Abnormal excitability of premotor-motor connections in de novo Parkinson's disease

The dorsal premotor cortex (PMd) is abnormally active in patients with idiopathic Parkinson's disease. This has been interpreted as a functional correlate of adaptive plasticity within the motor system to compensate for deficient activation of striato-mesial-frontal projections in these patients. Whether abnormal PMd activity influences excitability in the primary motor cortex (M1) in untreated Parkinson's disease patients and how this premotor-motor interaction might be altered by l-dopa is unclear. To this end, we studied the effects of 1 Hz premotor repetitive transcranial magnetic stimulation (rTMS) on M1 excitability in 10 previously untreated non-tremulous Parkinson's disease patients before (day 1) and after (day 8) their first ever l-dopa treatment and compared the results with those of a group of nine age- and sex-matched healthy controls. In each rTMS session, 1200 pulses of 1 Hz rTMS were applied at an intensity of 80% active motor threshold (AMT) to the PMd contralateral to the clinically more affected side in Parkinson's disease patients and to the left PMd in healthy controls. Intracortical paired pulse excitability of ipsilateral M1 was probed using a TMS paired pulse paradigm where subthreshold conditioning pulses (80% of AMT) were given 2-15 ms prior to a suprathreshold test pulse. In Parkinson's disease patients, abnormal baseline intracortical excitability at an interstimulus interval (ISI) of 5 ms was normalized by premotor rTMS. In contrast, rTMS led to an increased excitability at an ISI of 5 ms in healthy controls. Premotor rTMS effects lasted longer (for at least a week) in patients. These results show that the modifiability of premotor-motor connections is abnormal in untreated Parkinson's disease. A single dose of l-dopa reversed, i.e. normalized, the direction of excitability changes in M1 following premotor rTMS in Parkinson's disease patients, suggesting that dopamine depletion directly or indirectly influences premotor-motor interactions in Parkinson's disease. The rTMS conditioning approach described here provides a promising tool to delineate further the excitability changes in frontal motor areas in response to progressive degeneration of nigrostriatal dopaminergic neurons and also to chronic l-dopa treatment in Parkinson's disease.