Prefrontal circuit mechanisms of repetitive transcranial magnetic stimulation

重复经颅磁刺激的前额电路机制

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要重复的经颅磁刺激（RTMS）是一种非侵入性脑刺激方法FDA批准为治疗严重的抑郁症和强迫症神经和精神疾病。临床高频（HF）RTM通常针对前额叶皮质（PFC），被认为可以增强皮质兴奋性。但是，对活动和临床功效的影响是高度可变和详细的作用机理尚不清楚。限制障碍的主要调查细胞类型和电路特异性机制缺乏既有面部有效性的既定动物模型。我们的实验室获得了第一个啮齿动物TMS线圈，能够产生焦点，上方的刺激子区域。我们将使用此线圈来解决HF-RTMS修改的细胞类型特定机制体内兴奋性和抑制前额叶子网。通过将RTM与尖端神经科学工具相结合，我们将检验以下假设：HF-RTMS通过快速抑制活性来增强前额叶兴奋性抑制性神经元导致主神经元活性的增强。在AIM 1中，我们将使用纤维记录由兴奋性（EMX1+）和抑制性（PV+）前额叶网络引起的钙信号的光度法临床HF-RTMS之前，期间和之后。在AIM 2中，我们将结合这些细胞类型的特定记录神经活性的远程皮质输入的光遗传学刺激，以确定HF-RTMS如何修饰兴奋性与抑制性皮质网络中的突触诱发活性。该提案解决了一个紧迫的需要了解介导RTMS对皮质影响的细胞类型和电路特定机制功能。我们的研究可以告知更有效的RTMS治疗的合理设计，这是针对的精神疾病的病理生理学基础的具体缺陷。这些基础研究将支持未来的项目旨在确定慢性RTM如何逆转啮齿动物压力的变化型号。