RESPiRe-cSCI

Cervical spinal injury (cSCI) affects over 450,000 patients annually, leading to diaphragm paralysis and respiratory dysfunction due to damage to bulbospinal respiratory pathways and phrenic motoneurons. Our recent study demonstrated that trans-spinal theta burst stimulation (TBS) could improve transiently diaphragmatic activity in cSCI rats. This proposal aims to develop a novel respiration-triggered trans-spinal magnetic stimulation (rTSMS) protocol to enhance neurorespiratory function after chronic cSCI. We hypothesize that applying magnetic stimulation during specific respiratory phases (inspiration vs expiration) will differentially modulate diaphragmatic function and improve therapeutic outcomes. The project has four main aims: 1) Respiration-Triggered Stimulation by developing a system to deliver rTSMS based on diaphragmatic respiratory phases. Diaphragmatic motor evoked potential will be evaluated to assess phrenic motoneuronal excitability at various post-injury stages; 2) Theta Burst Stimulation by testing whether inspiration-triggered TBS induces better improvements in diaphragmatic activity with a depiction of the neurotransmitter (5-HT and A2A receptors) involved in this recovery; 3) Therapeutic Efficacy by assessing respiratory recovery following chronic TBS (5 days/week for 4 weeks) through plethysmography, along with spinal hemodynamics, phrenic motor circuit integrity, and diaphragm remodeling; 4) Non-Targeted Screening by using in situ transcriptomics and proteomics to identify cellular and molecular pathways in diaphragm, phrenic motoneurons and surrounding vascular, microglia, and astrocytes, providing insights into the mechanisms underlying TBS's therapeutic effects. This study establishes rTSMS as a novel treatment for respiratory dysfunction following cSCI, with potential applications in modulating neuroinflammation and promoting plasticity and muscle remodeling, laying the groundwork for future clinical trials in spinal-injured patients.