Altered lateralization of the cingulum in deployment-related traumatic brain injury: An ENIGMA military-relevant brain injury study.

Traumatic brain injury (TBI) in military populations can cause disruptions in brain structure and function, along with cognitive and psychological dysfunction. Diffusion magnetic resonance imaging (dMRI) can detect alterations in white matter (WM) microstructure, but few studies have examined brain asymmetry. Examining asymmetry in large samples may increase sensitivity to detect heterogeneous areas of WM alteration in mild TBI. Through the Enhancing Neuroimaging Genetics Through Meta-Analysis Military-Relevant Brain Injury working group, we conducted a mega-analysis of neuroimaging and clinical data from 16 cohorts of Active Duty Service Members and Veterans (n = 2598). dMRI data were processed together along with harmonized demographic, injury, psychiatric, and cognitive measures. Fractional anisotropy in the cingulum showed greater asymmetry in individuals with deployment-related TBI, driven by greater left lateralization in TBI. Results remained significant after accounting for potentially confounding variables including posttraumatic stress disorder, depression, and handedness, and were driven primarily by individuals whose worst TBI occurred before age 40. Alterations in the cingulum were also associated with slower processing speed and poorer set shifting. The results indicate an enhancement of the natural left laterality of the cingulum, possibly due to vulnerability of the nondominant hemisphere or compensatory mechanisms in the dominant hemisphere. The cingulum is one of the last WM tracts to mature, reaching peak FA around 42 years old. This effect was primarily detected in individuals whose worst injury occurred before age 40, suggesting that the protracted development of the cingulum may lead to increased vulnerability to insults, such as TBI.

Can quantitative susceptibility mapping help diagnose and predict recovery of concussion in children? An A-CAP study.

BACKGROUND: Quantitative susceptibility mapping (QSM) is an MRI technique that is a potential biomarker for concussion. We performed QSM in children following concussion or orthopaedic injury (OI), to assess QSM performance as a diagnostic and prognostic biomarker. METHODS: Children aged 8-17 years with either concussion (N=255) or OI (N=116) were recruited from four Canadian paediatric emergency departments and underwent QSM postacutely (2-33 days postinjury) using 3 Tesla MRI. QSM Z-scores within nine regions of interest (ROI) were compared between groups. QSM Z-scores were also compared with the 5P score, the current clinical benchmark for predicting persistent postconcussion symptoms (PPCS), at 4 weeks postinjury, with PPCS defined using reliable change methods based on both participant and parent reports. RESULTS: Concussion and OI groups did not differ significantly in QSM Z-scores for any ROI. Higher QSM Z-scores within frontal white matter (WM) independently predicted PPCS based on parent ratings of cognitive symptoms (p=0.001). The combination of frontal WM QSM Z-score and 5P score was better at predicting PPCS than 5P score alone (p=0.004). The area under the curve was 0.72 (95% CI 0.63 to 0.81) for frontal WM susceptibility, 0.69 (95% CI 0.59 to 0.79) for the 5P score and 0.74 (95% CI 0.65 to 0.83) for both. CONCLUSION: The findings suggest that QSM is a potential MRI biomarker that can help predict PPCS in children with concussion, over and above the current clinical benchmark, and thereby aid in clinical management. They also suggest a frontal lobe substrate for PPCS, highlighting the potential for QSM to clarify the neurophysiology of paediatric concussion.

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.

Harmonization of multi-site MRS data with ComBat.

Magnetic resonance spectroscopy (MRS) is a non-invasive neuroimaging technique used to measure brain chemistry in vivo and has been used to study the healthy brain as well as neuropathology in numerous neurological disorders. The number of multi-site studies using MRS are increasing; however, non-biological variability introduced during data collection across multiple sites, such as differences in scanner vendors and site-specific acquisition implementations for MRS, can obscure detection of biological effects of interest. ComBat is a data harmonization technique that can remove non-biological sources of variance in multisite studies. It has been validated for use with structural and functional MRI metrics but not for MRS measured metabolites. This study investigated the validity of using ComBat to harmonize MRS metabolites for vendor and site differences. Analyses were performed using data acquired across 20 sites and included edited MRS for GABA+ (N = 218) and macromolecule-suppressed GABA data (N = 209), as well as standard PRESS data to quantify NAA, creatine, choline, and glutamate (N = 190). ComBat harmonization successfully mitigated vendor and site differences for all metabolites of interest. Moreover, significant associations were detected between sex and choline levels and between age and glutamate and GABA+ levels that were not detectable prior to harmonization, confirming the importance of removing site and vendor effects in multi-site data. In conclusion, ComBat harmonization can be successfully applied to MRS data in multi-site MRS studies.

Structural connectome differences in pediatric mild traumatic brain and orthopedic injury.

Sophisticated network-based approaches such as structural connectomics may help to detect a biomarker of mild traumatic brain injury (mTBI) in children. This study compared the structural connectome of children with mTBI or mild orthopedic injury (OI) to that of typically developing (TD) children. Children aged 8-16.99 years with mTBI (n = 83) or OI (n = 37) were recruited from the emergency department and completed 3T diffusion MRI 2-20 days postinjury. TD children (n = 39) were recruited from the community and completed diffusion MRI. Graph theory metrics were calculated for the binarized average fractional anisotropy among 90 regions. Multivariable linear regression and linear mixed effects models were used to compare groups, with covariates age, hemisphere, and sex, correcting for multiple comparisons. The two injury groups did not differ on graph theory metrics, but both differed from TD children in global metrics (local network efficiency: TD > OI, mTBI, d = 0.49; clustering coefficient: TD < OI, mTBI, d = 0.49) and regional metrics for the fusiform gyrus (lower degree centrality and nodal efficiency: TD > OI, mTBI, d = 0.80 to 0.96; characteristic path length: TD < OI, mTBI, d = -0.75 to -0.90) and in the superior and middle orbital frontal gyrus, paracentral lobule, insula, and thalamus (clustering coefficient: TD > OI, mTBI, d = 0.66 to 0.68). Both mTBI and OI demonstrated reduced global and regional network efficiency and segregation as compared to TD children. Findings suggest a general effect of childhood injury that could reflect pre- and postinjury factors that can alter brain structure. An OI group provides a more conservative comparison group than TD children for structural neuroimaging research in pediatric mTBI.

Longitudinal white matter microstructural changes in pediatric mild traumatic brain injury: An A-CAP study.

In the largest sample studied to date, white matter microstructural trajectories and their relation to persistent symptoms were examined after pediatric mild traumatic brain injury (mTBI). This prospective, longitudinal cohort study recruited children aged 8-16.99 years with mTBI or mild orthopedic injury (OI) from five pediatric emergency departments. Children's pre-injury and 1-month post-injury symptom ratings were used to classify mTBI with or without persistent symptoms. Children completed diffusion-weighted imaging at post-acute (2-33 days post-injury) and chronic (3 or 6 months via random assignment) post-injury assessments. Mean diffusivity (MD) and fractional anisotropy (FA) were derived for 18 white matter tracts in 560 children (362 mTBI/198 OI), 407 with longitudinal data. Superior longitudinal fasciculus FA was higher in mTBI without persistent symptoms relative to OI, d (95% confidence interval) = 0.31 to 0.37 (0.02, 0.68), across time. In younger children, MD of the anterior thalamic radiations was higher in mTBI with persistent symptoms relative to both mTBI without persistent symptoms, 1.43 (0.59, 2.27), and OI, 1.94 (1.07, 2.81). MD of the arcuate fasciculus, -0.58 (-1.04, -0.11), and superior longitudinal fasciculus, -0.49 (-0.90, -0.09) was lower in mTBI without persistent symptoms relative to OI at 6 months post-injury. White matter microstructural changes suggesting neuroinflammation and axonal swelling occurred chronically and continued 6 months post injury in children with mTBI, especially in younger children with persistent symptoms, relative to OI. White matter microstructure appears more organized in children without persistent symptoms, consistent with their better clinical outcomes.

Long-Term Intellectual and Fine Motor Outcomes in Spina Bifida Are Related to Myelomeningocele Repair and Shunt Intervention History.

OBJECTIVE: Lifespan outcomes of simultaneous versus sequential myelomeningocele repair and shunt placement or effects of repeated shunt revisions on specific domains of IQ or fine motor dexterity are largely unknown. The current study addressed these gaps in a large cohort of children and adults with spina bifida myelomeningocele (SBM). METHODS: Participants between 7 and 44 years of age with SBM and shunted hydrocephalus were recruited from international clinics at two time points. Each participant completed a standardized neuropsychological evaluation that included estimates of IQ and fine motor dexterity. Simultaneous versus sequential surgical repair and number of shunt revisions were examined in relation to long-term IQ and fine motor scores. RESULTS: Simultaneous myelomeningocele repair and shunting were associated with more frequent shunt revisions, as well as to lower Full Scale and verbal IQ scores, controlling for number of shunt revisions. More shunt revisions across study time points were associated with higher nonverbal IQ (NVIQ) scores. No effects were observed on fine motor dexterity. CONCLUSIONS: Findings indicate generally greater influence of surgery type over shunt revision history on outcomes in well-managed hydrocephalus. Findings supported apparent, domain-specific benefits of sequential compared to simultaneous surgery across the lifespan in SBM. Higher NVIQ scores with greater number of additional shunt revisions across surgery type supported positive outcomes with effective surgical management for hydrocephalus.

Role of Neurocognitive Factors in Academic Fluency for Children and Adults With Spina Bifida Myelomeningocele.

OBJECTIVES: Fluency is a major problem for individuals with neurodevelopmental disorders, including fluency deficits for academic skills. The aim of this study was to determine neurocognitive predictors of academic fluency within and across domains of reading, writing, and math, in children and adults, with and without spina bifida. In addition to group differences, we expected some neurocognitive predictors (reaction time, inattention) to have similar effects for each academic fluency outcome, and others (dexterity, vocabulary, nonverbal reasoning) to have differential effects across outcomes. METHODS: Neurocognitive predictors were reaction time, inattention, dexterity, vocabulary, and nonverbal reasoning; other factors included group (individuals with spina bifida, n=180; and without, n=81), age, and demographic and untimed academic content skill covariates. Univariate and multivariate regressions evaluated hypotheses. RESULTS: Univariate regressions were significant and robust (R 2 =.78, .70, .73, for reading, writing, and math fluency, respectively), with consistent effects of covariates, age, reaction time, and vocabulary; group and group moderation showed small effect sizes (<2%). Multivariate contrasts showed differential prediction across academic fluency outcomes for reaction time and vocabulary. CONCLUSIONS: The novelty of the present work is determining neurocognitive predictors for an important outcome (academic fluency), within and across fluency domains, across population (spina bifida versus typical), over a large developmental span, in the context of well-known covariates. Results offer insight into similarities and differences regarding prediction of different domains of academic fluency, with implications for addressing academic weakness in spina bifida, and for evaluating similar questions in other neurodevelopmental disorders. (JINS, 2019, 25, 249-265).

Are Shunt Revisions Associated with IQ in Congenital Hydrocephalus? A Meta -Analysis.

Although it is generally acknowledged that shunt revisions are associated with reductions in cognitive functions in individuals with congenital hydrocephalus, the literature yields mixed results and is inconclusive. The current study used meta-analytic methods to empirically synthesize studies addressing the association of shunt revisions and IQ in individuals with congenital hydrocephalus. Six studies and three in-house datasets yielded 11 independent samples for meta-analysis. Groups representing lower and higher numbers of shunt revisions were coded to generate effect sizes for differences in IQ scores. Mean effect size across studies was statistically significant, but small (Hedges' g = 0.25, p < 0.001, 95 % CI [0.08, 0.43]) with more shunt revisions associated with lower IQ scores. Results show an association of lower IQ and more shunt revisions of about 3 IQ points, a small effect, but within the error of measurement associated with IQ tests. Although clinical significance of this effect is not clear, results suggest that repeated shunt revisions because of shunt failure is associated with a reduction in cognitive functions.

Effects of prenatal alcohol exposure and attention-deficit/hyperactivity disorder on adaptive functioning.

BACKGROUND: Heavy prenatal alcohol exposure and attention-deficit/hyperactivity disorder (ADHD) are associated with adaptive behavior deficits. This study examined the interaction between these 2 factors on parent ratings of adaptive behavior. METHODS: As part of a multisite study, primary caregivers of 317 children (8 to 16 years, M = 12.38) completed the Vineland Adaptive Behavior Scales-Second Edition (VABS-II). Four groups of subjects were included: children with prenatal alcohol exposure with ADHD (AE+, n = 82), children with prenatal alcohol exposure without ADHD (AE-, n = 34), children with ADHD (ADHD, n = 71), and control children (CON, n = 130). VABS-II domain scores (Communication, Daily Living Skills, Socialization) were examined using separate 2 (Alcohol Exposure [AE]) × 2 (ADHD diagnosis) between-subjects analyses of covariance. RESULTS: There were significant main effects of AE (p < 0.001) and ADHD (p < 0.001) on all VABS-II domains; alcohol-exposed children had lower scores than children without prenatal alcohol exposure and children with ADHD had lower scores than those without ADHD. There was a significant AE × ADHD interaction effect for Communication, F(1, 308) = 7.49, p = 0.007, partial η(2) = 0.024, but not Daily Living Skills or Socialization domains (ps > 0.27). Follow-up analyses in the Communication domain indicated the effects of ADHD were stronger in comparison subjects (ADHD vs. CON) than exposed subjects (AE+ vs. AE-), and the effects of alcohol exposure were stronger in subjects without ADHD (AE- vs. CON) than in subjects with ADHD (AE+ vs. ADHD) CONCLUSION: As found previously, both prenatal alcohol exposure and ADHD increase adaptive behavior deficits in all domains. However, these 2 factors interact to cause the greatest impairment in children with both prenatal alcohol exposure and ADHD for communication abilities. These results further demonstrate the deleterious effects of prenatal alcohol exposure and broaden our understanding of how ADHD exacerbates behavioral outcomes in this population.

Association of Psychological Resilience, Cognitive Reserve, and Brain Reserve with Post-Concussive Symptoms in Children with Mild Traumatic Brain Injury and Orthopedic Injury: An A-CAP Study.

Protective factors, including psychological resilience, cognitive reserve, and brain reserve, may be positively associated with recovery after pediatric mild traumatic brain injury (mTBI) but are yet to be studied concurrently. We sought to examine these factors as moderators of post-concussive symptoms (PCS) in pediatric mTBI compared with mild orthopedic injury (OI). Participants included 967 children (633 mTBI, 334 OI) aged 8-16.99 years, recruited from 5 Canadian pediatric emergency departments as part of a prospective longitudinal cohort study. At 10 days post-injury, psychological resilience was measured using the Connor-Davidson Resilience Scale and brain reserve was measured using total brain volume derived from structural magnetic resonance imaging. Cognitive reserve was measured at 3 months post-injury using IQ scores from the Wechsler Abbreviated Scale of Intelligence-Second Edition. Cognitive and somatic PCS were measured using child and parent ratings on the Health and Behavior Inventory, completed weekly for 3 months and biweekly to 6 months. Analyses involved generalized least-squares regression models using restricted cubic splines. Covariates included age at injury, sex, racialized identity, material and social deprivation, pre-injury migraine and concussion history, and retrospective pre-injury PCS. Psychological resilience moderated group differences in parent-reported PCS. At 30 days post-injury, estimated group differences in parent-reported cognitive and somatic PCS (mTBI > OI) were larger at higher (75th percentile) resilience scores (Est = 2.25 [0.87, 3.64] and Est = 2.38 [1.76, 3.00], respectively) than at lower (25th percentile) resilience scores (Est = 1.44 [0.01, 2.86] and Est = 2.08 [1.45, 2.71], respectively). Resilience did not moderate group differences in child-reported PCS but was negatively associated with child-reported PCS in both groups (ps ≤ 0.001). Brain reserve (i.e., total brain volume [TBV]) also moderated group differences, but only for parent-reported somatic PCS (p = 0.018). Group difference (mTBI > OI) at 30 days was larger at smaller (25th percentile) TBV (Est = 2.78 [2.17, 3.38]) than at larger (75th percentile) TBV (Est = 1.95 [1.31, 2.59]). TBV was not associated with parent-reported cognitive PCS or child-reported PCS. IQ did not moderate PCS in either group but had a significant non-linear association in both groups with child-reported somatic PCS (p = 0.018) and parent-reported PCS (p < 0.001), with higher PCS scores at both lower and higher IQs. These findings suggest that higher resilience predicts fewer PCS, but less strongly after mTBI than OI; greater brain reserve may reduce the effect of mTBI on somatic PCS; and cognitive reserve has an unexpected curvilinear association with PCS across injury types. The results highlight the importance of protective factors as predictors of recovery and potential targets for intervention following pediatric mTBI.

Longitudinal Functional Connectome in Pediatric Concussion: An Advancing Concussion Assessment in Pediatrics Study.

Advanced magnetic resonance imaging (MRI) techniques indicate that concussion (i.e., mild traumatic brain injury) disrupts brain structure and function in children. However, the functional connectivity of brain regions within global and local networks (i.e., functional connectome) is poorly understood in pediatric concussion. This prospective, longitudinal study addressed this gap using data from the largest neuroimaging study of pediatric concussion to date to study the functional connectome longitudinally after concussion as compared with mild orthopedic injury (OI). Children and adolescents (n = 967) 8-16.99 years with concussion or mild OI were recruited from pediatric emergency departments within 48 h post-injury. Pre-injury and 1-month post-injury symptom ratings were used to classify concussion with or without persistent symptoms based on reliable change. Subjects completed a post-acute (2-33 days) and chronic (3 or 6 months via random assignment) MRI scan. Graph theory metrics were derived from 918 resting-state functional MRI scans in 585 children (386 concussion/199 OI). Linear mixed-effects modeling was performed to assess group differences over time, correcting for multiple comparisons. Relative to OI, the global clustering coefficient was reduced at 3 months post-injury in older children with concussion and in females with concussion and persistent symptoms. Time post-injury and sex moderated group differences in local (regional) network metrics of several brain regions, including degree centrality, efficiency, and clustering coefficient of the angular gyrus, calcarine fissure, cuneus, and inferior occipital, lingual, middle occipital, post-central, and superior occipital gyrus. Relative to OI, degree centrality and nodal efficiency were reduced post-acutely, and nodal efficiency and clustering coefficient were reduced chronically after concussion (i.e., at 3 and 6 months post-injury in females; at 6 months post-injury in males). Functional network alterations were more robust and widespread chronically as opposed to post-acutely after concussion, and varied by sex, age, and symptom recovery at 1-month post-injury. Local network segregation reductions emerged globally (across the whole brain network) in older children and in females with poor recovery chronically after concussion. Reduced functioning between neighboring regions could negatively disrupt specialized information processing. Local network metric alterations were demonstrated in several posterior regions that are involved in vision and attention after concussion relative to OI. This indicates that functioning of superior parietal and occipital regions could be particularly susceptibile to the effects of concussion. Moreover, those regional alterations were especially apparent at later time periods post-injury, emerging after post-concussive symptoms resolved in most and persisted up to 6 months post-injury, and differed by biological sex. This indicates that neurobiological changes continue to occur up to 6 months after pediatric concussion, although changes emerge earlier in females than in males. Changes could reflect neural compensation mechanisms.

The effects of prenatal alcohol exposure and attention-deficit/hyperactivity disorder on psychopathology and behavior.

BACKGROUND: This study examined prevalence of psychiatric disorders and behavioral problems in children with and without prenatal alcohol exposure (AE) and attention-deficit/hyperactivity disorder (ADHD). METHODS: Primary caregivers of 344 children (8 to 16 years, M = 12.28) completed the Computerized Diagnostic Interview Schedule for Children-IV (C-DISC-4.0) and the Child Behavior Checklist (CBCL). Subjects comprised 4 groups: AE with ADHD (AE+, n = 85) and without ADHD (AE-, n = 52), and nonexposed with ADHD (ADHD, n = 74) and without ADHD (CON, n = 133). The frequency of specific psychiatric disorders, number of psychiatric disorders (comorbidity), and CBCL behavioral scores were examined using chi-square and analysis of covariance techniques. RESULTS: Clinical groups had greater frequency of all psychiatric disorders, except for anxiety, where the AE- and CON groups did not differ. There was a combined effect of AE and ADHD on conduct disorder. For comorbidity, children with ADHD had increased psychiatric disorders regardless of AE, which did not have an independent effect on comorbidity. For CBCL scores, there were significant main effects of AE and ADHD on all scores and significant AE × ADHD interactions for Withdrawn/Depressed, Somatic Complaints, Attention, and all Summary scores. There was a combined effect of AE and ADHD on Externalizing, Total Problems, and Attention Problems. CONCLUSIONS: Findings indicate that ADHD diagnosis elevates children's risk of psychiatric diagnoses, regardless of AE, but suggest an exacerbated relation between AE and ADHD on conduct disorder and externalizing behavioral problems in children. Findings affirm a poorer behavioral prognosis for alcohol-exposed children with ADHD and suggest that more than 1 neurobehavioral profile may exist for individuals with AE.

Preliminary evidence of prolonged timing effects of theta-burst stimulation in the reading system.

Theta-burst stimulation (TBS) is a repetitive transcranial magnetic stimulation technique that can be used to upregulate or downregulate different brain regions. However, the timing of its effects and the differing effects of continuous TBS (cTBS) versus intermittent TBS (iTBS) in the reading system have not been explored. This study assessed how stimulation type and post-stimulation timing affected change in performance during a phonological discrimination and sight word recognition task after stimulation of supramarginal gyrus (SMG). Fourteen right-handed young adults (age 18-27 years; 44% male) were block-randomized to receive either iTBS or cTBS to the supramarginal gyrus. Participants then performed a pseudoword discrimination task and an orthographic awareness task (behavioral control) at four different time points and change in reaction time compared to baseline was measured from each time point. There was no effect of stimulation type on change in reaction time [t(16) = -0.2, p = 0.9], suggesting that both types of TBS caused similar effects. Percent change in reaction time decreased over time in the pseudoword task [t(50) = -5.9, p < 0.001], indicating faster pseudoword processing speed with better performance 60-70 min after stimulation. In contrast, no change was demonstrated over time for the behavioral control task [t(43) = -0.6, p = 0.6], suggesting that the change over time seen in the test condition was not a learning effect. These findings provide insight into the effects of TBS on the reading system and can guide future study designs.

Cerebral Hemodynamics and Microvasculature Changes in Relation to White Matter Microstructure After Pediatric Mild Traumatic Brain Injury: An A-CAP Pilot Study.

Advanced neuroimaging techniques show promise as a biomarker for mild traumatic brain injury (mTBI). However, little research has evaluated cerebral hemodynamics or its relation to white matter microstructure post-mTBI in children. This novel pilot study examined differences in cerebral hemodynamics, as measured using functional near-infrared spectroscopy (fNIRS), and its association with diffusion tensor imaging (DTI) metrics in children with mTBI or mild orthopedic injury (OI) to address these gaps. Children 8.00-16.99 years of age with mTBI (n = 9) or OI (n = 6) were recruited in a pediatric emergency department, where acute injury characteristics were assessed. Participants completed DTI twice, post-acutely (2-33 days) and chronically (3 or 6 months), and fNIRS ∼1 month post-injury. Automated deterministic tractography was used to compute DTI metrics. There was reduced absolute phase globally and coherence in the dorsolateral pre-frontal cortex (DLPFC) after mTBI compared to the OI group. Coherence in the DLPFC and absolute phase globally showed distinct associations with fractional anisotropy in interhemispheric white matter pathways. Two fNIRS metrics (coherence and absolute phase) differentiated mTBI from OI in children. Variability in cerebral hemodynamics related to white matter microstructure. The results provide initial evidence that fNIRS may have utility as a clinical biomarker of pediatric mTBI.

Altered longitudinal structural connectome in paediatric mild traumatic brain injury: an Advancing Concussion Assessment in Paediatrics study.

Advanced diffusion-weighted imaging techniques have increased understanding of the neuropathology of paediatric mild traumatic brain injury (i.e. concussion). Most studies have examined discrete white-matter pathways, which may not capture the characteristically subtle, diffuse and heterogenous effects of paediatric concussion on brain microstructure. This study compared the structural connectome of children with concussion to those with mild orthopaedic injury to determine whether network metrics and their trajectories across time post-injury differentiate paediatric concussion from mild traumatic injury more generally. Data were drawn from of a large study of outcomes in paediatric concussion. Children aged 8-16.99 years were recruited from five paediatric emergency departments within 48 h of sustaining a concussion (n = 360; 56% male) or mild orthopaedic injury (n = 196; 62% male). A reliable change score was used to classify children with concussion into two groups: concussion with or without persistent symptoms. Children completed 3 T MRI at post-acute (2-33 days) and/or chronic (3 or 6 months, via random assignment) post-injury follow-ups. Diffusion-weighted images were used to calculate the diffusion tensor, conduct deterministic whole-brain fibre tractography and compute connectivity matrices in native (diffusion) space for 90 supratentorial regions. Weighted adjacency matrices were constructed using average fractional anisotropy and used to calculate global and local (regional) graph theory metrics. Linear mixed effects modelling was performed to compare groups, correcting for multiple comparisons. Groups did not differ in global network metrics. However, the clustering coefficient, betweenness centrality and efficiency of the insula, cingulate, parietal, occipital and subcortical regions differed among groups, with differences moderated by time (days) post-injury, biological sex and age at time of injury. Post-acute differences were minimal, whereas more robust alterations emerged at 3 and especially 6 months in children with concussion with persistent symptoms, albeit differently by sex and age. In the largest neuroimaging study to date, post-acute regional network metrics distinguished concussion from mild orthopaedic injury and predicted symptom recovery 1-month post-injury. Regional network parameters alterations were more robust and widespread at chronic timepoints than post-acutely after concussion. Results suggest that increased regional and local subnetwork segregation (modularity) and inefficiency occurs across time after concussion, emerging after post-concussive symptom resolve in most children. These differences persist up to 6 months after concussion, especially in children who showed persistent symptoms. While prognostic, the small to modest effect size of group differences and the moderating effects of sex likely would preclude effective clinical application in individual patients.

Longitudinal Gray Matter Trajectories in Pediatric Mild Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: This prospective, longitudinal cohort study examined trajectories of brain gray matter macrostructure after pediatric mild traumatic brain injury (mTBI). METHODS: Children aged 8-16.99 years with mTBI or mild orthopedic injury (OI) were recruited from 5 pediatric emergency departments. Reliable change between preinjury and 1 month postinjury symptom ratings was used to classify mTBI with or without persistent symptoms. Children completed postacute (2-33 days) and/or chronic (3 or 6 months) postinjury T1-weighted MRI, from which macrostructural metrics were derived using automated segmentation. Linear mixed-effects models were used, with multiple comparisons correction. RESULTS: Groups (N = 623; 407 mTBI/216 OI; 59% male; age mean = 12.03, SD = 2.38 years) did not differ in total brain, white, or gray matter volumes or regional subcortical gray matter volumes. However, time postinjury, age at injury, and biological sex-moderated differences among symptom groups in cortical thickness of the angular gyrus, basal forebrain, calcarine cortex, gyrus rectus, medial and posterior orbital gyrus, and the subcallosal area all corrected p < 0.05. Gray matter macrostructural metrics did not differ between groups postacutely. However, cortical thinning emerged chronically after mTBI relative to OI in the angular gyrus in older children (d [95% confidence interval] = -0.61 [-1.15 to -0.08]); and in the basal forebrain (-0.47 [-0.94 to -0.01]), subcallosal area (-0.55 [-1.01 to -0.08]), and the posterior orbital gyrus (-0.55 [-1.02 to -0.08]) in females. Cortical thinning was demonstrated for frontal and occipital regions 3 months postinjury in males with mTBI with persistent symptoms vs without persistent symptoms (-0.80 [-1.55 to -0.05] to -0.83 [-1.56 to -0.10]) and 6 months postinjury in females and younger children with mTBI with persistent symptoms relative to mTBI without persistent symptoms and OI (-1.42 [-2.29 to -0.45] to -0.91 [-1.81 to -0.01]). DISCUSSION: These findings signal little diagnostic and prognostic utility of postacute gray matter macrostructure in pediatric mTBI. However, mTBI altered the typical course of cortical gray matter thinning up to 6 months postinjury, even after symptoms typically abate in most children. Collapsing across symptom status obscured the neurobiological heterogeneity of discrete clinical outcomes after pediatric mTBI. The results illustrate the need to examine neurobiology in relation to clinical outcomes and within a neurodevelopmental framework.

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.

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.

Executive function predicts adaptive behavior in children with histories of heavy prenatal alcohol exposure and attention-deficit/hyperactivity disorder.

BACKGROUND: Prenatal exposure to alcohol often results in disruption to discrete cognitive and behavioral domains, including executive function (EF) and adaptive functioning. In the current study, the relation between these 2 domains was examined in children with histories of heavy prenatal alcohol exposure, nonexposed children with a diagnosis of attention-deficit/hyperactivity disorder (ADHD), and typically developing controls. METHODS: As part of a multisite study, 3 groups of children (8 to 18 years, M = 12.10) were tested: children with histories of heavy prenatal alcohol exposure (ALC, n = 142), nonexposed children with ADHD (ADHD, n = 82), and typically developing controls (CON, n = 133) who did not have ADHD or a history of prenatal alcohol exposure. Children completed subtests of the Delis-Kaplan Executive Function System (D-KEFS), and their primary caregivers completed the Vineland Adaptive Behavior Scales-II. Data were analyzed using regression analyses. RESULTS: Analyses showed that EF measures were predictive of adaptive abilities, and significant interactions between D-KEFS measures and group were present. For the ADHD group, the relation between adaptive abilities and EF was more general, with 3 of the 4 EF measures showing a significant relation with adaptive score. In contrast, for the ALC group, this relation was specific to the nonverbal EF measures. In the CON group, performance on EF tasks did not predict adaptive scores over the influence of age. CONCLUSIONS: These results support prior research in ADHD, suggesting that EF deficits are predictive of poorer adaptive behavior and extend this finding to include children with heavy prenatal exposure to alcohol. However, the relation between EF and adaptive ability differed by group, suggesting unique patterns of abilities in these children. These results provide enhanced understanding of adaptive deficits in these populations, as well as demonstrate the ecological validity of laboratory measures of EF.