Following spinal cord injury, a majority of patients develop maladaptive plastic changes within the central nervous system (CNS). These changes result in abnormal regulation of peripheral inputs, and impaired perception of tactile and painful stimuli. The majority of these patients suffer because conventional treatments fail to reverse these maladaptive changes. An alternative and potentially effective modality of treatment-motor cortex stimulation (MCS)-offers hope for these patients. However, treatment outcomes with MCS are variable mainly because of the lack of understanding of how stimulation of the motor cortex reverses these maladaptive changes in the CNS. The goal of this application is to elucidate the neurobiological basis of regained sensory processing in the CNS following MCS. To this end, we use a rodent model of spinal cord injury. We demonstrated recently that activity in the GABAergic nucleus zona incerta (ZI) is suppressed in animals following spinal cord injury, resulting in enhanced activity in the posterior thalamus (PO) and enhanced flow of peripheral inputs to the neocortex. We also demonstrate that electrical stimulation of ZI mimics the effects of MCS and reverses maladaptive plastic changes observed following spinal cord injury. Based on these findings, and because the motor cortex projects densely upon ZI, we propose that MCS produces pain relief by enhancing inhibitory inputs to the posterior thalamus from zona incerta and that chronic MCS results in long term synaptic changes in the incerto-thalamic circuit. We will test the following aims: Aim 1: MCS suppresses hyperalgesia by enhancing inhibitory inputs from ZI to PO. Aim 2: Reduction of hyperalgesia is causally related to the activation of the incerto-thalamic pathway. Aim 3: MCS produces long lasting changes in the incerto-thalamic circuitry. PUBLIC HEALTH RELEVANCE: One of the most debilitating consequences of spinal cord injury is the development of chronic intractable neuropathic pain (central pain syndrome). The pain is severe and relentless and current treatment methods offer no hope. Motor cortex stimulation (MCS) was introduced-almost 20 years ago-as a modality for the treatment of central pain syndrome when all other treatments have failed. However, the outcome of the treatment is variable. A major impediment to implementing MCS in the clinical setting and improving the success rate is the fact that the mechanisms by which MCS affects pain processing are unknown. Here, we take advantage of an animal model of central pain produced by spinal cord injury to study the mechanisms by which MCS affects the activity of specific neuronal circuits.