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

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。为了减轻这一负担，一种有希望的方法涉及到发现 针对特定神经元回路功能障碍的新治疗干预措施，特别是在疾病的早期，因此 改善这种疾病的病程。在最近的工作中，我们发现背外侧的振荡活动 经颅磁刺激(TMS)和脑电检查，前额叶皮质(DLPFC)明显 慢性精神分裂症(CH-SCZ)患者减少。DLPFC的振荡缺陷也出现在早期 (EC-SCZ)患者，并与他们工作记忆(WM)性能下降有关。但到目前为止的发现 受到相关/横截面设计的限制，留下了DLPFC振荡缺陷的潜在因果作用 在SCZ中，认知功能障碍尚不清楚。这项提案的首要目标是确定是否通过尖锐的 增强DLPFC的振荡活性，我们看到EC-SCZ患者的WM功能也有相应的改善。 除了用于评估皮质功能外，TMS还可以与EEG结合使用，在 重复的高频模式(RTM)，以调节大脑活动，包括前额叶皮质振荡。 Theta Burst刺激(TBS)是一种rTMS，它对神经活动的影响比 常规rTMS；持续性TBS(CTBS)和间歇性TBS(ITBS)可降低和增强皮质 兴奋性。最近的研究表明，DLPFC的ITBS可以显著增强前额叶 健康个体的兴奋性。然而，TBS对慢性阻塞性肺疾病患者DLPFC振荡活动的直接影响 SCZ仍然未知。这项提议的第一个广泛目标是使用ITBS来显著改善DLPFC的赤字 EC-SCZ患者的振荡活动。 WM依赖于以DLPFC为中心枢纽的神经网络。脑电研究报告称，SCZ 患者在WM任务中存在DLPFC振荡异常，我们最近发现DLPFC减少 振荡活动预测EC-SCZ患者的WM表现较差。因此，理所当然地认为 用TBS增强DLPFC的振荡活动可能有利于认知功能。这样做的第二个广泛目标是 建议使用ITBS来显著改善EC-SCZ患者的WM损害。 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例EC-SCZ患者在两次TBS治疗(ITBS和DLPFC的假TBS)前后的WM能力。 这项拟议的研究旨在提供初步证据，证明TBS可以显著增强DLPFC的振荡活性， 这反过来又预示着EC-SCZ患者更好的WM表现。在这些发现的基础上，未来 基于神经调节的治疗干预应用慢性剂量的TBS可能会更持久 改善/恢复SCZ患者早期的DLPFC振荡参数和相关的WM损害 因此，他们的认知功能和整体生活质量得到了显著改善。

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.