Neurostimulation for Respiratory Function After Spinal Cord Injury

Study Overview
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Brief Summary
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The purpose of this research study is to learn more about the connections between the brain, nerves, and diaphragm after experiencing a cervical spinal cord injury (SCI).The main question it aims to answer is: Changes in respiratory function and recovery using stimulation and respiratory exercise training in spinal cord-injured individuals. Participants will complete a maximum of 55 study visits. They will be asked to complete about 40 treatment sessions which include multiple stimulation sessions over the scalp and neck, followed by about 60 minutes of respiratory training. Assessment sessions will be completed prior at baseline, after 20 sessions and after 40 sessions of study treatment.

Detailed Description
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The purpose of this study is to test a strategy to potentiate functional recovery of respiratory function in individuals with spinal cord injury (SCI). Respiratory function is often impaired in individuals with high cervical spinal cord injury (SCI, C1-C5) leading to reduced quality of life and mortality. Currently, research has shown Spike-timing-dependent plasticity (STDP) targeting cortico-motoneuronal connections effectively promote recovery in upper and lower limbs, including functions such as grasping and locomotion. The overall goal of our proposal is to develop a non-invasive protocol using STDP that can be used to strengthen synaptic plasticity and voluntary motor output in the diaphragm muscle in humans with high cervical SCI. To assess the effect of STDP on respiratory function in humans with high cervical SCI, we propose a pilot study of efficacy trial with the specific aim below: The overall objective of this project is to investigate the efficacy of spike-timing-dependent plasticity (STDP) on respiratory function in humans with high cervical SCI. Specific Aim: Examine the effect of STDP in respiratory function in humans with chronic high cervical SCI.

Official Title
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Pilot Study: Spike-timing-dependent Plasticity for Respiratory Function After Spinal Cord Injury

Conditions
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Spinal Cord Injuries, Cervical Spinal Cord Injury, Respiratory Function Impaired

Intervention / Treatment
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* Device: Neurostimulation
* Other: Repiratory training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and females between ages 18-85 years SCI at least 6 months post-injury Spinal Cord injury at C1-C5 Demonstrate respiratory deficit following spinal cord injury as following: (1) Individuals using mechanical ventilation, and (2) individuals with pulmonary function testing (PFT) deficits corresponding to having a vital capacity (VC) < 80% (predicted) Must have a family member or caregiver who is trained and willing to operate the mechanical ventilator during study visits. Exclusion Criteria: Any illness or condition that based on the research team's assessment, will compromise with the participant's ability to comply with the protocol, patient safety, or the validity of the data collected during this study. Any debilitating disease prior to the SCI that caused exercise intolerance. Individuals entirely dependent on the support of a diaphragmatic pacer (24 hours per day). Premorbid, ongoing major depression or psychosis, altered cognitive status. History of head injury or stroke Vascular, traumatic, tumoral, infectious, or metabolic lesion of the brain, even without a history of seizure, and without anticonvulsant medication History of seizures or epilepsy Receiving drugs acting primarily on the central nervous system, which lower the seizure threshold Pregnant females If a woman of childbearing age is unsure of the pregnancy, and does not want to take the pregnancy test Ongoing cord compression or a syrinx in the spinal cord or who suffer from a spinal cord disease such as spinal stenosis, spina bifida, MS, or herniated disk Metal plate in skull Individuals with scalp shrapnel, cochlear implants, or aneurysm clips Individuals taking Bupropion, Dolutegravir, Lacosamide, Trilaciclib, or PR Interval prolonging drugs

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Participants with high cervical spinal cord injury will receive 40 treatment sessions (STDP stimulation and respiratory training) and will be asked to complete pre-, Post-20, and Post-40 assessment sessions.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neurostimulation for respiratory function after spinal cord injury<br>Efficacy of STDP on respiratory function. | Device: Neurostimulation<br>* Paired stimulation will be given to the spinal cord and to peripheral nerves so that the signals are received at the spinal cord at a specific interval.<br>* Other names: Neural plasticity;Other: Repiratory training<br>* Respiratory exercises will be completed immediately after completing neurostimulation. Respiratory exercises will involve inspiratory muscle training performing four sets of 6-10 breaths per day with two minutes of rest.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Motor evoked potentials (MEPs) | Transcranial magnetic stimuli (TMS) will be delivered to the optimal scalp position for activation of the diaphragm muscle. The optimal scalp position will be determined by moving the coil in small steps along the diaphragm representation of the primary motor cortex to find the region where the largest MEP can be evoked with the minimum intensity in the targeted muscles. | MEPs measured at baseline, 7 weeks (20 sessions), and 14 weeks (40 sessions) of STDP stimulation and respiratory training for the participants during study procedures. | 
| Change in Maximum Voluntary Contractions (MVCs) | Individuals will perform a maximum voluntary contraction (MVC) of diaphragm muscle through surface electrodes secured to the skin over the chest and belly region. | MVCs measured at baseline, 7 weeks (20 sessions), and 14 weeks (40 sessions) of STDP stimulation and respiratory training for the participants during study procedures. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cervicomedullary electric potentials (CMEPs) | Transcranial magnetic stimuli will be delivered to the optimal position of the cervical spine. A small device on the surface of the skin behind the ear will deliver pulses of electricity over the back of the neck. | CMEPs measured at baseline, 7 weeks (20 sessions), and 14 weeks (40 sessions) of STDP stimulation and respiratory training for the participants during study procedures. | 
| Change in Pulmonary function tests | Spirometry will be tested in upright and supine position to measure negative inspiratory force (NIF), vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and their ration (FEV1/FVC) | Change in pulmonary function tests measured at baseline, 7 weeks (20 sessions), and 14 weeks (40 sessions) of STDP stimulation and respiratory training for the participants during study procedures. | 
| Change in the Diaphragm ultrasound imaging | Ultrasound imaging will be acquired for optimal visualization of each hemidiaphragm. The diaphragm will be examined during quiet breathing and during maximal inspiration. MVCs measured at baseline, 7 weeks (20 sessions), and 14 weeks (40 sessions) of STDP stimulation and respiratory training for the participants during study procedures. | Change in the diaphragm ultrasound imaging measured at baseline, 7 weeks (20 sessions), and 14 weeks (40 sessions) of STDP stimulation and respiratory training for the participants during study procedures. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neural plasticity, Spinal cord injury, Diaphragm, Respiratory training, Spike-timing-dependent plasticity, Neurostimulation