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.
