Effects of Different Analysis Strategies on Paired Associative Stimulation. A Pooled Data Analysis from Three Research Labs

Abstract

Paired associative stimulation (PAS) is a widely used transcranial magnetic stimulation (TMS) paradigm to non-invasively induce synaptic plasticity in the human brain in vivo. Altered PAS-induced plasticity has been demonstrated for several diseases. However, researchers are faced with a high inter- and intra-subject variability of the PAS response. Here, we pooled original data from nine PAS studies from three centers and analyzed the combined dataset of 190 healthy subjects with regard to age dependency, the role of stimulation parameters and the effect of different statistical methods. We observed no main effect of the PAS intervention over all studies (F(2;362) = 0.44; p = 0.644). The rate of subjects showing the expected increase of motor evoked potential (MEP) amplitudes was 53%. The PAS effect differed significantly between studies as shown by a significant interaction effect (F(16;362) = 1.77; p = 0.034) but post-hoc testing did not reveal significant effects after correction for multiple tests. There was a trend toward increased variability of the PAS effect in older subjects. Acquisition parameters differed across studies but without systematically influencing changes in MEP-size. The use of post/baseline quotients systematically indicated stronger PAS effects than post/baseline difference or the logarithm of the post/baseline quotient. The non-significant PAS effects across studies and a wide range of responder rates between studies indicate a high variability of this method. We were thus not able to replicate findings from a previous meta-analysis showing robust effects of PAS. No pattern emerged regarding acquisition parameters that at this point could guide future studies to reduce variability and help increase response rate. For future studies, we propose to report the responder rate and recommend the use of the logarithmized post/baseline quotient for further analyses to better address the possibility that results are driven by few extreme cases.

Individual level reliability of PAS-induced neural plasticity

“…This is important since inter-individual response variability is poorly understood and confounds studies in healthy and diseased populations. Two previous studies examined intra-subject reproducibility and concluded that PAS is not reliable at individual subject level (Fratello et al, 2006;Lahr et al, 2016). However, to our knowledge, no previous study collected the amount of MEP data per subject collected and analyzed in the present study.…”

Research Priorities in Limb and Task-Specific Dystonias

“…Some of these conflicting results may be due to the inherent variability of the effects of PAS even in healthy subjects (89, 90). In addition, there is also variability in the PAS paradigms resulting in differing times between median nerve stimulation and TMS (e.g., 21.5 vs. 25 ms) (91).…”

Tuning noninvasive brain stimulation with MRI to cope with intersubject variability

“…Accordingly, the existing criteria for the definition of LTP at the synapse, more specifically persistence, input specificity, associativity, and cooperativity, could be employed as a starting point to justify the choice of terminology on the network level while also entailing separate analyses of network stimulation effects. Finding a bridge between local plasticity processes observed at the cellular level and the global network behaviour might provide researchers with crucial hints as to the underlying neurophysiological factors for the observed high interindividual variability [17][18][19], which impedes the efficacy and reliability of common tDCS paradigms [20,21 && ].…”