PROJECT SUMMARY Notwithstanding decades of work on the mechanisms and applications of transcranial direct current stimulation (tDCS), the translation of tDCS to a broadly-used and meaningful therapy is halted. We propose that this is a result of three factors that will be addressed in this proposal. First, the intensity of stimulation has remained limited; Second, there is a lack of clarity as to whether stimulation should be paired with a specific behavioral task; and third, there is a lack of consensus on the underlying mechanisms of action. We have shown in vitro that electric field stimulation can polarize neurons in proportion to the applied field, which interacts with concurrent induction of synaptic plasticity, and is thus functionally specific. In light of this, tDCS should inherit the specificity of concurrent behavioral training and effects should scale with intensity. This hypothesis will be tested here in parallel human and rat experiments in the context of motor learning. Aim 1 is to test the prediction that stimulation has to be concurrent to behavioral motor learning, and effects scale with intensity and reverse with polarity. In humans we will test this with a newly-developed electrode montage that achieves the highest field-intensities on the motor cortex to-date, resulting in strong effect sizes for motor sequence learning. For rats, we will use a new stimulation protocol with strong effects on learning in a pellet-reaching task. Aim 2 is to test the prediction, in humans and rats, that effects are specific to the stimulated motor cortex and, in humans, that effects are specific to the trained task. Outcome measures will be motor learning and motor cortex excitability (motor-evoked potentials). Aim 3 is to test the hypothesis in rats that behavioral benefits of tDCS are associated with spatially specific functional and structural changes in the motor cortex (measured with 2D motor map and synaptic markers), and causally depends on modulation of motor cortex activity (controlled with chemogenetic inactivation). The outcomes of these experiments, regardless of whether they confirm or refute the basic hypothesis, will directly address the factors that are limiting progress. By emphasizing rigor this project will yield robust go-to experiments that can serve as standard tools for future exploration. By focusing on motor learning, the work is immediately applicable to motor rehabilitation.

NARRATIVE Learning a new skill is thought to enhance the synaptic connection between neurons. Transcranial direct current stimulation can boost the process of synaptic enhancement. This project will establish whether and how this interaction can be used to boost learning of new movement skills, and may thus benefit future treatment strategies for motor rehabilitation.