Non-Invasive Interventions for Respiratory Recovery in Chronic Spinal Cord Injury
- Conditions
- Spinal Cord Injury, ChronicSpinal Cord Injury CervicalSpinal Cord Injury ThoracicIncomplete Spinal Cord Injury
- Registration Number
- NCT07135583
- Lead Sponsor
- Thomas Jefferson University
- Brief Summary
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, we hope to make breathing exercises more effective and improve overall respiratory health.
We are testing a combination of two non-invasive (non-surgical) techniques:
1. 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.
2. 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.
We 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, we are also collecting saliva and blood samples to look for biomarkers-biological clues that might help us predict who will benefit most from this therapy. These include genetic markers and signs of nerve damage in the blood.
________________________________________ Who Can Participate
We 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 We Will Measure
We 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, we can also move toward more personalized and effective care in the future.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 20
(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 at initial screening according to the American Spinal Injury Association Impairment Classification and the International Standards for the Neurological Classification of SCI (Kirshblum et al., 2011) or evidence of residual sensory and motor function below the level of injury; (4) medically stable with clearance from physician; (5) SCI due to non-progressive etiology; (6) >20% impairment in maximal inspiratory or expiratory pressure generation, relative to established normative values. Decrements in maximal inspiratory pressure generation is associated with declines in pulmonary function and reductions in expiratory pressures limits cough and airway clearance (Stolzmann et al., 2008; Postma et al., 2016).
-
Individuals will be excluded due to
- current diagnosis of an additional neurologic condition such as multiple sclerosis or stroke or loss of diaphragm EMG activity on forced respiratory tests;
- severe illness or infection, including non-healing decubitus ulcers, untreated bladder or urinary infections, cardiovascular disease, lung disease, active heterotopic ossification or uncontrolled hypertension;
- severe neuropathic pain;
- pregnancy because of unknown effects of AIH on a fetus, although women of childbearing age will not otherwise be excluded;
- severe recurrent and uncontrolled autonomic dysreflexia; and
- history of seizure disorder.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Primary Outcome Measures
Name Time Method change in mouth occlusion pressure at 0.1 secs (P0.1) Pre- Baseline (Day 1), Post 1(30 minute post day 4 intervention) and Post 2 ( 24 hours post day 4 intervention) It measures the pressure generated at the mouth in the first 0.1 second of inspiration when the airway is unexpectedly occluded at the end of expiration. The negative pressure generation in 0.1 seconds reflects respiratory motor drive without time for modification by sensory systems such as lung stretch or visual input. The inspiratory valve will be occluded prior to the onset of inspiration, without participant awareness, and maintained until the subsequent inspiratory effort. Negative pressure generation will be recorded using a pressure transducer connected to a non-rebreathable mask. All respiratory assessments will be performed in accordance with standard testing guidelines. Measurement indices of ventilation will be obtained using a mouthpiece attached to the pneumotach and nasal clips. The mouth pressure from the pneumotach will be converted to a digital signal using Powerlab C.
- Secondary Outcome Measures
Name Time Method Maximum Inspiratory (MIP) & Expiratory (MEP) Pressure Pre- Baseline (Day 1), Post 1(30 minute post day 4 intervention) and Post 2 ( 24 hours post day 4 intervention) Inspiratory pressure generation is indicative of inspiratory strength and is associated with pulmonary health and infection risk. Expiratory pressure generation reflects expiratory respiratory strength and is associated with airway clearance and cough. Inspiratory and expiratory pressure generation improve following weeks of respiratory strength training and after single-day sessions of AIH. Measurements will be obtained using a mouthpiece attached to the pneumotach to measure indices of ventilation, along with the use of nasal clips. To obtain MIP, participants will exhale to residual volume and attempt a maximal inspiration for at least 2 seconds with the inspired line occluded. MEP will be measured with forced expiration against an occluded expired line after the participant inhales to near total lung capacity.
Sniff nasal inspiratory pressure (SNIP) Pre- Baseline (Day 1), Post 1(30 minute post day 4 intervention) and Post 2 ( 24 hours post day 4 intervention) Sniff nasal inspiratory pressure (SNIP) is the measurement of esophageal pressure during maximal sniffs and can be useful in assessing inspiratory muscle strength. To obtain SNIP, the pressure measurement will be obtained through an occluded nostril using a nasal probe, as the participant performs a sniff through the contralateral nostril.
Transcranial Magnetic Stimulation (TMS) evoked Diaphragm Motor Evoked Potentials Pre- Baseline (Day 1), Post 1(30 minute post day 4 intervention) and Post 2 ( 24 hours post day 4 intervention) Subjects will be seated comfortably, fully supported, with their neck slightly flexed. Transcranial magnetic stimulation is performed using a standard technique. The vertex of the skull is identified by the intersection between nasion to inion and tragus to tragus. The region of the cortex responsible for diaphragm motor activation is located approximately 3 cm lateral and 2 cm anterior to the vertex. Single-pulse stimuli are delivered using a handheld double cone coil powered by a magnetic stimulator. The coil is held over the left hemisphere of the brain with current flowing in the anteroposterior direction. The coil is then moved slightly from the pre-determined site and rotated in 45° increments until the largest motor evoked potential (MEP) is observed. This location is marked on a tight-fitting TMS cap placed over the subject's head to ensure accurate coil positioning in future stimulations.
Cervical Magnetic Stimulation (CMS) Diaphragm motor evoked potentials Pre- Baseline (Day 1), Post 1(30 minute post day 4 intervention) and Post 2 ( 24 hours post day 4 intervention) Single-pulse stimuli will be delivered using a handheld circular coil placed over the cervical spine (C7). Recruitment curves are plotted by gradually increasing the intensity of stimulus from 40% to 100% of the maximal stimulator output in 5% increments. Approximately 15 stimulations will be performed at each intensity, separated by 30 seconds. If the subject wishes to take an extended break between stimulations, they may do so until ready to continue.
As with all procedures, participants will be closely monitored for any discomfort. During these stimulation procedures, subjects will be closely monitored for discomfort and are encouraged to inform the experimenter if they wish to pause testing, take a break, or discontinue stimulations.
Trial Locations
- Locations (1)
Thomas Jefferson University Center City Campus
🇺🇸Philadelphia, Pennsylvania, United States
Thomas Jefferson University Center City Campus🇺🇸Philadelphia, Pennsylvania, United StatesJayakrishnanContact3528715888jayakrishnan.nair@jefferson.edu