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.

Poorer sleep health is associated with altered brain activation during cognitive control processing in healthy adults.

This study investigated how proactive and reactive cognitive control processing in the brain was associated with habitual sleep health. BOLD fMRI data were acquired from 81 healthy adults with normal sleep (41 females, age 20.96-39.58 years) during a test of cognitive control (Not-X-CPT). Sleep health was assessed in the week before MRI scanning, using both objective (actigraphy) and self-report measures. Multiple measures indicating poorer sleep health-including later/more variable sleep timing, later chronotype preference, more insomnia symptoms, and lower sleep efficiency-were associated with stronger and more widespread BOLD activations in fronto-parietal and subcortical brain regions during cognitive control processing (adjusted for age, sex, education, and fMRI task performance). Most associations were found for reactive cognitive control activation, indicating that poorer sleep health is linked to a "hyper-reactive" brain state. Analysis of time-on-task effects showed that, with longer time on task, poorer sleep health was predominantly associated with increased proactive cognitive control activation, indicating recruitment of additional neural resources over time. Finally, shorter objective sleep duration was associated with lower BOLD activation with time on task and poorer task performance. In conclusion, even in "normal sleepers," relatively poorer sleep health is associated with altered cognitive control processing, possibly reflecting compensatory mechanisms and/or inefficient neural processing.

Bridging Big Data: Procedures for Combining Non-equivalent Cognitive Measures from the ENIGMA Consortium.

Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. These efforts unveil new questions about integrating data arising from distinct sources and instruments. We focus on the most frequently assessed cognitive domain - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated global raw data from 53 studies totaling N = 10,505 individuals. A mega-analysis was conducted using empirical bayes harmonization to remove site effects, followed by linear models adjusting for common covariates. A continuous item response theory (IRT) model estimated each individual's latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance while preserving covariate effects, and our conversion tool is freely available online. This demonstrates that large-scale data sharing and harmonization initiatives can address reproducibility and integration challenges across the behavioral sciences.

Frontoamygdala hyperconnectivity predicts affective dysregulation in adolescent moderate-severe TBI.

In survivors of moderate to severe traumatic brain injury (msTBI), affective disruptions often remain underdetected and undertreated, in part due to poor understanding of the underlying neural mechanisms. We hypothesized that limbic circuits are integral to affective dysregulation in msTBI. To test this, we studied 19 adolescents with msTBI 17 months post-injury (TBI: M age 15.6, 5 females) as well as 44 matched healthy controls (HC: M age 16.4, 21 females). We leveraged two previously identified, large-scale resting-state (rsfMRI) networks of the amygdala to determine whether connectivity strength correlated with affective problems in the adolescents with msTBI. We found that distinct amygdala networks differentially predicted externalizing and internalizing behavioral problems in patients with msTBI. Specifically, patients with the highest medial amygdala connectivity were rated by parents as having greater externalizing behavioral problems measured on the BRIEF and CBCL, but not cognitive problems. The most correlated voxels in that network localize to the rostral anterior cingulate (rACC) and posterior cingulate (PCC) cortices, predicting 48% of the variance in externalizing problems. Alternatively, patients with the highest ventrolateral amygdala connectivity were rated by parents as having greater internalizing behavioral problems measured on the CBCL, but not cognitive problems. The most correlated voxels in that network localize to the ventromedial prefrontal cortex (vmPFC), predicting 57% of the variance in internalizing problems. Both findings were independent of potential confounds including ratings of TBI severity, time since injury, lesion burden based on acute imaging, demographic variables, and other non-amygdalar rsfMRI metrics (e.g., rACC to PCC connectivity), as well as macro- and microstructural measures of limbic circuitry (e.g., amygdala volume and uncinate fasciculus fractional anisotropy). Supporting the clinical significance of these findings, patients with msTBI had significantly greater externalizing problem ratings than healthy control participants and all the brain-behavior findings were specific to the msTBI group in that no similar correlations were found in the healthy control participants. Taken together, frontoamygdala pathways may underlie chronic dysregulation of behavior and mood in patients with msTBI. Future work will focus on neuromodulation techniques to directly affect frontoamygdala pathways with the aim to mitigate such dysregulation problems.

Poor sleep quality is associated with greater negative consequences for cognitive control function and psychological health after mild traumatic brain injury than after orthopedic injury.

OBJECTIVE: To test the hypothesis that poor sleep quality has a stronger negative effect on cognitive control function and psychological health after mild traumatic brain injury (mTBI) than after orthopedic injury. METHOD: Patients with mTBI (n = 197) and trauma controls with orthopedic injuries (n = 82) were included in this prospective longitudinal study. The participants (age 16-60) completed three computerized neurocognitive tests assessing response speed and accuracy at 2 weeks and 3 months after injury, as well as questionnaires and interviews assessing sleep quality and psychological distress at 2 weeks, 3 months, and 12 months after injury. Separate Linear Mixed Models (LMMs) for each of the outcome measures (response speed, response accuracy, psychological distress) were performed. RESULTS: We observed a significant interaction effect between poor sleep quality and group (mTBI vs. trauma controls) in the response speed (p = .028) and psychological distress (p = .001) models, driven by a greater negative impact of poor sleep quality on response speed and psychological distress in the mTBI group. We found no such interaction effect for response accuracy (p = .825), and poor sleep quality was associated with worse accuracy to a similar extent for both groups. CONCLUSIONS: Our findings show that poor sleep quality has a more negative impact on cognitive control function and psychological outcome in patients with mTBI, compared to trauma controls. This indicates an increased vulnerability to poor sleep quality in patients who have suffered an mTBI. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Association of Attention-Deficit/Hyperactivity Disorder Diagnoses With Pediatric Traumatic Brain Injury: A Meta-analysis.

Importance: There are conflicting accounts about the risk for attention-deficit/hyperactivity disorder (ADHD) following traumatic brain injury (TBI), possibly owing to variations between studies in acute TBI severity or when ADHD was assessed postinjury. Analysis of these variations may aid in identifying the risk. Objective: To conduct a meta-analysis of studies assessing ADHD diagnoses in children between ages 4 and 18 years following concussions and mild, moderate, or severe TBI. Data Sources: PubMed, PsycInfo, and Cochrane Central Register of Controlled Trials (1981-December 19, 2019) were searched including the terms traumatic brain injury, brain injuries, closed head injury, blunt head trauma, concussion, attention deficit disorders, ADHD, and ADD in combination with childhood, adolescence, pediatric, infant, child, young adult, or teen. Study Selection: Limited to English-language publications in peer-reviewed journals and patient age (4-18 years). Differences about inclusion were resolved through consensus of 3 authors. Data Extraction and Synthesis: MOOSE guidelines for abstracting and assessing data quality and validity were used. Odds ratios with 95% credible intervals (CrIs) are reported. Main Outcomes and Measures: The planned study outcome was rate of ADHD diagnoses. Results: A total of 12 374 unique patients with TBI of all severity levels and 43 491 unique controls were included in the 24 studies in this review (predominantly male: TBI, 61.8%; noninjury control, 60.9%; other injury control, 66.1%). The rate of pre-TBI ADHD diagnoses was 16.0% (95% CrI, 11.3%-21.7%), which was significantly greater than the 10.8% (95% CrI, 10.2%-11.4%) incidence of ADHD in the general pediatric population. Compared with children without injuries, the odds for ADHD were not significantly increased following concussion (≤1 year: OR, 0.32; 95% CrI, 0.05-1.13), mild TBI (≤1 year: OR, 0.56; 0.16-1.43; >1 year: OR, 1.07; 95% CrI, 0.35-2.48), and moderate TBI (≤1 year: OR, 1.28; 95% CrI, 0.35-3.34; >1 year: OR, 3.67; 95% CrI, 0.83-10.56). The odds for ADHD also were not significantly increased compared with children with other injuries following mild TBI (≤1 year: OR, 1.07; 95% CrI, 0.33-2.47; >1 year: OR, 1.18; 95% CrI, 0.32-3.12) and moderate TBI (≤1 year: OR, 2.34; 95% CrI, 0.78-5.47; >1 year: OR, 3.78; 95% CrI, 0.93-10.33). In contrast, the odds for ADHD following severe TBI were increased at both time points following TBI compared with children with other injuries (≤1 year: OR, 4.81; 95% CrI, 1.66-11.03; >1 year: OR, 6.70; 95% CrI, 2.02-16.82) and noninjured controls (≤1 year: OR, 2.62; 95% CrI, 0.76-6.64; >1 year: OR, 6.25; 95% CrI, 2.06-15.06), as well as those with mild TBI (≤1 year OR, 5.69; 1.46-15.67: >1 year OR, 6.65; 2.14-16.44). Of 5920 children with severe TBI, 35.5% (95% CrI, 20.6%-53.2%) had ADHD more than 1 year postinjury. Conclusions and Relevance: This study noted a significant association between TBI severity and ADHD diagnosis. In children with severe but not mild and moderate TBI, there was an association with an increase in risk for ADHD. The high rate of preinjury ADHD in children with TBI suggests that clinicians should carefully review functioning before a TBI before initiating treatment.

White Matter Disruption in Pediatric Traumatic Brain Injury: Results from ENIGMA Pediatric Moderate to Severe Traumatic Brain Injury.

OBJECTIVE: Our study addressed aims: (1) test the hypothesis that moderate-severe TBI in pediatric patients is associated with widespread white matter (WM) disruption; (2) test the hypothesis that age and sex impact WM organization after injury; and (3) examine associations between WM organization and neurobehavioral outcomes. METHODS: Data from ten previously enrolled, existing cohorts recruited from local hospitals and clinics were shared with the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Pediatric msTBI working group. We conducted a coordinated analysis of diffusion MRI (dMRI) data using the ENIGMA dMRI processing pipeline. RESULTS: Five hundred and seven children and adolescents (244 with complicated mild to severe TBI [msTBI] and 263 controls) were included. Patients were clustered into three post-injury intervals: acute/subacute - <2 months, post-acute - 2-6 months, chronic - 6+ months. Outcomes were dMRI metrics and post-injury behavioral problems as indexed by the Child Behavior Checklist (CBCL). Our analyses revealed altered WM diffusion metrics across multiple tracts and all post-injury intervals (effect sizes ranging between d=-0.5 to -1.3). Injury severity is a significant contributor to the extent of WM alterations but explained less variance in dMRI measures with increasing time post-injury. We observed a sex-by-group interaction: females with TBI had significantly lower fractional anisotropy in the uncinate fasciculus than controls (𝞫=0.043), which coincided with more parent-reported behavioral problems (𝞫=-0.0027). CONCLUSIONS: WM 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.

Challenges and opportunities for neuroimaging in young patients with traumatic brain injury: a coordinated effort towards advancing discovery from the ENIGMA pediatric moderate/severe TBI group.

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.

Evidence of shared familial factors influencing neurocognitive endophenotypes in adult- and childhood-onset schizophrenia.

BACKGROUND: The aggregation of neurocognitive deficits among the non-psychotic first-degree relatives of adult- and childhood-onset schizophrenia patients suggests that there may be a common etiology for these deficits in childhood- and adult-onset illness. However, there is considerable heterogeneity in the presentation of neurobiological abnormalities, and whether there are differences in the extent of familial transmission for specific domains of cognitive function has not been systematically addressed. METHODS: We employed variance components analysis, as implemented in SOLAR-Eclipse, to evaluate the evidence of familial transmission for empirically derived composite scores representing attention, working memory, verbal learning, verbal retention, and memory for faces. We contrast estimates for adult- and childhood-onset schizophrenia families and matched community control pedigrees, and compare our findings to previous reports based on analogous neurocognitive assessments. RESULTS: We observed varying degrees of familial transmission; attention and working memory yielded comparable, significant estimates for adult-onset and community control pedigrees; verbal learning was significant for childhood-onset and community control pedigrees; and facial memory demonstrated significant familial transmission only for childhood-onset schizophrenia. Model-fitting analyses indicated significant differences in familiality between adult- and childhood-onset schizophrenia for attention, working memory, and verbal learning. CONCLUSIONS: By comprehensively assessing a wide range of neurocognitive domains in adult- and childhood-onset schizophrenia families, we provide additional support for specific neurocognitive domains as schizophrenia endophenotypes. Whereas comparable estimates of familial transmission for certain dimensions of cognitive functioning support a shared etiology of adult- and childhood-onset neurocognitive function, observed differences may be taken as preliminary evidence of partially divergent multifactorial architectures.

Functional Brain Hyperactivations Are Linked to an Electrophysiological Measure of Slow Interhemispheric Transfer Time after Pediatric Moderate/Severe Traumatic Brain Injury.

Increased task-related blood oxygen level dependent (BOLD) activation is commonly observed in functional magnetic resonance imaging (fMRI) studies of moderate/severe traumatic brain injury (msTBI), but the functional relevance of these hyperactivations and how they are linked to more direct measures of neuronal function remain largely unknown. Here, we investigated how working memory load (WML)-dependent BOLD activation was related to an electrophysiological measure of interhemispheric transfer time (IHTT) in a sample of 18 msTBI patients and 26 demographically matched controls from the UCLA RAPBI (Recovery after Pediatric Brain Injury) study. In the context of highly similar fMRI task performance, a subgroup of TBI patients with slow IHTT had greater BOLD activation with higher WML than both healthy control children and a subgroup of msTBI patients with normal IHTT. Slower IHTT treated as a continuous variable was also associated with BOLD hyperactivation in the full TBI sample and in controls. Higher WML-dependent BOLD activation was related to better performance on a clinical cognitive performance index, an association that was more pronounced within the patient group with slow IHTT. Our previous work has shown that a subgroup of children with slow IHTT after pediatric msTBI has increased risk for poor white matter organization, long-term neurodegeneration, and poor cognitive outcome. BOLD hyperactivations after msTBI may reflect neuronal compensatory processes supporting higher-order capacity demanding cognitive functions in the context of inefficient neuronal transfer of information. The link between BOLD hyperactivations and slow IHTT adds to the multi-modal validation of this electrophysiological measure as a promising biomarker.

Genetics of Childhood-onset Schizophrenia 2019 Update.

The genetic architecture of schizophrenia is complex and highly polygenic. This article discusses key findings from genetic studies of childhood-onset schizophrenia (COS) and the more common adult-onset schizophrenia (AOS), including studies of familial aggregation and common, rare, and copy number variants. Extant literature suggests that COS is a rare variant of AOS involving greater familial aggregation of schizophrenia spectrum disorders and a potentially higher occurrence of pathogenic copy number variants. The direct utility of genetics to clinical practice for COS is currently limited; however, identifying common pathways through which risk genes affect brain function offers promise for novel interventions.

Bridging the gap: Mechanisms of plasticity and repair after pediatric TBI.

Traumatic brain injury is the leading cause of death and disability in the United States, and may be associated with long lasting impairments into adulthood. The multitude of ongoing neurobiological processes that occur during brain maturation confer both considerable vulnerability to TBI but may also provide adaptability and potential for recovery. This review will examine and synthesize our current understanding of developmental neurobiology in the context of pediatric TBI. Delineating this biology will facilitate more targeted initial care, mechanism-based therapeutic interventions and better long-term prognostication and follow-up.

Prenatal Exposure to Perfluoroalkyl Substances and IQ Scores at Age 5; a Study in the Danish National Birth Cohort.

BACKGROUND: Perfluoroalkyl substances (PFASs) are widespread persistent organic compounds that have been suggested to affect neurodevelopment. OBJECTIVE: We aimed to evaluate whether prenatal exposure to PFASs is associated with IQ in children. METHODS: We studied 1,592 pregnancies enrolled in the Danish National Birth Cohort (DNBC) during 1996-2002. Sixteen PFASs were measured in maternal plasma collected in early gestation. Child IQ was assessed at 5 y of age using the Wechsler Primary and Preschool Scales of Intelligence-Revised (WPPSI-R) administered by trained psychologists. Using multivariable linear regression models, we estimated the differences in child IQ scores according to PFAS concentration [per natural-log (ng/mL) unit increase or values categorized in quartiles]. RESULTS: Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were detected in all samples, and five additional PFASs were quantified in >80% of the samples. Overall, we found no strong associations between a natural-log unit increase in each of the seven PFASs we evaluated and child IQ scores. A few positive and negative associations were found in the sex-stratified PFAS quartile analyses, but the patterns were inconsistent. CONCLUSION: Overall, we did not find consistent evidence to suggest prenatal exposure to PFASs to be associated with child IQ scores at 5 y of age in the DNBC. Some of the sex-specific observations warrant further investigation. Additional studies should examine offspring IQ at older ages and assess other functional cognitive and neuropsychiatric measures in addition to intelligence. Postnatal exposures to PFASs and mixture effects for PFASs and PFASs with other environmental pollutants should also be considered in future research. https://doi.org/10.1289/EHP2754.

Magnetic resonance spectroscopy of fiber tracts in children with traumatic brain injury: A combined MRS - Diffusion MRI study.

Traumatic brain injury can cause extensive damage to the white matter (WM) of the brain. These disruptions can be especially damaging in children, whose brains are still maturing. Diffusion magnetic resonance imaging (dMRI) is the most commonly used method to assess WM organization, but it has limited resolution to differentiate causes of WM disruption. Magnetic resonance spectroscopy (MRS) yields spectra showing the levels of neurometabolites that can indicate neuronal/axonal health, inflammation, membrane proliferation/turnover, and other cellular processes that are on-going post-injury. Previous analyses on this dataset revealed a significant division within the msTBI patient group, based on interhemispheric transfer time (IHTT); one subgroup of patients (TBI-normal) showed evidence of recovery over time, while the other showed continuing degeneration (TBI-slow). We combined dMRI with MRS to better understand WM disruptions in children with moderate-severe traumatic brain injury (msTBI). Tracts with poorer WM organization, as shown by lower FA and higher MD and RD, also showed lower N-acetylaspartate (NAA), a marker of neuronal and axonal health and myelination. We did not find lower NAA in tracts with normal WM organization. Choline, a marker of inflammation, membrane turnover, or gliosis, did not show such associations. We further show that multi-modal imaging can improve outcome prediction over a single modality, as well as over earlier cognitive function measures. Our results suggest that demyelination plays an important role in WM disruption post-injury in a subgroup of msTBI children and indicate the utility of multi-modal imaging.

Whole Brain Magnetic Resonance Spectroscopic Determinants of Functional Outcomes in Pediatric Moderate/Severe Traumatic Brain Injury.

Diffuse axonal injury contributes to the long-term functional morbidity observed after pediatric moderate/severe traumatic brain injury (msTBI). Whole-brain proton magnetic resonance echo-planar spectroscopic imaging was used to measure the neurometabolite levels in the brain to delineate the course of disruption/repair during the first year post-msTBI. The association between metabolite biomarkers and functional measures (cognitive functioning and corpus callosum [CC] function assessed by interhemispheric transfer time [IHTT] using an event related potential paradigm) was also explored. Pediatric patients with msTBI underwent assessments at two times (post-acutely at a mean of three months post-injury, n = 31, and chronically at a mean of 16 months post-injury, n = 24). Healthy controls also underwent two evaluations, approximately 12 months apart. Post-acutely, in patients with msTBI, there were elevations in choline (Cho; marker for inflammation and/or altered membrane metabolism) in all four brain lobes and the CC and decreases in N-acetylaspartate (NAA; marker for neuronal and axonal integrity) in the CC compared with controls, all of which normalized by the chronic time point. Subgroups of TBI showed variable patterns chronically. Patients with slow IHTT had lower lobar Cho chronically than those with normal IHTT; they also did not show normalization in CC NAA whereas those with normal IHTT showed significantly higher levels of CC NAA relative to controls. In the normal IHTT group only, chronic CC Cho and NAA together explained 70% of the variance in long-term cognitive functioning. MR based whole brain metabolic evaluations show different patterns of neurochemistry after msTBI in two subgroups with different outcomes. There is a dynamic relationship between prolonged inflammatory responses to brain damage, reparative processes/remyelination, and subsequent neurobehavioral outcomes. Multimodal studies allow us to test hypotheses about degenerative and reparative processes in patient groups that have divergent functional outcome, with the ultimate goal of developing targeted therapeutic agents.

Neuroimaging of the Injured Pediatric Brain: Methods and New Lessons.

Traumatic brain injury (TBI) is a significant public health problem in the United States, especially for children and adolescents. Current epidemiological data estimate over 600,000 patients younger than 20 years are treated for TBI in emergency rooms annually. While many patients experience a full recovery, for others there can be long-lasting cognitive, neurological, psychological, and behavioral disruptions. TBI in youth can disrupt ongoing brain development and create added family stress during a formative period. The neuroimaging methods used to assess brain injury improve each year, providing researchers a more detailed characterization of the injury and recovery process. In this review, we cover current imaging methods used to quantify brain disruption post-injury, including structural magnetic resonance imaging (MRI), diffusion MRI, functional MRI, resting state fMRI, and magnetic resonance spectroscopy (MRS), with brief coverage of other methods, including electroencephalography (EEG), single-photon emission computed tomography (SPECT), and positron emission tomography (PET). We include studies focusing on pediatric moderate-severe TBI from 2 months post-injury and beyond. While the morbidity of pediatric TBI is considerable, continuing advances in imaging methods have the potential to identify new treatment targets that can lead to significant improvements in outcome.

A NETWORK APPROACH TO EXAMINING INJURY SEVERITY IN PEDIATRIC TBI.

Traumatic brain injury (TBI) is the leading cause of death and disability in children, and can lead to long lasting functional impairment. Many factors influence outcome, but imaging studies examining effects of individual variables are limited by sample size. Roughly 20-40% of hospitalized TBI patients experience seizures, but not all of these patients go on to develop a recurrent seizure disorder. Here we examined differences in structural network connectivity in pediatric patients who had sustained a moderate-severe TBI (msTBI). We compared those who experienced early post-traumatic seizures to those who did not; we found network differences months after seizure activity stopped. We also examined correlations between network measures and a common measure of injury severity, the Glasgow Coma Scale (GCS). The global GCS score did not have a detectable relationship to brain integrity, but sub-scores of the GCS (eyes, motor, verbal) were more closely related to imaging measures.

Diffusion MRI in pediatric brain injury.

Traumatic brain injury (TBI) is a major public health issue around the world and can be especially devastating in children as TBI can derail cognitive and social development. White matter (WM) is particularly vulnerable to disruption post-TBI, as myelination is ongoing during this period. Diffusion magnetic resonance imaging (dMRI) is a versatile modality for identifying and quantifying WM disruption and can detect diffuse axonal injury (DAI or TAI (traumatic axonal injury)). This review covers dMRI studies of pediatric TBI, including mild to severe injuries, and covering all periods post-injury. While there have been considerable advances in our understanding of pediatric TBI through the use of dMRI, there are still large gaps in our knowledge, which will be filled in by larger studies and more longitudinal studies. Heterogeneity post-injury is an obstacle in all TBI studies, but we expect that larger better-characterized samples will aid in identifying clinically meaningful subgroups within the pediatric TBI patient population.

Diverging volumetric trajectories following pediatric traumatic brain injury.

Traumatic brain injury (TBI) is a significant public health concern, and can be especially disruptive in children, derailing on-going neuronal maturation in periods critical for cognitive development. There is considerable heterogeneity in post-injury outcomes, only partially explained by injury severity. Understanding the time course of recovery, and what factors may delay or promote recovery, will aid clinicians in decision-making and provide avenues for future mechanism-based therapeutics. We examined regional changes in brain volume in a pediatric/adolescent moderate-severe TBI (msTBI) cohort, assessed at two time points. Children were first assessed 2-5 months post-injury, and again 12 months later. We used tensor-based morphometry (TBM) to localize longitudinal volume expansion and reduction. We studied 21 msTBI patients (5 F, 8-18 years old) and 26 well-matched healthy control children, also assessed twice over the same interval. In a prior paper, we identified a subgroup of msTBI patients, based on interhemispheric transfer time (IHTT), with significant structural disruption of the white matter (WM) at 2-5 months post injury. We investigated how this subgroup (TBI-slow, N = 11) differed in longitudinal regional volume changes from msTBI patients (TBI-normal, N = 10) with normal WM structure and function. The TBI-slow group had longitudinal decreases in brain volume in several WM clusters, including the corpus callosum and hypothalamus, while the TBI-normal group showed increased volume in WM areas. Our results show prolonged atrophy of the WM over the first 18 months post-injury in the TBI-slow group. The TBI-normal group shows a different pattern that could indicate a return to a healthy trajectory.