Classical conditioning of the eyeblink reflex (EBC) is a simple form of associative motor learning. EBC is heavily dependent on cerebellar function, but experimental studies also suggest that the prefrontal cortex (PFC) orchestrates a neuronal network which interacts with the cerebellum to mediate the conditioned eyeblink responses (CR). To further investigate the role of PFC for EBC in humans, we aimed in this study at assessing whether acquisition of CR can be modulated by focal repetitive transcranial magnetic stimulation (rTMS) given as theta burst stimulation (TBS) over the dorsolateral PFC (DLPFC). A standard delay conditioning paradigm with a 540 ms tone as conditioned stimulus (CS) coterminating with a 100 ms air puff as unconditioned stimulus (US) was used in a total of 60 healthy subjects (35 female, 25 male, mean age 28.4 ± 2.4 years). One hundred paired CS-US trials and 30 extinction CS alone trials were given. TBS was applied over the DLPFC ipsilaterally to the US during the acquisition phase. Subjects were randomly assigned to three groups (n = 20) using excitatory intermittent TBS (iTBS), inhibitory continuous TBS (cTBS) or sham stimulation. CR acquisition was significantly enhanced by iTBS (mean total CR incidence 63.1 ± 6.5%) and significantly reduced by cTBS (13 ± 2%) compared to sham stimulation (25.1 ± 6.7%). We provide thus physiological evidence that the acquisition of this type of associative learning is critically modulated by PFC activity in humans.
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