Abstract
Transcranial magnetic stimulation (TMS) is a well-established tool in probing cortical plasticity in vivo. Changes in corticomotor excitability can be induced using paired associative stimulation (PAS) protocol, in which TMS over the primary motor cortex is conditioned with an electrical peripheral nerve stimulation of the contralateral hand. PAS with an inter-stimulus interval of 25 ms induces long-term potentiation (LTP)-like effects in cortical excitability. However, the response to a PAS protocol tends to vary substantially across individuals. In this study, we used univariate and multivariate data-driven methods to investigate various previously proposed determinants of inter-individual variability in PAS efficacy, such as demographic, cognitive, clinical, neurophysiological, and neuroimaging measures. Forty-one right-handed participants, comprising 22 patients with amnestic mild cognitive impairment (MCI) and 19 healthy controls (HC), underwent the PAS protocol. Prior to stimulation, demographic, genetic, clinical, as well as structural and resting-state functional MRI data were acquired. The two groups did not differ in any of the variables, except by global cognitive status. Univariate analysis showed that only 61% of all participants were classified as PAS responders, irrespective of group membership. Higher PAS response was associated with lower TMS intensity and with higher resting-state connectivity within the sensorimotor network, but only in responders, as opposed to non-responders. We also found an overall positive correlation between PAS response and structural connectivity within the corticospinal tract, which did not differ between groups. A multivariate random forest (RF) model identified age, gender, education, IQ, global cognitive status, sleep quality, alertness, TMS intensity, genetic factors, and neuroimaging measures (functional and structural connectivity, gray matter (GM) volume, and cortical thickness as poor predictors of PAS response. The model resulted in low accuracy of the RF classifier (58%; 95% CI: 42 − 74%), with a higher relative importance of brain connectivity measures compared to the other variables. We conclude that PAS variability in our sample was not well explained by factors known to influence PAS efficacy, emphasizing the need for future replication studies.
Highlights
Transcranial magnetic stimulation (TMS) is a well-established non-invasive brain stimulation tool that can be used to probe cortical plasticity
We hypothesize that a combination of different factors would be best suited to predict the efficiency of the paired associative stimulation (PAS) outcome, and, second, we aim to assess the hierarchical importance of these determinants of PAS variability, which could be used to inform future studies focusing on TMS-induced plasticity
No difference was found between genetic factors such as the presence of Apolipoprotein E (APOE) allele ε4 genotype (X2(1) = 0.138, p = 0.241) or brain-derived neurotrophic factor (BDNF) Val66mMet polymorphism (X2(1) = 0, p = 1)
Summary
Transcranial magnetic stimulation (TMS) is a well-established non-invasive brain stimulation tool that can be used to probe cortical plasticity. Changes in corticomotor excitability can be induced using a paired associative stimulation (PAS; Stefan et al, 2000). This involves the repeated application of an electrical peripheral nerve stimulus (e.g., median nerve stimulation; MNS) paired with a single-pulse TMS to the primary motor cortex. Depending on the inter-stimulus intervals and stimulation duration, PAS may induce either long-term potentiation (LTP)-like or long-term depression (LTD)-like effects (Ziemann et al, 2008). Such shifts in corticomotor excitability are quantified by topographically specific changes in the MEP amplitudes
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