The Cellular Effects of Transcranial Magnetic Stimulation in vivo in the rat

Abstract

Transcranial magnetic stimulation (TMS) is a form of non-invasive brain stimulation. A magnetic field is pulsed through the skull and into the brain where it induces electrical currents in underlying tissue and activates neural elements. Applying pulses of TMS repeatedly (repetitive TMS, rTMS) over a period of time has been shown to cause lasting changes in neural activity. Many attempts have been made to harness these long-term changes induced by rTMS to provide a potential treatment option for a wide range of neurological disorders. In the field of stroke rehabilitation, it is hypothesised that rTMS may be effective in increasing the plasticity of tissue surrounding the stroke core and therefore facilitating its ability to ‘take over’ the function of neurons that have died. Numerous clinical trials have tried different approaches to applying rTMS, but to date there is little evidence that rTMS provides any additional benefit in post-stroke rehabilitation compared to physiotherapy alone. We believe this is because the mechanisms of TMS are not well understood at a single neuron level.

The aim of this study was to develop a method for simultaneously stimulating the rat brain with TMS and recording both motor evoked potentials (MEPs) and in vivo, intracellular neural responses to this stimulation. Two rTMS protocols (intermittent theta burst stimulation (iTBS) and continuous theta burst stimulation (cTBS) were investigated for their ability to generate long term change in both muscle responses and single neuron activity. Under urethane anaesthesia, MEPs were difficult to generate and showed no change following iTBS. Combining urethane with ketamine and domitor slightly increased the ease with which MEPs could be generated, however iTBS was still ineffective in inducing lasting change in MEP amplitude.

A transpharyngeal surgical approach was developed to circumvent the spatial restrictions faced when combining the stimulating and intracellular recording apparatus. Single pulses of TMS were capable of generating post-synaptic potentials and also a transient change in the endogenous oscillation of the cortex, resetting the rhythm and driving a transition to a more depolarised membrane potential earlier than expected. Application of iTBS led to a transient facilitation of synaptic efficacy, and a significant increase in excitability in recorded neurons. Stimulation with cTBS had no effect on synaptic efficacy, however several measures of excitability were reduced. A second train of iTBS delivered 20 minutes following the first rTMS train led to significant depression of synaptic efficacy in animals that had received iTBS first. In animals that received cTBS first, no change in synaptic efficacy was observed following the second iTBS protocol, however responses of individual animals were variable.

These results indicate that both the efficacy of synapses with the recorded neurons and their intrinsic excitability can be modulated by rTMS, leading to changes in neural activity that may be influenced by the mechanisms of metaplasticity. This work provides new insights into the design of rTMS protocols where rTMS is used as a means of priming neural tissue for subsequent induction of long-term neural plasticity.