Sunday, May 18, 2025
5/18/2025
Closed-loop epidural stimulation: respiratory motor plasticity and neural underpinnings - PROJECT SUMMARY/ABSTRACT Each year there are more than 17,000 new spinal cord injuries in the United States, half of which occur at the cervical level. These cervical injuries lead to breathing dysfunction and reliance on mechanical ventilation, making respiratory failure the leading cause of mortality after injury. Sub-threshold (current amplitude below that necessary to directly activate motor pools) electrical stimulation of the dorsal epidural surface of the spinal cord can elicit voluntary locomotor function in injured patients, but its ability to improve breathing capacity is largely unexplored. Prior study from the Dale lab demonstrates that chronic application of closed-loop stimulation in unanesthetized rats leads to lasting increases in phrenic motor network excitability, and that this effect is blocked by removal of cervical dorsal afferents. Additionally, work recently published by the candidate shows that closed- loop stimulation recovers spontaneous diaphragm EMG immediately after injury and this lasts for short periods after stimulation has stopped. However, neither the conditions necessary to best elicit lasting increases in respiratory output nor closed-loop stimulation’s mechanism of action are well understood. Ideally, a stimulation paradigm which improves breathing function both during and after treatment would lead to device independence and improved quality of life. Therefore, it is critical to thoroughly understand the functional and neuroplastic effects of epidural stimulation as well as the neural populations responsible for its action. The central hypothesis of this fellowship is that multiple bouts of closed-loop epidural stimulation elicit lasting improvements in breathing function which requires sensory feedback which we propose to test through two aims: 1) Using a well-defined, acute C2-hemisection injury (e.g. maintaining contralesional diaphragm function), we will assess the effect of closed-loop epidural stimulation paradigms on evoked and spontaneous diaphragm EMG activity and inspiratory pressure generation during and after stimulation; 2) Using innovative mechanical ventilation techniques in our acute model, we will determine the necessity of sensory feedback and descending inputs in mediating epidural stimulation’s effects. Primary mentor Dr. Dale is well-funded, has extensive experience with both acute and chronic models of spinal cord injury, and initially developed the closed- loop stimulation paradigm utilized in this proposal. Co-sponsor Dr. David Fuller is a leading expert in respiratory neurobiology research and has an extensive track record in mentorship with over 80% of his trainees moving on to faculty or post-doctoral positions (2 prior mentees have received F31s). The training plan was designed to further the candidate’s goal of becoming an independent PI and includes attendance at local and national conferences, participation in seminars and journal clubs, and development of laboratory management, teaching, writing, and mentoring skills. This fellowship will provide critical understanding of epidural stimulation’s functional effects and mechanism necessary to translate this treatment to clinical populations while helping develop the career of a promising young scientist.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).