The goal of this project is to gain a better understanding of the neurophysiological substrates underlying interference of skill learning. Practicing motor tasks in close succession can interfere with learning, however, if sufficient time passes between the training of 2 skills (i.e. 6hrs), then interference is weaker. Despite extensive study about the behavioral consequences of interference, the neurophysiologic mechanisms underlying it are largely unknown. This is very important because the cortical plasticity changes associated with motor learning may represent the neurophysiological mechanisms that prevent learning of a second task. For instance, animal studies have shown motor learning induced long-term potentiation (LTP) changes in the trained primary motor cortex are also associated with a reduced capacity to sustain more LTP, a phenomenon known as LTP-saturation or homeostatic plasticity. Homeostatic plasticity has also been observed in humans. The overall purpose of this proposal is to test whether homeostatic plasticity following skill learning is one of the mechanisms underlying behavioral interference. This will be accomplished by using non-invasive transcranial direct current stimulation (tDCS) to induce LTP-like plasticity changes after training of a sequential visual isometric pinch task (SVIPT) either in the context of learning, performance with no learning, or learning with interference. To determine excitability changes in the motor cortex resulting from training and tDCS, transcranial magnetic stimulation (TMS) will be used to assess the magnitude of saturation (homeostatic plasticity) associated with practicing the task in these contexts. In Aim 1, I hypothesize that the acquisition of a skill will result in the saturation of the LTP-like plasticity effects of anodal tDCS (homeostatic plasticity phenomena), and that the magnitude of this homeostatic plasticity after learning a skill will be proportional to the magnitude of retention and interference. In addition, I will assess the effect of time on the neurophysiology of interference. In Aim 2, I hypothesize that 6 hours of time between training of 2 skills will be associated with a restoration of the LTP-like plasticity of anodal tDCS (lack of saturation), and that this restoration will be associated with a decrease in interference. These results would indicate that LTP-like changes in the primary motor cortex resulting from learning are at least one of the neural substrates underlying behavioral interference. If this holds true the homeostatic plasticity phenomena can become a predictor of interference. Importantly, improving our understanding of the basic mechanisms underlying skill learning and interference has clear clinical benefits. These findings have the potential to impact how individuals train motor skills, and perhaps more importantly, how rehabilitation training exercises are delivered in patients after brain lesions like stroke. Furthermore, this research may prove useful to develop interventions to enhance learning of multiple tasks. PUBLIC HEALTH RELEVANCE: This research will improve our understanding of some of the basic mechanisms underlying skill learning. These findings have the potential to impact how individuals train motor skills, and perhaps more importantly, how rehabilitation training exercises are delivered in patients with brain dysfunction. Furthermore, this work could also lead to interventions targeting these mechanisms as a means to augment motor learning and rehabilitation.