Differential Impacts of Fronto-Cerebellar tACS and tVNS on Motor Learning: Evidence for Sex-Related Neural Modulation

Noninvasive brain stimulation (NIBS) techniques rely on distinct mechanisms and engage different neural circuits. For instance, transcranial alternating current stimulation (tACS) targets cortical networks directly, while transcutaneous vagus nerve stimulation (tVNS) influences the brain via peripheral input, reflecting top-down versus bottom-up plasticity pathways. Despite their potentialities in modulating plasticity, reports of intra and inter-subjects variability hamper their reliability as therapeutic approaches for neurorehabilitation. Here, we tested whether sex can represent a possible source of variability. We examined whether tACS and tVNS protocols affect motor learning and explored sex differences among 96 healthy adults, employing a sham-controlled, between-subjects design. A total of 48 participants (24 females) received fronto-cerebellar tACS at an individualized gamma frequency (30-80 Hz), while 48 participants (24 females) underwent tVNS applied to the cymba conchae. Both stimulations were delivered during the performance of a unimanual visuomotor task. Participants used their right index finger to click and drag an object from the center of the screen to a target bin. Analyses were conducted on precision error (PE), the Euclidean distance between the target bin and drop point, and readiness, measured by reaction times (RTs) from paper appearance to click-to-collect. Results showed an influence of sex on tACS effects on PE: on average, female participants improved precision for near targets, whereas male participants improved for far targets, with substantial overlap between groups. This was accompanied by a slowing of RTs in both sexes. tVNS had no significant effect on PE for either sex but showed distinct effects on readiness: slowing RTs in the male participants and speeding them in the female participants. The results highlight the need to consider sex as a critical factor modulating the effects of NIBS and explore the underlying cognitive, neural, and physiological mechanisms.