Over the past 2 years my main research focus has been our ongoing work developing an electrical autonomic neuroprosthesis that delivers electrical stimulation in closed loop to stabilize hemodynamics. I examined previous studies that showed epidural electrical stimulation of the spinal cord transforms spinal circuits from a hypoactive to a highly active state, and can reinstate spinal circuit dynamics to restore walking after paralysis. We leveraged these concepts to develop epidural electrical stimulation protocols that restored hemodynamic stability after spinal cord injury. I established a new preclinical model that enabled the dissection of the topology and dynamics of sympathetic circuits engaged by epidural electrical stimulation (EES). I incorporated these spatial and temporal features into stimulation protocols to conceive a clinical-grade biomimetic hemodynamic regulator operating in closed-loop. This neuroprosthetic baroreflex controlled hemodynamics for extended periods of time in rodents, non-human primates, and humans, both after acute and chronic SCI. These results were published in Nature as a full article (Squair et al., Nature, 2021). We also published all our procedures in the form of open-source protocols for the field (Soriano*, Hudelle*, Squair* et al., Nature Protocols, in press).
We thus developed and validated what we termed a “neuroprosthetic baroreflex” that uses EES of the lower thoracic spinal cord to achieve ultrafast and precise control of hemodynamics. This development is based on a translational framework including rodent models, NHP models and clinical studies. This framework enabled us to understand the mechanisms of this treatment, and thus optimize the features of neuroprosthetic baroreflex. We then scaled up and validated the efficacy of our research-grade neuroprosthetic baroreflex technology in three rhesus monkeys. Finally, we validated all the key features of the neuroprosthetic baroreflex in one human who suffered severe orthostatic hypotension due to a clinically complete cervical SCI. This translational framework captures the core philosophy of .NeuroRestore, the center that the host supervisor (Courtine, Bloch) leads. We foster a continuing reciprocal transfer of ideas between our platforms in rodent models, NHP models, and clinical studies; in addition to tight collaborations with industries. This philosophy is uniquely suited to translate our ideas and technologies into real-life treatments. This transfer of ideas across the entire translational spectrum and to industry will continue to support the optimization of this treatment for clinical use. We have repeatedly experienced this bidirectional exchange during the development of our treatment to restore walking after paralysis.
The completion of the work contained within this fellowship established the necessary evidence to bring the neuroprosthetic baroreflex to clinical trials: Importantly, the results of the pilot clinical trial will inform the methodology for such a large-scale clinical trial with sufficient power to assess the immediate efficacy of the neuroprosthetic baroreflex, and the long-term efficacy of the neuroprosthetic baroreflex combined with autonomic neurorehabilitation.
We envision that the neuroprosthetic baroreflex combined with autonomic neurorehabilitation will become a new treatment to manage hemodynamic instability after SCI in people who do not respond to conservative management.
