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 ch...