Transcranial direct current stimulation (TDCS) is a technique with which neuronal activity, and therefore potentially behavior, is modulated by applying weak electrical currents to the scalp. Application of TDCS to enhance working memory (WM) has shown promising but also contradictory results, and little emphasis has been placed on repeated stimulation protocols, in which effects are expected to be increased. We aimed to characterize potential behavioral and electrophysiological changes induced by TDCS during WM training and evaluate whether repetitive anodal TDCS has a greater modulatory impact on the processes underpinning WM than single-session stimulation. We examined the effects of single-session and repetitive anodal TDCS to the dorsolateral prefrontal cortex (DLPFC), targeting the frontal-parietal network, during a WM task in 20 healthy participants. TDCS had no significant impact on behavioral measures, including reaction time and accuracy. Analyzing the electrophysiological response, the P300 amplitude significantly increased following repetitive anodal TDCS, however, positively correlating with task performance. P300 changes were identified over the parietal cortex, which is known to engage with the frontal cortex during WM processing. These findings support the hypothesis that repetitive anodal TDCS modulates electrophysiological processes underlying WM.

Cerebellum (CB) and primary motor cortex (M1) have been associated with motor learning, with different putative roles. Modulation of task performance through application of transcranial direct current stimulation (TDCS) to brain structures provides causal evidence for their engagement in the task. Studies evaluating and comparing TDCS to these structures have provided conflicting results, however, likely due to varying paradigms and stimulation parameters. Here we applied TDCS to CB and M1 within the same experimental design, to enable direct comparison of their roles in motor sequence learning. We examined the effects of anodal TDCS during motor sequence learning in 60 healthy participants, randomly allocated to CB-TDCS, M1-TDCS, or Sham stimulation groups during a serial reaction time task. Key to the design was an equal number of repeated and random sequences. Reaction times (RTs) to implicitly learned and random sequences were compared between groups using ANOVAs and post hoc t-tests. A speed–accuracy trade-off was excluded by analogous analysis of accuracy scores. An interaction was observed between whether responses were to learned or random sequences and the stimulation group. Post hoc analyses revealed a preferential slowing of RTs to implicitly learned sequences in the group receiving CB-TDCS. Our findings provide evidence that CB function can be modulated through transcranial application of a weak electrical current, that the CB and M1 cortex perform separable functions in the task, and that the CB plays a specific role in motor sequence learning during implicit motor sequence learning.

Ventrointermediate thalamic stimulation (VIM-DBS) modulates oscillatory activity in a cortical network including primary motor cortex, premotor cortex, and parietal cortex. Here we show that, beyond the beneficial effects of VIM-DBS on motor execution, this form of invasive stimulation facilitates production of sequential finger movements that follow a repeated sequence. These results highlight the role of thalamo–cortical activity in motor learning.

The cholinergic system plays a key role in motor function, but whether pharmacological modulation of cholinergic activity affects motor sequence learning is unknown. The acetylcholine receptor antagonist biperiden, an established treatment in movement disorders, reduces attentional modulation, but whether it influences motor sequence learning is not clear. Using a randomized, double‐blind placebo‐controlled crossover design, we tested 30 healthy young participants and showed that biperiden impairs the ability to learn sequential finger movements, accompanied by widespread oscillatory broadband power changes (4–25 Hz) in the motor sequence learning network after receiving biperiden, with greater power in the theta, alpha and beta bands over ipsilateral motor and bilateral parietal–occipital areas. The reduced early theta power during a repeated compared with random sequence, likely reflecting disengagement of top‐down attention to sensory processes, was disrupted by biperiden. Alpha synchronization during repeated sequences reflects sensory gating and lower visuospatial attention requirements compared with visuomotor responses to random sequences. After biperiden, alpha synchronization was greater, potentially reflecting excessive visuospatial attention reduction, affecting visuomotor responding required to enable sequence learning. Beta oscillations facilitate sequence learning by integrating visual and somatosensory inputs, stabilizing repeated sequences and promoting prediction of the next stimulus. The beta synchronization after biperiden fits with a disruption of the selective visuospatial attention enhancement associated with initial sequence learning. These findings highlight the role of cholinergic processes in motor sequence learning.

The cholinergic system plays a key role in motor function, but whether pharmacological modulation of cholinergic activity affects motor sequence learning is unknown. The acetylcholine receptor antagonist biperiden, an established treatment in movement disorders, reduces attentional modulation, but whether it influences motor sequence learning is not clear. Using a randomized, double-blind placebo-controlled crossover design, we tested thirty healthy young participants and show that biperiden impairs production of sequential finger movements following a fixed but not a random sequence. A similar interaction was observed in widespread oscillatory broadband power changes (4-25 Hz) in the motor sequence learning network after receiving biperiden, with greater power in the theta, alpha, and beta bands over ipsilateral motor and bilateral parietal–occipital areas. The reduced theta power during a fixed compared to random sequence, likely reflecting disengagement of top-down attention to sensory processes, was disrupted by biperiden. The alpha synchronization during learned sequences, reflecting sensory gating and lower visuospatial attention requirements for the learned, compared with visuomotor responses to a random sequence, was greater after biperiden, potentially reflecting excessive visuospatial attention reduction following biperiden, also affecting visuomotor responding required to enable sequence learning. Beta oscillations facilitate sequence learning by integrating visual and somatosensory inputs, stabilizing learned sequences, and promoting prediction of the next stimulus. The beta synchronization after biperiden fits with a disruption of the selective visuospatial attention enhancement associated with initial sequence learning. These findings highlight the role of cholinergic processes in motor sequence learning.

Ventrointermediate thalamic stimulation (VIM-DBS) modulates oscillatory activity in a cortical network including primary motor cortex, premotor cortex, and parietal cortex. Here we show that, beyond the beneficial effects of VIM-DBS on motor execution, this form of invasive stimulation facilitates production of sequential finger movements that follow a fixed sequence but not when the sequence is selected at random. These results highlight the role of thalamo–cortical activity in motor learning.