Motor-cortex excitability and response variability following paired-associative stimulation: a proof-of-concept study comparing individualized and fixed inter-stimulus intervals.

While diverging efficacy and inter-individual response variability have repeatedly been reported for paired-associative stimulation (PAS), approaches to overcome these issues are yet lacking. Hence, the aim of the present study was to determine whether response variability could be reduced through the application of an individualized PAS paradigm. Changes of transcranial magnetic stimulation (TMS) elicited motor-evoked potentials (MEP) following different PAS paradigms were assessed in three experimental conditions. According to a within-subjects design, 21 participants received three consecutive PAS paradigms differing with respect to the applied inter-stimulus intervals (ISI) between peripheral nerve stimulation (PNS) and TMS. Based on foregoing considerations, we compared fixed ISI of 25 ms (PAS 25) and 22 ms (PAS 22) to an individualized PAS paradigm accounting for conduction time differences on the single subject level (iPAS). Overall, we did not observe significantly increased post-stimulation MEP magnitudes in any of the three experimental paradigms. Explorative analyses revealed increased inter-individual response variability in case of PAS 25 and PAS 22 compared to higher rates of expected MEP magnitude increases in case of our iPAS paradigm. The findings of our proof-of-concept study points towards a potential association of decreased inter-individual variability with individually selected ISI that account for differences in conduction time. However, as our findings did not reach the significance threshold, our study highlights the issue of intra-individual variability in PAS paradigms. Further replication studies with larger sample sizes and repetitive designs are needed to confirm our findings.