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

项目概要/摘要 拟议研究的总体目标是确定儿童轻度神经行为的长期后果 创伤性脑损伤（mTBI）对发育中的大脑进行评估，并使用以下方法检查其对成瘾风险的贡献： 严格的 cotwin 控制设计、纵向随访以及多模式和创新的神经影像工具和 神经行为评估。 mTBI 在儿童期或青春期持续，即持续脑损伤的时期 发展和重组，由于其流行率高、持续时间长，已成为重大公共卫生问题。 与成瘾行为风险增加相关的神经行为后果。然而，进展 一些重要的因素阻碍了对 mTBI 的长期后遗症及其在成瘾中的作用的理解 方法论挑战：a) 病例对照研究是相关的，无法区分后果 先前存在的神经认知缺陷可能会增加 TBI 的风险； b) 匹配案例和 由于大脑结构的巨大（并且很大程度上是可遗传的）个体差异，控制是非常有问题的。 脑损伤的功能和异质性； c) 单一的神经影像学模式只能提供有限的洞察 mTBI 的后果； d) 在横断面研究中，mTBI 的影响可能会与 的物质使用。拟议的研究将结合使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：（i）双孪生控制设计，将为 mTBI 病例 - 无 TBI 病史的同卵双胞胎，(ii) 多模式神经影像评估 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) 对物质使用行为变化的纵向跟踪评估（开始、经常使用、物质使用 紊乱症状）。评估将包括结构、功能和扩散 MRI、定量梯度 回顾回声 (qGRE) MRI，一种对皮质细胞微结构、大脑敏感的新型神经成像技术 神经生理学，包括静息态脑电图和事件相关脑电位 (ERP)，这些方法 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： 目标 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 不一致的同卵对、终生患有 mTBI 病史的双胞胎将表现出大脑结构和 与没有 mTBI 病史的双胞胎相比，他们的功能和神经心理表现缺陷；目标 2：横断面和前瞻性地确定 mTBI 是否与高风险相关 成瘾行为。更好地理解持久神经行为的机制 儿童和青少年 mTBI 导致成瘾风险的后果将有助于更多人的发展 有效的治疗和康复方法，以及预防药物使用和滥用以及精神疾病 有 mTBI 病史的青少年患病。

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.