Enhancing prefrontal oscillatory activity and working memory performance with noninvasive brain stimulation in early-course schizophrenia

通过无创脑刺激治疗早期精神分裂症，增强前额叶振荡活动和工作记忆表现

• 批准号: 10483147
• 负责人: Fabio Ferrarelli
• 金额: $ 68.04万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-07 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10483147
• 关键词: Acute; Affect; Assessment tool; Attention; Biological Markers; Brain; Chronic; Chronic Schizophrenia; Conscious; Disease; Dose; Economic Burden; Economics; Electroencephalography; Electrophysiology (science); Frequencies; Functional disorder; Future; Goals; Impaired cognition; Impairment; Individual; Intervention; Measures; Memory; Memory impairment; Motivation; Neurons; Patients; Pattern; Performance; Physiologic pulse; Prefrontal Cortex; Quality of life; Reporting; Role; Schizophrenia; Short-Term Memory; Transcranial magnetic stimulation; Work; base; cognitive benefits; cognitive function; design; follow-up; improved; neural circuit; neural network; neuroimaging; neuronal circuitry; neuroregulation; noninvasive brain stimulation; novel; relating to nervous system; severe mental illness

Project Summary. Schizophrenia is a severe mental illness with an estimated economic burden of more than $160 billion per year in the US alone. To mitigate this burden, a promising approach involves the discovery of novel treatment interventions targeting specific neuronal circuit dysfunction, especially early in the illness, thus ameliorating the course of the disorder. In recent work, we found that the oscillatory activity of the dorsolateral prefrontal cortex (DLPFC), assessed with Transcranial Magnetic Stimulation (TMS) and EEG, was markedly reduced in chronic schizophrenia (Ch-SCZ) patients. DLPFC oscillatory deficits are also present in early course (EC-SCZ) patients and are associated to their reduced working memory (WM) performance. But findings to date are limited by a correlational/cross-sectional design, leaving the potential causal role of DLPFC oscillatory deficits in SCZ cognitive dysfunction unclear. The overarching goal of this proposal is to establish whether, by acutely enhancing DLPFC oscillatory activity, we see a corresponding improvement in WM function in EC-SCZ patients. In addition to being used to assess cortical function, as in combination with EEG, TMS can be delivered in repetitive, high-frequency patterns (rTMS), to modulate brain activity, including prefrontal cortical oscillations. Theta Burst Stimulation (TBS) is a type of rTMS that induces more rapid effects on neural activity than conventional rTMS; continuous TBS (cTBS) and intermittent TBS (iTBS) can decrease and enhance cortical excitability, respectively. Recent studies have shown that iTBS of DLPFC can acutely enhance prefrontal excitability in healthy individuals. Yet, the immediate impact of TBS on DLPFC oscillatory activity in patients with SCZ remains unknown. The first broad Aim of this proposal is to use iTBS to acutely ameliorate deficits in DLPFC oscillatory activity in EC-SCZ patients. WM relies on a neural network in which DLPFC serves as a central hub. EEG studies have reported that SCZ patients have DLPFC oscillatory abnormalities during WM tasks, and we recently found that reduced DLPFC oscillatory activity predicts poorer WM performance in EC-SCZ patients. It therefore stands to reason that enhancing DLPFC oscillatory activity with TBS may benefit cognitive functioning. The second broad Aim of this proposal is to use iTBS to acutely ameliorate WM impairments in EC-SCZ patients. To achieve these goals, we will perform TMS/EEG assessments of DLPFC oscillatory parameters and evaluate WM ability before and after two TBS sessions (iTBS and sham TBS of DLPFC) in seventy-five EC-SCZ patients. The proposed study aims to provide initial evidence that TBS can acutely enhance DLPFC oscillatory activity, which in turn predicts better WM performance, in EC-SCZ patients. Building on these findings, future neuromodulation-based treatment interventions applying chronic doses of TBS may more persistently ameliorate/restore DLPFC oscillatory parameters and related WM impairments in SCZ patients early during the illness, thus significantly improving their cognitive functioning and overall quality of life.

项目摘要。精神分裂症是一种严重的精神疾病，估计经济负担超过 仅在美国每年就有 1600 亿美元。为了减轻这种负担，一种有希望的方法是发现 针对特定神经元回路功能障碍的新型治疗干预措施，特别是在疾病早期，因此 改善疾病的进程。在最近的工作中，我们发现背外侧的振荡活动 通过经颅磁刺激 (TMS) 和脑电图评估，前额皮质 (DLPFC) 显着 慢性精神分裂症（Ch-SCZ）患者的水平降低。 DLPFC 振荡缺陷也出现在早期病程中 (EC-SCZ) 患者，并与其工作记忆 (WM) 表现降低有关。但迄今为止的调查结果 受到相关/横截面设计的限制，留下 DLPFC 振荡缺陷的潜在因果作用 SCZ 认知功能障碍尚不清楚。该提案的总体目标是确定是否通过敏锐地 增强 DLPFC 振荡活动，我们发现 EC-SCZ 患者 WM 功能相应改善。 除了与脑电图结合用于评估皮质功能外，TMS 还可以通过 重复的高频模式（rTMS）来调节大脑活动，包括前额皮质振荡。 Theta Burst Stimulation (TBS) 是一种 rTMS，它对神经活动的影响比 rTMS 更快 常规 rTMS；连续 TBS (cTBS) 和间歇性 TBS (iTBS) 可以降低和增强皮质 分别是兴奋性。最近的研究表明 DLPFC 的 iTBS 可以显着增强前额叶 健康个体的兴奋性。然而，TBS 对 DLPFC 振荡活动的直接影响 SCZ 仍然未知。该提案的第一个广泛目标是利用 iTBS 来急剧改善 DLPFC 的缺陷 EC-SCZ 患者的振荡活动。 WM 依赖于 DLPFC 作为中心枢纽的神经网络。脑电图研究表明 SCZ 患者在 WM 任务期间出现 DLPFC 振荡异常，我们最近发现 DLPFC 减少 振荡活动预示 EC-SCZ 患者的 WM 表现较差。因此，按理说 使用 TBS 增强 DLPFC 振荡活动可能有益于认知功能。本次会议的第二个总体目标 建议使用 iTBS 来急性改善 EC-SCZ 患者的 WM 损伤。 为了实现这些目标，我们将对 DLPFC 振荡参数进行 TMS/EEG 评估并评估 75 名 EC-SCZ 患者两次 TBS 疗程（iTBS 和 DLPFC 的假 TBS）前后的 WM 能力。 拟议的研究旨在提供初步证据，证明 TBS 可以急剧增强 DLPFC 振荡活动， 这反过来又预示着 EC-SCZ 患者的 WM 表现会更好。基于这些发现，未来 应用长期剂量的 TBS 进行基于神经调节的治疗干预可能会更持久 改善/恢复 SCZ 患者早期 DLPFC 振荡参数和相关 WM 损伤 疾病，从而显着改善他们的认知功能和整体生活质量。