Motor skills can take weeks to months to acquire and can diminish over time in the absence of continued practice. Thus, strategies that enhance skill acquisition or retention are of great scientific and practical interest. Here we investigated the effect of noninvasive cortical stimulation on the extended time course of learning a novel and challenging motor skill task. A skill measure was chosen to reflect shifts in the task's speed-accuracy tradeoff function (SAF), which prevented us from falsely interpreting variations in position along an unchanged SAF as a change in skill. Subjects practiced over 5 consecutive days while receiving transcranial direct current stimulation (tDCS) over the primary motor cortex (M1). Using the skill measure, we assessed the impact of anodal (relative to sham) tDCS on both within-day (online) and betweenday (offline) effects and on the rate of forgetting during a 3-month follow-up (long-term retention). There was greater total (online plus offline) skill acquisition with anodal tDCS compared to sham, which was mediated through a selective enhancement of offline effects. Anodal tDCS did not change the rate of forgetting relative to sham across the 3-month follow-up period, and consequently the skill measure remained greater with anodal tDCS at 3 months. This prolonged enhancement may hold promise for the rehabilitation of brain injury. Furthermore, these findings support the existence of a consolidation mechanism, susceptible to anodal tDCS, which contributes to offline effects but not to online effects or long-term retention.long-term retention ͉ motor cortex ͉ motor learning ͉ transcranial direct current stimulation (tDCS) ͉ transcranial magnetic stimulation (TMS) A ccurate motor performance is essential to almost everything we do, from typing, to driving, to playing sports. Having a motor skill implies a level of performance in a given task that is only achievable through practice (1). Evidence indicates that motor skill learning can continue over a prolonged time period (2-5). Within-session performance improvements (online effects) occur in the minutes or hours of a single training session and continue over days and weeks of repeated training sessions until performance nears asymptotic levels. Changes in performance can also occur between training sessions (offline effects), i.e., performance at the beginning of session n ϩ 1 is different from performance at the end of session n (6, 7). We have intentionally chosen to avoid the use of the term ''offline learning'' because it has been used to refer to both a physiological process (consolidation) (6) and a particular measurement result (a positive offline effect) (8). Offline effects could also be negative, presumably because of forgetting processes (7). Skills can be retained to varying degrees over weeks to months after the completion of training (long-term retention) (5). Here we investigated the effect of noninvasive cortical stimulation on measurements of these 3 temporal components of skill learning (online effects, of...

SUMMARY Despite its increasing use in experimental and clinical settings, the cellular and molecular mechanisms underlying transcranial direct current stimulation (tDCS) remain unknown. Anodal tDCS applied to human motor cortex (M1) improves motor skill learning. Here, we demonstrate in mouse M1 slices that DCS induces a long-lasting synaptic potentiation (DCS-LTP), which is polarity-specific, NMDA-receptor dependent and requires coupling of DCS with repetitive low-frequency synaptic activation (LFS). Combined DCS and LFS enhance BDNF-secretion and TrkB-activation, and DCS-LTP is absent in BDNF and TrkB mutant mice, suggesting that BDNF is a key mediator of this phenomenon. Moreover, the BDNF val66met polymorphism known to partially affect activity-dependent BDNF secretion impairs motor skill acquisition in humans and mice. Motor learning is enhanced by anodal tDCS, as long as activity-dependent BDNF secretion is in place. We propose that tDCS may improve motor skill learning through augmentation of synaptic plasticity that requires BDNF-secretion and TrkB-activation within M1.