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

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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.