Evaluating Neural Architecture as a Novel Biomarker for TMS Efficacy in AUD

项目摘要 酒精使用障碍（AUD）目前被定位为全球可预防死亡的第三大原因 美国，每年造成88，000人死亡。2019年，与以下疾病相关的医疗护理费用总额 澳元超过2240亿美元。AUD治疗工作的一个共同目标是防止复发饮酒。 虽然有几种药物治疗方法，但对这些治疗的依从性很低， 大约60%的参与者在6个月内复发。此外，这些治疗 以相对全局的方式调节大脑。来自AUD患者神经影像学研究的证据表明， 额叶-纹状体神经回路对酒精提示的反应活性升高， 预测复发。因此，有一个新兴的兴趣，在开发新的，神经回路特异性治疗 改善AUD治疗结果的工具。经颅磁刺激（TMS）是一种非- 侵入性神经回路专用工具通过电磁感应，可以应用TMS的重复脉冲 到MPFC以改变刺激部位的神经活动，并且可以沿着沿着完整的白色物质束行进， 改变下游连接（如纹状体）的神经活动。然而，众所周知， 患有AUD的人遭受灰质体积的广泛减少（影响刺激部位）， 白色物质完整性降低（影响MPFC和纹状体之间的通道）。的首要目标 本F31研究提案旨在确定MPFC中灰质体积的影响（目标1）， MPFC和纹状体之间的白色物质完整性（Aim 2）对MPFC中TMS相关变化的影响- 纹状体对酒精的反应此外，该提案计划将目标1和2与临床 AUD的生物标志物，如性别和饮酒严重程度，以评估这些因素的相对贡献 在酒精线索诱导的MPFC-纹状体活性的TMS相关变化中。这一建议得到了培训的补充 包括4个领域的计划：神经影像学分析、科学交流、AUD的临床观点，以及 多元统计这个为期2年的F31奖学金将通过利用我们的现有数据集进行分析。 实验室F31提案的母临床试验招募了50名寻求治疗的AUD患者， 在基线时接受MRI扫描，然后进行10天的真实的或假TMS，然后在治疗后进行MRI扫描， 治疗后1个月和治疗后2个月。每一次MRI扫描都包括一个高分辨率的解剖结构， 成像（Aim 1）、弥散峰度成像（Aim 2）和功能性MRI任务来测量酒精提示诱导的 MPFC-纹状体回路中的功能连接。将使用最先进的方法来分析数据 提出了一种基于体素的形态测量方法，包括：基于体素的形态测量、电场建模、扩散峰度 成像、功能连接分析和多元统计。候选人将纳入指导 来自神经影像学和AUD专家（Hanlon和詹森博士），以评估这些目标。

Project Summary Alcohol Use Disorders (AUDs) are currently positioned as the 3rd leading cause of preventable death in the United States, contributing to 88,000 deaths per year. In 2019, total allied costs of medical care associated with AUD exceeded $224 billion. A common goal among treatment efforts in AUD is to prevent relapse to drinking. Although several pharmacological treatments are available, adherence to these treatments is low and approximately 60% of individuals who engage in them relapse within 6 months. Further, these treatments modulate the brain in a relatively global fashion. Evidence from neuroimaging studies of AUD patients has shown that fronto-striatal neural-circuitry shows elevated activity in response to alcohol cues which may subsequently predict relapse. Thus, there is an emerging interest in developing novel, neural-circuit specific therapeutic tools to enhance AUD treatment outcomes. Transcranial magnetic stimulation (TMS) is one such non- invasive, neural-circuit specific tool. Through electromagnetic induction, repetitive pulses of TMS can be applied to the MPFC to change neural activity at the site of stimulation and can travel along intact white matter tracts to change neural activity in downstream connections such as the striatum. However, it is well known that individuals with AUD suffer from widespread reductions in gray matter volume (impacting the site of stimulation) as well as reductions in white matter integrity (impacting the tract between the MPFC and striatum). The primary goal of this F31 research proposal is to determine the influence of gray matter volume in the MPFC (Aim 1) and white matter integrity between the MPFC and striatum (Aim 2) on TMS associated change in MPFC- striatal activity in response to alcohol cues. Further, this proposal plans to integrate Aims 1 & 2 with clinical biomarkers for AUD such as gender and drinking severity to evaluate the relative contributions of these factors in TMS related change in alcohol cue-induced MPFC-striatal activity. This proposal is complimented by a training plan that includes 4 domains: neuroimaging analysis, scientific communication, clinical perspective of AUD, and multivariate statistics. This 2-year F31 fellowship will be analyzed by leveraging an existing data set from our laboratory. The parent clinical trial for this F31 proposal recruited 50 treatment-seeking individuals with AUD to receive MRI scans at baseline, followed by 10 days of real or sham TMS, followed by MRI scans after treatment, 1 month after treatment, and 2 months after treatment. Each MRI scan consisted of a high-resolution anatomical image (Aim 1), diffusion kurtosis imaging (Aim 2) and a functional MRI task to measure alcohol cue-induced functional connectivity in the MPFC-striatal circuit. Cutting-edge methodologies will be used to analyze the data presented in this proposal, including: voxel-based morphometry, electrical field modeling, diffusion kurtosis imaging, functional connectivity analysis, and multivariate statistics. The candidate will incorporate guidance from experts in neuroimaging and AUD (Drs. Hanlon and Jensen) to evaluate these aims.