Hypothalamic deep brain stimulation augments walking after spinal cord injury.

A spinal cord injury (SCI) disrupts the neuronal projections from the brain to the region of the spinal cord that produces walking, leading to various degrees of paralysis. Here, we aimed to identify brain regions that steer the recovery of walking after incomplete SCI and that could be targeted to augment this recovery. To uncover these regions, we constructed a space-time brain-wide atlas of transcriptionally active and spinal cord-projecting neurons underlying the recovery of walking after incomplete SCI.

Single-cell and spatial atlases of spinal cord injury in the Tabulae Paralytica.

Here, we introduce the Tabulae Paralytica-a compilation of four atlases of spinal cord injury (SCI) comprising a single-nucleus transcriptome atlas of half a million cells, a multiome atlas pairing transcriptomic and epigenomic measurements within the same nuclei, and two spatial transcriptomic atlases of the injured spinal cord spanning four spatial and temporal dimensions. We integrated these atlases into a common framework to dissect the molecular logic that governs the responses to injury within the spinal cord. The Tabulae Paralytica uncovered new biological principles that dictate the consequences of SCI, including conserved and divergent neuronal responses to injury; the priming of specific neuronal subpopulations to upregulate circuit-reorganizing programs after injury; an inverse relationship between neuronal stress responses and the activation of circuit reorganization programs; the necessity of re-establishing a tripartite neuroprotective barrier between immune-privileged and extra-neural environments after SCI and a failure to form this barrier in old mice.

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.

Lateral medullary vascular compression manifesting as paroxysmal hypertension.

Neurovascular compression of the rostral ventrolateral medulla (RVLM) has been described as a possible cause of refractory essential hypertension. We present the case of a patient affected by episodes of severe paroxysmal hypertension, some episodes associated with vago-glossopharyngeal neuralgia. Classical secondary forms of hypertension were excluded.

A spinal cord neuroprosthesis for locomotor deficits due to Parkinson's disease.

People with late-stage Parkinson's disease (PD) often suffer from debilitating locomotor deficits that are resistant to currently available therapies. To alleviate these deficits, we developed a neuroprosthesis operating in closed loop that targets the dorsal root entry zones innervating lumbosacral segments to reproduce the natural spatiotemporal activation of the lumbosacral spinal cord during walking. We first developed this neuroprosthesis in a non-human primate model that replicates locomotor deficits due to PD.

Invisible consequences of paralysis.

Neuroprosthetic technologies can control blood pressure and restore walking.

Longitudinal interrogation of sympathetic neural circuits and hemodynamics in preclinical models.

Neurological disorders, including spinal cord injury, result in hemodynamic instability due to the disruption of supraspinal projections to the sympathetic circuits located in the spinal cord. We recently developed a preclinical model that allows the identification of the topology and dynamics through which sympathetic circuits modulate hemodynamics, supporting the development of a neuroprosthetic baroreflex that precisely controls blood pressure in rats, monkeys and humans with spinal cord injuries. Here, we describe the continuous monitoring of arterial blood pressure and sympathetic nerve activity over several months in preclinical models of chronic neurological disorders using commercially available telemetry technologies, as well as optogenetic and neuronal tract-tracing procedures specifically adapted to the sympathetic circuitry.

Natural and targeted circuit reorganization after spinal cord injury.

A spinal cord injury disrupts communication between the brain and the circuits in the spinal cord that regulate neurological functions. The consequences are permanent paralysis, loss of sensation and debilitating dysautonomia. However, the majority of circuits located above and below the injury remain anatomically intact, and these circuits can reorganize naturally to improve function.

Common carotid artery responses to the cold-pressor test are impaired in individuals with cervical spinal cord injury.

Cervical spinal cord injury (SCI) leads to autonomic cardiovascular dysfunction that underlies the three- to fourfold elevated risk of cardiovascular disease in this population. Reduced common carotid artery (CCA) dilatory responsiveness during the cold-pressor test (CPT) is associated with greater cardiovascular disease risk and progression. The cardiovascular and CCA responses to the CPT may provide insight into cardiovascular autonomic dysfunction and cardiovascular disease risk in individuals with cervical SCI.

The neurons that restore walking after paralysis.

A spinal cord injury interrupts pathways from the brain and brainstem that project to the lumbar spinal cord, leading to paralysis. Here we show that spatiotemporal epidural electrical stimulation (EES) of the lumbar spinal cord applied during neurorehabilitation (EES) restored walking in nine individuals with chronic spinal cord injury. This recovery involved a reduction in neuronal activity in the lumbar spinal cord of humans during walking.

Single cell atlas of spinal cord injury in mice reveals a pro-regenerative signature in spinocerebellar neurons.

After spinal cord injury, tissue distal to the lesion contains undamaged cells that could support or augment recovery. Targeting these cells requires a clearer understanding of their injury responses and capacity for repair. Here, we use single nucleus RNA sequencing to profile how each cell type in the lumbar spinal cord changes after a thoracic injury in mice.

Implanted System for Orthostatic Hypotension in Multiple-System Atrophy.

Orthostatic hypotension is a cardinal feature of multiple-system atrophy. The upright posture provokes syncopal episodes that prevent patients from standing and walking for more than brief periods. We implanted a system to restore regulation of blood pressure and enable a patient with multiple-system atrophy to stand and walk after having lost these abilities because of orthostatic hypotension.

Spinal cord injury impairs cardiac function due to impaired bulbospinal sympathetic control.

Spinal cord injury chronically alters cardiac structure and function and is associated with increased odds for cardiovascular disease. Here, we investigate the cardiac consequences of spinal cord injury on the acute-to-chronic continuum, and the contribution of altered bulbospinal sympathetic control to the decline in cardiac function following spinal cord injury. By combining experimental rat models of spinal cord injury with prospective clinical studies, we demonstrate that spinal cord injury causes a rapid and sustained reduction in left ventricular contractile function that precedes structural changes.

A national survey of physical activity after spinal cord injury.

Physical activity is a powerful modifiable risk factor for disease and mortality. Physical activity levels in people with spinal cord injury (SCI) have not been quantified relative to uninjured individuals in a large population-based sample. We aimed to quantify and compare physical activity in people with and without SCI, and to examine the associations between physical activity, lifestyle, and socioeconomic factors.

Engineering spinal cord repair.

Neurological damage caused by spinal cord injury in humans has been observed for over three thousand years and impacts the lives of several hundred thousand people worldwide. Despite this prevalence and its associated consequences, there is no treatment to repair the injured spinal cord. Evidence gathered over the last several decades has provided mechanistic information on the complex cascade of events following traumatic spinal cord injury and this is paving the way towards mechanism based repair strategies.

Confronting false discoveries in single-cell differential expression.

Differential expression analysis in single-cell transcriptomics enables the dissection of cell-type-specific responses to perturbations such as disease, trauma, or experimental manipulations. While many statistical methods are available to identify differentially expressed genes, the principles that distinguish these methods and their performance remain unclear. Here, we show that the relative performance of these methods is contingent on their ability to account for variation between biological replicates.

Markers of susceptibility to cardiac arrhythmia in experimental spinal cord injury and the impact of sympathetic stimulation and exercise training.

Injury to descending autonomic (sympathetic) pathways is common after high-level spinal cord injury (SCI) and associated with abnormal blood pressure and heart rate regulation. In individuals with high-level SCI, abnormal sympathovagal balance (such as during autonomic dysreflexia; paroxysmal hypertension provoked by sensory stimuli below the injury) is proarrhythmogenic. Exercise training is a key component of SCI rehabilitation and management of cardiovascular disease risk, but it is unclear whether exercise training influences susceptibility to cardiac arrhythmia.

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.