Long-term neuroprosthetic hemotherapy treats autonomic dysreflexia after spinal cord injury.

Disrupted descending supraspinal control results in a hyper-excitable sympathetic nervous system connectome after spinal cord injury (SCI). A condition termed "autonomic dysreflexia" (AD) results, which is characterized by severe elevations in blood pressure that are life-threatening. There are no effective therapies for AD. Long-term epidural stimulation below the level of the SCI can promote functionally-relevant plasticity of volitional motor circuits, and this paradigm may prevent the hyper-excitable sympathetic connectome after SCI. Here we studied the potential rehabilitative effect of long-term epidural stimulation, as well as the mechanisms that are responsible for the development of AD. For this experiment, we compared SCI rats that underwent 30 minutes of epidural stimulation 5x/week for 6 weeks to SCI rats receiving normal care. Long-term epidural stimulation abrogated AD induced by colorectal distension (p<0.0001; Figure 1). Viral tracing of ascending propriospinal neurons was also performed in these groups. Long-term epidural stimulation normalized the sympathetic connectome as the axons and synapses were significantly reduced compared to SCI rats (p=0.0021; p=0.0127). We next performed chemogenetic silencing of excitatory and inhibitory interneurons, as well as sympathetic preganglionic neurons, in the lower thoracic spinal segments while experimentally inducing AD. Preliminary data indicate that AD is, at least in part, mediated by excitatory interneuronal connections to sympathetic preganglionic neurons. Long-term epidural stimulation may be an effective hemotherapy for preventing AD after SCI. This project may provide direction for basic and clinical research to develop treatments for sympathetic nervous system dysfunction after SCI, and thereby improve health and patient quality of life over the long term.