Disrupted Maturation of White Matter Microstructure After Concussion Is Associated With Internalizing Behavior Scores in Female Children.

BACKGROUND: Some children who experience concussions, particularly females, develop long-lasting emotional and behavioral problems. Establishing the potential contribution of preexisting behavioral problems and disrupted white matter maturation has been challenging due to a lack of preinjury data. METHODS: From the Adolescent Brain Cognitive Development cohort, 239 (90 female) children age 12.1 ± 0.6 years who experienced a concussion after study entry at 10.0 ± 0.6 years were compared to 6438 (3245 female) children without head injuries who were age 9.9 ± 0.6 years at baseline and 12.0 ± 0.6 years at follow-up. The Child Behavior Checklist was used to assess internalizing and externalizing behavior at study entry and follow-up. In the children with magnetic resonance imaging data available (concussion n = 134, comparison n = 3520), deep and superficial white matter was characterized by neurite density from restriction spectrum image modeling of diffusion magnetic resonance imaging. Longitudinal ComBat harmonization removed scanner effects. Linear regressions modeled 1) behavior problems at follow-up controlling for baseline behavior, 2) impact of concussion on white matter maturation, and 3) contribution of deviations in white matter maturation to postconcussion behavior problems. RESULTS: Only female children with concussion had higher internalizing behavior problem scores. The youngest children with concussion showed less change in superficial white matter neurite density over 2 years than children with no concussion. In females with concussion, less change in superficial white matter neurite density was correlated with increased internalizing behavior problem scores. CONCLUSIONS: Concussions in female children are associated with emotional problems beyond preinjury levels. Injury to superficial white matter may contribute to persistent internalizing behavior problems in females.

Premature white matter microstructure in female children with a history of concussion.

Childhood concussion may interfere with neurodevelopment and influence cognition. Females are more likely to experience persistent symptoms after concussion, yet the sex-specific impact of concussion on brain microstructure in children is understudied. This study examined white matter and cortical microstructure, based on neurite density (ND) from diffusion-weighted MRI, in 9-to-10-year-old children in the Adolescent Brain Cognitive Development Study with (n = 336) and without (n = 7368) a history of concussion, and its relationship with cognitive performance. Multivariate regression was used to investigate relationships between ND and group, sex, and age in deep and superficial white matter, subcortical structures, and cortex. Partial least square correlation was performed to identify associations between ND and performance on NIH Toolbox tasks in children with concussion. All tissue types demonstrated higher ND with age, reflecting brain maturation. Group comparisons revealed higher ND in deep and superficial white matter in females with concussion. In female but not male children with concussion, there were significant associations between ND and performance on cognitive tests. These results demonstrate a greater long-term impact of childhood concussion on white matter microstructure in females compared to males that is associated with cognitive function. The increase in ND in females may reflect premature white matter maturation.

Preliminary Observations of Resting-State Magnetoencephalography in Nonmedicated Children with Obsessive-Compulsive Disorder.

Background: Cortico-striato-thalamo-cortical (CSTC) network alterations are hypothesized to contribute to symptoms of obsessive-compulsive disorder (OCD). To date, very few studies have examined whether CSTC network alterations are present in children with OCD, who are medication naive. Medication-naive pediatric imaging samples may be optimal to study neural correlates of illness and identify brain-based markers, given the proximity to illness onset. Methods: Magnetoencephalography (MEG) data were analyzed at rest, in 18 medication-naive children with OCD (M = 12.1 years ±2.0 standard deviation [SD]; 10 M/8 F) and 13 typically developing children (M = 12.3 years ±2.2 SD; 6 M/7 F). Whole-brain MEG-derived resting-state functional connectivity (rs-fc), for alpha- and gamma-band frequencies were compared between OCD and typically developing (control) groups. Results: Increased MEG-derived rs-fc across alpha- and gamma-band frequencies was found in the OCD group compared to the control group. Increased MEG-derived rs-fc at alpha-band frequencies was evident across a number of regions within the CSTC circuitry and beyond, including the cerebellum and limbic regions. Increased MEG-derived rs-fc at gamma-band frequencies was restricted to the frontal and temporal cortices. Conclusions: This MEG study provides preliminary evidence of altered alpha and gamma networks, at rest, in medication-naive children with OCD. These results support prior findings pointing to the relevance of CSTC circuitry in pediatric OCD and further support accumulating evidence of altered connectivity between regions that extend beyond this network, including the cerebellum and limbic regions. Given the substantial portion of children and youth whose OCD symptoms do not respond to conventional treatments, our findings have implications for future treatment innovation research aiming to target and track whether brain patterns associated with having OCD may change with treatment and/or predict treatment response.

Multi-tract multi-symptom relationships in pediatric concussion.

Background: The heterogeneity of white matter damage and symptoms in concussion has been identified as a major obstacle to therapeutic innovation. In contrast, most diffusion MRI (dMRI) studies on concussion have traditionally relied on group-comparison approaches that average out heterogeneity. To leverage, rather than average out, concussion heterogeneity, we combined dMRI and multivariate statistics to characterize multi-tract multi-symptom relationships. Methods: Using cross-sectional data from 306 previously concussed children aged 9-10 from the Adolescent Brain Cognitive Development Study, we built connectomes weighted by classical and emerging diffusion measures. These measures were combined into two informative indices, the first representing microstructural complexity, the second representing axonal density. We deployed pattern-learning algorithms to jointly decompose these connectivity features and 19 symptom measures. Results: Early multi-tract multi-symptom pairs explained the most covariance and represented broad symptom categories, such as a general problems pair, or a pair representing all cognitive symptoms, and implicated more distributed networks of white matter tracts. Further pairs represented more specific symptom combinations, such as a pair representing attention problems exclusively, and were associated with more localized white matter abnormalities. Symptom representation was not systematically related to tract representation across pairs. Sleep problems were implicated across most pairs, but were related to different connections across these pairs. Expression of multi-tract features was not driven by sociodemographic and injury-related variables, as well as by clinical subgroups defined by the presence of ADHD. Analyses performed on a replication dataset showed consistent results. Conclusions: Using a double-multivariate approach, we identified clinically-informative, cross-demographic multi-tract multi-symptom relationships. These results suggest that rather than clear one-to-one symptom-connectivity disturbances, concussions may be characterized by subtypes of symptom/connectivity relationships. The symptom/connectivity relationships identified in multi-tract multi-symptom pairs were not apparent in single-tract/single-symptom analyses. Future studies aiming to better understand connectivity/symptom relationships should take into account multi-tract multi-symptom heterogeneity. Funding: Financial support for this work came from a Vanier Canada Graduate Scholarship from the Canadian Institutes of Health Research (G.I.G.), an Ontario Graduate Scholarship (S.S.), a Restracomp Research Fellowship provided by the Hospital for Sick Children (S.S.), an Institutional Research Chair in Neuroinformatics (M.D.), as well as a Natural Sciences and Engineering Research Council CREATE grant (M.D.).

Concussions can damage networks of connections in the brain. Scientists have spent decades and millions of dollars studying concussions and potential treatments. Yet, no new treatments are available or in the pipeline. A major reason for this stagnation is that no two concussions are exactly alike. People affected by concussions may have different genetic or socioeconomic backgrounds. The nature of the injury or how its effects change over time may also vary among people with concussions. One central question facing scientists is whether there are multiple types of concussions. If so, what distinguishes them and what characteristics do they share. Some studies have looked at differences among subgroups of patients with concussions. But questions remain about whether ­ beyond differences between the patients ­ the brain injury itself differs and what impact that has on symptoms or patient trajectory. To better characterize different types of concussion, Guberman et al. analyzed diffusion magnetic resonance imaging scans from 306 nine or ten-year-old children with a previous concussion. The children were participants in the Adolescent Brain Cognitive Development Study. Using specialized statistical techniques, the researchers outlined subgroups of concussions in terms of connections and symptoms and studied how many of these subgroups each patient had. Some types of injury were linked with a category of symptoms like cognitive, mood, or physical symptoms. Some types of damage were linked with specific symptoms. Guberman et al. also found that one symptom, sleep problems, was part of many different injury subtypes. Sleep problems may occur in different patients for different reasons. For example, one patient with sleep difficulties may have experienced damage in brain regions controlling sleep and wakefulness. Another person with sleep problems may have injured parts of the brain responsible for mood and may have depression, which causes excessive sleepiness and difficulties waking up. Guberman et al. suggest a new way of thinking about concussions. If more studies confirm these concussion subgroups, scientists might use them to explore which types of therapies might be beneficial for patients with specific subgroups. Developing subgroup-targeted treatments may help scientists overcome the challenges of trying to develop therapies that work across a range of injuries. Similar disease subgrouping strategies may also help researchers study other brain diseases that may vary from patient to patient.

Visuomotor Activation of Inhibition-Processing in Pediatric Obsessive Compulsive Disorder: A Magnetoencephalography Study.

Background: Response inhibition engages the cortico-striato-thalamo-cortical (CSTC) circuit, which has been implicated in children, and youth with obsessive compulsive disorder (OCD). This study explored whether CSTC engagement during response inhibition, measured using magnetoencephalography (MEG), differed in a sample of medication-naïve youth with OCD, compared to typically developing controls (TDC). Methods: Data was analyzed in 17 medication-naïve children and youth with OCD (11.7 ± 2.2 SD years) and 13 TDC (12.6 ± 2.2 SD years). MEG was used to localize and characterize neural activity during a Go/No-Go task. Task performance on Go/No-Go conditions and regional differences in amplitude of activity during Go and No-Go condition between OCD vs. TDC were examined using two-sample t-tests. Post-hoc analysis with Bayesian t-tests was used to estimate the certainty of outcomes. Results: No differences in Go/No-Go performance were found between OCD and TDC groups. In response to the visual cue presented during the Go condition, participants with OCD showed significantly increased amplitude of activity in the primary motor (MI) cortex compared to TDC. In addition, significantly reduced amplitude of PCu was found following successful stopping to No-Go cues in OCD vs. TDC during No-Go task performance. Bayesian t-tests indicated high probability and large effect sizes for the differences in MI and PCu amplitude found between groups. Conclusion: Our preliminary study in a small medication-naïve sample extends previous work indicating intact response inhibition in pediatric OCD. While altered neural response in the current study was found during response inhibition performance in OCD, differences localized to regions outside of the CSTC. Our findings suggest that additional imaging research in medication-naïve samples is needed to clarify regional differences associated with OCD vs. influenced by medication effects, and suggest that MEG may be sensitive to detecting such differences.