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

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

Spinal cord injuries (SCI) can seriously affect a person's ability to breathe. This happens because the injury can damage the nerves that control the muscles used for breathing. As a result, people with SCI often face breathing problems, a higher risk of lung infections, and even early death. While breathing exercises can help strengthen these muscles, they often aren't intense enough to make a big difference, especially in people with long-term injuries.

This research project is exploring a new way to improve breathing in people with chronic SCI. The goal is to "wake up" the remaining nerve pathways that still connect the brain and spinal cord to the breathing muscles. By doing this, the investigators hope to make breathing exercises more effective and improve overall respiratory health.

The investigators are testing a combination of two non-invasive (non-surgical) techniques:

Transcutaneous Spinal Cord Stimulation (tSCS): This uses small electrical pulses delivered through the skin to stimulate the spinal cord and help activate the muscles used for breathing.

Hypercapnic-Hypoxia Protocol (HiCO₂-AIH): This involves breathing air with lower oxygen and higher carbon dioxide for short periods. This naturally increases the brain's drive to breathe and may help strengthen the breathing muscles.

The investigators believe that using these two techniques together will "prime" the nervous system, making it more responsive to breathing exercises. This could lead to better outcomes for people with SCI.

In addition to testing this treatment, the investigators are also collecting saliva and blood samples to look for biomarkers-biological clues that might help predict who will benefit most from this therapy. These include genetic markers and signs of nerve damage in the blood.

Who Can Participate

The investigators are looking for adults aged 18 to 70 who:

Have had a spinal cord injury for at least one year. Have an injury between the neck and upper back (from C3 to T8). Have an incomplete injury (some nerve function remains). Are medically stable and cleared by a doctor. Have at least a 20% reduction in breathing strength. What Participants Will Do

Each participant will complete four rounds of treatment. Each round includes four days in a row of therapy, followed by a three-week break before the next round.

Each daily session lasts about two hours and includes:

Breathing special air mixtures (low oxygen and high carbon dioxide) for short periods, followed by normal air.

A short break. Then, spinal cord stimulation combined with breathing exercises that use resistance (like breathing through a straw).

What the Investigators Will Measure

The investigators will track:

Breathing ability using lung function tests and pressure measurements. Nerve activity using brain and spinal cord stimulation to see how well the diaphragm (the main breathing muscle) responds.

Safety by monitoring oxygen levels, heart rate, blood pressure, and breathing responses during each session.

Biological Samples

Participants will provide:

A one-time saliva sample for genetic testing. A one-time blood sample to look for markers of nerve injury. Why This Matters

This study could lead to new, non-invasive treatments that improve breathing and quality of life for people living with spinal cord injuries. By identifying who is most likely to benefit from this therapy, the investigators can also move toward more personalized and effective care in the future.

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.

Inclusion Criteria:

1. adults 18 to 70 years of age (the latter to reduce likelihood of cardiovascular disease);
2. chronic SCI for ≥ 1 year at or below C-3 to T-8
3. incomplete SCI based on classification of incomplete-B, C or D
4. medically stable with clearance from physician
5. SCI due to non-progressive etiology
6. >20% impairment in maximal inspiratory or expiratory pressure generation

Exclusion Criteria:

• Individuals will be excluded due to (1) current diagnosis of an additional neurologic condition (eg. multiple sclerosis or stroke) (2) loss of diaphragm EMG activity on forced respiratory tests; (3) severe illness or infection (4) non-healing decubitus ulcers (5) untreated bladder or urinary infections (6) cardiovascular disease (7) lung disease (8) active heterotopic ossification (9) uncontrolled hypertension; (10) severe neuropathic pain; (11) pregnancy (5) severe recurrent and uncontrolled autonomic dysreflexia (6) history of seizure disorder.