The proposed projects will investigate synaptic plasticity in the primate motor system, using a novel bidirectional brain-computer interface (BBCI). The BBCI records neural activity and uses a programmable computer chip to deliver activity-contingent stimuli in real time to nervous system sites during hours of free behavior. We will use the BBCI to produce spike timing-dependent plasticity through neurally-triggered and paired stimulation, which can strengthen physiological connections. The effects of the conditioning will be documented by changes in cortical connectivity, as measured by spike- and stimulus-triggered averages of cortical field potentials and correlational measures of spontaneous activity. We will attempt to generate plasticity with surface stimulation, which is less invasive than intracortical stimulation and would be easier to translate to clinical applications. To further investigate the neural elements mediating plasticity we will compare the conditioning effects produced by optogenetic stimulation of excitatory neurons with those produced by electrical stimulation at the same sites. Also, we will investigate for the first time whether the stimulation-induced plasticity can be prolonged through additional interventions and whether more than one pair of cortical sites can be simultaneously conditioned. Finally, we will investigate the influence of behavioral state, such as sleep and waking, on cortical connectivity and the efficacy of inducing plasticity. These studies will provide crucial evidence to inform clinical applications of closed-loop stimulation targeting neural plasticity. The results will advance development of novel therapies to improve recovery after stroke, traumatic brain injury and spinal cord injury.