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Longitudinal neuroimaging studies aid our understanding of recovery mechanisms in moderate-to-severe traumatic brain injury (TBI); however, there is a dearth of longitudinal functional connectivity research. Our aim was to characterize longitudinal functional connectivity patterns in two clinically-important brain networks, the frontoparietal and default mode networks, in moderate-to-severe TBI. This inception cohort study of prospectively-collected longitudinal data used resting-state fMRI to characterize functional connectivity patterns in the frontoparietal and default mode networks. Forty adults with moderate-to-severe TBI (mean ± standard deviation; age=39.53±16.49 years, education=13.92±3.20 years, lowest Glasgow Coma Scale score=6.63±3.24, sex=70% male) were scanned at approximately 0.5, 1-1.5, and 3+ years post-injury. Seventeen healthy, uninjured participants (mean ± standard deviation; age=38.91±15.57 years, education=15.11±2.71 years, sex=29% male) were scanned at baseline and approximately 11 months afterwards. Group independent component analyses and linear mixed-effects modeling with linear splines that contained a knot at 1.5 years post-injury were employed to investigate longitudinal network changes, and associations with covariates, including age, sex, and injury severity. In TBI patients, functional connectivity in the right frontoparietal network increased from approximately 0.5 to 1.5 years post-injury (unstandardized estimate=0.19, standard error (SE)=0.07, p=0.009), contained a slope change in the opposite direction, from positive to negative at 1.5 years post-injury (estimate=-0.21, SE=0.11, p=0.009), and marginally declined afterwards (estimate=-0.10, SE=0.06, p=0.079). Functional connectivity in the default mode network increased from approximately 0.5 to 1.5 years (estimate=0.15, SE=0.05, p=0.006), contained a slope change in the opposite direction, from positive to negative at 1.5 years post-injury (estimate=-0.19, SE=0.08, p=0.021), and was estimated to decline from 1.5 to 3+ years (estimate=-0.04, SE=0.04, p=0.303). Similarly, the left frontoparietal network increased in functional connectivity from approximately 0.5 to 1.5 years post-injury (estimate=0.15, SE=0.05, p=0.002), contained a slope change in the opposite direction, from positive to negative at 1.5 years post-injury (estimate=-0.18, SE=0.07, p=0.008), and was estimated to decline thereafter (estimate=-0.04, SE=0.03, p=0.254). At approximately 0.5 years post-injury, patients showed hypoconnectivity compared to healthy, uninjured participants at baseline. Covariates were not significantly associated in any of the models. Findings of early improvement but a tapering and possible decline in connectivity thereafter suggest that compensatory effects are time-limited. These later reductions in connectivity mirror growing evidence of behavioural and structural decline in chronic moderate-to-severe TBI. Targeting such declines represents a novel avenue of research and offers potential for improving clinical outcomes.

FMR1premutation cytosine-guanine-guanine repeat expansion alleles are relatively common mutations in the general population that are associated with a neurodegenerative disease (fragile X-associated tremor/ataxia syndrome), reproductive health problems and potentially a wide range of additional mental and general health conditions that are not yet well-characterised. The International Fragile X Premutation Registry (IFXPR) was developed to facilitate and encourage research to better understand theFMR1premutation and its impact on human health, to facilitate clinical trial readiness by identifying and characterising diverse cohorts of individuals interested in study participation, and to build community and collaboration among carriers, family members, researchers and clinicians around the world. Here, we describe the development and content of the IFXPR, characterise its first 747 registrants from 32 countries and invite investigators to apply for recruitment support for their project(s). With larger numbers, increased diversity and potentially the future clinical characterisation of registrants, the IFXPR will contribute to a more comprehensive and accurate understanding of the fragile X premutation in human health and support treatment studies.

ImportanceApproximately 15% to 30% of individuals with a history of concussion present with persistent postconcussion symptoms (PPCS). Individuals with PPCS are at greater risk of experiencing depressive symptoms.ObjectiveTo synthesize the association between depressive symptoms and PPCS in children, adolescents, and adults via meta-analysis and to investigate potential moderators of that association.Data SourcesSystematic search of Ovid Medline, CINAHL, PsycInfo, and Embase from 1995 to January 2022 was performed. Additionally, references from included studies were hand-searched to ensure relevant articles were captured in the search.Study SelectionStudies that involved participants who experienced PPCS and quantified depressive symptoms were included. The definition of PPCS was limited to physician-diagnosed or self-reported concussion, with symptoms lasting for a minimum of 4 weeks postinjury. Two authors independently screened all articles to determine study eligibility.Data Extraction and SynthesisStudy characteristics were extracted independently by 2 trained investigators. Study data were meta-analyzed using a random-effects meta-analysis.ExposurePPCS.Main Outcomes and MeasuresThe the primary outcome was depressive symptoms.ResultsData were extracted from 18 studies with a total of 9101 participants. Of the 18 studies, all were cohort studies, and 13 (72%) comprised adult populations. The mean (SD) time since concussion was 21.3 (18.7) weeks. After accounting for potential publication bias, the random-effects meta-analysis found a significant positive association between PPCS and depressive symptoms, (odds ratio, 4.56; 95% CI, 2.82-7.37; P Conclusions and RelevanceIn this meta-analysis, experiencing PPCS was associated with a higher risk of experiencing depressive symptoms. There are several important clinical and health policy implications of the findings. Most notably, the development of strategies for effective prevention and earlier intervention to optimize mental health recovery following a concussion should be supported.

While traditionally ignored as a region purely responsible for motor function, the cerebellum is increasingly being appreciated for its contributions to higher order functions through various cerebro-cerebellar networks. Traumatic brain injury (TBI) research generally focuses on the cerebrum, in part because acute pathology is not found in the cerebellum as often. Acute pathology is an important predictor of outcome, but neural disruption also evolves over time in ways that have implications for daily-life functioning. Here we examine these changes in a multi-modal, multi-cohort study.Combining 12 datasets from the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Pediatric msTBI (moderate-severe TBI) working group, we measured volume of the total cerebellum and 17 subregions using a state-of-the-art, deep learning-based approach for automated parcellation in 598 children and adolescents with or without TBI (msTBI; n = 314 | non-TBI; n = 284; age M = 14.0 ± 3.1 years). Further, we investigated brain-behavior relations between cerebellar volumes and a measure of executive functioning (i.e., Behavioral Rating Inventory of Executive Function [BRIEF]). In a subsample with longitudinal data, we then assessed whether late changes in cerebellar volume were associated with early white matter microstructural organization using diffusion tensor imaging (DTI).Significantly smaller total cerebellar volume was observed in the msTBI group (Cohen’sd= −0.37). In addition, lower regional cerebellar volume was found in posterior lobe regions including crus II, lobule VIIB, lobule VIIIB, vermis VII, and IX (Cohen’sdrange = −0.22 to −0.43). Smaller cerebellum volumes were associated with more parent-reported executive function problems. These alterations were primarily driven by participants in the chronic phase of injury (> 6 months). In a subset of participants with longitudinal data (n = 80), we found evidence of altered growth in total cerebellum volume, with younger msTBI participants showing secondary degeneration in the form of volume reductions, and older participants showing disrupted development reflected in slower growth rates. Changes in total cerebellum volume over time were also associated with white matter microstructural organization in the first weeks and months post-injury, such that poorer white matter organization in the first months post-injury was associated with decreases in volume longitudinally.Pediatric msTBI was characterized by smaller cerebellar volumes, primarily in the posterior lobe and vermis. The course of these alterations, along with group differences in longitudinal volume changes as well as injury-specific associations between DTI measures and volume changes, is suggestive of secondary cerebellar atrophy, possibly related to supra-tentorial lesions, and/or disruption in cerebellar structural and functional circuits. Moreover, evidence for robust brain-behavior relationships underscore the potential cognitive and behavioral consequences of cerebellar disruption during a critical period of brain development.

Objective: The objective of this study was to identify the age of diagnosis for children with one of three neurogenetic conditions resulting from changes on chromosome 15 (Angelman syndrome [AS], Prader-Willi syndrome [PWS], and Duplication 15q syndrome [Dup15q]). Methods: Data about diagnostic process for each condition were contributed by the advocacy organizations. Median and interquartile ranges were calculated for each condition by molecular subtype and year. Comparison tests were run to explore group differences. Results. The median age of diagnosis was 1.8 years for both AS and Dup15q. PWS was diagnosed significantly younger at a median age of 1 month. Deletion subtypes for both PWS and AS were diagnosed earlier than nondeletion subtypes, and children with isodicentric duplications in Dup15q were diagnosed earlier than those with interstitial duplications. Conclusion. Understanding variability in age of diagnosis for chromosome 15 disorders is an important step in reducing the diagnostic odyssey and improving access to interventions for these populations. Results from this study provide a baseline by which to evaluate efforts to reduce the age of diagnosis for individuals with these conditions.