Introduction. Transcranial Magnetic Stimulation (TMS) is a non-invasive method for stimulating the human brain. Classical conditioning is a phenomenon in which an association is developed between two stimuli. Most, if not all, prior examples of classical conditioning have established contingencies through two sensory-initiated systems. The objective of this work was to determine if classical conditioning principles could be applied to emerging methods for direct brain stimulation, such as TMS.;Methods. A TMS coil was placed over the motor cortex to generate a motor evoked potential (MEP). Exploring various parameters, a compound auditory/visual stimulus was then paired with TMS. Thus TMS was utilized as the unconditioned stimulus (US), with the MEP being the unconditioned response (UR). The compound sensory stimulus was employed as the conditioned stimulus (CS+), with assessments for MEPs as evidence of a conditioned response (CR). In a separate set of experiments, TMS was presented alone after pairing (US+/CS-) as an alternative method for examining the development of a CS-US contingency.;Results. Following pairing, the auditory/visual stimulus alone (CS+) elicited MEPs (CR) in a rapid pairing paradigm, but not in an optimized pairing paradigm. The conditioned responses were smaller in magnitude than TMS-induced or volitionally-induced MEPS, but had similar temporal characteristics. Furthermore with TMS presented alone (US+/CS-) following pairing, a robust increase in the MEP magnitude was noted in the optimized pairing paradigm, but this finding was not as evident in the rapid paring paradigm.;Conclusions. These results support the idea that classical conditioning principles can be applied to direct brain stimulation techniques. Additionally, pre-pulse inhibition may counteract the capacity to induce conditioned responses. These findings have significance for basic science research regarding the development of associations in the brain, as well as for developing the therapeutic uses of brain stimulation.
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