A Circuit Approach to Mechanisms and Predictors of Topiramate Response

总结 创伤后应激障碍（PTSD）是一种慢性致残性疾病，目前有效的治疗方法有限， 治疗。其严重性和功能障碍是复杂的，经常共病酒精使用障碍 (AUD)，其单独或与PTSD组合的有效治疗也有限。酒精的使用可以 在创伤后应激障碍的情绪失调的更广泛的框架内考虑，因为它往往是最初追求的， 一种（通常是不适应的）科普痛苦情绪的方法。如果长期过量饮酒， 酒精依赖可能随之而来，表现为更大的功能障碍和缺乏 前额叶功能和情绪调节。总之，这些证据表明：a）降低了 调节过度的负面影响是PTSD+AUD中酒精使用的主要脆弱性因素;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治疗结果的机制决定因素。因此，临床上迫切需要 推进PTSD+AUD的治疗，这是通过了解谁最有效地完成， 对特定治疗的最佳反应以及治疗的作用机制是什么。这里我们 我建议使用复杂的适度/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的人脑回路功能评估 PTSD+AUD与托吡酯相比。有证据表明托吡酯的效用， 抑制性γ-氨基丁酸（GABA）信号传导，拮抗兴奋性谷氨酸信号传导， 治疗AUD，初步证据表明PTSD+AUD的效用，使其成为治疗AUD的有希望的靶点。 神经机制研究因此，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（使用功能性磁共振成像（fMRI））。这是一个切割的补充- 在神经生理学水平上使用并行经颅磁共振成像对相同脑回路进行边缘映射 刺激和EEG（TMS/EEG）。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。 是直接研究其神经生理作用的理想工具。这是因为TMS/EEG指标不同， 兴奋相关和抑制相关的神经生理反应，以脑回路为靶点， 神经刺激，EEG反应源定位到特定的皮层结构， fMRI任务，并在神经元的时间尺度上进行了研究。

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.