Changes in cortical excitability during paired associative stimulation in Parkinson's disease patients and healthy subjects

•PNS conditioned TMS responses are suppressed during facilitatory PAS intervention.•Inhibition during PAS is impaired in both drug-naïve and treated PD patients.•PAS-related cortical networks are damaged at the clinical onset of the disease.•PAS-related cortical networks are not influenced by subsequent PD treatment. Paired associative stimulation (PAS) combines repetitive peripheral nerve stimulation with motor cortex (M1) transcranial magnetic stimulation (TMS), to induce plastic-like changes of cortical excitability. While much attention has been dedicated to post-PAS effects little is known about processes during PAS. We compared the time-course of changes in M1 excitability during standard facilitatory PAS intervention among patients with Parkinson’s disease (PD), known to have diminished post-PAS response, and healthy subjects. Compared to baseline pre-PAS MEPs, conditioned MEPs during PAS decreased significantly in both groups. The decrease was significantly larger in healthy subjects than in PD patients, regardless whether patients were drug-naïve or not. Although post-PAS excitability increase was also larger in healthy subjects than in PD patients, there was no significant correlation between the two phenomena, i.e. the extent of MEP decrease during PAS and the extent of the post-PAS excitability increase. The results highlight an apparent physiological paradox that repetitive application of an inhibitory stimulation pattern leads to subsequent prolonged facilitation, thus broadening the understanding of the phenomenology of PAS response. Results also suggest that in PD cortical circuits involved in conveying inhibition during PAS, are impaired at the clinical onset of the disease and are not influenced by subsequent PD treatment.