Neuromodulation of Social Cognitive Circuitry in People with Schizophrenia Spectrum Disorders

项目摘要 精神分裂症谱系障碍（SSD）患者（即，情感性精神分裂症 障碍、精神分裂症样障碍）在社会功能方面表现出相当大的损害。 目前的治疗方法效果甚微，而且损伤往往会持续存在。我们最近 一项多中心协作研究增加了关于社会神经生物学的知识， SSD患者的认知（SCog）障碍，识别SCog的神经回路 损伤及其行为和功能相关性。本研究旨在利用 重复经颅磁刺激（rTMS），一种神经调节形式， SSD患者SCog损伤的神经回路。在为期两年的R61阶段， 应用程序，我们将随机分配60人与固态硬盘分为三组：20到传统的形式 的rTMS（即，10 Hz rTMS）; 20到一种更新、更快速的形式，称为间歇性θ波爆发 刺激（iTBS）;和20至假10 Hz rTMS刺激或假iTBS。我们将 确定这些治疗是否可以改变关键SCog大脑的功能连接 通过瞄准被称为背内侧前额叶皮层（DMPFC）的大脑区域来控制神经回路。以来 每个人的大脑解剖和功能概况略有不同，我们将优化 每个个体中脑刺激线圈放置的方向和位置，使用 我们的团队成员和其他人开创的新方法，以最大限度地提高对 大脑功能如果我们发现任何一种形式的主动脑刺激（与假刺激相比）， 以预定的效果改变假设的SCog大脑回路中的功能连接 我们将达到我们的“去/不去标准”，然后将请求允许继续进行 3年R33阶段。在R33阶段，我们将应用脑刺激4周（5 天/周），推进最佳地接合目标的脑刺激模态，以及 对比一下sham。我们将在我们的三个站点随机分配120名SSD用户。我们的首要 结果衡量标准将是SCog在四周结束时的表现，我们的 次要结局指标将是SCog电路中的FC变化。我们将确定这是否 治疗可以改善SSD患者的SCog表现， 伴随着SCog电路FC的变化。我们还将评估SCog在8 以确定大脑刺激的持续效果。总的来说，我们的建议是仿照 直接在NIMH临床试验目标参与框架上，包括关于 测试脑刺激参数（即，rTMS vs. iTBS）和个性化线圈放置， 最佳瞄准我们预计大脑刺激将证明目标参与， 可能改善SSD患者的SCog缺陷。本研究的主要目的是 证明和优化一种新的SCog损伤的治疗方法，我们希望 最终将导致确认疗效的工作，理想情况下， 帮助人们使用SSD的从业人员。

PROJECT SUMMARY People with schizophrenia spectrum disorders (SSDs) (i.e., schizophrenia, schizoaffective disorder, schizophreniform disorder) exhibit considerable impairment in social functioning. Current treatments are minimally effective, and impairments tend to persist. Our recent collaborative multi-center study increased knowledge regarding the neurobiology of social cognitive (SCog) impairment in people with SSDs, identifying the neural circuitry of SCog impairments and their behavioral and functional correlates. The present study aims to use repetitive transcranial magnetic stimulation (rTMS), a form of neuromodulation, to target the neural circuitry of SCog impairments in people with SSDs. In the 2-year R61 phase of this application, we will randomize 60 people with SSDs to three groups: 20 to a conventional form of rTMS (i.e., 10Hz rTMS); 20 to a newer, more rapid form known as intermittent theta burst stimulation (iTBS); and 20 to either sham 10 Hz rTMS stimulation or sham iTBS. We will determine whether these treatments can change the functional connectivity of key SCog brain circuits by targeting a brain region known as the dorsomedial prefrontal cortex (DMPFC). Since each person’s anatomical and functional brain profile is slightly different, we will optimize the orientation and location of the placement of the brain stimulation coils in each individual, using novel approaches pioneered by members of our team and others, to maximize the impact on brain function. If we find that either form of active brain stimulation (compared to sham) we can changes functional connectivity in the hypothesized SCog brain circuit at a predetermined effect size, we will have achieved our ‘Go/No-Go criterion’ and will then request permission to proceed to the 3-year R33 phase. In the R33 phase, we will apply brain stimulation for 4 -weeks (5 days/week), carrying forward the brain stimulation modality which best engaged the target, and compare to sham. Wewill randomize 120 people with an SSD across our three sites. Our primary outcome measure will be SCog performance at the end of the four week period, and our secondary outcome measure will be FC change in SCog circuitry. We will determine if this treatment can lead to improvements in SCog performance in people with SSDs, and accompanying changes in FC of SCog circuitry. We will also evaluate SCog performance at 8 weeks to determine the sustained effect of brain stimulation. Overall, our proposal is modeled directly on the NIMH clinical trials target engagement framework, including specifics regarding testing brain stimulation parameters (i.e., rTMS vs. iTBS) and individualizing coil placement for optimal targeting. We anticipate that brain stimulation will demonstrate target engagement, and potentially ameliorate SCog deficits in people with SSDs. The main goal of the current study is to demonstrate and optimize a novel therapeutic approach for SCog impairment, which we hope will ultimately lead to confirmatory efficacy work, and ideally broader uptake by mental health practitioners helping people with SSDs.