Investigating the electrophysiological and pharmacological basis of neuronal network function in sensorimotor cortex

The sensorimotor cortex plays a significant functional role in the control of movement and sensation. It is now possible to study the electrophysiology of the sensorimotor cortex using the technique of magnetoencephalography (MEG), which measures tiny magnetic fields outside the head that are produced by electrical activity in the brain. There is no contact with the participant making it an ideal non-invasive method to monitor human brain activity. In our laboratory we are particularly interested in properties of the brain rhythms, such as those in the beta (15-30Hz) and mu (8-14Hz) frequencies, which are present in the sensorimotor cortex both at rest and during different tasks. This is an important area of research as abnormalities in these brain rhythms have been implicated in a number of movement disorders such as Parkinson's disease and somatosensory disorders such as chronic pain. Drugs which act upon GABA receptors in the human brain have been found to modify sensorimotor brain rhythms. We are particularly interested in the effects of one such drug called zolpidem as recent MEG recordings taken from a stroke patient in our laboratory have indicated that it may act to improve motor dysfunction by reducing the power of pathological brain rhythms. We will examine this further by using the MEG method to record the brain activity of normal human subjects before and after the ingestion of zolpidem. In addition to measuring resting brain activity we will also measure the activity elicited by a brief sensory stimulation of the finger and the activity generated during the performance of self and externally paced finger movements. This will allow us to determine the way in which zolpidem modifies the profile of resting and functional sensorimotor rhythms. Transcranial magnetic stimulation (TMS) is a non-invasive technique which uses magnetic fields to generate electrical currents in the human brain. A specific form of TMS, termed theta burst stimulation (TBS) temporally reduces the excitability of the human motor cortex and can produce a transient impairment of motor function. The way in which TBS produces these remarkable effects is not yet fully understood, however, similar work in animals suggests that TBS may disrupt the intrinsic sensorimotor rhythms. We, therefore, aim to establish whether TBS affects the resting and functional brain rhythms of normal human participants in similar manner to those found in the animal models. To examine this we will use MEG recordings to measure the profile of the resting and functional sensorimotor rhythms before and after a brief period of TBS. The results of this study will aid our understanding of the neuronal mechanisms behind the functional effects of TBS and may lead to the development of a non-invasive model of pathological brain rhythms in normal humans. Recent work conducted in our laboratory using animal models has also shown that the disruptive effects of electrical brain stimulation on sensorimotor rhythms can be blocked in the presence of zolpidem. We would like to test whether this is also the case in the normal human brain. To examine this we will use MEG to obtain a baseline measure of the resting and functional sensorimotor rhythms. We will then give our participants a small dose of zolpidem. Once the drug begins to act we will apply a brief period of TBS and then we will use MEG recordings to determine the profile of the resting and functional sensorimotor rhythms. We will then compare these profiles to the brain activity recorded following TBS in trials in which the participants did not take the drug to establish whether zolpidem can modified the effects of the brain stimulation. The potential applications of this study are widespread as the results will provide important information both about the way in which the brain stimulation and the drug exert their effects on the sensorimotor cortex.

The experimental programme is based around two fundamental components of sensorimotor function; intrinsic ongoing oscillations and functionally related oscillations; to be measured using magnetoencephalography (MEG). The project will use an experimental 'block' that incorporates self-paced movement, externally paced movement and sensory stimulation of left and right index fingers, interspersed with periods of passive inactivity. The project includes 3 phases: GABAergic modulation (phase 1), theta burst stimulation (TBS) (phase 2) and TBS during GABAergic modulation (phase 3). The experimental block will repeated throughout each phase in order to determine the effects on sensorimotor mu (8-12Hz), beta (15-30Hz) and gamma (30-80Hz) oscillations. A screening phase will ensure that study participants demonstrate reduced cortical excitation in response to TBS. Data analysis in each phase will first use the SAM beamforming method to identify the primary motor cortex (M1) and somatosensory cortex (S1) in response to the sensorimotor paradigms. These loci will then form the focus of investigation for all subsequent analyses in all phases, using virtual electrode analysis to determine envelopes of intrinsic oscillatory power and profiles of specific functional oscillations. The objectives of phase 1 are to determine (1) the profile of oscillatory change specific to M1 and S1 induced by sensorimotor tasks, (2) the effects of GABAergic modulation on intrinsic M1 and S1 oscillations and (3) the impact of GABAergic modulation on M1 and S1 functional oscillations. The objectives of phase 2 are to determine (1) the effects of TBS on intrinsic M1 and S1 oscillations and (2) the impact of TBS on functionally mediated M1 and S1 oscillations. The objectives of phase 3 are to determine (1) the effects of GABA-A alpha1 upon TBS modulation of intrinsic M1 and S1 oscillations and (2) the impact of GABA-A alpha1 upon TBS modulation of functional M1 and S1 oscillations.