Prefrontal circuit mechanisms of repetitive transcranial magnetic stimulation

重复经颅磁刺激的前额电路机制

• 批准号: 10649292
• 负责人: Scott Allen Wilke
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649292
• 关键词: Action Potentials; Acute; Address; Affect; Animal Model; Brain; Brain region; Calcium Signaling; Cells; Chemosensitization; Chronic; Clinical; Collaborations; Disinhibition; Electromagnetics; Equilibrium; Excitatory Synapse; FDA approved; Face; Fiber; Frequencies; Functional disorder; Future; Head; Hour; Human; Interneurons; Investigation; Long-Term Potentiation; Major Depressive Disorder; Measures; Mediating; Mental disorders; Methods; Modeling; Motor; Mus; National Institute of Mental Health; Neurons; Neurosciences; Obsessive-Compulsive Disorder; Pathologic; Photometry; Physiologic pulse; Prefrontal Cortex; Protocols documentation; Research; Rodent; Stress; Synapses; Synaptic plasticity; System; Techniques; Testing; Thalamic structure; Therapeutic; Therapeutic Effect; Time; Treatment Protocols; United States National Institutes of Health; awake; cell cortex; cell type; clinical effect; clinical efficacy; design; effective intervention; effective therapy; excitatory neuron; experimental study; in vivo; inhibitory neuron; nervous system disorder; neural; neurotransmission; noninvasive brain stimulation; novel; off-label use; optogenetics; permissiveness; rational design; redshift; repetitive transcranial magnetic stimulation; response; targeted delivery; therapeutic target; tool

PROJECT SUMMARY Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method FDA-approved to treat major depression and obsessive compulsive disorder, and also used off-label for treating numerous neurological and psychiatric disorders. Clinical high frequency (HF) rTMS is typically targeted to the prefrontal cortex (PFC) and is thought to enhance cortical excitability. However, effects on activity and clinical efficacy are highly variable and the detailed mechanisms of action are not known. The primary obstacle limiting investigation of cell-type and circuit-specific mechanisms is lack of established animal models with strong face validity. Our lab has acquired the first rodent TMS coil capable of generating focal, suprathreshold stimulation of a cortical subregion. We will use this coil to address the cell-type specific mechanisms by which HF-rTMS modifies excitatory and inhibitory prefrontal subnetworks in vivo. By combining rTMS with cutting edge neuroscience tools, we will test the hypothesis that HF-rTMS enhances prefrontal excitability by rapidly suppressing activity in inhibitory neurons leading to subsequent enhancement of principal neuron activity. In Aim 1, we will use fiber photometry to record calcium signals arising from excitatory (Emx1+) and inhibitory (PV+) prefrontal networks before, during and after delivery of clinical HF-rTMS. In Aim 2, we will combine these cell-type specific recordings of neural activity with optogenetic stimulation of long-range cortical inputs to determine how HF-rTMS modifies synaptically-evoked activity in excitatory vs. inhibitory cortical networks. This proposal addresses a pressing need to understand the cell-type and circuit specific mechanisms that mediate the effects of rTMS on cortical function. Our research can inform the rational design of more effective rTMS treatments that precisely target specific deficits underlying the pathophysiology of psychiatric disorders. These foundational studies will support future projects aimed at determining how chronic rTMS can reverse pathological circuit changes in rodent stress models.

项目摘要 重复经颅磁刺激（rTMS）是FDA批准的一种非侵入性脑刺激方法， 治疗严重抑郁症和强迫症，也用于治疗许多 神经和精神疾病。临床高频（HF）rTMS通常针对前额叶 皮质（PFC），并被认为是增强皮质兴奋性。然而，对活动和临床疗效的影响是 高度可变，详细的作用机制尚不清楚。限制调查的主要障碍 细胞类型和电路特异性机制的研究缺乏表面效度较强的动物模型。我们 实验室已经获得了第一个啮齿动物TMS线圈，能够产生局灶性，阈上刺激皮层 次区域。我们将使用这种线圈来解决HF-rTMS修饰细胞类型的特异性机制， 兴奋性和抑制性前额叶子网络。通过将rTMS与尖端神经科学工具相结合， 我们将检验HF-rTMS通过快速抑制大脑皮层的活动来增强前额叶兴奋性的假设。 抑制性神经元导致随后的主要神经元活动的增强。在目标1中，我们将使用纤维 光度法记录兴奋性（Emx 1+）和抑制性（PV+）前额叶网络产生的钙信号 在临床HF-rTMS输送之前、期间和之后。在目标2中，我们将联合收割机组合这些特定于细胞类型的记录 用长距离皮层输入的光遗传学刺激神经活动，以确定HF-rTMS如何改变 兴奋性与抑制性皮质网络中的突触诱发活动。这一建议解决了一个紧迫的 需要了解细胞类型和电路的具体机制，介导的影响，rTMS对皮层 功能我们的研究可以为更有效的rTMS治疗的合理设计提供信息， 精神疾病病理生理学基础的特定缺陷。这些基础研究将支持 未来的项目旨在确定慢性rTMS如何逆转啮齿动物应激中的病理性回路变化 模型