Epigenetic Effects on Traumatic Brain Injury Recovery

Study Overview
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Brief Summary
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Methylation of the brain-derived neurotrophic factor (BDNF) gene is involved in both the biological encoding of childhood adversity and neuroplasticity following traumatic brain injury (TBI). This research will characterize BDNF methylation during recovery from TBI in children and investigate this novel biomarker as a potential biological mechanism underlying the known association between childhood adversity and poorer neurobehavioral outcomes following TBI in childhood. Findings from this research will contribute to an improved understanding of why some children display good recovery following TBI, whereas many others suffer from chronic neurobehavioral impairments.

Detailed Description
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Unexplained heterogeneity in outcomes following pediatric traumatic brain injury (TBI) is one of the most critical barriers to the development of effective prognostic tools and therapeutics. The addition of personal biological factors to our prediction models may account for a significant portion of unexplained variance and advance the field towards precision rehabilitation medicine. The overarching goal of the Epigenetic Effects on Pediatric Traumatic Brain Injury Recovery (EETR) study is to investigate an epigenetic biomarker involved in both childhood adversity and post-injury neuroplasticity to better understand heterogeneity in neurobehavioral outcomes following pediatric TBI. The primary hypothesis is that childhood adversity will be associated with poorer neurobehavioral recovery in part through an epigenetically mediated reduction in brain-derived neurotrophic factor (BDNF) expression in response to TBI. EETR is an observational, prospective, longitudinal concurrent cohort study of children aged 3-18 years with either TBI (n=200) or orthopedic injury (n=100), recruited from the UPMC Children's Hospital of Pittsburgh. Participants complete study visits acutely and at 6- and 12-months post-injury. Blood and saliva biosamples are collected at all time points-and CSF when available acutely-for epigenetic and proteomic analysis of BDNF. Additional measures assess injury characteristics, pre- and post-injury child neurobehavioral functioning, childhood adversity, and potential covariates/confounders. Analyses will characterize BDNF DNA methylation and protein levels over the recovery period and investigate this novel biomarker as a potential biological mechanism underlying the known association between childhood adversity and poorer neurobehavioral outcomes following pediatric TBI.

Official Title
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Epigegenetic Influences on Neurobehavioral Recovery Following Pediatric Traumatic Brain Injury

Conditions
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Traumatic Brain Injury, Orthopedic Injury

Participation Criteria
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Eligibility Criteria
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Inclusion criteria: -hospitalized overnight for a non-penetrating complicated mild to severe TBI as defined by the lowest post-resuscitation Glasgow Coma Scale (GCS) score or orthopedic injury. Complicated mild TBI is defined as a GCS of 13-15 with neuroimaging indicating intracranial or parenchymal injury or depressed/displaced skull fracture. Moderate TBI is defined as GCS 9-12. Severe TBI is defined as GCS 3-8. Children are included in the OI group if they sustain a bone fracture, excluding to the skull or face, without any signs of head trauma or brain injury (e.g. nausea/vomiting, headache, loss of consciousness, GCS below 15 at any point). Exclusion criteria: non-English-speaking child or non-English-speaking parents/guardians documented or parent-reported history of previous TBI/concussion requiring overnight hospitalization pre-injury neurological disorder or intellectual disability pre-injury psychiatric disorder requiring hospitalization sensory or motor impairment precluding study measure completion pregnancy at the time of study participation participants are also excluded if at least one biosample is not able to be collected within 7 days of the injury

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| traumatic brain injury<br>Children with traumatic brain injury | |
| orthopedic injury<br>Children with orthopedic injury | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NIH Toolbox Cognition Battery (NIHTB-CB) | The NIHTB-CB is a 30-minute battery of standardized neuropsychological tests administered on an iPad. The NIHTB-CB provides norm-referenced scores for the domains of language, episodic memory, processing speed, working memory, and executive function, as well as an overall cognitive function composite score. Higher T scores indicate better neuropsychological performance. | 6 months post-injury | 
| NIH Toolbox Cognition Battery (NIHTB-CB) | The NIHTB-CB is a 30-minute battery of standardized neuropsychological tests administered on an iPad. The NIHTB-CB provides norm-referenced scores for the domains of language, episodic memory, processing speed, working memory, and executive function, as well as an overall cognitive function composite score. Higher T scores indicate better neuropsychological performance. | 12 months post-injury | 
| Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2) or Preschool Version (BRIEF-P) | To assess everyday executive functioning, parents complete the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2) or Preschool Version (BRIEF-P). Three composite scores are computed for behavioral regulation, emotion regulation, and cognitive regulation, as well as a global executive composite. Higher T scores indicate poorer executive function. | 6 months post-injury | 
| Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2) or Preschool Version (BRIEF-P) | To assess everyday executive functioning, parents complete the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2) or Preschool Version (BRIEF-P). Three composite scores are computed for behavioral regulation, emotion regulation, and cognitive regulation, as well as a global executive composite. Higher T scores indicate poorer executive function. | 12 months post-injury | 
| Strengths and Difficulties Questionnaire | The Strengths and Difficulties Questionnaire (SDQ) measures psychological adjustment. Subscales include Emotional Symptoms, Conduct Problems, Hyperactivity-Inattention, Peer Problems, and Prosocial Behavior. A Total Difficulties score is also provided. Four different versions are administered based on the child's age. Higher raw scores on all scales except for Prosocial Behavior indicate more difficulties; higher raw scores on Prosocial Behavior indicate greater prosocial behavior. | 6 months post-injury | 
| Strengths and Difficulties Questionnaire | The Strengths and Difficulties Questionnaire (SDQ) measures psychological adjustment. Subscales include Emotional Symptoms, Conduct Problems, Hyperactivity-Inattention, Peer Problems, and Prosocial Behavior. A Total Difficulties score is also provided. Four different versions are administered based on the child's age. Higher raw scores on all scales except for Prosocial Behavior indicate more difficulties; higher raw scores on Prosocial Behavior indicate greater prosocial behavior. | 12 months post-injury | 
| Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) | Adaptive functioning is measured using the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3). Parents complete items designed to assess their child's ability to perform day-to-day activities in the domains of Communication, Daily Living, and Socialization. Composite scores are computed for each domain, as well as a general Adaptive Behavior Composite. Higher standard scores indicate higher adaptive functioning. | 6 months post-injury | 
| Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) | Adaptive functioning is measured using the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3). Parents complete items designed to assess their child's ability to perform day-to-day activities in the domains of Communication, Daily Living, and Socialization. Composite scores are computed for each domain, as well as a general Adaptive Behavior Composite. Higher standard scores indicate higher adaptive functioning. | 12 months post-injury | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neurobehavioral outcomes, childhood adversity, biomarkers, traumatic brain injury, rehabilitation, neuropsychology, precision medicine, epigenetic, proteomic, brain-derived neurotrophic factor, recovery, children