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

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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.