n = 15). EF were assessed with performance-based tasks and a parent-report of everyday EF. TBI patients' EF scores 6 months and 2 years post-injury were compared to those of typically developing (TD) controls (n = 42). Brain lesions were identified using susceptibility weighted imaging (SWI). Results indicated that inhibitory control performance 2 years post-injury was differentially affected by the impact of TBI depending on age at injury. Follow-up analyses did not reveal significant differences within the age groups, preventing drawing strong conclusions regarding the contribution of age at injury to EF outcome after TBI. Tentatively, large effect sizes suggest that vulnerability is most apparent in early childhood and adolescence. Everyday inhibitory control behaviour was worse for children with TBI than TD children across childhood and adolescence at the 2-year assessment. There was no evidence for impairment in working memory or cognitive flexibility after TBI at the group level. Given small group sizes, findings from analyses into correlations between EF and SWI lesions should be interpreted with caution. Extent, number and volume of brain lesions correlated with adolescent everyday EF behaviour 6 months post-injury. Taken together, the results emphasize the need for long-term follow-up after paediatric TBI during sensitive developmental periods given negative outcomes 2-year post injury. Inhibitory control seems to be particular vulnerable to the impact of TBI. Findings of associations between EF and SWI lesions need to be replicated with larger samples.

BackgroundDeficits in social cognition may be among the most profound and disabling sequelae of paediatric traumatic brain injury (TBI); however, the neuroanatomical correlates of longitudinal outcomes in this domain remain unexplored. This study aimed to characterize social cognitive outcomes longitudinally after paediatric TBI, and to evaluate the use of sub-acute diffusion tensor imaging (DTI) to predict these outcomes.MethodsThe sample included 52 children with mild complex-severe TBI who were assessed on cognitive theory of mind (ToM), pragmatic language and affective ToM at 6- and 24-months post-injury. For comparison, 43 typically developing controls (TDCs) of similar age and sex were recruited. DTI data were acquired sub-acutely (mean = 5.5 weeks post-injury) in a subset of 65 children (TBI = 35; TDC = 30) to evaluate longitudinal prospective relationships between white matter microstructure assessed using Tract-Based Spatial Statistics and social cognitive outcomes.ResultsWhole brain voxel-wise analysis revealed significantly higher mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in the sub-acute TBI group compared with TDC, with differences observed predominantly in the splenium of the corpus callosum (sCC), sagittal stratum (SS), dorsal cingulum (DC), uncinate fasciculus (UF) and middle and superior cerebellar peduncles (MCP & SCP, respectively). Relative to TDCs, children with TBI showed poorer cognitive ToM, affective ToM and pragmatic language at 6-months post-insult, and those deficits were related to abnormal diffusivity of the sCC, SS, DC, UF, MCP and SCP. Moreover, children with TBI showed poorer affective ToM and pragmatic language at 24-months post-injury, and those outcomes were predicted by sub-acute alterations in diffusivity of the DC and MCP.ConclusionsAbnormal microstructure within frontal-temporal, limbic and cerebro-cerebellar white matter may be a risk factor for long-term social difficulties observed in children with TBI. DTI may have potential to unlock early prognostic markers of long-term social outcomes.

Executive functions (EFs), such as inhibition and cognitive flexibility, are essential for everyday functioning, including regulation of socially appropriate emotional responses. These skills develop during childhood and continue maturing into early adulthood. The current study aimed to investigate the very long-term impact of childhood traumatic brain injury (TBI) on inhibition and cognitive flexibility, and to examine whether global white matter is associated with these abilities. Twenty-eight young adult survivors of childhood TBI (mean age at 16-year follow-up = 21.67 years, SD = 2.70) and 16 typically developing controls (TDCs), group-matched for age, sex, and socioeconomic status, completed tests of inhibition and cognitive flexibility and underwent structural MRI. Survivors of childhood TBI did not significantly differ from TDCs on EF or white matter volume. However, the relationship between EF and white matter volume differed between survivors of TBI and TDCs. Survivors of TBI did not mimic the brain behavior relationship that characterized EF in TDCs. The inverse brain behavior relationship, exhibited by childhood TBI survivors, suggests disruptions in the whole brain underpinning EF following childhood TBI.

Deficits in theory of mind (ToM) are common after neurological insult acquired in the first and second decade of life, however the contribution of large-scale neural networks to ToM deficits in children with brain injury is unclear. Using paediatric traumatic brain injury (TBI) as a model, this study investigated the sub-acute effect of paediatric traumatic brain injury on grey-matter volume of three large-scale, domain-general brain networks (the Default Mode Network, DMN; the Central Executive Network, CEN; and the Salience Network, SN), as well as two domain-specific neural networks implicated in social-affective processes (the Cerebro-Cerebellar Mentalizing Network, CCMN and the Mirror Neuron/Empathy Network, MNEN). We also evaluated prospective structure–function relationships between these large-scale neural networks and cognitive, affective and conative ToM. 3D T1- weighted magnetic resonance imaging sequences were acquired sub-acutely in 137 children [TBI: n = 103; typically developing (TD) children: n = 34]. All children were assessed on measures of ToM at 24-months post-injury. Children with severe TBI showed sub-acute volumetric reductions in the CCMN, SN, MNEN, CEN and DMN, as well as reduced grey-matter volumes of several hub regions of these neural networks. Volumetric reductions in the CCMN and several of its hub regions, including the cerebellum, predicted poorer cognitive ToM. In contrast, poorer affective and conative ToM were predicted by volumetric reductions in the SN and MNEN, respectively. Overall, results suggest that cognitive, affective and conative ToM may be prospectively predicted by individual differences in structure of different neural systems—the CCMN, SN and MNEN, respectively. The prospective relationship between cerebellar volume and cognitive ToM outcomes is a novel finding in our paediatric brain injury sample and suggests that the cerebellum may play a role in the neural networks important for ToM. These findings are discussed in relation to neurocognitive models of ToM. We conclude that detection of sub-acute volumetric abnormalities of large-scale neural networks and their hub regions may aid in the early identification of children at risk for chronic social-cognitive impairment.

Social dysfunction is a common and disabling outcome of childhood traumatic brain injury (TBI); however, the mechanisms that link early brain injury to impaired social behavior are unclear. This longitudinal prospective study involved 129 children, including 86 children with TBI (53 mild, 33 moderate-severe TBI) and 43 age-matched typically developing control (TDC) children. Children with TBI were recruited via consecutive admissions to the emergency department of the Royal Children's Hospital, Melbourne Australia. At 6 months post-injury, all participants were assessed on measures of intellectual functioning, and parents provided ratings of children's self-regulation skills using gold standard measures of everyday executive function. At 12-month follow up, parents rated children's social adjustment using standardized measures of social skills, communication, and behavior. As expected, children with moderate-severe TBI were rated by parents as having greater self-regulation problems, worse social skills, and poorer communication than the mild TBI and TDC groups. In mediation models, greater self-regulation problems at 6 months post-injury were predictive of poorer social skills and worse overall social adjustment at 12-month follow-up. Moreover, self-regulation skills mediated the effect of moderate-severe TBI, but not mild TBI, on social skills and overall social adjustment. Our findings show that, while impaired social adjustment is common at 12 months following moderate-severe child TBI, the impact of TBI on these outcomes is likely mediated by its effect on self-regulation skills. Evidence for robust prospective associations between self-regulation deficits and later social adjustment difficulties have implications for early identification of children at high risk for chronic social problems.

Previous studies in pediatric traumatic brain injury (TBI) have been variable in describing the effects of injury severity on white-matter development. The present study used diffusion tensor imaging to investigate prospective sub-acute and longitudinal relationships between early clinical indicators of injury severity, diffusion metrics, and neuropsychological outcomes. Pediatric patients with TBI underwent magnetic resonance imaging (MRI) (n = 78, mean [M] = 10.56, standard deviation [SD] = 2.21 years) at the sub-acute stage after injury (M = 5.55, SD = 3.05 weeks), and typically developing children were also included and imaged (n = 30, M = 10.60, SD = 2.88 years). A sub-set of the patients with TBI (n = 15) was followed up with MRI 2 years post-injury. Diffusion MRI images were acquired at sub-acute and 2-year follow-up time points and analyzed using Tract-Based Spatial Statistics. At the sub-acute stage, mean diffusivity and axial diffusivity were significantly higher in the TBI group compared with matched controls (p

Childhood and adolescence coincide with rapid structural and functional maturation of brain networks implicated in Theory of Mind (ToM); however, the impact of paediatric traumatic brain injury (TBI) on the development of these higher order skills is not well understood. ToM can be partitioned intoconative ToM, defined as the ability to understand how indirect speech acts involving irony and empathy are used to influence the mental or affective state of the listener; andaffective ToM, concerned with understanding that facial expressions are often used for social purposes to convey emotions that we want people to think we feel. In a sample of 84 children with mild-severe TBI and 40 typically developing controls, this study examined the effect of paediatric TBI on affective and conative ToM; and evaluated the respective contributions of injury-related factors (injury severity/lesion location) and non-injury-related environmental variables (socio-economic status (SES)/family functioning) to long-term ToM outcomes. Results showed that the poorest ToM outcomes were documented in association with mild-complicated and moderate TBI, rather than severe TBI. Lesion location and SES did not significantly contribute to conative or affective ToM. Post-injury family affective responsiveness was the strongest and most significant predictor of conative ToM. Results suggest that clinicians should exercise caution when prognosticating based on early clinical indicators, and that group and individual-level outcome prediction should incorporate assessment of a range of injury- and non-injury-related factors. Moreover, the affective quality of post-injury family interactions represents a potentially modifiable risk factor, and might be a useful target for family-centred interventions designed to optimise social cognitive outcomes after paediatric TBI.

Childhood and adolescence are critical periods for maturation of neurobiological processes that underlie complex social and emotional behavior including Theory of Mind (ToM). While structural correlates of ToM are well described in adults, less is known about the anatomical regions subsuming these skills in the developing brain or the impact of cerebral insult on the acquisition and establishment of high-level social cognitive skills. This study aimed to examine the differential influence of age-at-insult and brain pathology on ToM in a sample of children and adolescents with traumatic brain injury (TBI). Children and adolescents with TBI (n = 112) were categorized according to timing of brain insult: (i) middle childhood (5-9 years; n = 41); (ii) late childhood (10-11 years; n = 39); and (iii) adolescence (12-15 years; n = 32) and group-matched for age, gender, and socioeconomic status to a typically developing (TD) control group (n = 43). Participants underwent magnetic resonance imaging including a susceptibility-weighted imaging (SWI) sequence 2-8 weeks postinjury and were assessed on a battery of ToM tasks at 6- and 24-months after injury. Results showed that for adolescents with TBI, social cognitive dysfunction at 6- and 24-months postinjury was associated with diffuse neuropathology and a greater number of lesions detected using SWI. In the late childhood TBI group, we found a time-dependent emergence of social cognitive impairment, linked to diffuse neuropathology. The middle childhood TBI group demonstrated performance unrelated to SWI pathology and comparable to TD controls. Findings indicate that the full extent of social cognitive deficits may not be realized until the associated skills reach maturity. Evidence for brain structure-function relationships suggests that the integrity of an anatomically distributed network of brain regions and their connections is necessary for the acquisition and establishment of high-level social cognitive skills.

Cognitive fatigue is among the most profound and disabling sequelae of pediatric acquired brain disorders, however the neural correlates of these symptoms in children remains unexplored. One hypothesis suggests that cognitive fatigue may arise from dysfunction of cortico-striatal networks (CSNs) implicated in effort output and outcome valuation. Using pediatric traumatic brain injury (TBI) as a model, this study investigated (i) the sub-acute effect of brain injury on CSN volume; and (ii) potential relationships between cognitive fatigue and sub-acute volumetric abnormalities of the CSN. 3D T1 weighted magnetic resonance imaging sequences were acquired sub-acutely in 137 children (TBI: n = 103; typically developing - TD children: n = 34). 67 of the original 137 participants (49%) completed measures of cognitive fatigue and psychological functioning at 24-months post-injury. Results showed that compared to TD controls and children with milder injuries, children with severe TBI showed volumetric reductions in the overall CSN package, as well as regional gray matter volumetric change in cortical and subcortical regions of the CSN. Significantly greater cognitive fatigue in the TBI patients was associated with volumetric reductions in the CSN and its putative hub regions, even after adjusting for injury severity, socioeconomic status (SES) and depression. In the first study to evaluate prospective neuroanatomical correlates of cognitive fatigue in pediatric acquired brain disorder, these findings suggest that post-injury cognitive fatigue is related to structural abnormalities of cortico-striatal brain networks implicated in effort output and outcome valuation. Morphometric magnetic resonance imaging (MRI) may have potential to unlock early prognostic markers that may assist to identify children at elevated risk for cognitive fatigue post-TBI.

Social dysfunction is common after traumatic brain injury (TBI), contributing to reduced quality of life for survivors. Factors which influence the development or persistence of social deficits after injury remain poorly understood, particularly in the context of ongoing brain maturation during childhood and adolescence. Aberrant social interactions have recently been modeled in adult and juvenile rodents after experimental TBI, providing an opportunity to gain new insights into the underlying neurobiology of these behaviors. Here, we review our current understanding of social dysfunction in both humans and rodent models of TBI, with a focus on brain injuries acquired during early development. Modulators of social outcomes are discussed, including injury-related and environmental risk and resilience factors. Disruption of social brain network connectivity and aberrant neuroendocrine function are identified as potential mechanisms of social impairments after pediatric TBI. Throughout, we highlight the overlap and disparities between outcome measures and findings from clinical and experimental approaches, and explore the translational potential of future research to prevent or ameliorate social dysfunction after childhood TBI.

Pediatric traumatic brain injury (TBI) can result in a range of social impairments, however longitudinal recovery is not well characterized, and clinicians are poorly equipped to identify children at risk for persisting difficulties. Using a longitudinal prospective design, this study aimed to evaluate the contribution of injury and non-injury related risk and resilience factors to longitudinal outcome and recovery of social problems from 12- to 24-months post-TBI. 78 children with TBI (injury age: 5.0-15.0 years) and 40 age and gender-matched typically developing (TD) children underwent magnetic resonance imaging including a susceptibility-weighted imaging (SWI) sequence 2-8 weeks post-injury (M=39.25, SD=27.64 days). At 12 and 24-months post- injury, parents completed questionnaires rating their child's social functioning, and environmental factors including socioeconomic status, caregiver mental health and family functioning. Results revealed that longitudinal recovery profiles differed as a function of injury severity, such that among children with severe TBI, social problems significantly increased from 12- to 24-months post-injury, and were found to be significantly worse than TD controls and children with mild and moderate TBI. In contrast, children with mild and moderate injuries showed few problems at 12-months post-injury and little change over time. Pre-injury environment and SWI did not significantly contribute to outcome at 24-months, however concurrent caregiver mental health and family functioning explained a large and significant proportion of variance in these outcomes. Overall, this study shows that longitudinal recovery profiles differ as a function of injury severity, with evidence for late-emerging social problems among children with severe TBI. Poorer long-term social outcomes were associated with family dysfunction and poorer caregiver mental health at 24-months post injury, suggesting that efforts to optimize the child's environment and bolster family coping resources may enhance recovery of social problems following pediatric TBI.

Childhood and adolescence coincide with rapid maturation and synaptic reorganization of distributed neural networks that underlie complex cognitive-affective behaviors. These regions, referred to collectively as the 'social brain network' (SBN) are commonly vulnerable to disruption from pediatric traumatic brain injury (TBI); however, the mechanisms that link morphological changes in the SBN to behavior problems in this population remain unclear. In 98 children and adolescents with mild to severe TBI, we acquired 3D T1-weighted MRIs at 2-8 weeks post-injury. For comparison, 33 typically developing controls of similar age, sex and education were scanned. All participants were assessed on measures of Theory of Mind (ToM) at 6 months post-injury and parents provided ratings of behavior problems at 24-months post-injury. Severe TBI was associated with volumetric reductions in the overall SBN package, as well as regional gray matter structural change in multiple component regions of the SBN. When compared with TD controls and children with milder injuries, the severe TBI group had significantly poorer ToM, which was associated with more frequent behavior problems and abnormal SBN morphology. Mediation analysis indicated that impaired theory of mind mediated the prospective relationship between abnormal SBN morphology and more frequent chronic behavior problems. Our findings suggest that sub-acute alterations in SBN morphology indirectly contribute to long-term behavior problems via their influence on ToM. Volumetric change in the SBN and its putative hub regions may represent useful imaging biomarkers for prediction of post-acute social cognitive impairment, which may in turn elevate risk for chronic behavior problems.

OBJECTIVES:: To investigate rates of clinically significant externalizing behavior (EB) in young adult survivors of pediatric traumatic brain injury (TBI) and evaluate the contribution of pre- and postinjury risk and resilience factors to EB outcomes 16 years after injury. SETTING:: Melbourne, Australia. PARTICIPANTS:: Fifty-five young adults (mean age = 23.85 years; injury age: 1.0-12 years) admitted to an emergency department following TBI between 1993 and 1997. DESIGN:: Longitudinal prospective study with data collected at the acute, 10-year, and 16-year postinjury time points. MAIN MEASURES:: Severity of TBI, adaptive functioning, family functioning, full-scale IQ, executive functioning, social communication, and symptoms of EB. RESULTS:: One of every 4 young people with a history of pediatric TBI demonstrated clinical or subthreshold levels of EB in young adulthood. More frequent EB was associated with poorer preinjury adaptive functioning, lower full-scale IQ, and more frequent pragmatic communication difficulty. CONCLUSION:: Pediatric TBI is associated with an elevated risk for externalizing disorders in the transition to adulthood. RESULTS underscore the need for screening and assessment of TBI among young offenders and suggest that early and long-term targeted interventions may be required to address risk factors for EB in children and young people with TBI. Language: en

The purpose of the present investigation was to evaluate the contribution of age-at-insult and brain pathology on longitudinal outcome and recovery of pragmatic language in a sample of children and adolescents with traumatic brain injury (TBI). Children and adolescents with mild to severe TBI (n=112) were categorized according to timing of brain insult: (i) Middle Childhood (5-9 years; n=41); (ii) Late Childhood (10-11 years; n=39); and (iii) Adolescence (12-15 years; n=32) and group-matched for age, gender and socio-economic status (SES) to a typically developing (TD) control group (n=43). Participants underwent magnetic resonance imaging (MRI) including a susceptibility weighted imaging (SWI) sequence 2-8 weeks after injury and were assessed on measures of pragmatic language and behavioural functioning at 6- and 24-months after injury. Children and adolescents with TBI of all severity levels demonstrated impairments in these domains at 6-months injury before returning to age-expected levels at 2-years post-TBI. However, while adolescent TBI was associated with post-acute disruption to skills that preceded recovery to age-expected levels by 2-years post injury, the middle childhood TBI group demonstrated impairments at 6-months post-injury that were maintained at 2-year follow up. Reduced pragmatic communication was associated with frontal, temporal and corpus callosum lesions, as well as more frequent externalizing behaviour at 24-months post injury. Findings show that persisting pragmatic language impairment after pediatric TBI is related to younger age at brain insult, as well as microhemorrhagic pathology in brain regions that contribute to the anatomically distributed social brain network. Relationships between reduced pragmatic communication and more frequent externalizing behavior underscore the need for context-sensitive rehabilitation programs that aim to increase interpersonal effectiveness and reduce risk for maladaptive behavior trajectories into the long-term post injury.

Theory of Mind (ToM) forms an integral component of socially skilled behavior, and is critical for attaining developmentally appropriate goals. The protracted development of ToM is mediated by increasing connectivity between regions of the anatomically distributed ‘mentalizing network’, and may be vulnerable to disruption from pediatric traumatic brain injury (TBI). The present study aimed to evaluate the post-acute effects of TBI on first-order ToM, and examine relations between ToM and both local and global indices of macrostructural damage detected using susceptibility-weighted imaging (SWI). 104 children and adolescents with TBI and 43 age-matched typically developing (TD) controls underwent magnetic resonance imaging including a susceptibility-weighted imaging (SWI) sequence 2–8 weeks post-injury and were assessed on cognitive ToM tasks at 6-months after injury. Compared to TD controls and children with mild-moderate injuries, children with severe TBI showed significantly poorer ToM. Moreover, impairments in ToM were related to diffuse neuropathology, and parietal lobe lesions. Our findings support the vulnerability of the immature social brain network to disruption from TBI, and suggest that global macrostructural damage commonly associated with traumatic axonal injury (TAI) may contribute to structural disconnection of anatomically distributed regions that underlie ToM. This study suggests that SWI may be a valuable imaging biomarker to predict outcome and recovery of social cognition after pediatric TBI.

Emotion perception (EP) forms an integral part of social communication and is critical to attain developmentally appropriate goals. This skill, which emerges relatively early in development, is driven by increasing connectivity among regions of a distributed sociocognitive neural network and may be vulnerable to disruption from early-childhood traumatic brain injury (TBI). The present study aimed to evaluate the very-long-term effect of childhood TBI on EP, as well as examine the contribution of injury- and non-injury-related risk and resilience factors to variability in sociocognitive outcomes. Thirty-four young adult survivors of early-childhood TBI (mean [M], 20.62 years; M time since injury, 16.55 years) and 16 typically developing controls matched for age, gender, and socioeconomic status were assessed using tasks that required recognition and interpretation of facial and prosodic emotional cues. Survivors of severe childhood TBI were found to have significantly poorer emotion perception than controls and young adults with mild-to-moderate injuries. Further, poorer emotion perception was associated with reduced volume of the posterior corpus callosum, presence of frontal pathology, lower SES, and a less-intimate family environment. Our findings lend support to the vulnerability of the immature "social brain" network to early disruption and underscore the need for context-sensitive rehabilitation that optimizes early family environments to enhance recovery of EP skills after childhood TBI.

Traumatic brain injury (TBI) is a common cause of childhood disability, and is associated with elevated risk for long-term social impairment. Though social (pragmatic) communication deficits may be among the most debilitating consequences of childhood TBI, few studies have examined very long-term communication outcomes as children with TBI make the transition to young adulthood. In addition, the extent to which reduced social function contributes to externalizing behaviors in survivors of childhood TBI remains poorly understood. The present study aimed to evaluate the extent of social communication difficulty among young adult survivors of childhood TBI (n=34, injury age: 1.0-7.0 years; M time since injury: 16.55 years) and examine relations among aspects of social function including emotion perception, social communication and externalizing behaviors rated by close-other proxies. Compared to controls the TBI group had significantly greater social communication difficulty, which was associated with more frequent externalizing behaviors and poorer emotion perception. Analyses demonstrated that reduced social communication mediated the association between poorer emotion perception and more frequent externalizing behaviors. Our findings indicate that socio-cognitive impairments may indirectly increase the risk for externalizing behaviors among young adult survivors of childhood TBI, and underscore the need for targeted social skills interventions delivered soon after injury, and into the very long-term.