In this proof-of-concept study, we questioned whether the influence of TMS on cortical excitability can be applied to classical conditioning. More specifically, we investigated whether the faciliatory influence of paired-pulse TMS on the excitability of the human motor cortex can be transferred to a simultaneously presented auditory stimulus through conditioning. During the conditioning phase, 75 healthy young participants received 170 faciliatory paired TMS pulses (1st pulse at 95% resting motor threshold, 2nd at 130%, interstimulus interval 12 ms), always presented simultaneously with one out of two acoustic stimuli. In the test phase, 20 min later, we pseudorandomly applied 100 single TMS pulses (at 130% MT), 50 paired with the conditioned tone—50 paired with a control tone. Using the Wilcoxon-Signed Rank test, we found significantly enhanced median amplitudes of motor evoked potentials (MEPs) paired with the conditioned tone as compared to the control tone, suggesting successful conditioning (p = 0.031, responder rate 55%, small effect size of r = − 0.248). The same comparison in only those participants with a paired-pulse amplitude < 2 mV in the conditioning phase, increased the responder rate to 61% (n = 38) and effect size to moderate (r = − 0.389). If we considered only those participants with a median paired-pulse amplitude < 1 mV, responder rate increased further to 79% (n = 14) and effect size to r = − 0.727 (i.e., large effect). These findings suggest increasingly stronger conditioning effects for smaller MEP amplitudes during paired-pulse TMS conditioning. These proof-of-concept findings extend the scope of classical conditioning to faciliatory paired-pulse TMS.

Background In this proof-of-concept study, we questioned whether the transient influence of TMS on cortical excitability can be applied to classical conditioning. Objective More specifically, we investigated whether the faciliatory influence of paired-pulse TMS on the excitability of the human motor cortex can be transferred to a simultaneously presented auditory stimulus through conditioning. Methods During the conditioning phase, 75 healthy young participants received 170 faciliatory paired TMS pulses (1st pulse at 95% resting motor threshold (MT), 2nd at 130% MT, interstimulus interval 12ms), always presented simultaneously with one out of two acoustic stimuli. In the test phase, 20 min later, we pseudorandomly applied 100 single TMS pulses (at 130% MT), 50 paired with the conditioned tone − 50 paired with a control tone. Results Comparing the amplitude of the motor evoked potential (MEP) paired with the conditioned tone to the control tone, we found significantly enhanced MEP amplitudes, suggesting successful conditioning (p = 0.03, 55% responder rate). Correlation analyses revealed that the MEP amplitude after paired-pulse stimulation in the conditioning phase related to the MEP single-pulse amplitude combined with the conditioned tone in the test phase (r = 0.603, p < 0.001), and the overall effect of conditioning (i.e., amplitude conditioned tone/control tone; r=-0.213, p = 0.068), suggesting that the higher the amplitudes during conditioning, the higher also the amplitudes during the following test phase and the weaker the effect of conditioning. We next compared single-pulse amplitudes paired with the conditioned tone vs. control tone only in those participants with a paired-pulse amplitude < 2mV in the conditioning phase. Responder rate in this group increased from 55–61% (n = 38, p = 0.01), and even further to 79% (n = 14, p = 0.005) if we considered only those participants with a median paired-pulse amplitude < 1mV, suggesting increasingly stronger conditioning effects for smaller MEP amplitudes after paired-pulse stimulation during conditioning. Conclusion Present findings extend the scope of classical conditioning to paired-pulse TMS induced intracortical facilitation.