Accelerated Neuromodulation of Prefrontal Circuitry during Clozapine Treatment

氯氮平治疗期间前额叶回路的加速神经调节

• 批准号: 10726660
• 负责人: Deepak K Sarpal
• 金额: $ 42.07万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10726660
• 关键词: Acceleration; Address; Adopted; Affect; Aftercare; Antipsychotic Agents; Biological; Caring; Clinical; Clinical Trials; Clozapine; Cognition; Cognitive; Cognitive deficits; Coupled; Crossover Design; Data; Disease; Dose; Economic Burden; Foundations; Functional Magnetic Resonance Imaging; Future; Goals; Impaired cognition; Impairment; Individual; Intervention; Link; Major Depressive Disorder; Methods; Morbidity - disease rate; Muscarinics; National Institute of Mental Health; Neural Pathways; Neurocognition; Neurocognitive; Neuronal Plasticity; Participant; Performance; Pharmacology; Physiologic pulse; Plasma; Positioning Attribute; Prefrontal Cortex; Psychopharmacology; Psychoses; Randomized; Research; Research Infrastructure; Resistance; Rest; Scanning; Schizophrenia; Short-Term Memory; Strategic Planning; Syndrome; System; Testing; Transcranial magnetic stimulation; Treatment Efficacy; Treatment Protocols; Treatment outcome; Vocation; Work; basal forebrain; burden of illness; cholinergic; cingulate cortex; clinical efficacy; cognitive benefits; cohort; daily functioning; economic cost; follow-up; functional MRI scan; functional outcomes; healthy volunteer; mortality; neural; neuroimaging; neuromechanism; neuroregulation; novel; optimal treatments; performance tests; pharmacologic; programs; psychosocial; social; societal costs; socioeconomics; success; treatment optimization; treatment strategy; treatment trial; treatment-resistant depression

PROJECT SUMMARY Schizophrenia is associated with significant morbidity and mortality across the world, largely due to poor functional outcomes driven by cognitive impairments. Treatment-resistant schizophrenia (TRS), a more severe manifestation of the syndrome, is associated with worse functional outcomes and disproportionately higher individual and socioeconomic burden. Treatment options typically consist of psychosocial interventions and clozapine (CLZ), which remains the sole pharmacologic agent that has demonstrated a unique efficacy for TRS. However, even after success with CLZ, the cognitive deficits and global impairments that limit daily social and vocational functioning remain in most individuals. Thus, there is an urgent need for additional strategies that address the cognitive deficits and the biological complexity associated with TRS. A core cognitive deficit often linked with functional outcomes in schizophrenia is working memory (WM). Our recent work, focused on longitudinal CLZ treatment for TRS, showed that higher WM performance correlates with a greater post- treatment anticorrelation between the dorsolateral prefrontal cortex (DLPFC) and the cholinergic basal forebrain (BF). Critically, this functional circuit overlaps with connectivity findings associated with transcranial magnetic stimulation for major depressive disorder. Recent work has advanced a more efficacious method for transcranial magnetic stimulation that utilizes a connectivity-based, accelerated intermittent theta burst stimulation (iTBS) protocol for treatment-resistant depression. Studies with similar methods suggest that DLPFC stimulation may enhance WM performance. Given the crucial need for WM enhancement in TRS, and based on our work with CLZ, we will adopt this accelerated iTBS method to target DPLFC-BF functional connectivity. In a within-subject, randomized, crossover design, individuals with TRS receiving CLZ treatment will complete sessions of both accelerated iTBS and sham stimulation. Participants will undergo fMRI scanning at rest and while performing a WM task at baseline and immediately after both iTBS and sham stimulation. We will examine whether accelerated iTBS results in: (1) greater DLPFC-BF anticorrelation, and (2) increased WM activation and performance. We will also explore whether CLZ/norclozapine ratios, which characterize cholinergic contributions to treatment, relate both to connectivity and WM activation or performance following accelerated iTBS delivery. Consistent with goals of the NIMH Strategic Plan, our proposal will collect critical preliminary data that will lay the foundation for a larger mechanistic trial focused on WM enhancement in TRS within CLZ’s robust pharmacologic setting.

项目摘要 精神分裂症与全球的发病率和死亡率显着相关，主要是由于较差 认知障碍驱动的功能结果。耐治疗精神分裂症（TRS），更严重 该综合征的表现与功能较差的结果相关，并且不成比例地较高 个人和社会经济负担。治疗方案通常包括社会心理干预措施和 氯氮平（CLZ），它仍然是唯一的药物，它证明了独特的效率 tr。但是，即使在CLZ成功之后，认知定义了限制日常社会的全球障碍 在大多数人中，发布功能仍然存在。那迫切需要其他策略 解决了与TRS相关的认知定义和生物复杂性。核心认知定义 通常与精神分裂症的功能结果有关的是工作记忆（WM）。我们最近的工作着重于 TRS的纵向CLZ治疗表明，较高的WM性能与较大的后期相关 治疗背外侧前额叶皮层（DLPFC）与胆碱能碱基之间的抗相关性 前脑（BF）。至关重要的是，该功能电路与与经颅相关的连通性发现重叠 主要抑郁症的磁刺激。最近的工作提出了一种更有效的方法 使用基于连通性的，加速的间歇性theta爆发的经颅磁刺激 抗治疗抑郁症的刺激（ITB）方案。具有类似方法的研究表明 DLPFC模拟可以增强WM性能。鉴于对TRS的WM提高至关重要，并且 根据我们与CLZ的工作，我们将采用这种加速的ITB方法来靶向DPLFC-BF功能 连接性。在受试者内，随机，分频器设计中，接受CLZ处理的人 将完成加速ITB和假刺激的会议。参与者将接受fMRI扫描 在基线和ITB和假刺激后立即执行WM任务时，在休息和执行WM任务时。 我们将检查加速ITB是否会导致：（1）较大的DLPFC-BF抗相关性，（2）增加 WM激活和性能。我们还将探索CLZ/NORCOLOZAPINE比率是否为特征 胆碱能对治疗的贡献，与连通性和WM激活或性能有关 加速ITB的交付。与NIMH战略计划的目标一致，我们的建议将收集关键 初步数据将为大型机械试验奠定基础，该试验的重点是TRS的WM增强 在CLZ强大的药学环境中。