Synchronized stimulation to prevent diaphragm atrophy, promote neural regeneration and reduce respiratory disability in tetraplegia – RECOVDIA

Spinal cord injuries (SCI) are among the most devastating that an individual can sustain. They affect more than 2.5 million people worldwide. Among SCI, 60% are at cervical level (cSCI), causing both locomotor paralysis and dramatically altered respiratory capacity. Injuries located high in the spine (C4 or above), can leave survivors ventilator-dependent, compromising quality of life and increasing mortality rates. Today, mechanical ventilation (MV) is the only treatment available to patients who cannot breathe spontaneously. Rare alternatives to MV such as diaphragm pacing can generally be implemented only months or years after SCI, and have a very low success rate (10%). Electrical stimulation of extra-diaphragmatic muscles could be a promising solution to induce neuroplasticity and to improve/preserve diaphragm structure and function, but the few devices currently available are not designed for these purposes.

PARTNER 1 recently developed a new system to non-invasively stimulate extra-diaphragmatic muscles (intercostal and abdominal muscles) in mice, in synchrony with breathing (rSynES). Preliminary results suggest that this indirect stimulation leads to diaphragm and respiratory function recovery. Consequently, spinal neuron networks could be activated, and axonal regeneration may occur, representing a beacon of hope for patients who are currently dependent on MV. However, the system must be further developed to perfectly synchronize its action with ventilation, and to demonstrate the link between extra-diaphragmatic neuromuscular stimulation and diaphragm structure and function.

PARTNER 2 has recognized expertise in the development of methods to acquire and analyze functional magnetic resonance imaging (fMRI) data for the brain, and has recently developed a set-up for mouse spinal cord MRI. This set-up could provide unique information on neuronal activation during rSynES to help optimize its functionality.

PARTNER 3 has developed expertise in chemical exchange saturation transfer (CEST)-MRI of glutamate (gluCEST), a recently-emerged modality allowing in-vivo glutamate imaging. This complementary approach can be used to map glutamate distribution in the mouse spinal cord, providing information on neuronal integrity and axonal myelinization.

The RECOVDIA project aims to optimize rSynES in mice and to provide a translational proof-of-concept of the efficacy of this therapeutic strategy. Its objectives are to: 1/ Optimize rSynES development by fine-tuning parameters and determining effects at the spinal cord level using MRI. 2/ Test the efficacy of the device on respiratory function and conduct a proof-of-concept, longitudinal MRI study of neuronal activation at the spinal level, while identifying new biomarkers of neuroplasticity sensitive to changes after SCI and therapeutic interventions. 3/ Determine the main mechanisms through which rSynES induces diaphragm recovery after cSCI by examining motoneuron plasticity, spinal cord inflammation, and diaphragm structure and function. Classical structural and molecular approaches will be combined with state-of-the-art functional and metabolic MRI of the spinal cord.

The consortium’s complementary expertise in respiratory physiology, imaging and neurobiology, will allow us to develop a new stimulation strategy with a high potential for clinical translation. This project will notably be pivotal for the success of a maturation project related to a patented algorithm that is currently being adapted for use in humans. During the RECOVDIA project, we also hope to identify spinal cord MRI parameters that can serve as new biomarkers for regenerative medicine. The project is a unique opportunity to associate technological developments related to both stimulation therapy and MRI biomarkers with both clinical goals – development of new therapeutic approaches to respiratory disability in MV-reliant people with cSCI – and scientific goals – refining current concepts of neuromodulation.