Accelerated Aging after Traumatic Brain Injury: An ENIGMA Multi-Cohort Mega-Analysis.

OBJECTIVE: The long-term consequences of traumatic brain injury (TBI) on brain structure remain uncertain. Given evidence that a single significant brain injury event increases the risk of dementia, brain-age estimation could provide a novel and efficient indexing of the long-term consequences of TBI. Brain-age procedures use predictive modeling to calculate brain-age scores for an individual using structural magnetic resonance imaging (MRI) data. Complicated mild, moderate, and severe TBI (cmsTBI) is associated with a higher predicted age difference (PAD), but the progression of PAD over time remains unclear. We sought to examine whether PAD increases as a function of time since injury (TSI) and if injury severity and sex interacted to influence this progression. METHODS: Through the ENIGMA Adult Moderate and Severe (AMS)-TBI working group, we examine the largest TBI sample to date (n = 343), along with controls, for a total sample size of n = 540, to replicate and extend prior findings in the study of TBI brain age. Cross-sectional T1w-MRI data were aggregated across 7 cohorts, and brain age was established using a similar brain age algorithm to prior work in TBI. RESULTS: Findings show that PAD widens with longer TSI, and there was evidence for differences between sexes in PAD, with men showing more advanced brain age. We did not find strong evidence supporting a link between PAD and cognitive performance. INTERPRETATION: This work provides evidence that changes in brain structure after cmsTBI are dynamic, with an initial period of change, followed by relative stability in brain morphometry, eventually leading to further changes in the decades after a single cmsTBI. ANN NEUROL 2024.

Reduced lateralization of multiple functional brain networks in autistic males.

BACKGROUND: Autism spectrum disorder has been linked to a variety of organizational and developmental deviations in the brain. One such organizational difference involves hemispheric lateralization, which may be localized to language-relevant regions of the brain or distributed more broadly. METHODS: In the present study, we estimated brain hemispheric lateralization in autism based on each participant's unique functional neuroanatomy rather than relying on group-averaged data. Additionally, we explored potential relationships between the lateralization of the language network and behavioral phenotypes including verbal ability, language delay, and autism symptom severity. We hypothesized that differences in hemispheric asymmetries in autism would be limited to the language network, with the alternative hypothesis of pervasive differences in lateralization. We tested this and other hypotheses by employing a cross-sectional dataset of 118 individuals (48 autistic, 70 neurotypical). Using resting-state fMRI, we generated individual network parcellations and estimated network asymmetries using a surface area-based approach. A series of multiple regressions were then used to compare network asymmetries for eight significantly lateralized networks between groups. RESULTS: We found significant group differences in lateralization for the left-lateralized Language (d = -0.89), right-lateralized Salience/Ventral Attention-A (d = 0.55), and right-lateralized Control-B (d = 0.51) networks, with the direction of these group differences indicating less asymmetry in autistic males. These differences were robust across different datasets from the same participants. Furthermore, we found that language delay stratified language lateralization, with the greatest group differences in language lateralization occurring between autistic males with language delay and neurotypical individuals. CONCLUSIONS: These findings evidence a complex pattern of functional lateralization differences in autism, extending beyond the Language network to the Salience/Ventral Attention-A and Control-B networks, yet not encompassing all networks, indicating a selective divergence rather than a pervasive one. Moreover, we observed an association between Language network lateralization and language delay in autistic males.

PREFACE to what traditional neuropsychological assessment got wrong about mild traumatic brain injury. A four-part opinion review.

This Preface overviews a four-part opinion series on the role of tradtional neuropsychological tests in evaluating mild traumatic brain injury (mTBI), juxtaposed to all of the progress that has occurred with advanced neuroimaging and allied technologies. The four areas of review and critique are: I. Neuropathology; II: Limitations in Test Development, Statistical and Psychometric Issues; III. Implications of Advanced Neuroimaging Findings inn the Neuropsychological Assessment of the mTBI Patient, and IV: Clinical Applications and Future Directions. The example is made that since their inception in the early to mid-20th Century, traditional neuropsychological measures mostly have remained invariant, have been used as omnibus measures for assessing all types of neurological and neuropsychiatric conditions, and were never specifically designed to asses the effects of mTBI. Extensive discussion is provided across all four parts concerning the limits of traditional neuropsychological methods, especially in the absences of any integration with advanced neuroimaging and biomarker findings. Part IV provides an outline for future research and clinical application in the development of novel neuropsychological assessment mesasures specific to mTBI.

Persistent MRI Findings Unique to Blast and Repetitive Mild TBI: Analysis of the CENC/LIMBIC Cohort Injury Characteristics.

INTRODUCTION: MRI represents one of the clinical tools at the forefront of research efforts aimed at identifying diagnostic and prognostic biomarkers following traumatic brain injury (TBI). Both volumetric and diffusion MRI findings in mild TBI (mTBI) are mixed, making the findings difficult to interpret. As such, additional research is needed to continue to elucidate the relationship between the clinical features of mTBI and quantitative MRI measurements. MATERIAL AND METHODS: Volumetric and diffusion imaging data in a sample of 976 veterans and service members from the Chronic Effects of Neurotrauma Consortium and now the Long-Term Impact of Military-Relevant Brain Injury Consortium observational study of the late effects of mTBI in combat with and without a history of mTBI were examined. A series of regression models with link functions appropriate for the model outcome were used to evaluate the relationships among imaging measures and clinical features of mTBI. Each model included acquisition site, participant sex, and age as covariates. Separate regression models were fit for each region of interest where said region was a predictor. RESULTS: After controlling for multiple comparisons, no significant main effect was noted for comparisons between veterans and service members with and without a history of mTBI. However, blast-related mTBI were associated with volumetric reductions of several subregions of the corpus callosum compared to non-blast-related mTBI. Several volumetric (i.e., hippocampal subfields, etc.) and diffusion (i.e., corona radiata, superior longitudinal fasciculus, etc.) MRI findings were noted to be associated with an increased number of repetitive mTBIs versus. CONCLUSIONS: In deployment-related mTBI, significant findings in this cohort were only observed when considering mTBI sub-groups (blast mechanism and total number/dose). Simply comparing healthy controls and those with a positive mTBI history is likely an oversimplification that may lead to non-significant findings, even in consortium analyses.

Novel Oppositional Defiant Disorder or Conduct Disorder 24 Months After Traumatic Brain Injury in Children and Adolescents.

OBJECTIVE: The authors sought to identify predictive factors of new-onset or novel oppositional defiant disorder or conduct disorder assessed 24 months after traumatic brain injury (TBI). METHODS: Children ages 5 to 14 years who had experienced TBI were recruited from consecutive hospital admissions. Soon after injury, participants were assessed for preinjury characteristics, including psychiatric disorders, socioeconomic status (SES), psychosocial adversity, and family function, and the presence and location of lesions were documented by MRI. Psychiatric outcomes, including novel oppositional defiant disorder or conduct disorder, were assessed 24 months after injury. RESULTS: Of the children without preinjury oppositional defiant disorder, conduct disorder, or disruptive behavior disorder not otherwise specified who were recruited in this study, 165 were included in this sample; 95 of these children returned for the 24-month assessment. Multiple imputation was used to address attrition. The prevalence of novel oppositional defiant disorder or conduct disorder was 23.7 out of 165 (14%). In univariable analyses, novel oppositional defiant disorder or conduct disorder was significantly associated with psychosocial adversity (p=0.049) and frontal white matter lesions (p=0.016) and was marginally but not significantly associated with SES. In the final multipredictor model, frontal white matter lesions were significantly associated with novel oppositional defiant disorder or conduct disorder (p=0.021), and psychosocial adversity score was marginally but not significantly associated with the outcome. The odds ratio of novel oppositional defiant disorder or conduct disorder among the children with versus those without novel depressive disorder was significantly higher for girls than boys (p=0.025), and the odds ratio of novel oppositional defiant disorder or conduct disorder among the children with versus those without novel attention-deficit hyperactivity disorder (ADHD) was significantly higher for boys than girls (p=0.006). CONCLUSION: Approximately 14% of children with TBI developed oppositional defiant disorder or conduct disorder. The risk for novel oppositional defiant disorder or conduct disorder can be understood from a biopsychosocial perspective. Sex differences were evident for comorbid novel depressive disorder and comorbid novel ADHD.

Multi-modal MRI of hippocampal morphometry and connectivity after pediatric severe TBI.

This investigation explores memory performance using the California Verbal Learning Test in relation to morphometric and connectivity measures of the memory network in severe traumatic brain injury. Twenty-two adolescents with severe traumatic brain injury were recruited for multimodal MRI scanning 1-2 years post-injury at 13 participating sites. Analyses included hippocampal volume derived from anatomical T1-weighted imaging, fornix white matter microstructure from diffusion tensor imaging, and hippocampal resting-state functional magnetic resonance imaging connectivity as well as diffusion-based structural connectivity. A typically developing control cohort of forty-nine age-matched children also underwent scanning and neurocognitive assessment. Results showed hippocampus volume was decreased in traumatic brain injury with respect to controls. Further, hippocampal volume loss was associated with worse performance on memory and learning in traumatic brain injury subjects. Similarly, hippocampal fornix fractional anisotropy was reduced in traumatic brain injury with respect to controls, while decreased fractional anisotropy in the hippocampal fornix also was associated with worse performance on memory and learning in traumatic brain injury subjects. Additionally, reduced structural connectivity of left hippocampus to thalamus and calcarine sulcus was associated with memory and learning in traumatic brain injury subjects. Functional connectivity in the left hippocampal network was also associated with memory and learning in traumatic brain injury subjects. These regional findings from a multi-modal neuroimaging approach should not only be useful for gaining valuable insight into traumatic brain injury induced memory and learning disfunction, but may also be informative for monitoring injury progression, recovery, and for developing rehabilitation as well as therapy strategies.

Microstructural Organization of Distributed White Matter Associated With Fine Motor Control in US Service Members With Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) is the most common form of brain injury. While most individuals recover from mTBI, roughly 20% experience persistent symptoms, potentially including reduced fine motor control. We investigate relationships between regional white matter organization and subcortical volumes associated with performance on the Grooved Pegboard (GPB) test in a large cohort of military Service Members and Veterans (SM&Vs) with and without a history of mTBI(s). Participants were enrolled in the Long-term Impact of Military-relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium. SM&Vs with a history of mTBI(s) (n = 847) and without mTBI (n = 190) underwent magnetic resonance imaging and the GPB test. We first examined between-group differences in GPB completion time. We then investigated associations between GPB performance and regional structural imaging measures (tractwise diffusivity, subcortical volumes, and cortical thickness) in SM&Vs with a history of mTBI(s). Lastly, we explored whether mTBI history moderated associations between imaging measures and GPB performance. SM&Vs with mTBI(s) performed worse than those without mTBI(s) on the non-dominant hand GPB test at a trend level (p < 0.1). Higher fractional anisotropy (FA) of tracts including the posterior corona radiata, superior longitudinal fasciculus, and uncinate fasciculus were associated with better GPB performance in the dominant hand in SM&Vs with mTBI(s). These findings support that the organization of several white matter bundles are associated with fine motor performance in SM&Vs. We did not observe that mTBI history moderated associations between regional FA and GPB test completion time, suggesting that chronic mTBI may not significantly influence fine motor control.

Scheltens ratings, clinical white matter hyperintensities and executive functioning in the Cache County Memory Study.

OBJECTIVE: Examine the association between neuropsychologically assessed executive function and clinically identifiable white matter burden from magnetic resonance imaging, using a visual rating system (Scheltens Rating System) applied to the Cache County Memory Study (CCMS) archival database. METHOD: We used the Scheltens Ratings Scale to quantify white matter lesion burden in the CCMS sample and used this metric as a predictor of executive function. The sample included 60 individuals with dementia and 13 healthy controls. RESULTS: Higher Scheltens ratings were associated with poorer task performance on an Executive Function composite score of common neuropsychological tests. This association held true for both controls and dementing cases. CONCLUSIONS: The current findings support extensive prior literature demonstrating the association between brain vascular health determined by white matter burden and clinical outcomes based on neuropsychological assessment of cognitive performance.

Multimodal Analysis of Secondary Cerebellar Alterations After Pediatric Traumatic Brain Injury.

Importance: Traumatic brain injury (TBI) is known to cause widespread neural disruption in the cerebrum. However, less is known about the association of TBI with cerebellar structure and how such changes may alter executive functioning. Objective: To investigate alterations in subregional cerebellum volume and cerebral white matter microstructure after pediatric TBI and examine subsequent changes in executive function. Design, Setting, and Participants: This retrospective cohort study combined 12 data sets (collected between 2006 and 2020) from 9 sites in the Enhancing Neuroimaging Genetics Through Meta-Analysis Consortium Pediatric TBI working group in a mega-analysis of cerebellar structure. Participants with TBI or healthy controls (some with orthopedic injury) were recruited from trauma centers, clinics, and institutional trauma registries, some of which were followed longitudinally over a period of 0.7 to 1.9 years. Healthy controls were recruited from the surrounding community. Data analysis occurred from October to December 2022. Exposure: Accidental mild complicated-severe TBI (msTBI) for those in the TBI group. Some controls received a diagnosis of orthopedic injury. Main Outcomes and Measures: Volume of 18 cerebellar lobules and vermal regions were estimated from 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. White matter organization in 28 regions of interest was assessed with diffusion tensor MRI. Executive function was measured by parent-reported scores from the Behavior Rating Inventory of Executive Functioning. Results: A total of 598 children and adolescents (mean [SD] age, 14.05 [3.06] years; range, 5.45-19.70 years; 386 male participants [64.5%]; 212 female participants [35.5%]) were included in the study, with 314 participants in the msTBI group, and 284 participants in the non-TBI group (133 healthy individuals and 151 orthopedically injured individuals). Significantly smaller total cerebellum volume (d = -0.37; 95% CI, -0.52 to -0.22; P < .001) and subregional cerebellum volumes (eg, corpus medullare; d = -0.43; 95% CI, -0.58 to -0.28; P < .001) were observed in the msTBI group. These alterations were primarily seen in participants in the chronic phase (ie, >6 months postinjury) of injury (total cerebellar volume, d = -0.55; 95% CI, -0.75 to -0.35; P < .001). Smaller cerebellum volumes were associated with higher scores on the Behavior Rating Inventory of Executive Functioning Global Executive Composite score (ß = -208.9 mm3; 95% CI, -319.0 to -98.0 mm3; P = .008) and Metacognition Index score (ß = -202.5 mm3; 95% CI, -319.0 to -85.0 mm3; P = .02). In a subset of 185 participants with longitudinal data, younger msTBI participants exhibited cerebellum volume reductions (ß = 0.0052 mm3; 95% CI, 0.0013 to 0.0090 mm3; P = .01), and older participants slower growth rates. Poorer white matter organization in the first months postinjury was associated with decreases in cerebellum volume over time (ß=0.52 mm3; 95% CI, 0.19 to 0.84 mm3; P = .005). Conclusions and Relevance: In this cohort study of pediatric msTBI, our results demonstrated robust cerebellar volume alterations associated with pediatric TBI, localized to the posterior lobe. Furthermore, longitudinal cerebellum changes were associated with baseline diffusion tensor MRI metrics, suggesting secondary cerebellar atrophy. These results provide further understanding of secondary injury mechanisms and may point to new opportunities for intervention.

Tract- and gray matter- based spatial statistics show white matter and gray matter microstructural differences in autistic males.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition commonly studied in the context of early childhood. As ASD is a life-long condition, understanding the characteristics of brain microstructure from adolescence into adulthood and associations to clinical features is critical for improving outcomes across the lifespan. In the current work, we utilized Tract Based Spatial Statistics (TBSS) and Gray Matter Based Spatial Statistics (GBSS) to examine the white matter (WM) and gray matter (GM) microstructure in neurotypical (NT) and autistic males. Methods: Multi-shell diffusion MRI was acquired from 78 autistic and 81 NT males (12-to-46-years) and fit to the DTI and NODDI diffusion models. TBSS and GBSS were performed to analyze WM and GM microstructure, respectively. General linear models were used to investigate group and age-related group differences. Within the ASD group, relationships between WM and GM microstructure and measures of autistic symptoms were investigated. Results: All dMRI measures were significantly associated with age across WM and GM. Significant group differences were observed across WM and GM. No significant age-by-group interactions were detected. Within the ASD group, positive relationships with WM microstructure were observed with ADOS-2 Calibrated Severity Scores. Conclusion: Using TBSS and GBSS our findings provide new insights into group differences of WM and GM microstructure in autistic males from adolescence into adulthood. Detection of microstructural differences across the lifespan as well as their relationship to the level of autistic symptoms will deepen to our understanding of brain-behavior relationships of ASD and may aid in the improvement of intervention options for autistic adults.

IQ After Pediatric Concussion.

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

Regional Cortical Thickness Correlates of Intellectual Abilities Differ in Children With Traumatic Brain Injury Versus Those With Orthopedic Injury in the Chronic Post-Injury Phase.

A decline in intellectual functioning (intelligence quotient [IQ]) is often observed following more severe forms of traumatic brain injury (TBI) and is a useful index for long-term outcome. Identifying brain correlates of IQ can serve to inform developmental trajectories of behavior in this population. Using magnetic resonance imaging (MRI), we examined the relationship between intellectual abilities and patterns of cortical thickness in children with a history of TBI or with orthopedic injury (OI) in the chronic phase of injury recovery. Participants were 47 children with OI and 58 children with TBI, with TBI severity ranging from complicated-mild to severe. Ages ranged from 8 to 14 years old, with an average age of 10.47 years, and an injury-to-test range of ∼1-5 years. The groups did not differ in age or sex. The intellectual ability estimate (full-scale [FS]IQ-2) was derived from a two-form (Vocabulary and Matrix Reasoning subtests) Wechsler Abbreviated Scale of Intelligence (WASI). MRI data were processed using the FreeSurfer toolkit and harmonized across data collection sites using neuroComBat procedures, while holding demographic features (i.e., sex, socioeconomic status [SES]), TBI status, and FSIQ-2 constant. Separate general linear models per group (TBI and OI) and a single interaction model with all participants were conducted with all significant results withstanding correction for multiple comparisons via permutation testing. Intellectual ability was higher (p < 0.001) in the OI group (FSIQ-2 = 110.81) than in the TBI group (FSIQ-2 = 99.81). In children with OI, bi-hemispheric regions, including the right pre-central gyrus and precuneus and bilateral inferior temporal and left occipital areas were related to IQ, such that higher IQ was associated with thicker cortex in these regions. In contrast, only cortical thickness in the right pre-central gyrus and bilateral cuneus positively related to IQ in children with TBI. Significant interaction effects were found in the bilateral temporal, parietal, and occipital lobes and left frontal regions, indicating that the relationship between IQ and cortical thickness differed between groups in these regions. Changes in cortical associations with IQ after TBI may reflect direct injury effects and/or adaptation in cortical structure and intellectual functioning, particularly in the bilateral posterior parietal and inferior temporal regions. This suggests that the substrates of intellectual ability are particularly susceptible to acquired injury in the integrative association cortex. Longitudinal work is needed to account for normal developmental changes and to investigate how cortical thickness and intellectual functioning and their association change over time following TBI. Improved understanding of how TBI-related cortical thickness alterations relate to cognitive outcome could lead to improved predictions of outcome following brain injury.

Longitudinal trajectories of posttraumatic headache after pediatric mild traumatic brain injury.

OBJECTIVE: This prospective, longitudinal cohort study examined the trajectory, classification, and features of posttraumatic headache after pediatric mild traumatic brain injury. METHODS: Children (N = 213; ages 8.00 to 16.99 years) were recruited from two pediatric emergency departments <24 hours of sustaining a mild traumatic brain injury or mild orthopedic injury. At 10 days, three months, and six months postinjury, parents completed a standardized questionnaire that was used to classify premorbid and posttraumatic headache as migraine, tension-type headache, or not otherwise classified. Multilevel mixed effects models were used to examine posttraumatic headache rate, severity, frequency, and duration in relation to group, time postinjury, and premorbid headache, controlling for age, sex, and site. RESULTS: PTH risk was greater after mild traumatic brain injury than mild orthopedic injury at 10 days (odds ratio = 197.41, p < .001) and three months postinjury (odds ratio = 3.50, p = .030), especially in children without premorbid headache. Posttraumatic headache was more frequent after mild traumatic brain injury than mild orthopedic injury, ß (95% confidence interval) = 0.80 (0.05, 1.55). Groups did not differ in other examined headache features and classification any time postinjury. CONCLUSIONS: Posttraumatic headache risk increases after mild traumatic brain injury relative to mild orthopedic injury for approximately three months postinjury, but is not clearly associated with a distinct phenotype.

Interhemispheric transfer time and concussion in adolescents: A longitudinal study using response time and event-related potential measures.

Introduction: Concussion in children and adolescents is a public health concern with higher concussion incidence than adults and increased susceptibility to axonal injury. The corpus callosum is a vulnerable location of concussion-related white matter damage that can be associated with short- and long-term effects of concussion. Interhemispheric transfer time (IHTT) of visual information across the corpus callosum can be used as a direct measure of corpus callosum functioning that may be impacted by adolescent concussion with slower IHTT relative to matched controls. Longitudinal studies and studies testing physiological measures of IHTT following concussion in adolescents are lacking. Methods: We used the N1 and P1 components of the scalp-recorded brain event-related potential (ERP) to measure IHTT in 20 adolescents (ages 12-19 years old) with confirmed concussion and 16 neurologically-healthy control participants within 3 weeks of concussion (subacute stage) and approximately 10 months after injury (longitudinal). Results: Separate two-group (concussion, control) by two-time (3 weeks, 10 months) repeated measures ANOVAs on difference response times and IHTT latencies of the P1 and N1 components showed no significant differences by group (ps ≥ 0.25) nor by time (ps ≥ 0.64), with no significant interactions (ps ≥ 0.15). Discussion: Results from the current sample suggest that measures of IHTT may not be strongly influenced at 3 weeks or longitudinally following adolescent concussion using the current IHTT paradigm.

Assessing Pediatric Mild Traumatic Brain Injury and Its Recovery Using Resting-State Magnetoencephalography Source Magnitude Imaging and Machine Learning.

The objectives of this machine-learning (ML) resting-state magnetoencephalography (rs-MEG) study involving children with mild traumatic brain injury (mTBI) and orthopedic injury (OI) controls were to define a neural injury signature of mTBI and to delineate the pattern(s) of neural injury that determine behavioral recovery. Children ages 8-15 years with mTBI (n = 59) and OI (n = 39) from consecutive admissions to an emergency department were studied prospectively for parent-rated post-concussion symptoms (PCS) at: 1) baseline (average of 3 weeks post-injury) to measure pre-injury symptoms and also concurrent symptoms; and 2) at 3-months post-injury. rs-MEG was conducted at the baseline assessment. The ML algorithm predicted cases of mTBI versus OI with sensitivity of 95.5 ± 1.6% and specificity of 90.2 ± 2.7% at 3-weeks post-injury for the combined delta-gamma frequencies. The sensitivity and specificity were significantly better (p < 0.0001) for the combined delta-gamma frequencies compared with the delta-only and gamma-only frequencies. There were also spatial differences in rs-MEG activity between mTBI and OI groups in both delta and gamma bands in frontal and temporal lobe, as well as more widespread differences in the brain. The ML algorithm accounted for 84.5% of the variance in predicting recovery measured by PCS changes between 3 weeks and 3 months post-injury in the mTBI group, and this was significantly lower (p < 10-4) in the OI group (65.6%). Frontal lobe pole (higher) gamma activity was significantly (p < 0.001) associated with (worse) PCS recovery exclusively in the mTBI group. These findings demonstrate a neural injury signature of pediatric mTBI and patterns of mTBI-induced neural injury related to behavioral recovery.

Volumetric MRI Findings in Mild Traumatic Brain Injury (mTBI) and Neuropsychological Outcome.

Region of interest (ROI) volumetric assessment has become a standard technique in quantitative neuroimaging. ROI volume is thought to represent a coarse proxy for making inferences about the structural integrity of a brain region when compared to normative values representative of a healthy sample, adjusted for age and various demographic factors. This review focuses on structural volumetric analyses that have been performed in the study of neuropathological effects from mild traumatic brain injury (mTBI) in relation to neuropsychological outcome. From a ROI perspective, the probable candidate structures that are most likely affected in mTBI represent the target regions covered in this review. These include the corpus callosum, cingulate, thalamus, pituitary-hypothalamic area, basal ganglia, amygdala, and hippocampus and associated structures including the fornix and mammillary bodies, as well as whole brain and cerebral cortex along with the cerebellum. Ventricular volumetrics are also reviewed as an indirect assessment of parenchymal change in response to injury. This review demonstrates the potential role and limitations of examining structural changes in the ROIs mentioned above in relation to neuropsychological outcome. There is also discussion and review of the role that post-traumatic stress disorder (PTSD) may play in structural outcome in mTBI. As emphasized in the conclusions, structural volumetric findings in mTBI are likely just a single facet of what should be a multimodality approach to image analysis in mTBI, with an emphasis on how the injury damages or disrupts neural network integrity. The review provides an historical context to quantitative neuroimaging in neuropsychology along with commentary about future directions for volumetric neuroimaging research in mTBI.

Novel Psychiatric Disorder 6 Months After Traumatic Brain Injury in Children and Adolescents.

OBJECTIVE: To investigate the factors predictive of novel psychiatric disorders in the interval 0-6 months following traumatic brain injury (TBI). METHODS: Children ages 5-14 years consecutively hospitalized for mild to severe TBI at five hospitals were recruited. Participants were evaluated at baseline (soon after injury) for pre-injury characteristics including psychiatric disorders, socioeconomic status (SES), psychosocial adversity, family function, family psychiatric history, and adaptive function. In addition to the psychosocial variables, injury severity and lesion location detected with acquisition of a research MRI were measured to develop a biopsychosocial predictive model for development of novel psychiatric disorders. Psychiatric outcome, including occurrence of a novel psychiatric disorder, was assessed 6 months after the injury. RESULTS: The recruited sample numbered 177 children, and 141 children (80%) returned for the six-month assessment. Of the 141 children, 58 (41%) developed a novel psychiatric disorder. In univariable analyses, novel psychiatric disorder was significantly associated with lower SES, higher psychosocial adversity, and lesions in frontal lobe locations, such as frontal white matter, superior frontal gyrus, inferior frontal gyrus, and orbital gyrus. Multivariable analyses found that novel psychiatric disorder was independently and significantly associated with frontal-lobe white matter, superior frontal gyrus, and orbital gyrus lesions. CONCLUSION: The results demonstrate that occurrence of novel psychiatric disorders following pediatric TBI requiring hospitalization is common and has identifiable psychosocial and specific biological predictors. However, only the lesion predictors were independently related to this adverse psychiatric outcome.

Reduced Lateralization of Multiple Functional Brain Networks in Autistic Males.

Background: Autism spectrum disorder has been linked to a variety of organizational and developmental deviations in the brain. One such organizational difference involves hemispheric lateralization, which may be localized to language-relevant regions of the brain or distributed more broadly. Methods: In the present study, we estimated brain hemispheric lateralization in autism based on each participant's unique functional neuroanatomy rather than relying on group-averaged data. Additionally, we explored potential relationships between the lateralization of the language network and behavioral phenotypes including verbal ability, language delay, and autism symptom severity. We hypothesized that differences in hemispheric asymmetries in autism would be limited to the language network, with the alternative hypothesis of pervasive differences in lateralization. We tested this and other hypotheses by employing a cross-sectional dataset of 118 individuals (48 autistic, 70 neurotypical). Using resting-state fMRI, we generated individual network parcellations and estimated network asymmetries using a surface area-based approach. A series of multiple regressions were then used to compare network asymmetries for eight significantly lateralized networks between groups. Results: We found significant group differences in lateralization for the left-lateralized Language (d = -0.89), right-lateralized Salience/Ventral Attention-A (d = 0.55), and right-lateralized Control-B (d = 0.51) networks, with the direction of these group differences indicating less asymmetry in autistic individuals. These differences were robust across different datasets from the same participants. Furthermore, we found that language delay stratified language lateralization, with the greatest group differences in language lateralization occurring between autistic individuals with language delay and neurotypical individuals. Limitations: The generalizability of our findings is restricted due to the male-only sample and greater representation of individuals with high verbal and cognitive performance. Conclusions: These findings evidence a complex pattern of functional lateralization differences in autism, extending beyond the Language network to the Salience/Ventral Attention-A and Control-B networks, yet not encompassing all networks, indicating a selective divergence rather than a pervasive one. Furthermore, a differential relationship was identified between Language network lateralization and specific symptom profiles (namely, language delay) of autism.

Social determinants of participant recruitment and retention in a prospective cohort study of pediatric mild traumatic brain injury.

Background: Prior studies have shown poor recruitment and retention of minoritized groups in clinical trials. Objective: To examine several social determinants as predictors of consent to participate and retention as part of a prospective, longitudinal cohort study of children 8-16 with either mild traumatic brain injury (mild TBI) or orthopedic injury (OI). Methods: Children and families were recruited during acute visits to emergency departments (ED) in two large children's hospitals in the midwestern United States for a prospective, longitudinal cohort study of children 8-16 with either mild TBI or OI. Results: A total of 588 (mild TBI = 307; OI = 281) eligible children were approached in the ED and 315 (mild TBI = 195; OI = 120) were consented. Children who consented did not differ significantly from those who did not consent in sex or age. Consent rates were higher among Black (60.9%) and multi-racial (76.3%) children than white (45.3%) children. Among the 315 children who consented, 217 returned for a post-acute assessment (mild TBI = 143; OI = 74), a retention rate of 68.9%. Participants who were multi-racial (96.6%) or white (79.8%) were more likely to return for the post-acute visit than those who were Black (54.3%). Conclusions: Racial differences exist in both recruitment and retention of participants in a prospective, longitudinal cohort of children with mild TBI or OI. Further work is needed to understand these differences to ensure equitable participation of minoritized groups in brain injury research.