Diversity of Reactive Astrogliosis in CNS Pathology: Heterogeneity or Plasticity?

Astrocytes are essential for the development and homeostatic maintenance of the central nervous system (CNS). They are also critical players in the CNS injury response during which they undergo a process referred to as "reactive astrogliosis." Diversity in astrocyte morphology and gene expression, as revealed by transcriptional analysis, is well-recognized and has been reported in several CNS pathologies, including ischemic stroke, CNS demyelination, and traumatic injury. This diversity appears unique to the specific pathology, with significant variance across temporal, topographical, age, and sex-specific variables. Despite this, there is limited functional data corroborating this diversity. Furthermore, as reactive astrocytes display significant environmental-dependent plasticity and fate-mapping data on astrocyte subsets in the adult CNS is limited, it remains unclear whether this diversity represents heterogeneity or plasticity. As astrocytes are important for neuronal survival and CNS function post-injury, establishing to what extent this diversity reflects distinct established heterogeneous astrocyte subpopulations vs. environmentally dependent plasticity within established astrocyte subsets will be critical for guiding therapeutic development. To that end, we review the current state of knowledge on astrocyte diversity in the context of three representative CNS pathologies: ischemic stroke, demyelination, and traumatic injury, with the goal of identifying key limitations in our current knowledge and suggesting future areas of research needed to address them. We suggest that the majority of identified astrocyte diversity in CNS pathologies to date represents plasticity in response to dynamically changing post-injury environments as opposed to heterogeneity, an important consideration for the understanding of disease pathogenesis and the development of therapeutic interventions

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Cortical and vestibular stimulation reveal preserved descending motor pathways in individuals with motor-complete spinal cord injury.

OBJECTIVE: To use a combination of electrophysiological techniques to determine the extent of preserved muscle activity below the clinically-defined level of motor-complete spinal cord injury. METHODS: Transcranial magnetic stimulation and vestibular-evoked myogenic potentials were used to investigate whether there was any preserved muscle activity in trunk, hip and leg muscles of 16 individuals with motor-complete spinal cord injury (C4-T12) and 16 able-bodied matched controls. RESULTS: Most individuals (14/16) with motor-complete spinal cord injury were found to have transcranial magnetic stimulation evoked, and/or voluntary evoked muscle activity in muscles innervated below the clinically classified lesion level. In most cases voluntary muscle activation was accompanied by a present transcranial magnetic stimulation response. Furthermore, motor-evoked potentials to transcranial magnetic stimulation could be observed in muscles that could not be voluntarily activated. Vestibular-evoked myogenic potentials responses were also observed in a small number of subjects, indicating the potential preservation of other descending pathways. CONCLUSION: These results highlight the importance of using multiple electrophysiological techniques to assist in determining the potential preservation of muscle activity below the clinically-defined level of injury in individuals with a motor-complete spinal cord injury. These techniques may provide clinicians with more accurate information about the state of various motor pathways, and could offer a method to more accurately target rehabilitation

Cell type prioritization in single-cell data

The cell types affected by biological perturbations in complex tissues are uncovered by single-cell analysis.We present Augur, a method to prioritize the cell types most responsive to biological perturbations in single-cell data. Augur employs a machine-learning framework to quantify the separability of perturbed and unperturbed cells within a high-dimensional space. We validate our method on single-cell RNA sequencing, chromatin accessibility and imaging transcriptomics datasets, and show that Augur outperforms existing methods based on differential gene expression. Augur identified the neural circuits restoring locomotion in mice following spinal cord neurostimulation

Non-invasive spinal cord electrical stimulation for arm and hand function in chronic tetraplegia: a safety and efficacy trial

Cervical spinal cord injury (SCI) leads to permanent impairment of arm and hand functions. Here we conducted a prospective, single-arm, multicenter, open-label, non-significant risk trial that evaluated the safety and efficacy of ARC Therapy to improve arm and hand functions in people with chronic SCI. ARC Therapy involves the delivery of externally applied electrical stimulation over the cervical spinal cord during structured rehabilitation. The primary endpoints were safety and efficacy as measured by whether the majority of participants exhibited significant improvement in both strength and functional performance in response to ARC Therapy compared to the end of an equivalent period of rehabilitation alone. Sixty participants completed the protocol. No serious adverse events related to ARC Therapy were reported, and the primary effectiveness endpoint was met. Seventy-two percent of participants demonstrated improvements greater than the minimally important difference criteria for both strength and functional domains. Secondary endpoint analysis revealed significant improvements in fingertip pinch force, hand prehension and strength, upper extremity motor and sensory abilities and self-reported increases in quality of life. These results demonstrate the safety and efficacy of ARC Therapy to improve hand and arm functions in people living with cervical SCI. ClinicalTrials.gov identifier: NCT04697472