A Circuit Approach to Mechanisms and Predictors of Topiramate Response

托吡酯反应机制和预测因子的电路方法

• 批准号: 10237286
• 负责人: Amit Etkin
• 金额: $ 43.96万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10237286
• 关键词: Afghanistan; Aftercare; Alcohol consumption; Alcohol dependence; Alcohols; Amygdaloid structure; Award; Biological Markers; Biology; Brain; Butyric Acids; Chronic; Clinical; Complement; Disease; Distress; Electroencephalography; Emotional; Emotions; Functional Magnetic Resonance Imaging; Genotype; Glutamates; Heart; Human; Individual; Individual Differences; Intervention; Iraq; Lateral; Magnetic Resonance Spectroscopy; Measures; Mediating; Mediation; Mediator of activation protein; Neurons; Neurosciences; Outcome; Patients; Pharmacologic Actions; Placebos; Post-Traumatic Stress Disorders; Prefrontal Cortex; Psychotherapy; Randomized Clinical Trials; Regulation; Rest; Severities; Signal Transduction; Stimulus; Structure; Symptoms; Task Performances; Testing; Transcranial magnetic stimulation; Treatment outcome; United States National Institutes of Health; Veterans; Waiting Lists; Work; alcohol abuse therapy; alcohol comorbidity; alcohol cue; alcohol use disorder; arm; cognitive neuroscience; cognitive task; comorbidity; drinking; effective therapy; emotion dysregulation; emotion regulation; executive function; experience; functional disability; gamma-Aminobutyric Acid; indexing; innovation; multimodality; negative affect; neural circuit; neuroimaging; neurophysiology; personalized medicine; response; source localization; tool; topiramate; treatment comparison

SUMMARY Post-traumatic stress disorder (PTSD) is a chronic and disabling disorder with currently limited effective treatments. Its severity and functional impairment is compounded by frequently comorbid alcohol use disorder (AUD), which also has limited effective treatments in isolation or in combination with PTSD. Alcohol use can be considered within the broader framework of emotion dysregulation in PTSD, as it is often pursued initially as an (often maladaptive) way to cope with distressing emotions. When alcohol use is prolonged and excessive, alcohol dependence can ensue, manifesting in substantially greater functional impairment and deficiency of prefrontal function and emotion regulation. Together, these lines of evidence suggest that: a) reduced ability to regulate excessive negative affect presents a primary vulnerability factor for alcohol use in PTSD+AUD; and b) individual differences in prefrontal-amygdala neural circuit interactions may be important predictors and/or mechanistic determinants of outcomes for PTSD + AUD treatments. As such, there is a pressing clinical need to advance the treatment of PTSD+AUD, which is most efficiently accomplished by understanding who responds best to a given treatment and what are the mechanisms by which that treatment works. Here we propose to answer these questions using a sophisticated moderation/mediation framework and multi-modal human brain circuit functional assessments in the context of a randomized clinical trial comparing the treatment of PTSD+AUD with topiramate versus placebo. Evidence exists for the utility of topiramate, which facilitates inhibitory γ-amino-butyric acid (GABA) signaling and antagonizes excitatory glutamatergric signaling, in the treatment of AUD, with initial evidence of utility for PTSD+AUD, making it a promising target for neuromechanistic study. Therefore, at the heart of our approach is a thorough cognitive neuroscience assessment of emotional reactivity and regulation to general negative stimuli and reactivity to alcohol cues more specifically (using functional magnetic resonance imaging (fMRI)). This is complemented by a cutting- edge mapping of the same brain circuits at the neurophysiological level using concurrent transcranial magnetic stimulation and EEG (TMS/EEG). Given the pharmacological action of topiramate, concurrent TMS/EEG is an ideal tool for direct interrogation of its neurophysiological actions. This is because TMS/EEG indexes distinct excitation-related and inhibition-related neurophysiological responses to brain circuit-targeted targeted neurostimulation, with EEG responses source-localized to the specific cortical structures investigated by the fMRI tasks above and investigated at a neuronal temporal scale.

概括 创伤后应激障碍（PTSD）是一种慢性和残疾疾病，目前有效有效 治疗。它的严重程度和功能障碍经常通过合并性酒精障碍而加重 （AUD），它在隔离或与PTSD结合使用的有效治疗方面也有限。饮酒可以 在PTSD中情绪失调的更广泛的框架内被考虑，因为它通常被认为是 一种（通常是适应不良的）方式来应对令人痛苦的情绪。当饮酒延长且超越 可以随之而来的酒精依赖性，表现出更大的功能障碍和缺陷 前额叶功能和情绪调节。这些证据共同表明：a）降低的能力 调节过度负面影响是PTSD+AUD中酒精使用的主要脆弱因素；和b） 前额叶 - 杏仁核神经回路相互作用的个体差异可能是重要的预测因子和/或 PTSD + AUD处理结果的机械决定者。因此，有紧迫的临床需求 促进PTSD+AUD的处理，这是通过了解谁而最有效地完成的 对给定治疗的反应最佳，该治疗方法是什么机制。我们在这里 提议使用复杂的适度/中介框架和多模式来回答这些问题 在比较治疗的随机临床试验的背景下，人脑电路的功能评估 具有托吡酯与安慰剂的PTSD+aud的作品。存在托吡酯的效用的证据，哪些设施 抑制性γ-氨基丁酸（GABA）信号传导，并在兴奋性谷氨酸甲状腺毒性信号中拮抗 AUD的处理，具有PTSD+AUD实用性的初始证据，使其成为有望的目标 神经力学研究。因此，我们方法的核心是彻底的认知神经科学 评估情绪反应性和对一般负面刺激和对酒精提示的反应性的调节 更具体地说（使用功能磁共振成像（fMRI））。这是由一个加油完成的 使用并发的trancranial磁 刺激和脑电图（TMS/EEG）。鉴于Topramate的药物作用，并发TMS/EEG是 直接询问其神经生理作用的理想工具。这是因为TMS/EEG索引不同 兴奋相关和抑制相关的神经生理学对脑电路的靶向靶向反应 神经刺激，脑电图反应源源定位于由该特定皮质结构所研究的特定皮质结构 上面的fMRI任务并按照神经元临时量表进行了研究。