Accelerated Neuromodulation of Prefrontal Circuitry during Clozapine Treatment

项目总结 精神分裂症在世界范围内与严重的发病率和死亡率有关，主要是由于贫困 由认知障碍驱动的功能结果。难治性精神分裂症(TRS)，一种更严重的 综合征的表现，与较差的功能结局和不成比例的高 个人和社会经济负担。治疗方案通常包括心理社会干预和 氯氮平(CLZ)，它仍然是唯一显示出独特疗效的药物 TRS。然而，即使在CLZ取得成功后，限制日常社交活动的认知缺陷和全球障碍 而职业功能仍然存在于大多数人身上。因此，迫切需要更多的战略。 这解决了与TRS相关的认知缺陷和生物学复杂性。核心认知缺陷 工作记忆(WM)通常与精神分裂症的功能结果有关。我们最近的工作，重点是 纵向CLZ治疗TRS，显示较高的WM表现与较大的后遗症相关。 背外侧前额叶皮质与胆碱能基础的治疗反相关 前脑(BF)。关键是，这个功能回路与经颅相关的连通性发现重叠。 磁刺激治疗重度抑郁障碍。最近的工作提出了一种更有效的方法来治疗 利用基于连接性的加速间歇性theta爆发的经颅磁刺激 治疗难治性抑郁症的刺激(ITBS)方案。采用类似方法的研究表明， 刺激DLPFC可提高WM成绩。鉴于TRS迫切需要加强WM，以及 在与CLZ合作的基础上，我们将采用这种加速的ITBS方法来定位DPLFC-BF功能 连通性。在受试者内、随机、交叉设计中，患有TRS的个体接受CLZ治疗 将完成加速的ITBS和虚假刺激的疗程。参与者将接受功能磁共振扫描 在休息时、在基线时以及在ITBS和假刺激后立即执行WM任务时。 我们将检查加速的ITBS是否导致：(1)更大的DLPFC-BF反相关性，和(2)增加 WM的激活和性能。我们还将探索CLZ/去甲氯氮平的比率，这是 胆碱能对治疗的贡献，既与连接性有关，也与WM激活或以下表现有关 加快了ITBS的交付。与NIMH战略计划的目标一致，我们的提案将收集关键的 初步数据将为TRS中以WM增强为重点的更大规模的机械性试验奠定基础 在CLZ强大的药理环境中。

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.