Spinal cord injury (SCI) disrupts the structural and functional connectivity between the higher center and the spinal cord, resulting in severe motor, sensory, and autonomic dysfunction with a variety of complications. The pathophysiology of SCI is complicated and multifaceted, and thus individual treatments acting on a specific aspect or process are inadequate to elicit neuronal regeneration and functional recovery after SCI. Combinatory strategies targeting multiple aspects of SCI pathology have achieved greater beneficial effects than individual therapy alone. Although many problems and challenges remain, the encouraging outcomes that have been achieved in preclinical models offer a promising foothold for the development of novel clinical strategies to treat SCI. In this review, we characterize the mechanisms underlying axon regeneration of adult neurons and summarize recent advances in facilitating functional recovery following SCI at both the acute and chronic stages. In addition, we analyze the current status, remaining problems, and realistic challenges towards clinical translation. Finally, we consider the future of SCI treatment and provide insights into how to narrow the translational gap that currently exists between preclinical studies and clinical practice. Going forward, clinical trials should emphasize multidisciplinary conversation and cooperation to identify optimal combinatorial approaches to maximize therapeutic benefit in humans with SCI.
Humans ; Axons/pathology* ; Nerve Regeneration/physiology* ; Spinal Cord Injuries/therapy* ; Neurons/pathology* ; Recovery of Function

OBJECTIVES: To investigate the effect of torso training on unstable surface on lower limb motor function in patients with incomplete spinal cord injury. METHODS: A total of 80 patients with incomplete spinal cord injury caused by thoracolumbar fracture admitted in Ningbo Yinzhou No.2 Hospital from April 2020 to December 2021 were randomly divided into control group and study group, with 40 cases in each group. In addition to routine training, the control group received torso training on stable surface and the study group received torso training on unstable surface. The gait, lower limb muscle strength, balance function, lower limb function, mobility and nerve function of the two groups were compared. RESULTS: After treatment, the stride length, stride frequency and comfortable walking speed improved in the two groups (all P<0.05), and the improvements in study group were more significant (all P<0.05). The muscle strength of quadriceps femoris, gluteus maximus, hamstring, anterior tibialis and gastrocnemius were improved in the two groups (all P<0.05), and the improvements in study group were more significant (all P<0.05); the total trajectories of static eye opening and static eye closing gravity center movement in the two groups were significantly shorter (all P<0.05), and the improvements in the study group were more significant (all P<0.05). The dynamic stability limit range and the American Spinal Injury Association (ASIA) lower extremity motor score, Berg balance scale, modified Barthel index scale in the two groups were significantly higher (all P<0.05), and these scores in study group were significantly higher than those in the control group (all P<0.05). Both groups showed a significant improvement in ASIA grade (all P<0.05), and the improvement in the study group was significantly better (P<0.05). CONCLUSIONS Torso training on unstable surface can effectively improve the gait and lower limb muscle strength of patients with incomplete spinal cord injury and improve the lower limb motor function.
Humans ; Walking/physiology* ; Spinal Cord Injuries ; Gait/physiology* ; Lower Extremity ; Torso

To understand how the nervous system develops from a small pool of progenitors during early embryonic development, it is fundamentally important to identify the diversity of neuronal subtypes, decode the origin of neuronal diversity, and uncover the principles governing neuronal specification across different regions. Recent single-cell analyses have systematically identified neuronal diversity at unprecedented scale and speed, leaving the deconstruction of spatiotemporal mechanisms for generating neuronal diversity an imperative and paramount challenge. In this review, we highlight three distinct strategies deployed by neural progenitors to produce diverse neuronal subtypes, including predetermined, stochastic, and cascade diversifying models, and elaborate how these strategies are implemented in distinct regions such as the neocortex, spinal cord, retina, and hypothalamus. Importantly, the identity of neural progenitors is defined by their spatial position and temporal patterning factors, and each type of progenitor cell gives rise to distinguishable cohorts of neuronal subtypes. Microenvironmental cues, spontaneous activity, and connectional pattern further reshape and diversify the fate of unspecialized neurons in particular regions. The illumination of how neuronal diversity is generated will pave the way for producing specific brain organoids to model human disease and desired neuronal subtypes for cell therapy, as well as understanding the organization of functional neural circuits and the evolution of the nervous system.
Humans ; Neural Stem Cells/physiology* ; Neurons/physiology* ; Brain ; Spinal Cord ; Embryonic Development ; Cell Differentiation/physiology*

A decline in the activities of oxidative phosphorylation (OXPHOS) complexes has been consistently reported in amyotrophic lateral sclerosis (ALS) patients and animal models of ALS, although the underlying molecular mechanisms are still elusive. Here, we report that receptor expression enhancing protein 1 (REEP1) acts as an important regulator of complex IV assembly, which is pivotal to preserving motor neurons in SOD1^G93A mice. We found the expression of REEP1 was greatly reduced in transgenic SOD1^G93A mice with ALS. Moreover, forced expression of REEP1 in the spinal cord extended the lifespan, decelerated symptom progression, and improved the motor performance of SOD1^G93A mice. The neuromuscular synaptic loss, gliosis, and even motor neuron loss in SOD1^G93A mice were alleviated by increased REEP1 through augmentation of mitochondrial function. Mechanistically, REEP1 associates with NDUFA4, and plays an important role in preserving the integrity of mitochondrial complex IV. Our findings offer insights into the pathogenic mechanism of REEP1 deficiency in neurodegenerative diseases and suggest a new therapeutic target for ALS.
Mice ; Animals ; Amyotrophic Lateral Sclerosis/metabolism* ; Superoxide Dismutase-1/metabolism* ; Superoxide Dismutase/metabolism* ; Mice, Transgenic ; Spinal Cord/pathology* ; Mitochondria/physiology* ; Disease Models, Animal

Persistent neurogenesis exists in the subventricular zone (SVZ) of the ventricles and the subgranular zone (SGZ) of the dentate gyrus of the hippocampus in the adult mammalian brain. Adult endogenous neurogenesis not only plays an important role in the normal brain function, but also has important significance in the repair and treatment of brain injury or brain diseases. This article reviews the process of adult endogenous neurogenesis and its application in the repair of traumatic brain injury (TBI) or ischemic stroke, and discusses the strategies of activating adult endogenous neurogenesis to repair brain injury and its practical significance in promoting functional recovery after brain injury.
Adult ; Animals ; Humans ; Brain/physiopathology* ; Hippocampus/physiopathology* ; Mammals/physiology* ; Neurogenesis/physiology* ; Brain Hemorrhage, Traumatic/therapy* ; Ischemic Stroke/therapy* ; Recovery of Function ; Spinal Cord/physiopathology*

Pain is a multi-dimensional emotional experience, and pain sensation and pain emotion are the two main components. As for pain, previous studies only focused on a certain link of the pain transmission pathway or a certain key brain region, and there is a lack of evidence that connectivity of brain regions is involved in pain or pain regulation in the overall state. The establishment of new experimental tools and techniques has brought light to the study of neural pathways of pain sensation and pain emotion. In this paper, the structure and functional basis of the neural pathways involved in the formation of pain sensation and the regulation of pain emotion in the nervous system above the spinal cord level, including thalamus, amygdala, midbrain periaqueductal gray (PAG), parabrachial nucleus (PB) and medial prefrontal cortex (mPFC), are reviewed in recent years, providing clues for the in-depth study of pain.
Humans ; Pain ; Neural Pathways/physiology* ; Periaqueductal Gray/physiology* ; Brain ; Spinal Cord/physiology* ; Magnetic Resonance Imaging

OBJECTIVE: To summarize the research progress of stem cell transplantation in treating spinal cord injury (SCI) at different stages based on the pathophysiological mechanism of SCI. METHODS: The relevant research literature at home and abroad was extensively reviewed to explore the impact of transplantation timing on the effectiveness of stem cell transplantation in treating SCI. RESULTS: Researchers performed different types of stem cell transplantation for subjects at different stages of SCI through different transplantation approaches. Clinical trials have proved the safety and feasibility of stem cell transplantation at acute, subacute, and chronic stages, which can alleviate inflammation at the injured site and restore the function of the damaged nerve cells. But the reliable clinical trials comparing the effectiveness of stem cell transplantation at different stages of SCI are still lacking. CONCLUSION Stem cell transplantation has a good prospect in treating SCI. In the future, the multi-center, large sample randomized controlled clinical trials are needed, with a focus on the long-term effectiveness of stem cell transplantation.
Humans ; Hematopoietic Stem Cell Transplantation ; Neurons ; Recovery of Function/physiology* ; Spinal Cord ; Spinal Cord Injuries/surgery* ; Stem Cell Transplantation

Spinal cord stimulation (SCS)-induced analgesia was characterized, and its underlying mechanisms were examined in a spared nerve injury model of neuropathic pain in rats. The analgesic effect of SCS with moderate mechanical hypersensitivity was increased with increasing stimulation intensity between the 20% and 80% motor thresholds. Various frequencies (2, 15, 50, 100, 10000 Hz, and 2/100 Hz dense-dispersed) of SCS were similarly effective. SCS-induced analgesia was maintained without tolerance within 24 h of continuous stimulation. SCS at 2 Hz significantly increased methionine enkephalin content in the cerebrospinal fluid. The analgesic effect of 2 Hz was abolished by μ or κ opioid receptor antagonist. The effect of 100 Hz was prevented by a κ antagonist, and that of 10 kHz was blocked by any of the μ, δ, or κ receptor antagonists, suggesting that the analgesic effect of SCS at different frequencies is mediated by different endorphins and opioid receptors.
Analgesics ; Animals ; Narcotic Antagonists/pharmacology* ; Neuralgia/therapy* ; Opioid Peptides ; Rats ; Receptors, Opioid/physiology* ; Receptors, Opioid, kappa ; Spinal Cord ; Spinal Cord Stimulation

Electric field stimulation (EFS) can effectively inhibit local Ca ²⁺ influx and secondary injury after spinal cord injury (SCI). However, after the EFS, the Ca ²⁺ in the injured spinal cord restarts and subsequent biochemical reactions are stimulated, which affect the long-term effect of EFS. Polyethylene glycol (PEG) is a hydrophilic polymer material that can promote cell membrane fusion and repair damaged cell membranes. This article aims to study the combined effects of EFS and PEG on the treatment of SCI. Sprague-Dawley (SD) rats were subjected to SCI and then divided into control group (no treatment, n = 10), EFS group (EFS for 30 min, n = 10), PEG group (covered with 50% PEG gelatin sponge for 5 min, n = 10) and combination group (combined treatment of EFS and PEG, n = 10). The measurement of motor evoked potential (MEP), the motor behavior score and spinal cord section fast blue staining were performed at different times after SCI. Eight weeks after the operation, the results showed that the latency difference of MEP, the amplitude difference of MEP and the ratio of cavity area of spinal cords in the combination group were significantly lower than those of the control group, EFS group and PEG group. The motor function score and the ratio of residual nerve tissue area in the spinal cords of the combination group were significantly higher than those in the control group, EFS group and PEG group. The results suggest that the combined treatment can reduce the pathological damage and promote the recovery of motor function in rats after SCI, and the therapeutic effects are significantly better than those of EFS and PEG alone.
Animals ; Electric Stimulation ; Polyethylene Glycols/therapeutic use* ; Rats ; Rats, Sprague-Dawley ; Recovery of Function/physiology* ; Spinal Cord ; Spinal Cord Injuries/therapy*

Animals ; Mice ; Motor Neurons/physiology* ; Spinal Cord