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.

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.

Patterns of change in cortical morphometry following traumatic brain injury in adults.

Progressive cortical volumetric loss following moderate-severe traumatic brain injury (TBI) has been observed; however, regionally specific changes in the structural determinants of cortical volume, namely, cortical thickness (CT) and cortical surface area (CSA), are unknown and may inform the patterns and neural substrates of neurodegeneration and plasticity following injury. We aimed to (a) assess differences in CT and CSA between TBI participants and controls in the early chronic stage post-injury, (b) describe longitudinal changes in cortical morphometry following TBI, and (c) examine how regional changes in CT and CSA are associated. We acquired magnetic resonance images for 67 participants with TBI at up to 4 time-points spanning 5 months to 7 years post-injury, and 18 controls at 2 time-points. In the early chronic stage, TBI participants displayed thinner cortices than controls, predominantly in frontal regions, but no CSA differences. Throughout the chronic period, TBI participants showed widespread CT reductions in posterior cingulate/precuneus regions and moderate CT increase in frontal regions. Additionally, CSA showed a significant decrease in the orbitofrontal cortex and circumscribed increase in posterior regions. No changes were identified in controls. Relationships between regional cortical changes in the same morphological measure revealed coordinated patterns within participants, whereas correlations between regions with CT and CSA change yielded bi-directional relationships. This suggests that these measures may be differentially affected by neurodegenerative mechanisms such as transneuronal degeneration following TBI and that degeneration may be localized to the depths of cortical sulci. These findings emphasize the importance of dissecting morphometric contributions to cortical volume change.

A Systematic Scoping Review of New Attention Problems Following Traumatic Brain Injury in Children.

Objective: To summarize existing knowledge about the characteristics of attention problems secondary to traumatic brain injuries (TBI) of all severities in children. Methods: Computerized databases PubMed and PsychINFO and gray literature sources were used to identify relevant studies. Search terms were selected to identify original research examining new ADHD diagnosis or attention problems after TBI in children. Studies were included if they investigated any severity of TBI, assessed attention or ADHD after brain injury, investigated children as a primary or sub-analysis, and controlled for or excluded participants with preinjury ADHD or attention problems. Results: Thirty-nine studies were included in the review. Studies examined the prevalence of and risk factors for new attention problems and ADHD following TBI in children as well as behavioral and neuropsychological factors associated with these attention problems. Studies report a wide range of prevalence rates of new ADHD diagnosis or attention problems after TBI. Evidence indicates that more severe injury, injury in early childhood, or preinjury adaptive functioning problems, increases the risk for new ADHD and attention problems after TBI and both sexes appear to be equally vulnerable. Further, literature suggests that cases of new ADHD often co-occurs with neuropsychiatric impairment in other domains. Identified gaps in our understanding of new attention problems and ADHD include if mild TBI, the most common type of injury, increases risk and what brain abnormalities are associated with the emergence of these problems. Conclusion: This scoping review describes existing studies of new attention problems and ADHD following TBI in children and highlights important risk factors and comorbidities. Important future research directions are identified that will inform the extent of this outcome across TBI severities, its neural basis and points of intervention to minimize its impact.

Microstructural abnormalities in deep and superficial white matter in youths with mild traumatic brain injury.

BACKGROUND: Diffusion Tensor Imaging (DTI) studies of traumatic brain injury (TBI) have focused on alterations in microstructural features of deep white matter fibers (DWM), though post-mortem studies have demonstrated that injured axons are often observed at the gray-white matter interface where superficial white matter fibers (SWM) mediate local connectivity. OBJECTIVES: To examine microstructural alterations in SWM and DWM in youths with a history of mild TBI and examine the relationship between white matter alterations and attention. METHODS: Using DTIDWM fractional anisotropy (FA) and SWM FA in youths with mild TBI (TBI, n=63) were compared to typically developing and psychopathology matched control groups (n=63 each). Following tract-based spatial statistics, SWM FA was assessed by applying a probabilistic tractography derived SWM mask, and DWM FA was captured with a white matter fiber tract mask. Voxel-wise z-score calculations were used to derive a count of voxels with abnormally high and low FA for each participant. Analyses examined DWM and SWM FA differences between TBI and control groups, the relationship between attention and DWM and SWM FA and the relative susceptibility of SWM compared to DWM FA to alterations associated with mild TBI. RESULTS: Case-based comparisons revealed more voxels with low FA and fewer voxels with high FA in SWM in youths with mild TBI compared to both control groups. Equivalent comparisons in DWM revealed a similar pattern of results, however, no group differences for low FA in DWM were found between mild TBI and the control group with matched psychopathology. Slower processing speed on the attention task was correlated with the number of voxels with low FA in SWM in youths with mild TBI. CONCLUSIONS: Within a sample of youths with a history of mild TBI, this study identified abnormalities in SWM microstructure associated with processing speed. The majority of DTI studies of TBI have focused on long-range DWM fiber tracts, often overlooking the SWM fiber type.

Developmentally divergent sexual dimorphism in the cortico-striatal-thalamic-cortical psychosis risk pathway.

Structural and functional cortico-striatal-thalamic-cortical (CSTC) circuit abnormalities have been observed in schizophrenia and the clinical high-risk state. However, this circuit is sexually dimorphic and changes across neurodevelopment. We examined effects of sex and age on structural and functional properties of the CSTC circuit in a large sample of youth with and without psychosis spectrum symptoms (PSS) from the Philadelphia Neurodevelopmental Cohort. T1-weighted and resting-state functional MRI scans were collected on a 3T Siemens scanner, in addition to participants' cognitive and psychopathology data. After quality control, the total sample (aged 11-21) was n = 1095 (males = 485, females = 610). Structural subdivisions of the striatum and thalamus were identified using the MAGeT Brain segmentation tool. Functional seeds were segmented based on brain network connectivity. Interaction effects among PSS group, sex, and age on striatum, thalamus, and subdivision volumes were examined. A similar model was used to test effects on functional connectivity of the CSTC circuit. A sex by PSS group interaction was identified, whereby PSS males had higher volumes and PSS females had lower volumes in striatal and thalamic subdivisions. Reduced functional striato-cortical connectivity was found in PSS youth, primarily driven by males, whereby younger male PSS youth also exhibited thalamo-cortical hypo-connectivity (compared to non-PSS youth), vs. striato-cortical hyper-connectivity in older male PSS youth (compared to non-PSS youth). Youth with PSS demonstrate sex and age-dependent differences in striatal and thalamic subdivision structure and functional connectivity. Further efforts at biomarker discovery and early therapeutic intervention targeting the CSTC circuit in psychosis should consider effects of sex and age.

Polygenic Risk and Neural Substrates of Attention-Deficit/Hyperactivity Disorder Symptoms in Youths With a History of Mild Traumatic Brain Injury.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a major sequela of traumatic brain injury (TBI) in youths. The objective of this study was to examine whether ADHD symptoms are differentially associated with genetic risk and brain structure in youths with and without a history of TBI. METHODS: Medical history, ADHD symptoms, genetic data, and neuroimaging data were obtained from a community sample of youths. ADHD symptom severity was compared between those with and without TBI (TBI n = 418, no TBI n = 3193). The relationship of TBI history, genetic vulnerability, brain structure, and ADHD symptoms was examined by assessing 1) ADHD polygenic score (discovery sample ADHD n = 19,099, control sample n = 34,194), 2) basal ganglia volumes, and 3) fractional anisotropy in the corpus callosum and corona radiata. RESULTS: Youths with TBI reported greater ADHD symptom severity compared with those without TBI. Polygenic score was positively associated with ADHD symptoms in youths without TBI but not in youths with TBI. The negative association between the caudate volume and ADHD symptoms was not moderated by a history of TBI. However, the relationship between ADHD symptoms and structure of the genu of the corpus callosum was negative in youths with TBI and positive in youths without TBI. CONCLUSIONS: The identification of distinct ADHD etiology in youths with TBI provides neurobiological insight into the clinical heterogeneity in the disorder. Results indicate that genetic predisposition to ADHD does not increase the risk for ADHD symptoms associated with TBI. ADHD symptoms associated with TBI may be a result of a mechanical insult rather than neurodevelopmental factors.

BDNF-Dependent Effects on Amygdala-Cortical Circuitry and Depression Risk in Children and Youth.

The brain-derived neurotrophic factor (BDNF) is critical for brain development, and the functional BDNF Val66Met polymorphism is implicated in risk for mood disorders. The objective of this study was to determine how the Val66Met polymorphism influences amygdala-cortical connectivity during neurodevelopment and assess the relevance for mood disorders. Age- and sex-specific effects of the BDNF Val66Met polymorphism on amygdala-cortical connectivity were assessed by examining covariance of amygdala volumes with thickness throughout the cortex in a sample of Caucasian youths ages 8-22 that were part of the Philadelphia Neurodevelopmental Cohort (n = 339). Follow-up analyses assessed corresponding BDNF genotype effects on resting-state functional connectivity (n = 186) and the association between BDNF genotype and major depressive disorder (MDD) (n = 2749). In adolescents, amygdala-cortical covariance was significantly stronger in Met allele carriers compared with Val/Val homozygotes in amygdala-cortical networks implicated in depression; these differences were driven by females. In follow-up analyses, the Met allele was also associated with stronger resting-state functional connectivity in adolescents and increased likelihood of MDD in adolescent females. The BDNF Val66Met polymorphism may confer risk for mood disorders in females through effects on amygdala-cortical connectivity during adolescence, coinciding with a period in the lifespan when onset of depression often occurs, more commonly in females.

Self-Harm and Suicidality in Children Referred for Gender Dysphoria.

OBJECTIVE: This study examined rates of self-harm and suicidality (ideation and behavior) in children referred clinically for gender dysphoria compared with their siblings, and referred and nonreferred children from the Child Behavior Checklist (CBCL) standardization sample. Predictors or correlates of self-harm/suicidality were also examined. METHOD: The sample consisted of 572 gender-referred children, 425 siblings, 878 referred children, and 903 nonreferred children. Parent report for 2 CBCL items was used to assess self-harm and suicidality. CBCL total behavior problems and a metric of peer relationship problems were also used. RESULTS: The gender-referred children and the referred children from the standardization sample had significantly higher scores than siblings and nonreferred children in terms of self-harm/suicidality, total behavior problems, and poor peer relations. Based on logistic regression analyses, gender-referred children were 5.1 times more likely than nonreferred children to talk about suicide and 8.6 times more likely to self-harm/attempt suicide, even after overall behavior problems and peer relationship problems were accounted for. In the final models, group, older age, and more total behavior problems, but not poor peer relations, were significantly associated with an increased likelihood of self-harm/suicidality. CONCLUSION: By parent report, children with gender dysphoria show an increased rate of self-harm/suicidality as they get older. This risk was not simply an artifact of the presence of behavioral and emotional problems, although these problems were significant correlates of self-harm/suicidality. Clinicians should routinely screen for the presence of suicidal ideation and behavior in children with gender dysphoria, particularly during the second half of childhood.