Neural Target Identification for Functional Disability Associated with Alcohol Related Characteristics Among Veterans with Co-occurring Alcohol Use Disorder and Traumatic Brain Injury

酒精使用障碍(AUD)和轻度创伤性脑损伤(MTBI)影响功能能力。AUD出现在UP中 到35%患有创伤性脑损伤的退伍军人。有证据表明，AUD和mTBI(AUD+mTBI)同时出现会导致 脑部功能障碍的恶化，症状表现，并最终导致功能性残疾。酒精- 相关特征根据AUD症状和结果在操作上定义，包括但不限于， 饮酒、饮酒渴求和AUD严重程度。重复经颅磁刺激(RTMS)是 一种非侵入性神经调节治疗，很快将成为全国30个VAS的治疗选择。 使用不同的神经靶点，初步证实了rTMS对AUD和mTBI的初步疗效。 因此，rTMS是治疗AUD+mTBI的一种有前途的治疗方法。本研究的目的是：1)鉴定神经细胞 与酒精相关特征和自我报告的功能相关的靶点(即刺激部位) 2)评估应用于以下项目的高频rTMS方案的初步疗效和可持续性 这些定制的神经靶点相对于常用的左背外侧前额叶皮质(DLPFC)部位。 解决这些目标是迈向我们长期研究目标的重要步骤[定制和 临床实施rTMS治疗]可以改善脑功能，从而实现最佳康复 患有澳元+mTBI的退伍军人。为了达到第一个研究目标，将招募退伍军人并将其分类为 基于结构化访谈、自我报告测量和神经心理学评估的两组中的一组： 1)AUD+mTBI，2)没有mTBI或AUD病史或症状的[退伍军人对照]。与酒精有关的 将通过酒精使用的客观测量、自我报告测量和 结构化面谈。将使用世界卫生组织对自我报告的功能性残疾进行评估 残疾评估表2.0(WHODAS)。神经成像指标将通过多项 模式、功能和结构磁共振成像(MRI)扫描。参与者将完成一份 功能磁共振成像(FMRI)协议，其中将根据查看相关图像来测量大脑激活 酒精，而不是中性的图像。先进的神经成像程序来确定结构 大脑中白质纤维的完整性和大脑网络中的自发活动，这一过程称为休息 还将进行状态功能连接(RsFC)。为了解决第二个研究目标，澳元+mTBI 退伍军人将在一个随机分配的4个地点接受rTMS：3个定制的神经靶点 在本研究中确定，和常用的左DLPFC。澳大利亚+mTBI退伍军人将完成10个安慰剂， 然后在受试者内部设计10个活动的rTMS会话。后续WHODAS评估将在2- 活动后1周、1个月和6个月的rTMS。目标1将确定rTMS治疗的独特神经靶点 AUD+mTBI通过确定哪些多模式神经成像指标与这两项指标关联最强 与酒精相关的特征和功能残疾。目标2将[测试高频治疗的初步疗效 通过定制的神经靶点实施rTMS]治疗患有以下疾病的退伍军人的功能障碍 AUD+mTBI。AIM 3将评估rTMS对患有以下疾病的退伍军人功能残疾的可持续性影响 AUD+mTBI。我们推测，对于患有AUD+mTBI的退伍军人来说，AUD的神经底物与 功能障碍，这些底物的神经调节将与功能障碍的增加有关 残疾。我们的创新方法代表着神经康复领域的进步，因为 在rTMS初步疗效之前，将使用多模式神经成像系统地定义神经靶点 和可持续性测试。这些步骤是为以下人群定制rTMS治疗所必需的 具有共同疾病和独特医疗保健需求的退伍军人。因此，这项研究的结果将 用AUD+mTBI优化退伍军人的功能。

Alcohol use disorder (AUD) and mild traumatic brain injury (mTBI) impact functional abilities. AUD occurs in up to 35% of Veterans with mTBI. Evidence suggests that co-occurrence of AUD and mTBI (AUD+mTBI) leads to an exacerbation of brain dysfunction, symptom manifestation, and ultimately, functional disability. Alcohol- related characteristics are operationally defined per AUD symptoms and outcomes including, but not limited to, alcohol consumption, alcohol craving, and AUD severity. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulatory treatment that will soon be a treatment option at 30 VAs nationwide. Preliminary rTMS efficacy is demonstrated for AUD alone and mTBI alone using a variety of neural targets. rTMS is, thus, a promising treatment for AUD+mTBI. The objectives of this study are to 1) identify neural targets (i.e. site of stimulation) associated with both alcohol-related characteristics and self-reported functional disability, and 2) assess preliminary efficacy and sustainability of a high frequency rTMS protocol applied to these customized neural targets relative to the commonly used left dorsolateral prefrontal cortex (DLPFC) site. Addressing these objectives are essential steps towards our long-term research goal [to customize and clinically implement a rTMS treatment] that can improve brain function resulting in optimal recovery for Veterans with AUD+mTBI. To address the first study objective, Veterans will be recruited and classified into one of two groups based on structured-interviews, self-report measures, and neuropsychological assessments: 1) AUD+mTBI, and 2) [Veteran controls] without a history or symptoms of mTBI or AUD. Alcohol-related characteristics will be assessed through objective measures of alcohol use, self-report measures, and structured interviews. Self-reported functional disability will be assessed using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS). Neuroimaging metrics will be assessed through a multi- modal, functional and structural Magnetic Resonance Imaging (MRI) scan. Participants will complete a functional MRI (fMRI) protocol where brain activation will be measured in response to viewing images related to alcohol, compared to neutral images. Advanced neuroimaging procedures to determine the structural integrity of white matter fibers in the brain and spontaneous activity in brain networks, a process called resting state functional connectivity (rsFC), will also be conducted. To address the second study objective, AUD+mTBI Veterans will receive rTMS at one site randomly assigned from a set of 4 sites: 3 customized neural targets identified in this study, and the commonly used left DLPFC. AUD+mTBI Veterans will complete 10 PLACEBO, then 10 ACTIVE rTMS sessions in a within-subjects design. Follow-up WHODAS assessments will occur at 2- weeks, 1-month and 6-months post-ACTIVE rTMS. Aim 1 will identify unique neural targets for rTMS to treat AUD+mTBI by determining which multi-modal neuroimaging metrics are most strongly associated with both alcohol-related characteristics and functional disability. Aim 2 will [test preliminary efficacy of high-frequency rTMS administered over the customized neural targets] to treat functional disability among Veterans with AUD+mTBI. Aim 3 will assess sustainability of rTMS effects on functional disability for Veterans with AUD+mTBI. We hypothesize that for Veterans with AUD+mTBI, there are neural substrates of AUD related to functional disability, and that neuromodulation of these substrates will be related to gains in functional disability. Our innovative approach represents an advancement in the field of neurorehabilitation because a neural target will be systematically defined, using multi-modal neuroimaging, prior to preliminary rTMS efficacy and sustainability testing. These steps are necessary to customize rTMS treatment for a population of Veterans with co-occurring conditions and unique health care needs. Thus, the outcomes of this research will optimize function for Veterans with AUD+mTBI.