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

基本信息

批准号：
10473684
负责人：
Amit Etkin
金额：
$ 44.11万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10473684
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

项目摘要

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) 是一种慢性致残性疾病，目前效果有限其严重性和功能障碍因经常合并的酒精使用障碍而变得更加严重。（AUD），单独使用或与酒精使用结合使用的有效治疗方法也有限。应该在 PTSD 情绪失调的更广泛框架内进行考虑，因为它通常被视为当长期过量饮酒时，一种（通常是适应不良的）应对痛苦情绪的方法。随之而来的是酒精依赖，表现为严重的功能障碍和缺乏这些证据共同表明：前额功能和情绪调节能力下降。调节过度的负面影响是 PTSD+AUD 中饮酒的主要脆弱因素；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 治疗结果的机制决定因素因此，存在紧迫的临床需求。推进 PTSD+AUD 的治疗，通过了解谁可以最有效地实现这一目标对特定治疗的反应最好，以及该治疗的作用机制是什么。建议使用复杂的调节/调解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背景下进行人脑回路功能评估托吡酯与安慰剂相比，有证据表明托吡酯的效用，这有助于促进治疗。抑制性 γ-氨基丁酸 (GABA) 信号传导并拮抗兴奋性谷氨酸信号传导， AUD 的治疗，初步证据表明它对 PTSD+AUD 有用，使其成为一个有希望的目标因此，我们方法的核心是彻底的认知神经科学。评估对一般负面刺激的情绪反应和调节以及对酒精暗示的反应更具体地说（使用功能磁共振成像（fMRI））。使用并发经颅磁在神经生理学水平上对相同脑回路进行边缘映射考虑到托吡酯的药理作用，同时进行 TMS/EEG 是一种有效的方法。这是直接询问其神经生理学行为的理想工具，因为 TMS/EEG 指标不同。对脑回路靶向的兴奋相关和抑制相关的神经生理反应神经刺激，脑电图反应源定位于由研究人员研究的特定皮质结构 fMRI 任务如上所述，并在神经时间尺度上进行研究。