Anatomical and Functional Changes induced by Repetitive Transmagnetic Stimulation in the Primate Motor Cortex

摘要 重复经颅磁刺激（rTMS）是一种非侵入性的刺激大脑皮层的技术 通过局部暴露于短暂的磁场。该技术已被批准或用于临床研究， 几种精神和神经疾病rTMS的一个潜在的治疗应用是其用于 脑卒中康复，其中低频rTMS（LF-rTMS）在对侧病变初级运动皮层（M1）上 具有抗麻痹作用，这可能是通过与同侧M1的半球间连接介导的。 对人类的研究表明，rTMS产生电生理和（可能）形态学变化 在受刺激的皮层区域，以及与之相连的其他（未受刺激的）大脑区域。然而， 这些原发性和继发性效应的程度以及rTMS的一般作用机制仍然是 辩论的问题。对麻醉啮齿类动物的研究支持了rTMS导致 频率依赖性的大脑解剖结构的变化，但啮齿类动物的大脑相对于TMS的小尺寸 线圈，啮齿类动物和灵长类动物之间运动皮层功能解剖的实质性差异， 麻醉剂对rTMS介导效应的影响显著限制了啮齿动物数据的翻译， 暴露于rTMS的人类为了克服这些问题，我们将研究LF-rTMS在清醒状态下的作用。 恒河猴是一种灵长类动物，其大脑比啮齿动物更接近人类大脑， 在大脑大小和运动皮质区的功能解剖学方面。我们将检验这个假设， M1手区的单侧LF-rTMS会话可增强M1手区的功能、细胞和超微结构变化。 在这些动物中，刺激的M1手区域和对侧M1的连接的同伦区域中。我们 我们的解剖学研究将集中在细胞计数、突触密度和形态学以及生物化学方面的变化上。 变化（如GABA能中间神经元活性的解剖标志物的变化）。数据 通过这些实验收集的数据将为未来的大规模（R 01资助）研究提供基础， 非人灵长类动物，旨在了解LF-rTMS介导其生物学机制。 生理和治疗效果。鉴于rTMS作为治疗糖尿病的一种方式的使用越来越多， 神经和精神疾病，适当的动物模型的发展是必不可少的，以达到一个 更好地了解rTMS的脑网络效应，并评估其安全性。

ABSTRACT Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique to stimulate the cerebral cortex via focal exposure to brief magnetic fields. This technique is in approved or investigational clinical use for several psychiatric and neurologic conditions. One potential therapeutic application of rTMS has been its use in stroke rehabilitation where low frequency rTMS (LF-rTMS) over the contralesional primary motor cortex (M1) has anti-paretic effects which are possibly mediated by interhemispheric connections with the ipsilesional M1. Studies in humans have shown that rTMS produces electrophysiological and (possibly) morphological changes in the stimulated cortical area, and in other (non-stimulated) brain regions that are connected to it. However, the extent of these primary and secondary effects, and the general mechanism(s) of action of rTMS remain a matter of debate. Studies in anesthetized rodents have provided support for the notion that rTMS leads to frequency-dependent brain anatomy changes, but the small size of the rodent brain relative to that of the TMS coil, the substantial differences in the functional anatomy of motor cortices between rodents and primates, and the impact of anesthetics on rTMS-mediated effects significantly limit the translation of the rodent data to humans exposed to rTMS. To overcome these problems, we will examine the effects of LF-rTMS in awake Rhesus monkeys, a primate species whose brain is much closer to the human brain than that of rodents, both in terms of brain size and functional anatomy of motor cortical areas. We will test the hypothesis that repeated sessions of unilateral LF-rTMS of the M1 hand area elicits functional, cellular and ultrastructural changes in the stimulated M1 hand area and in the connected homotopic area of the contralateral M1 in these animals. We will focus our anatomical studies on changes in cell counts, synapse density and morphology, and biochemical changes (such as changes in anatomical markers of the activity of GABAergic interneurons). The data gathered through these experiments will provide a foundation for future large-scale (R01-funded) studies in nonhuman primates aimed at understanding the biological mechanisms through which LF-rTMS mediates its physiological and therapeutic effects. Given the increased use of rTMS as a modality for treatment of neurological and psychiatric diseases, the development of appropriate animal models is essential to arrive at a better understanding of the brain network effects of rTMS, and to assess its safety.