Study of Motor Inhibition in Parkinson's Disease and Focal Hand Dystonia

Overview

The current research protocol aims at studying preparatory inhibition in two populations of patients suffering from movement disorders. First, in PART 1, we will work with Parkinson's disease (PD) patients to investigate the contribution of the basal ganglia in preparatory inhibition (Project 1 \[P1\] and Project 2 \[P2\]). Then, in PART 2, we will consider patients with focal hand dystonia (FHD), to test the hypothesis that altered muscle selectivity in this pathological condition is, at least in part, due to a lack of preparatory inhibition.

Any movement requires some planning, relying substantially on neural cells in the frontal cortex connected with spinal circuits, which themselves help regulating muscle activity. These corticospinal projections provide a critical route through which the brain controls motor behaviour. Interestingly, the excitability of the corticospinal pathway can be investigated non-invasively in humans by applying single-pulse transcranial magnetic stimulation (TMS) over the primary motor cortex (M1), eliciting motor-evoked potentials (MEPs) in targeted contralateral muscles. MEPs are useful indicators of motor excitability, as their amplitude provides a muscle-specific assay of the net impact of facilitatory and inhibitory inputs at the time of the stimulation. Critically, TMS studies have revealed that the corticospinal pathway shows profound inhibitory changes during action preparation, consistent with the contribution of inhibitory processes to movement control. This effect, referred to as preparatory inhibition, has been evidenced in reaction time (RT) tasks, regardless of whether the subjects have to select a response within a set of predefined options (choice RT task) or have to specify the same response on every trial, in the absence of choice (simple RT task). In these tasks, as expected, the amplitude of MEPs elicited in the selected effector rises during the pre-movement period. However, before activity begins to ramp up, there is an initial decrease in the amplitude of MEPs, indicating the suppression of the corticospinal pathway associated with the selected movement. A reduction in MEP amplitude is also observed in non-selected and irrelevant effectors, and here, the amplitude further drops over the course of action preparation. Preparatory inhibition is not only present preceding movement onset; it is also manifest before the go signal in instructed-delay RT tasks, when a cue provides advance information about the forthcoming response, but the subject must then wait until the go signal is presented to release his response. At that time, suppression is evident for MEPs elicited in finger effectors, including those that are selected, non-selected or task-irrelevant; leg muscle MEPs can also show some suppression during preparation of finger responses but to a much weaker extent , indicating that preparatory inhibition of the motor system is broad, but with some degree of restriction; it is most prominent for motor representations that are from the same body segment as the selected effector and attenuated in other limb representations. Several hypotheses have been advanced to explain the broad suppression of corticospinal excitability observed during action preparation, with some related to impulse control and others to neural gain modulation. Yet, the functional role of preparatory inhibition remains intensively debated. Further, there is very little knowledge about the brain regions involved in generating this suppression in the corticospinal pathway. The current research protocol aims at studying preparatory inhibition in two populations of patients suffering from movement disorders. First, we will work with Parkinson's disease (PD) patients to investigate the contribution of the basal ganglia in preparatory inhibition (Project 1 \[P1\] and Project 2 \[P2\], see below). Then, we will consider patients with focal hand dystonia (FHD), to test the hypothesis that altered muscle selectivity in this pathological condition is, at least in part, due to a lack of preparatory inhibition (Project 3 \[P3\], described below). Beyond its fundamental goals, the present proposal may also provide scientific knowledge to guide intervention strategies that improve motor function in PD and FHD patients. This issue is of great relevance given the increasing life expectancy in our society and the increasing incidence of PD (in particular) that goes with it. The present proposal may also help develop intervention strategies in other pathologies associated with inhibitory deficits, including impulsive decision-making (e.g. PD; drug addiction). This issue is of great importance given the prevalence of such pathologies in our contemporary society.