Non-Invasive Interventions for Respiratory Recovery in Chronic Spinal Cord Injury

The overall objectives of this study are: To determine whether combining hypercapnic-hypoxia protocol (HiCO₂-AIH) and transcutaneous spinal cord stimulation (tSCS) can enhance the effects of respiratory resistance training in individuals with chronic spinal cord injury (SCI). To explore whether genetic and blood-based biomarkers can help predict how individuals respond to this combined intervention. We will test these objectives in adults with chronic SCI using a Williams cross-over design. The study will include 16 participants (with statistical power \>0.8 and α=0.05), accounting for a 20% dropout rate, for a total enrollment of 20 participants. Specific Aims Aim 1: To determine whether four consecutive days of combined HiCO₂-AIH and tSCS will improve the effectiveness of respiratory resistance training compared to either intervention alone. Outcomes (measured from PRE to 1 day POST intervention): Primary Outcome: Change in mouth occlusion pressure at 0.1 seconds (P0.1). Secondary Outcomes: Maximal inspiratory and expiratory pressure generation, forced vital capacity (FVC), neurophysiological measures of cortico-spinal drive (amplitude of transcranial magnetic stimulation \[TMS\]) and local spinal excitability (amplitude of cervical magnetic stimulation \[CMS\]) in the diaphragm. Safety Outcomes: Continuous monitoring of respiratory parameters (end tidal oxygen \[O₂\] and carbon dioxide \[CO₂\] concentration, oxygen saturation \[SpO₂\]) and cardiovascular parameters (blood pressure \[BP\], heart rate \[HR\], and electrocardiogram \[ECG\]) during each session. Aim 2: To identify predictive factors for treatment response to the combined HiCO₂-AIH and tSCS intervention using: 1. Genetic polymorphisms related to intermittent hypoxia signaling pathways. 2. Molecular markers of neurotrauma and inflammation found in blood extracellular vesicles (EVs). Outcomes: Regression analyses will be conducted to examine the relationship between treatment outcomes and: Specific genetic single nucleotide polymorphisms (SNPs). Blood-based molecular markers of neurotrauma and inflammation.