Neurobehavioral consequences of Mild Traumatic Brain Injury and addiction risk: a cotwin-control study

项目概要/摘要 这项研究的总体目标是确定儿童期轻度抑郁症的长期神经行为后果。 创伤性脑损伤（mTBI）的大脑发育，并检查其贡献成瘾风险使用 严格的双对照设计，纵向随访，多模式和创新的神经成像工具， 神经行为评估在儿童期或青春期持续的mTBI，持续的大脑 发展和重组，是一个重大的公共卫生问题，由于其高流行率和持久性 与成瘾行为风险增加相关的神经行为后果。然而， 理解mTBI的长期后遗症及其在成瘾中的作用受到许多重要因素的阻碍， 方法上的挑战：a）病例对照研究是相关的，无法区分结果 来自预先存在的神经认知缺陷的TBI可能增加TBI的风险; B）匹配病例，以及 由于大脑结构的个体差异性很大（并且很大程度上是遗传的）， 脑损伤的功能和异质性; c）单一的神经成像方式仅提供有限的洞察力， mTBI的后果; d）在横断面研究中，mTBI的影响可能与 物质使用。拟议的研究将利用以下方法来解决这些阻碍进展的关键障碍： 严格和创新的方法：（一）共同孪生控制设计，将提供最好的控制， mTBI病例-无TBI病史的同卵双胞胎，（ii）多模式神经成像评估 利用MRI的高空间分辨率和脑电生理学的高时间分辨率，以及（iii） 对物质使用行为（开始、经常使用、物质使用）变化的纵向随访评估 疾病症状）。评估将包括结构、功能和弥散MRI，定量梯度 回顾回波（qGRE）MRI，一种对皮层细胞微结构敏感的新型神经成像技术， 包括静息状态EEG和事件相关脑电位（ERP）的神经生理学方法， 对神经元动力学的异常定时和同步敏感。将追求以下具体目标： 目的1：确定青春期早期mTBI的长期后果，并将其与先前存在的后果区分开来。 使用cotwin控制设计，与mTBI风险潜在相关的因素。我们假设，在mTBI中- 不一致的单卵双胞胎，具有mTBI终身史的双胞胎将显示脑结构的改变， 与无mTBI病史的双生子相比，神经心理学表现的功能和缺陷;目的 2：确定mTBI是否与以下风险升高相关：横断面和前瞻性 成瘾行为更好地理解长期神经行为的机制 儿童和青少年mTBI的后果有助于成瘾风险将告知更多的发展 有效的治疗和康复方法，以及预防药物使用和滥用以及 有mTBI病史的年轻人的疾病。

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.