A Baboon Model of TMS/PET as a Vehicle for Rational Development of TMS Treatments

描述（由申请人提供）：本R21的目的是开发TMS脑刺激的非人灵长类动物（NHP）模型。TMS的NHP模型的长期效用是加快人类治疗的发展步伐。目前，人类治疗试验缺乏强有力的理论或经验基础，用于为无数的治疗参数选择最佳范围，包括刺激位置、刺激强度、刺激速率和刺激脉冲模式、会话持续时间、会话间隔和会话数量。虽然这些治疗参数都可以在人类中进行彻底的探索，但这将是非常昂贵和耗时的。NHP模型一旦开发出来，将允许以快速、具有成本效益的方式系统地探索各种治疗参数。我们设想系统的治疗参数的探索作为主题的RO 1提交后，NHP模型已成功实施，并通过拟议的目标进行验证。由于确定了TMS治疗参数的有希望的范围，因此将从NHP模型中转换该信息用于人体治疗试验。该提案的主要重点是表征麻醉狒狒模型中TMS驱动的脑反应的幅度和空间分布特性，从而相对于我们先前和正在进行的人类工作验证和校准这个新模型。为了实现这一点，我们将系统地改变TMS诱导的电场的方向和强度，同时用PET和EMG作为生物标志物测量TMS诱导的反应。选择这两个刺激参数（方向和强度）是因为我们先前的人体电生理学和成像研究提供了强有力的证据，表明它们共同决定了TMS诱导反应的空间分布和幅度。根据这些先前的研究，PI及其同事开发了数学模型，将假设的关系形式化，明确预测任何给定线圈几何形状、位置、方向和电流下每个大脑位置的响应幅度。在NHP和人类中使用相同的建模结构将促进物种间的翻译。该提案有两个具体目标。目的1是确认C3模型的取向响应预测（Fox等人，2004年，在NHP。目的2是确认PRP模型的强度响应预测（Captain等人，1997; Fox等人，2006年，在NHP。公共卫生相关性：经颅磁刺激（TMS）在基础神经科学中有着广泛的应用，在神经和精神疾病中有着广阔的应用前景。为了充分利用TMS的潜在效用，需要更好地了解基本TMS参数对神经生理学的影响。激发该提案的研究计划的长期目标是开发能够指导经颅磁刺激（TMS）合理开发的知识库：1）神经和精神疾病的潜在治疗;以及2）用于绘制区域间连接和量化学习和康复引起的突触功效变化的工具。

DESCRIPTION (provided by applicant): The purpose of this R21 is to develop a non-human primate (NHP) model of TMS brain stimulation. The long- range utility of a NHP model of TMS is to accelerate the pace of development of human treatments. At present, human treatment trials lack a strong theoretical or empirical basis for selecting optimal ranges for a myriad of treatment parameters, including stimulus location, stimulus intensity, stimulus rate and stimulus pulse pattern, session duration, session spacing and session number. While these treatment parameters could all be exhaustively explored in humans, this would be inordinately costly and time consuming. A NHP model, once developed, will allow a wide range of treatment parameters to be explored systematically in a rapid, cost- effective manner. We envision systematic exploration of treatment parameters as the theme of an RO1 to be submitted after the NHP model has been successfully implemented and validated through the proposed aims. As promising ranges of TMS treatment parameters are determined, this information will be translated from the NHP model for human treatment trials. The primary focus of this proposal is to characterize the magnitude and spatial distribution properties of TMS-driven cerebral responses in an anesthetized baboon model, thereby validating and calibrating this new model relative to our prior and ongoing human work. To achieve this, we will systematically vary the orientation and intensity of the TMS-induced E-field, while measuring the TMS-induced responses with PET and EMG as biomarkers. These two stimulation parameters (orientation and intensity) were chosen because our prior human electrophysiological and imaging studies have provided strong evidence that they jointly determine the spatial distribution and magnitude of the TMS-induced response. From these prior studies, the PI and colleagues have developed mathematical models which formalize the postulated relationships, making explicit predictions of response magnitude at each brain location for any given coil geometry, location, orientation, and current. Use of the same modeling constructs in NHP and humans will facilitate inter-species translation. This proposal has two Specific Aims. Aim 1 is to confirm the orientation response predictions of the C3 model (Fox et al., 2004) in the NHP. Aim 2 is to confirm the intensity response predictions of the PRP model (Capaday et al., 1997; Fox et al., 2006) in the NHP. PUBLIC HEALTH RELEVANCE: Transcranial magnetic stimulation (TMS) has well-established applications in basic neuroscience and promising applications in neurological and psychiatric disorders. To fully capitalize on the potential utility of TMS, a better understanding of the effects of basic TMS parameters on neurophysiology is needed. The long- range goal of the research program motivating this proposal is to develop a knowledge base capable of guiding the rational development of transcranial magnetic stimulation (TMS) as: 1) a potential treatment for neurological and psychiatric disorders; and, 2) a tool for mapping inter-regional connectivity and for quantifying changes in synaptic efficacy induced by learning and rehabilitation.