Periodic Reporting for period 4 - HOW2WALKAGAIN (Mechanisms of recovery after severe spinal cord injury)
Periodo di rendicontazione: 2021-01-01 al 2021-06-30
Worldwide, an estimated 3 million people live with a chronic spinal cord injury (SCI), and more than half do not recover the ability to stand or walk with current standards of care. Through an ERC Starting Grant, we had developed a new therapy based on electrical spinal cord stimulation that restored standing and walking in rodent models of SCI.
The objective of HOW2WALKAGAIN was to leverage the most advanced neurotechnologies to identify the neural mechanisms underlying the recovery of walking during electrical spinal cord stimulation. Our ultimate goal was to exploit this fundamental knowledge to translate this therapy in humans.
During this project, we found that electrical spinal cord stimulation modulates specific neuronal subpopulations in the spinal cord through the recruitment of afferent fibers innervating sensory receptors embedded into muscles, called proprioceptors. This understanding allowed us to develop more advanced stimulation protocols that exploit the anatomical organization of the proprioceptive system to mediate a more robust facilitation of leg movements. Translation of these protocols in clinical settings allowed nine individuals with chronic SCI to regain the ability to walk. Moreover, neurorehabilitation enabled many individuals to regain voluntary control over the activity of previously paralyzed muscles, even when the stimulation was turned off. This neurological recovery had not been observed with conventional stimulation protocols. Consequently, we modelled all the features observed in humans in rodent models in order to identify the mechanisms underlying this unexpected recovery. We thus deployed whole-nervous system imaging, single-cell technologies, and cell-specific interrogations in transgenic mice to catalogue the molecular choreography of recovery from spinal cord damage during neurorehabilitation supported by electrical spinal cord stimulation. We discovered that this therapy promotes the directed growth of neural projections from specific brain regions onto specific neuronal subpopulations in the spinal cord that become essential to walk after paralysis.
This understanding also allowed us to target other neurological functions that are impacted by SCI. For example, many individuals with severe SCI showed abnormally low levels of blood pressure, called orthostatic hypotension, that escalate risks of cardiovascular diseases and dramatically impact the quality of life. We found that we could use the same principles to modulate the sympathetic circuits that regulate blood pressure. This understanding supported the development of a spinal cord neuroprosthesis that precisely regulates blood pressure in real-time.
Our ERC proof-of-concept is enabling the translation of these scientific advances into tailored clinical devices for the recovery of mobility and hemodynamic stability. To accelerate this translation, we founded the start-up ONWARD Medical, which aims to bring this therapy to the market. Our ultimate goal is to bring these clinical innovations to the community of people with SCI.
The objective of HOW2WALKAGAIN was to leverage the most advanced neurotechnologies to identify the neural mechanisms underlying the recovery of walking during electrical spinal cord stimulation. Our ultimate goal was to exploit this fundamental knowledge to translate this therapy in humans.
During this project, we found that electrical spinal cord stimulation modulates specific neuronal subpopulations in the spinal cord through the recruitment of afferent fibers innervating sensory receptors embedded into muscles, called proprioceptors. This understanding allowed us to develop more advanced stimulation protocols that exploit the anatomical organization of the proprioceptive system to mediate a more robust facilitation of leg movements. Translation of these protocols in clinical settings allowed nine individuals with chronic SCI to regain the ability to walk. Moreover, neurorehabilitation enabled many individuals to regain voluntary control over the activity of previously paralyzed muscles, even when the stimulation was turned off. This neurological recovery had not been observed with conventional stimulation protocols. Consequently, we modelled all the features observed in humans in rodent models in order to identify the mechanisms underlying this unexpected recovery. We thus deployed whole-nervous system imaging, single-cell technologies, and cell-specific interrogations in transgenic mice to catalogue the molecular choreography of recovery from spinal cord damage during neurorehabilitation supported by electrical spinal cord stimulation. We discovered that this therapy promotes the directed growth of neural projections from specific brain regions onto specific neuronal subpopulations in the spinal cord that become essential to walk after paralysis.
This understanding also allowed us to target other neurological functions that are impacted by SCI. For example, many individuals with severe SCI showed abnormally low levels of blood pressure, called orthostatic hypotension, that escalate risks of cardiovascular diseases and dramatically impact the quality of life. We found that we could use the same principles to modulate the sympathetic circuits that regulate blood pressure. This understanding supported the development of a spinal cord neuroprosthesis that precisely regulates blood pressure in real-time.
Our ERC proof-of-concept is enabling the translation of these scientific advances into tailored clinical devices for the recovery of mobility and hemodynamic stability. To accelerate this translation, we founded the start-up ONWARD Medical, which aims to bring this therapy to the market. Our ultimate goal is to bring these clinical innovations to the community of people with SCI.
We have developed and optimized a series of innovative neurotechnologies to record, manipulate and disrupt neural activity over short timescales or extensive periods of time in chronic rodent models of SCI. These methods are allowing us to dissect the function of brain and spinal circuits involved in controlling leg movements in response to electrical spinal cord stimulation, and how these circuits are reorganizing during the course of neurorehabilitation.
We also implemented an advanced pipeline to characterize the anatomical and functional organization of projection circuits across the entire brain. This pipeline combines virus-mediated tract tracing, whole brain-spinal cord tissue clearing, activity-dependent labeling of neurons, 3D light-sheet microscopy, cell registration in Allen Institute anatomical atlas, and functional connectome analysis. This unbiased analysis is uncovering specific networks of circuits involved in the recovery of leg movements after SCI, thus opening the possibility to target these circuits to further enhance functional recovery.
Moreover, we are conducting single-nucleus sequencing analysis to identify transcriptomic changes of neurons and supporting cells in the spinal cord that underlie improvement of function in response to rehabilitation. This analysis is identifying neurons with unique molecular profiles that are involved in the production of locomotion after rehabilitation and could become new targets to further improve recovery. These results also informed the design of regeneration therapies that allowed us to promote the regrowth of nerve fibers across and beyond a complete SCI.
These combined methodologies and studies are thus yielding scientific results that are modifying our understanding of the recovery mechanisms after SCI, and how electrical spinal cord stimulation and intensive rehabilitation training are improving functional recovery. Many results have been disseminated in high profile journals and in clinical trials.
We also implemented an advanced pipeline to characterize the anatomical and functional organization of projection circuits across the entire brain. This pipeline combines virus-mediated tract tracing, whole brain-spinal cord tissue clearing, activity-dependent labeling of neurons, 3D light-sheet microscopy, cell registration in Allen Institute anatomical atlas, and functional connectome analysis. This unbiased analysis is uncovering specific networks of circuits involved in the recovery of leg movements after SCI, thus opening the possibility to target these circuits to further enhance functional recovery.
Moreover, we are conducting single-nucleus sequencing analysis to identify transcriptomic changes of neurons and supporting cells in the spinal cord that underlie improvement of function in response to rehabilitation. This analysis is identifying neurons with unique molecular profiles that are involved in the production of locomotion after rehabilitation and could become new targets to further improve recovery. These results also informed the design of regeneration therapies that allowed us to promote the regrowth of nerve fibers across and beyond a complete SCI.
These combined methodologies and studies are thus yielding scientific results that are modifying our understanding of the recovery mechanisms after SCI, and how electrical spinal cord stimulation and intensive rehabilitation training are improving functional recovery. Many results have been disseminated in high profile journals and in clinical trials.
Understanding the anatomical and functional logic of the motor-circuit communication system that produces locomotion, and how it can be controlled and remodeled after injury, remains one of the most prominent scientific and medical questions in the fields of motor control and movement disorders. HOW2WALKAGAIN already provided important insights into these questions. For example, we showed that electrical spinal cord stimulation facilitates leg movement after SCI through the recruitment of proprioceptive fibers. However, we also showed that the longer length of proprioceptive afferent fibers in humans compared to rats led to a cancellation of proprioception, and thus, a poor efficacy of this paradigm in patients with SCI. We found strategies to remedy these limitations, which led to a recent clinical breakthrough. Three patients with chronic paralysis were able to regain the ability to walk overground during stimulation. After training, they regained voluntary control over previously paralyzed muscles without stimulation. Experiments in rodent models performed within HOW2WALKAGAIN have described the circuit-level mechanisms that enable the brain to regain such control. Our experiments are also contributing to identifying new targeted strategies to further enhance neurological recovery from SCI. We also achieved the first regrowth of nerve fibers across a complete SCI.