Investigating the neurochemical response to repetitive transcranial magnetic stimulation induced plasticity changes using proton and carbon-13 magnetic resonance spectroscopy.

重复经颅磁刺激（rTMS）涉及在大脑中集中应用短暂而强烈的磁场，允许对神经活动进行安全，非侵入性的刺激。尽管rTMS在治疗疾病方面具有疗效，但由于其诱导可塑性变化的能力，它在研究脑功能方面也具有巨大的潜力。rTMS诱导的可塑性变化具有持续性和频率依赖性，高频（bb0 ~ 5Hz）刺激导致皮质兴奋性增加，低频（<1Hz）刺激导致皮质兴奋性降低。然而，目前，rTMS诱导可塑性变化的潜在生理机制尚不清楚，也不清楚高频和低频刺激对可塑性的影响差异。有证据表明，rTMS诱导的皮质可塑性变化可能是由神经递质（谷氨酸、GABA）功能的改变介导的，但这种可能性需要进一步的详细研究来证实。体内磁共振波谱（MRS）提供了一种非侵入性的方法来研究人类和小动物大脑中的神经递质功能。具体来说，质子（1H） MRS可以测量大脑中主要神经递质的静态（时间平均）水平，而动态碳-13 (13C) MRS可以直接定量测量大脑中神经递质循环率和细胞特异性能量代谢率。因此，体内质子和13C-MRS为研究rTMS的神经化学机制提供了一套实用而强大的工具。提出的研究计划旨在，首先，开发最先进的方法（硬件和软件），用于大鼠脑和人脑的体内质子核磁共振和体内动态13C核磁共振，其次，将这些方法应用于研究高频和低频rTMS诱导可塑性变化的神经化学作用机制。该研究计划涉及几个重要成果：首先，它将使一个专门设计和建造用于磁共振成像和光谱学的射频线圈的实验室得以发展。这将使我们能够构建动态体内13C MRS所需的双调谐射频线圈，并在我们的实验室中建立强大的MRI硬件专业知识基础。其次，它将能够建立一个独特的平台，用于使用质子和13C mrs进行体内神经能量学和神经递质循环的非侵入性研究。据我们所知，这样的平台将是加拿大唯一的同类平台，并将吸引本地和国际合作与对非侵入性研究神经化学过程感兴趣的研究人员。最后，本研究的结果将有助于提高我们对rTMS诱导大脑可塑性变化的神经化学机制的理解。通过提高我们对可塑性机制的理解，本研究的结果可能最终有助于开发新的药理学或神经调节方法，以选择性地增强大脑中的可塑性过程，如学习或损伤康复。

Repetitive transcranial magnetic stimulation (rTMS) involves the focal application of brief and intense magnetic fields in the brain, allowing for safe, non-invasive stimulation of neural activity. Notwithstanding its therapeutic benefits in the treatment of diseases, rTMS also has tremendous potential for studying brain function due to its ability to induce plasticity changes. The plasticity changes induced by rTMS are lasting and frequency dependent, with high-frequency (>5Hz) stimulation resulting in an increase in cortical excitability, and low-frequency (<1Hz) stimulation resulting in a decrease in cortical excitability. Currently, however, the underlying physiological mechanisms of rTMS induced plasticity changes are not well understood, and it is not clear how high- and low- frequency stimulation might differentially affect plasticity. Some evidence suggests that rTMS induced plasticity changes in the cortex may be mediated by changes in neurotransmitter (glutamate, GABA) function, but further detailed investigation is required to confirm this possibility. In-vivo magnetic resonance spectroscopy (MRS) provides a non-invasive means to investigate neurotransmitter function in the brain in both humans and small animals. Specifically, proton (1H) MRS enables measurement of the static (time-averaged) levels of major neurotransmitters in the brain, while dynamic carbon-13 (13C) MRS, enables direct, quantitative measurement of neurotransmitter cycling rates and cell-specific energy metabolism rates in the brain. Therefore, in vivo proton and 13C-MRS MRS provide a practical and powerful set of tools with which to investigate the neurochemical mechanisms of rTMS. The proposed programme of research is aimed at, first, developing state of the art methods (hardware and software) for in vivo proton MRS and in vivo dynamic 13C MRS in both the rat brain and the human brain, and secondly, applying these methods towards investigations of the neurochemical mechanisms of action of both high- and low-frequency rTMS induced plasticity changes. This programme of research involves several important outcomes: Firstly, it will enable the development of a laboratory specializing in the design and construction of radiofrequency coils for magnetic resonance imaging and spectroscopy. This will enable us to construct the requisite dual-tuned radiofrequency coils for dynamic in-vivo 13C MRS, and to develop a strong base of MRI hardware expertise within our laboratory. Secondly, it will enable the establishment of a unique platform for the non-invasive study of neuroenergetics and neurotransmitter cycling in vivo using both proton and 13C MRS. Such a platform would be, to our knowledge, the only one of its kind in Canada, and would attract both local and international collaborations with researchers interested in studying neurochemical processes non-invasively. Finally, the results of the proposed studies will contribute to improving our understanding of the neurochemical mechanisms of rTMS induced plasticity changes in the brain. By improving our understanding of the mechanisms of plasticity, the results of this study may eventually contribute to the development of new pharmacologic or neuromodulative methods to selectively enhance plastic processes in the brain such as learning or injury rehabilitation.