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BACKGROUND: Advanced understanding of brain structure and function has improved the diagnosis and treatment of neurological disorders such as epilepsy, stroke, and spinal cord injury (SCI). Over half a century ago, the pioneering studies of Penfield used electrical stimulation of motor and sensory areas of cerebral cortex and revealed a distinct somatotopic organization of the brain. Today, this and additional knowledge of neuronal coding functions are being used to develop revolutionary devices that interface directly with motor and sensory neurons in the brain to establish functional connections with prosthetic and assistive devices. These so-called brain-computer interfaces (BCIs) require electrodes to be placed precisely in brain areas responsible for volitional control and sensation of limb movements, particularly the arm and hand regions. Mapping those brain regions is possible using functional magnetic resonance imaging (fMRI). However, such mapping studies are difficult to perform in persons with motor and sensory impairments. People with ALS and SCI have disrupted efferent and afferent pathways between the cortex and the limbs making it necessary to rely on covert techniques, such as kinesthetic motor imagery, to map sensorimotor brain activity in order to guide BCI electrode placement or to study cortical plasticity resulting from injury or intervention. Challenges associated with brain mapping after injury likely contribute to the widely varying reports regarding the extent and prevalence of functional reorganization occurring in the brain following SCI. fMRI is a non-invasive tool that allows for measurement of motor and sensory-related brain activity with minimal risk to study participants. SIGNIFICANCE: Restoration of upper limb function is a top priority for individuals with tetraplegia. It is estimated that 236,000-327,000 people in the United States have a spinal cord injury. Approximately 17% of people with SCI have high tetraplegia (injury at cervical levels C1-C4) although this percentage has been increasing in recent years. People with high tetraplegia are the most likely group to benefit from BCI-controlled neuroprosthetics, although the covert mapping strategies developed in this proposal could be used to study sensorimotor activation and plasticity in anyone with motor or sensory impairment including amputation. Sophisticated, motorized prostheses are being developed that enable natural upper limb movement and have advanced sensing capabilities. People with tetraplegia would like to restore function to their own limbs using FES, but this technology needs further advancement and does not replace sensation, which may still require a BCI. While FES research and development continues, people with tetraplegia could take advantage of motorized prostheses by mounting them to their wheelchair. Motorized prostheses can provide function comparable to that of an intact limb, but a high degree-of-freedom control interface is needed and BCI is one possible solution. Functional neuroimaging can be used to guide BCI electrode placement in order to tap into existing sensorimotor circuits. Imagery-based brain mapping also enables the study of cortical plasticity which could be useful for understanding maladaptive cortical changes that occur after injury or beneficial changes resulting from rehabilitation interventions. Just as pre-surgical brain mapping may help identify individuals who are best suited for a BCI, covert brain mapping in someone with motor and sensory impairments may inform the type of rehabilitation paradigm that is most likely to have a benefit. The potential benefit of being able to study cortical plasticity in the absence of movement or sensation is wide-reaching as it could be applied to patients with SCI, amputation, stroke, neurodegenerative diseases like amyotrophic lateral sclerosis, or other sensorimotor impairment.