The neural correlates of the effects of psilocybin in OCD: randomized controlled study

项目摘要/摘要 申请K23以患者为导向的研究事业发展奖将提供 申请人，临床神经学家，在翻译神经科学方面有广泛的背景，受过高级培训， 有影响力的指导性研究体验，保护研究时间。我的长期目标是成为一名 独立的内科医生-科学家，专注于确定神经生物学相关因素和预测因素 新疗法的疗效，尤其是那些具有急性效应的疗法。通过应用这些见解，我的目标是 制定针对情绪和焦虑症的个体化治疗策略。为了实现这些目标，我提议 培训计划，以获得转化性临床调查和神经成像方法方面的专业知识。这将是 通过综合职业发展计划实现，由具有毒品专业知识的指导团队监督 发展、神经成像和神经生物学。 这项拟议的研究将首次检验裸盖菇素在强迫症患者中的作用的神经相关性。 许多最近的研究报告了急性的，有时是持续的临床 在情绪和焦虑症、成瘾和强迫症中单剂量服用裸盖菇素后受益。 急性中毒消退后很久仍有临床效果，这意味着脑部发生了持久的变化，但 这些持久的治疗效果背后的机制仍然知之甚少。我们建议使用 用于探测神经元的静息功能磁共振成像数据的连通性分析 在独立资助的一项研究中，强迫症患者单次服用裸盖菇素后临床变化的相关性 我们在耶鲁大学刚刚开始的随机、安慰剂对照的试验有效性和耐受性试验。一致 在实验治疗学的框架下，我们在这里检验裸盖菇素假想的大脑效应； 虽然我们预测这些将与症状改善有关，但我们的分析将提供信息 在这项对照试验中，裸盖菇素是否证明具有有益的临床效果。我们关注的是违约问题 模式网络(DMN)，已知参与内部状态评估的网络，在OCD中中断，以及 在其他种群中受到裸盖菇素的影响。我们假设裸盖菇素将导致增加(即 强迫症患者DMN内功能连接正常化，这将与任何临床变化相关(AIM 1)。预计基线DMN连接可预测随后的神经和临床变化(目标2)。最后， 我们将检查皮质纹状体回路内的连通性(目标3)；而这一回路以前从未被 在裸盖菇素的背景下进行研究，它与强迫症密切相关。 这项工作将阐明持久的临床和行为效应的神经生物学基础。 裸盖菇素在神经精神疾病中的作用及其对其他速效药理学的潜在影响 干预措施。它将同时为我的训练提供一个理想的工具，因为我正在朝着 在临床神经科学领域的独立性和有影响力的研究事业的发展。 强迫症(OCD)。

PROJECT SUMMARY/ABSTRACT This application for a K23 mentored patient-oriented research career development award will provide the applicant, a clinical neuroscientist with a broad background in translational neuroscience, with advanced training, an impactful mentored research experience, and protected research time. My long-term goal is to become an independent physician-scientist, focused on identifying neurobiological correlates and predictors of the therapeutic effects of novel treatments, especially those with acute effects. By applying such insights, I aim to develop individualized treatment strategies for mood and anxiety disorders. In line with these goals, I propose a training plan to gain expertise in translational clinical investigations and neuroimaging methods. This will be achieved through an integrated career development plan, overseen by a mentoring team with expertise in drug development, neuroimaging, and neurobiology. This proposed study will be the first to examine the neural correlates of the effects of psilocybin in obsessive- Numerous recent studies have reported acute, and sometimes persisting, clinical benefit after the administration of a single dose of psilocybin in mood and anxiety disorders, addiction, and OCD. The persistence of clinical effects long after acute intoxication has worn off implies lasting brain changes, but the mechanisms underlying these lasting therapeutic effects remain poorly understood. We propose to use connectivity analysis of resting-state functional magnetic resonance imaging (rs-fMRI) data to probe the neuronal correlates of clinical change after a single dose of psilocybin in OCD, in the context of an independently funded randomized, placebo-controlled pilot efficacy and tolerability trial that we have just begun at Yale. Consistent with the experimental therapeutics framework, we here examine the hypothesized brain effects of psilocybin; while we predict that these will be associated with symptom improvement, our analyses will be informative whether or not psilocybin proves to have a beneficial clinical effect in this controlled trial. We focus on the default mode network (DMN), a network known to be involved in the evaluation of internal states, disrupted in OCD, and affected by psilocybin in other populations. We hypothesize that psilocybin will result in increased (i.e. normalized) intra-DMN functional connectivity in OCD, and that this will correlate with any clinical change (Aim 1). Baseline DMN connectivity is anticipated to predict subsequent neural and clinical change (Aim 2). Finally, we will examine connectivity within the corticostriatal circuitry (Aim 3); while this circuitry has not previously been investigated in the context of psilocybin, it is robustly implicated in OCD. This work will shed light on the neurobiological underpinnings of lasting clinical and behavioral effects effects of psilocybin in neuropsychiatric disease, with potential implications for other rapid-acting pharmacological interventions. It will simultaneously provide an ideal vehicle for my training as I progress towards increasing independence and the development of an impactful research career in clinical neuroscience. compulsive disorder (OCD).