Abstract
In recent decades, transcranial magnetic stimulation (TMS) has emerged as one of the most promising techniques for clinical therapies. It has been proposed for use in a wide number of neurophysiological disorders including Alzheimer’s, depression and stroke rehabilitation. The technique produces a heterogeneous magnetic field, which induces a suprathreshold electric field in a small focal zone of underlying cortical tissue, depolarising a population of neurons. When these pulses are applied in a repetitive fashion, known as repetitive TMS (rTMS), the excitability of the cortex can be altered. Outside of the small focal zone, broad areas of cortex are subject to much weaker induced current intensities, below the threshold for action potential generation, however, increasing evidence suggests they may have a measurable physiological impact. Despite great initial promise, clinical results for various rTMS treatment paradigms have been mixed, with response rates between and within patients showing high-variability. One potential source of this variability may be unintended effects of the low-intensity fields outside of the targeted population. The aim of the experiments in this thesis were to investigate the impact of rTMS at high- and low-intensities on measures of cortical excitability in the neocortex, using rodent models. The first study explored the effects of two separate anaesthetics on rTMS-induced changes in cortical excitability, using a high-intensity coil and measured using motor evoked potentials. Animals were anaesthetised with either a xylazine/zoletil combination or urethane. In contrast to previously reported success, high-intensity excitatory rTMS here was unable to increase MEP amplitudes, under either anaesthetic. The xylazine/zoletil combination however, was found to increase measures of excitability in the baseline recording, compared to animals anaesthetised with urethane. To investigate low-intensity rTMS, an 8-mm rodent specific coil was used for all subsequent experiments. This produced a magnetic field strength of 120 milliTesla, an order of magnitude below the 1-2 Tesla for human coils. Magnetic fields this powerful are comparable to those emitted by human coils outside of the focal zone. In the final two studies, the ability of low-intensity rTMS to depress or facilitate cortical excitability was measured directly using both local field potentials (LFPs) in vivo and calcium imaging of cortical neurons in vitro. Local field potentials were measured as contralaterally evoked waveforms in anaesthetised rats, recorded from layer V of the motor cortex. Brain slices of juvenile mice were prepared to measure the somatic levels of calcium in layer V neurons, as well as the amplitude of electrically evoked calcium transients. In both cases, rats or mouse brain slices were treated with low-intensity rTMS in the form of theta-burst stimulation or quadripulse stimulation. Overall, no significant effect of low-intensity rTMS was found in LFPs or somatic calcium levels. These data suggest that the effects of low-intensity rTMS, if any, may be subtle changes and as such, the population based techniques used here lacked the required sensitivity to detect these alterations. Consequently, it is unlikely that low-intensity magnetic fields during human application of rTMS are able to significantly influence electrophysiological outcomes and thus contribute to the variability observed.