PROJECT SUMMARY / ABSTRACT Trauma to the spinal cord disrupts neural pathways that convey signals between the brain and spinal sensorimotor networks (SSN) that reside below the injury site, resulting in chronic paralysis. There is currently no cure for spinal cord injury (SCI); however, recent studies involving a small number of humans with SCI have shown that paralyzed functions can be restored by electrically stimulating the dorsal surface of the lumbosacral spinal cord. Last year, our team reported the use of lumbosacral epidural stimulation (ES) with intense rehabilitation enabled recovery of independent standing and stepping by a man with complete paralysis due to a mid-thoracic SCI that occurred several years prior. The stimulation systems that are implanted in humans with SCI were originally developed, and subsequently approved by the U.S. Food and Drug Administration, for use in humans to treat intractable neuropathic pain. The mechanism of action through which ES alleviates pain is thought to involve inhibition of pathologic signals transmitted through the dorsal sensory roots and ascending dorsal columns of the spinal cord. Contrary to pain treatment, computational modeling and electrophysiological studies indicate ES enables motor functions after SCI via excitation of dorsal root signaling to downstream SSNs. Assuming appropriate parameters of ES (e.g., pulse frequency, pulse width, pulse amplitude, location on the dura mater) are applied, SSNs are capable of producing robust motor outputs that result in functions such as weight bearing standing and/or walking. However, currently available scientific evidence does not explain how ES interacts with nearby spinal structures to produce functional gains in humans with chronic paralysis. To address this gap in knowledge, we will temporarily implant spinal electrodes in 32 humans with lower extremity paralysis to stimulate the dorsal sensory roots and/or dorsal surface of the spinal cord during 10 days of rehabilitation. Dorsal root stimulation (DRS) and ES waveforms will be independently-controlled to inhibit and/or activate nearby structures. Each stimulus pulse will be synchronized to electrophysiologic recordings of downstream neuromuscular activity in order to characterize SSN activity in response to DRS and/or ES stimulation. We hypothesize unilateral DRS during motor-enabling ES will result in ipsilateral suppression of SSN outputs. We further hypothesize that bilateral DRS alone will enable motor functions that are similar to those generated by ES. To investigate the role of rehabilitation during stimulation-enabled motor recovery, we hypothesize that stimulation-enabled motor performance will improve significantly across 10 motor rehabilitation sessions with DRS/ES. Completion of this work will generate new information on the interactions that occur during SSN facilitation via spinal stimulation. This information will be used to develop algorithms that correlate stimulation waveform...