Project Summary/Abstract The overall goal of the proposed study is to identify long-term neurobehavioral consequences of childhood mild traumatic brain injury (mTBI) for the developing brain and examine their contribution to addiction risk using a rigorous cotwin-control design, longitudinal follow-up, and multimodal and innovative neuroimaging tools and neurobehavioral assessments. mTBI sustained during childhood or adolescence, periods of continuing brain development and reorganization, is a major public health problem due to its high prevalence and long-lasting neurobehavioral consequences associated with increased risk for addictive behaviors. However, progress in understanding long-term sequelae of mTBI and their role in addiction is hindered by a number of significant methodological challenges: a) case-control studies are correlative and do not allow to distinguish consequences of TBI from pre-existing neurocognitive deficits potentially increasing the risk for TBI; b) matching cases and controls is very problematic due to substantial (and largely heritable) individual variability in brain structure and function and heterogeneity of brain damage; c) single neuroimaging modalities provide only a limited insight into the consequences of mTBI; d) in cross-sectional studies, the effects of mTBI may be confounded with the effects of substance use. The proposed study will address these critical barriers to progress using a combination of rigorous and innovative approaches: (i) the co-twin control design that will provide the best-possible controls for mTBI cases - their monozygotic co-twins without TBI history, (ii) multimodal neuroimaging assessments leveraging high spatial resolution of MRI and high temporal resolution of brain electrophysiology, and (iii) a longitudinal follow-up assessment of changes in substance use behaviors (onset, regular use, substance use disorder symptoms). Assessment will include structural, functional, and diffusion MRI, quantitative Gradient Recalled Echo (qGRE) MRI, a novel neuroimaging technique sensitive to cortical cellular microstructure, brain neurophysiology including resting-state EEG, and event-related brain potentials (ERP), methods that are sensitive to abnormal timing and synchrony of neuronal dynamics. The following Specific Aims will be pursued: Aim 1: To identify long-term consequences of mTBI in early adolescence and distinguish them from pre-existing factors potentially associated with risk for mTBI using a cotwin control design. We hypothesize that, in mTBI- discordant monozygotic pairs, twins with lifetime history of mTBI will show alterations in brain structure and function and deficits in neuropsychological performance compared with their cotwins without mTBI history; Aim 2: To determine, both cross-sectionally and prospectively, whether mTBI is associated with elevated risk for addictive behaviors. A better understanding of the mechanisms by which long-lasting neurobehavioral consequences of childhood and adolescent mTBI contribute to addiction risk will inform the development of more efficient treatment and rehabilitation approaches, as well as prevention of substance use and abuse and mental illness in youth with a history of mTBI.

PROJECT NARRATIVE Mild traumatic brain injury (mTBI) is highly prevalent and can potentially have long-lasting consequences for the brain, cognitive function, and behavior, including elevated risk for substance abuse and psychopathology. In this study, we will use a powerful and rigorous cotwin control approach to identify causal effects of TBI by comparing twins with mTBI history with their identical cotwins who never had a TBI. A better understanding of long-lasting consequences of childhood and adolescent mTBI will promote the development of more efficient treatment and rehabilitation efforts, as well as prevention of substance abuse and psychopathology frequently associated with mTBI history.