The goal of this proposal is demonstrate the efficacy of deep brain stimulation (DBS) in enhancing recovery following traumatic brain injury (TBI) in rodents and non- human primates. Over the past decade our group has extensively studied the role of the striatum and cortex in learning, and found that stimulation in the caudate can enhance learning. More recently, we have made an important breakthrough in demonstrating, in a preliminary fashion, that this approach can be used to accelerate and enhance recovery in an animal model of TBI. In this proposal, we will test specific hypotheses regarding the optimal brain location and mode of stimulation for maximal effect in the treatment of TBI. We have a considerable amount of preliminary data, in both rodents and primates, demonstrating that there is a significant improvement in recovery by using appropriately targeted and timed DBS. This work has great public health significance and may lead to a new treatment modality for TBI patients and potentially for patients with other disorders such as stroke, Alzheimer disease or autism. Work from our group, and others, has demonstrated that connections between the Caudate (Cd), Nucleus Accumbens (NAcc), and prefrontal cortex play a critical role in learning and motivation which are key aspects of recovery from brain injury. Our group has also published studies demonstrating that Cd stimulation enhances learning beyond baseline rates in normal animals. Recently, we have gathered preliminary data that combined stimulation of the Cd and NAcc leads to an even greater enhancement of learning, compared to isolated Cd stimulation. We have evidence suggesting that stimulation works by enhancing efficacy of the intrinsic learning circuitry and not by being simply rewarding. In addition, we have developed a new capability in our laboratory to use a validated animal model of TBI. We have very promising preliminary data that intermittent stimulation can enhance recovery after TBI. We now seek support to provide definitive evidence that timed DBS of the Cd and NAcc can be used to accelerate recovery following TBI. We will use models of TBI in rodents and primates to rigorously and systematically assess the effects of intermittent stimulation on functional recovery. In addition, we will employ histological studies of neuronal plasticity and neurogenesis to provide evidence regarding the biological effects of stimulation. By the end of the funding period, we will be positioned to initiate a Phase I human trial.