Patch-clamp recordings of rat neurons from acute brain slices of the somatosensory cortex during magnetic stimulation.

Although transcranial magnetic stimulation (TMS) is a popular tool for both basic research and clinical applications, its actions on nerve cells are only partially understood. We have previously predicted, using compartmental modeling, that magnetic stimulation of central nervous system neurons depolarized the soma followed by initiation of an action potential in the initial segment of the axon. The simulations also predict that neurons with low current threshold are more susceptible to magnetic stimulation. Here we tested these theoretical predictions by combining in vitro patch-clamp recordings from rat brain slices with magnetic stimulation and compartmental modeling. In agreement with the modeling, our recordings demonstrate the dependence of magnetic stimulation-triggered action potentials on the type and state of the neuron and its orientation within the magnetic field. Our results suggest that the observed effects of TMS are deeply rooted in the biophysical properties of single neurons in the central nervous system and provide a framework both for interpreting existing TMS data and developing new simulation-based tools and therapies.

Mechanisms of magnetic stimulation of central nervous system neurons.

Transcranial magnetic stimulation (TMS) is a stimulation method in which a magnetic coil generates a magnetic field in an area of interest in the brain. This magnetic field induces an electric field that modulates neuronal activity. The spatial distribution of the induced electric field is determined by the geometry and location of the coil relative to the brain. Although TMS has been used for several decades, the biophysical basis underlying the stimulation of neurons in the central nervous system (CNS) is still unknown. To address this problem we developed a numerical scheme enabling us to combine realistic magnetic stimulation (MS) with compartmental modeling of neurons with arbitrary morphology. The induced electric field for each location in space was combined with standard compartmental modeling software to calculate the membrane current generated by the electromagnetic field for each segment of the neuron. In agreement with previous studies, the simulations suggested that peripheral axons were excited by the spatial gradients of the induced electric field. In both peripheral and central neurons, MS amplitude required for action potential generation was inversely proportional to the square of the diameter of the stimulated compartment. Due to the importance of the fiber's diameter, magnetic stimulation of CNS neurons depolarized the soma followed by initiation of an action potential in the initial segment of the axon. Passive dendrites affect this process primarily as current sinks, not sources. The simulations predict that neurons with low current threshold are more susceptible to magnetic stimulation. Moreover, they suggest that MS does not directly trigger dendritic regenerative mechanisms. These insights into the mechanism of MS may be relevant for the design of multi-intensity TMS protocols, may facilitate the construction of magnetic stimulators, and may aid the interpretation of results of TMS of the CNS.

Mini-coil for magnetic stimulation in the behaving primate.

Transcranial magnetic stimulation (TMS) is rapidly becoming a leading method in both cognitive neuroscience and clinical neurology. However, the cellular and network level effects of stimulation are still unclear and their study relies heavily on indirect physiological measurements in humans. Direct electrophysiological studies of the effect of magnetic stimulation on neuronal activity in behaving animals are severely limited by both the size of the stimulating coils, which affect large regions of the animal brain, and the large artifacts generated on the recording electrodes. We present a novel mini-coil which is specifically aimed at studying the neurophysiological mechanism of magnetic stimulation in behaving primates. The mini-coil fits into a chronic recording chamber and provides focal activation of brain areas while enabling simultaneous extracellular multi-electrode recordings. We present a comparison of this coil to a commercial coil based on the theoretical and recorded magnetic fields and induced electric fields they generate. Subsequently, we present the signal recorded in the behaving primate during stimulation and demonstrate the ability to extract the spike trains of multiple single units from each of the electrodes with minimal periods affected by the stimulus artifact (median period <2.5 ms). The directly recorded effect of the magnetic stimulation on cortical neurons is in line with peripheral recordings obtained in humans. This novel mini-coil is a key part of the infrastructure for studying the neurophysiological basis of magnetic stimulation, thereby enabling the development and testing of better magnetic stimulation tools and protocols for both neuroscientists and clinicians.