Genetic Influences on Behavioral Outcomes After Childhood TBI: A Novel Systems Biology-Informed Approach

Objectives: To test whether genetic associations with behavioral outcomes after early childhood traumatic brain injury (TBI) are enriched for biologic pathways underpinning neurocognitive and behavioral networks.Design: Cross-sectional evaluation of the association of genetic factors with early (~ 6 months) and long-term (~ 7 years) post-TBI behavioral outcomes. We combined systems biology and genetic association testing methodologies to identify biologic pathways associated with neurocognitive and behavior outcomes after TBI. We then evaluated whether genes/single nucleotide polymorphism (SNPs) associated with these biologic pathways were more likely to demonstrate a relationship (i.e., enrichment) with short and long-term behavioral outcomes after early childhood TBI compared to genes/SNPs not associated with these biologic pathways.Setting: Outpatient research setting.Participants:140 children, ages 3–6:11 years at time of injury, admitted for a TBI or orthopedic injury (OI).Interventions: Not Applicable.Main Outcome Measures: Child behavior checklist total problems T score.Results: Systems biology methodology identified neuronal systems and neurotransmitter signaling (Glutamate receptor, dopamine, serotonin, and calcium signaling), inflammatory response, cell death, immune systems, and brain development as important biologic pathways to neurocognitive and behavioral outcomes after TBI. At 6 months post injury, the group (TBI versus OI) by polymorphism interaction was significant when the aggregate signal from the highest ranked 40% of case gene associations was compared to the control set of genes. At ~ 7 years post injury, the selected polymorphisms had a significant main effect after controlling for injury type when the aggregate signal from the highest ranked 10% of the case genes were compared to the control set of genesConclusions: Findings demonstrate the promise of applying a genomics approach, informed by systems biology, to understanding behavioral recovery after pediatric TBI. A mixture of biologic pathways and processes are associated with behavioral recovery, specifically genes associated with cell death, inflammatory response, neurotransmitter signaling, and brain development. These results provide insights into the complex biology of TBI recovery

Prospective and episodic memory in relation to hippocampal volume in adults with spina bifida myelomeningocele

The present study examined prospective and episodic memory in relation to age, functional independence, and hippocampal volume in younger to middle-aged adults with spina bifida myelomeningocele (SBM) and typically developing (TD) adults. Prospective and episodic memory, as well as hippocampal volume, was reduced in adults with SBM relative to TD adults. Neither memory performance nor hippocampal volume showed greater decrements in older adults. Lower hippocampal volume was associated with reduced prospective memory in adults with SBM, and this relation was specific to the hippocampus and not to a contrast structure, the amygdala. Prospective memory mediated the relation between hippocampal volume and functional independence in adults with SBM. The results add to emerging evidence for reduced memory function in adults with SBM and provide quantitative evidence for compromised hippocampal macrostructure as a neural correlate of reduced memory in this population

Brain-Derived Neurotrophic Factor in Pediatric Acquired Brain Injury and Recovery

We review emerging preclinical and clinical evidence regarding brain-derived neurotrophic factor (BDNF) protein, genotype, and DNA methylation (DNAm) as biomarkers of outcomes in three important etiologies of pediatric acquired brain injury (ABI), traumatic brain injury, global cerebral ischemia, and stroke. We also summarize evidence suggesting that BDNF is (1) involved in the biological embedding of the psychosocial environment, (2) responsive to rehabilitative therapies, and (3) potentially modifiable. BDNF’s unique potential as a biomarker of neuroplasticity and neural repair that is reflective of and responsive to both pre- and post-injury environmental influences separates it from traditional protein biomarkers of structural brain injury with exciting potential to advance pediatric ABI management by increasing the accuracy of prognostic tools and informing clinical decision making through the monitoring of therapeutic effects

Attention in spina bifida myelomeningocele: Relations with brain volume and integrity

This study investigated the relations of tectal volume and superior parietal cortex, as well as alterations in tectocortical white matter connectivity, with the orienting and executive control attention networks in individuals with spina bifida myelomeningocele (SBM). Probabilistic diffusion tractography and quantification of tectal and superior parietal cortical volume were performed on 74 individuals aged 8–29 with SBM and a history of hydrocephalus. Behavioral assessments measured posterior (covert orienting) and anterior (conflict resolution, attentional control) attention network functions. Reduced tectal volume was associated with slower covert orienting; reduced superior parietal cortical volume was associated with slower conflict resolution; and increased axial diffusivity and radial diffusivity along both frontal and parietal tectocortical pathways were associated with reduced attentional control. Results suggest that components of both the orienting and executive control attention networks are impaired in SBM. Neuroanatomical disruption to the orienting network appears more robust and a direct consequence of characteristic midbrain dysmorphology; whereas, executive control difficulties may emerge from parietal cortical anomalies and reduced frontal and parietal cortical–subcortical white matter pathways susceptible to the pathophysiological effects of congenital hydrocephalus

Patient-report and caregiver-report measures of rehabilitation service use following acquired brain injury: a systematic review

Objective To review patient-report/caregiver-report measures of rehabilitation service use following acquired brain injury (ABI).Data sources Medline, APA PsycINFO, Embase and CINAHL were searched on November 2021 and November 2022. Authors were contacted if measures were not included in manuscripts/appendices.Study selection Included articles were empirical research or a research protocol, available in English and described measures of patient report/caregiver report of rehabilitation service use post-ABI via quantitative or qualitative methods. Two reviewers independently screened 5290 records using DistillerSR. Discrepancies were resolved by team adjudication.Data extraction Data extraction was piloted with high levels of agreement (k=.94). Data were extracted by a single member with team meetings to seek guidance as needed. Data included administration characteristics (reporter, mode of administration, recall period), psychometric evidence and dimensions assessed (types of services, setting, frequency, duration, intensity, qualitative aspects).Data synthesis One hundred and fifty-two measures were identified from 85 quantitative, 56 qualitative and 3 psychometric studies. Psychometric properties were reported for four measures, all of which focused on satisfaction. Most measures inquired about the type of rehabilitation services used, with more than half assessing functional (eg, physical therapy) and behavioural health rehabilitation services, but fewer than half assessing community and academic reintegration (eg, special education, vocational rehabilitation) or cognitive (eg, neuropsychology) services. Fewer than half assessed qualitative aspects (eg, satisfaction). Recall periods ranged from 1 month to ‘since the ABI event’ or focused on current use. Of measures that could be accessed (n=71), many included a limited checklist of types of services used. Very few measures assessed setting, frequency, intensity or duration.Conclusions Despite widespread interest, the vast majority of measures have not been validated and are limited in scope. Use of gold-standard psychometric methods to develop and validate a comprehensive patient-report/caregiver-report measure of rehabilitation service use would have wide-ranging implications for improving rehabilitation research in ABI

Table2_Elucidating a genomic signature associated with behavioral and executive function after moderate to severe pediatric TBI: a systems biology informed approach.XLSX

Introduction: There is significant unexplained variability in behavioral and executive functioning after pediatric traumatic brain injury (TBI). Prior research indicates that there are likely genetic contributions; however, current research is limited. The purpose of this study is to use a systems biology informed approach to characterize the genomic signature related to behavioral and executive functioning ∼12 months after moderate through severe TBI in children.Methods: Participants were from two prospective cohorts of children with severe TBI (Cohort #1) and moderate-severe TBI and an orthopedic injury (OI) group (Cohort #2). Participants included 196 children (n = 72 and n = 124 total from each respective cohort), ranging in age between 0–17 years at the time of injury. In total, 86 children had severe TBI, 49 had moderate TBI, and 61 had an OI. Global behavioral functioning assessed via the Child Behavior Checklist and executive function assessed via the Behavioral Rating Inventory of Executive Function at ∼ 12 months post injury served as outcomes. To test for a genomic signature, we compared the number of nominally significant (p Results: At 12 months post injury, injury type (TBI vs OI) by polymorphism interaction was significantly enriched in systems biology selected genes for behavioral and executive function outcomes, suggesting these genes form a genomic signature. Effect sizes of the associations from our genes of interest ranged from .2–.5 for the top 5% of variants. Systems biology analysis of the variants associated with the top 5% effect sizes indicated enrichment in several specific biologic processes and systems.Discussion: Findings indicate that a genomic signature may explain heterogeneity of behavioral and executive outcomes after moderate and severe TBI. This work provides the foundation for constructing genomic signatures and integrating systems biology and genetic information into future recovery, prognostic, and treatment algorithms.</p