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

Cognitieve revalidatie voor kinderen en jongeren met niet-aangeboren hersenletsel:wat zijn de effectieve componenten?

Veel kinderen en jongeren met niet-aangeboren hersenletsel (nah) ervaren problemen met cognitief functioneren, zoals een verminderd geheugen of slechtere concentratie. Dit artikel is gebaseerd op bevindingen en inzichten uit het proefschrift ‘executive functions of children and adolescents: novel perspectives on assessment and intervention’. Een belangrijk doel van het promotietraject was beter inzicht te krijgen in hoe we cognitieve functies en bijbehorende problemen bij kinderen en jongeren met nah kunnen verbeteren. Cognitieve problemen bij kinderen en jongeren kunnen mogelijk worden behandeld met cognitieve revalidatie. Interventies voor cognitieve revalidatie kunnen worden gecategoriseerd op basis van hun hoofdcomponenten: 1) strategiegebruik en/of metacognitie, 2) herhaald oefenen, en 3) externe hulpmiddelen. Resultaten van een literatuurstudie naar cognitieve revalidatie laten zien dat door interventies die zijn gebaseerd op metacognitie en/of strategiegebruik vooral adaptief gedrag en sociaal functioneren verbeteren. Interventies op basis van herhaald oefenen verbeterden de prestaties op taken die vergelijkbaar zijn met de geoefende taken. Multi-componenten-interventies die deze twee componenten combineren, leken te leiden tot verbeteringen in zowel cognitief als adaptief gedrag en sociaal functioneren. Externe hulpmiddelen verbeterden het functioneren in het specifieke gebied waarop het hulpmiddel was gericht, bijvoorbeeld het geheugen. De beschikbare gegevens suggereren dat interventies bestaande uit meerdere componenten, zoals een combinatie van metacognitie- en/of strategiegebruik en herhaald oefenen, veelbelovend zijn, omdat deze kunnen leiden tot verbeteringen in zowel het cognitieve als psychosociale functioneren van kinderen en adolescenten met nah

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