Cellular Mechanisms Underlying State-Dependent Neural Inhibition with Magnetic Stimulation - Neural modulation with repetitive transcranial magnetic stimulation (rTMS) is widely used for the treatment of many neurological diseases. Output of magnetic stimulation is largely dependent on the stimulation parameters, such as the duration, frequency, and intensity of the magnetic field, because they affect the excitation of individual neurons, synaptic transmission, and ion channel dynamics. Recent clinical evidence suggests that the excitation state of the nervous system plays a significant role in the outcome of magnetic stimulation (termed “state-dependent”). For example, magnetic stimulation produces different perceptual or behavioral outcomes that are dependent on the excitability levels of the brain. The instantaneous brain state has been used to promote efficacious induction of plasticity by TMS. In comparison to the clinical success, the neural mechanisms underlying state-dependent magnetic stimulation is largely unknown. Previously, this question has been difficult to address at the cellular and ion channel levels because the large sized TMS coil could not provide highly specific stimulation. Recent development of the micro-coil technology improved the cellular specificity of coil stimulation. These sub-millimeter sized coils allow the study of single cell responses to the magnetic stimulation, and the observation of its state-dependency. Preliminary data report an interesting “state-dependent” phenomena at the single cell level – neurons in a low active state are easier to be completely inhibited by the same magnetic stimulation than the neurons in a high active state. This advocates for monitoring the dynamics of the brain’s excitation states for the optimal design, practice, and analysis of magnetic stimulation on the brain. In this proposal, we will use combined tools of electrophysiology, pharmacology, and computer simulation to investigate the cellular and molecular mechanisms underlying state-dependent neural inhibition by magnetic stimulation with the novel micro-coil technology. Since the level of neural activity is essential in the neuronal response to magnetic inhibition, Aim 1.1 will investigate the state-dependent magnetic stimulation under a spectrum of in vitro physiological/pathological conditions. The biophysics properties of single neurons, such as the size, shape, and membrane conductivity of the neuron, play important roles in magnetic stimulation. Cells of different types have also been found to have different sensitivities in magnetic stimulation. Aim 1.2 will investigate the impact of biophysics properties and types of neurons on state-dependent stimulation. Computational modeling provides insights on the cellular and ion channel mechanisms underlying state-dependent inhibition. We will test the hypothesis that high frequency magnetic stimulation causes a significant reduction in sodium channel conductance, which leads to the state-dependent suppression of neuron activity. Aim 2.1 seeks to directly observe the reduced sodium channel conductance with voltage clamp experiments. Aim 2.2 will use pharmacological tools to directly activate the sodium channels and observe its impact on state-dependent magnetic stimulation. Individual neurons are the building units of the nervous system. The state-dependent inhibition by the magnetic field could have significant implications to the mechanistically-based design of TMS practice in clinical settings. Micro-coil technology is brand new, and only a few labs are able to combine fabrication of the next generation micro-coil devices with an understanding of the technique's effects at a molecular level. Understanding the cellular and molecular mechanisms of micro-coil stimulation will provide guidelines for the development of this cutting-edge technology.
