Within-subject Consistency of Paired Associative Stimulation as Assessed by Linear Mixed Models

Abstract

Keywords: transcranial magnetic stimulation (TMS); paired associative stimulation 22(PAS); reproducibility; intra-individual variability; linear mixed models; long-term 23 potentiation (LTP); spike-timing dependent plasticity (STDP). 25Abstract 26Paired associative stimulation (PAS) is a frequently used TMS paradigm that induces long-27 term potentiation in the human cortex. However, little is known about the within-subject 28 consistency of PAS-induced effects. We determined PAS-induced effects and their 29 consistency in healthy volunteers between two PAS sessions. Additionally, we assessed the 30 benefit of applying linear mixed models (LMMs) to PAS data. Thirty-eight healthy volunteers 31 underwent two identical PAS sessions with a >1 week interval. During each session, motor 32 evoked potentials (MEPs) were assessed once before PAS induction and 3 times after at 30 33 min intervals. We did not detect any significant potentiation of MEP size after PAS induction. 34However, MEP size during PAS induction showed significant potentiation over time in both 35 sessions (LR (1)=13.36, p<0.001). Nevertheless, there was poor within-subject consistency of 36 PAS-induced effects both during (ICC=0.15) and after induction (ICC=0.04-0.09). 37 Additionally, statistical model selection procedures demonstrate that a LMM with an 38 unstructured covariance matrix better estimated PAS-induced effects than one with a 39 conventional compound symmetry matrix (LR(34)=214.73, p<0.001). While our results are 40 supportive of a high intra-individual variability of PAS-induced effects, the generalizability of 41 our results is unclear, as we were only partially successful in replicating results from previous 42 PAS studies typically showing potentiation of MEPs during and after PAS induction. We do, 43 however, demonstrate that linear mixed models can improve the reliability of PAS-induced 44 effects estimation. 45 46