Spinal Cord Injury Research Articles

Identification of a New Role of miR-199a-5p as Factor Implied in Neuronal Damage: Decreasing the Expression of Its Target X-Linked Anti-Apoptotic Protein (XIAP) After SCI

Spinal cord injury (SCI) results in a cascade of primary and secondary damage, with apoptosis being a prominent cause of neuronal cell death. The X-linked inhibitor of apoptosis (XIAP) plays a critical role in inhibiting apoptosis, but its expression is reduced following SCI, contributing to increased neuronal vulnerability. This study investigates the regulatory role of miR-199a-5p on XIAP expression in the context of SCI. Using bioinformatic tools, luciferase reporter assays, and in vitro and in vivo models of SCI, we identified miR-199a-5p as a post-transcriptional regulator of XIAP. Overexpression of miR-199a-5p significantly reduced XIAP protein levels, although no changes were observed at the mRNA level, suggesting translational repression. In vivo, miR-199a-5p expression was upregulated at 3 and 7 days post-injury, while XIAP expression inversely decreased in both neurons and oligodendrocytes, being particularly significant in the latter at 7 dpi. These findings suggest that miR-199a-5p contributes to the downregulation of XIAP and may exacerbate neuronal apoptosis after SCI. Targeting miR-199a-5p could offer a potential therapeutic strategy to modulate XIAP levels and reduce apoptotic cell death in SCI.

Case characteristics and surgical efficacy in elderly patients over 65 years of age with cervical spinal cord injury without fracture and dislocation: a retrospective study

Case characteristics and surgical efficacy in elderly patients over 65 years of age with cervical spinal cord injury without fracture and dislocation: a retrospective study

Lentivirus-mediated Knockdown of Ski Improves Neurological Function After Spinal Cord Injury in Rats.

The glial scar that forms at the site of injury after spinal cord injury (SCI) is an important physical and biochemical barrier that prevents axonal regeneration and thus delays functional recovery. Ski is a multifunctional transcriptional co-regulator that is involved in a wide range of physiological and pathological processes in humans. Previous studies by our group found that Ski is significantly upregulated in the spinal cord after in vivo injury and in astrocytes after in vitro activation, suggesting that Ski may be a novel molecule regulating astrocyte activation after spinal cord injury. Further studies revealed that knockdown or overexpression intervention of Ski expression could significantly affect the proliferation and migration of activated astrocytes. To further verify the effect of knockdown of Ski expression in vivo on glial scar formation and neurological function after spinal cord injury, we prepared a rat spinal cord injury model using Allen's percussion method and used lentivirus as a vector to mediate the downregulation of Ski in the injured spinal cord. The results showed that knockdown of Ski expression after spinal cord injury significantly suppressed the expression of glial fibrillary acidic protein (Gfap) and vimentin, hallmark molecules of glial scarring, and increased the expression of neurofilament protein-200 (Nf-200) and growth-associated protein (Gap43), key molecules of axon regeneration, as well as Synaptophysin, a key molecule of synapse formation expression. In addition, knockdown of Ski after spinal cord injury also promoted the recovery of motor function. Taken together, these results suggest that Ski is able to inhibit the expression of key molecules of glial scar formation, and at the same time promotes the expression of molecules that are markers of axonal regeneration and synapse formation after spinal cord injury, making it a potential target for targeted therapy after spinal cord injury.

Resveratrol Enhances the Efficacy of Combined BM-MSCs Therapy for Rat Spinal Cord Injury via Modulation of the Sirt-1/NF-κB Signaling Pathway.

Spinal cord injury (SCI) represents a severe trauma to the central nervous system, resulting in significant disability and imposing heavy burdens on families and society. Pathophysiological changes following SCI often trigger secondary injuries that complicate treatment. Bone marrow mesenchymal stem cells (BM-MSCs) have become a focal point of research due to their multifunctionality and self-renewal capabilities; however, their survival and neuroprotective functions are compromised in inflammatory environments. Resveratrol, known for its anti-inflammatory, anti-aging, and anti-oxidative stress properties, has been extensively studied. This research focuses on the anti-inflammatory effects of resveratrol post-SCI and its combined application with BM-MSCs to treat rat spinal cord injuries, exploring both efficacy and mechanisms. In vivo experiments investigated changes in the Sirt-1 signaling pathway post-SCI, while in vitro studies examined the effects of resveratrol on BM-MSCs under inflammatory conditions. The assessment included recovery of motor function, neuronal survival, and apoptosis in SCI rats treated with resveratrol alone or in combination with BM-MSCs. Findings reveal a correlation between Sirt-1 and inflammation signaling pathways post-injury. Resveratrol significantly enhanced the survival and efficacy of BM-MSCs in inflammatory environments by upregulating Sirt-1 and downregulating NF-κB and other inflammatory markers, thereby reducing apoptosis. Combined treatment with resveratrol and BM-MSCs showed superior outcomes in motor function recovery and neuronal survival compared to treatment with BM-MSCs alone. This study offers a novel therapeutic strategy for SCI, enhancing stem cell survival and function through modulation of the Sirt-1/NF-κB pathway, providing a theoretical and experimental foundation for clinical applications.

"What should a rehabilitation hospital be like?" Priorities and expectations of people with spinal cord injury in Türkiye.

Survey study OBJECTIVES: To understand the priorities and expectations of individuals with disabilities caused by spinal cord injuries(SCI) who require long-term inpatient rehabilitation at a rehabilitation hospital. Başakşehir Çam and Sakura City Hospital, İstanbul, Türkiye METHODS: This cross-sectional clinical study included individuals over the age of 18 with SCI who had previously been hospitalized in a rehabilitation hospital. The 18-question survey, titled "What should a rehabilitation hospital be like according to persons with spinal cord injuries?" was administered to individuals hospitalized in the inpatient service of Çam Sakura City Hospital. It was also disseminated to people with SCI through social media. The participants' demographic data was recorded. The survey was completed by 120 participants, comprising 70 males and 50 females. The mean age was 37.47 ± 11.63 years. The time since the SCI was less than one year for 20 individuals and more than one year for 100 individuals. The results showed that robotic rehabilitation and psychological support were the most requested rehabilitation domains, while interest in sexual rehabilitation was less than that in other rehabilitation domains. Furthermore, in the correlation analysis, elderly participants indicated that there should be more specialized services and outpatient clinics exclusive to the SCI. The study revealed a striking trend - participants expressed a strong desire for SCI-specific rehabilitation units and robotic rehabilitation. Additionally, the significance and necessity of sexual rehabilitation should be conveyed to people with SCI.

Satisfaction With Home Care Services and Its Related Factors for Persons With Spinal Cord Injury: A National Community Survey

In order to live independently at home, persons with spinal cord injury (SCI) often require professional home care. The role of the care coordinator remains unclear, as it can be fulfilled by the general practitioner or an SCI specialist, as well as by informal caregivers. We aimed to quantify satisfaction with professional home care among persons with SCI living in Switzerland and the association between first contact for care and having an informal caregiver with satisfaction with home care. Measurements were obtained from the national community survey of the Swiss Spinal Cord Injury Cohort Study. Logistic regression was used to determine the association between first contact for care, having an informal caregiver, and satisfaction with home care, adjusted for sociodemographic factors, SCI characteristics, and functional level. Overall satisfaction with professional home care was high, with 84% of participants reporting being either very satisfied or satisfied. Neither first contact for care nor availability of an informal caregiver was statistically significantly associated with satisfaction. The results showed that women (odds ratio 0.56, 95% CI 0.31-1.00) were statistically significantly less satisfied with home care than men. There was also variation by language region. These findings highlight the importance of providing personalized and culturally sensitive home care that takes into account the diverse preferences and expectations of persons with SCI, especially regarding gender and language region.

Tetramethylpyrazine inhibits ferroptosis in spinal cord injury by regulating iron metabolism through the NRF2/ARE pathway

BackgroundTetramethylpyrazine (TMP) is a natural alkaloid compound with antioxidant and neuroprotective effects. We hypothesized that TMP could exert neuroprotective effects by inhibiting ferroptosis through modulating iron metabolism, but its mechanism is unclear. Through in vivo and in vitro experiments, we have explored how TMP can regulate neurons’ iron metabolism through the NRF2/ARE pathway to Inhibit ferroptosis.MethodsIn the in vivo experiment, the effects of TMP on nerve function and secondary spinal cord injury were observed through behavioral tests and morphology staining. Transmission electron microscopy, molecular biology tests and immunofluorescence staining were used to investigate the role of TMP in the regulation of iron metabolism and ferroptosis through the Nrf2/ARE pathway. Using in vitro experiments to investigate the mechanism of TMP in inhibiting ferroptosis through the Nrf2/ARE pathway.ResultsFirstly, through in vivo experiments, we found that TMP improves motor function of rats with spinal cord injury, reduces spinal cord tissue damage and nerve cell death caused by secondary injury. Moreover, neuronal death and the formation of spinal cord cavities are inhibited by TMP. By regulating lipid peroxidation, TMP can inhibit mitochondrial damage and reduce ROS accumulation. Our study also demonstrated that TMP regulates iron metabolism through the NRF2/ARE pathway to inhibit ferroptosis and repair spinal cord injury. To further explore the regulatory mechanisms of TMP we down-regulating Nrf2 expression in subsequent in vitro experiments. We find that a key ferroptosis pathway, lipid peroxidation, can be regulated by TMP. Additionally, TMP inhibits iron overload-mediated ferroptosis by increasing Nrf2 transcriptional activity.ConclusionA regulatory effect of TMP on the NRF2/ARE pathway was found in both in vitro and in vivo experiments. It promotes the transcription and translation of iron metabolizing and antioxidant molecules. Our study explored the inhibitory effect of TMP on ferroptosis from the iron metabolism pathway and provided new ideas for the treatment of SCI.

Targeting resident astrocytes attenuates neuropathic pain after spinal cord injury.

Astrocytes derive from different lineages and play a critical role in neuropathic pain after spinal cord injury (SCI). Whether selectively eliminating these main origins of astrocytes in lumbar enlargement could attenuate SCI-induced neuropathic pain remains unclear. Through transgenic mice injected with an adeno-associated virus vector and diphtheria toxin, astrocytes in lumbar enlargement were lineage traced, targeted, and selectively eliminated. Pain-related behaviors were measured with an electronic von Frey apparatus and a cold/hot plate after SCI. RNA sequencing, bioinformatics analysis, molecular experiment, and immunohistochemistry were used to explore the potential mechanisms after astrocyte elimination. Lineage tracing revealed that the resident astrocytes but not ependymal cells were the main origins of astrocytes-induced neuropathic pain. SCI-induced mice to obtain significant pain symptoms and astrocyte activation in lumbar enlargement. Selective resident astrocyte elimination in lumbar enlargement could attenuate neuropathic pain and activate microglia. Interestingly, the type I interferons (IFNs) signal was significantly activated after astrocytes elimination, and the most activated Gene Ontology terms and pathways were associated with the type I IFNs signal which was mainly activated in microglia and further verified in vitro and in vivo. Furthermore, different concentrations of interferon and Stimulator of interferon genes (STING) agonist could activate the type I IFNs signal in microglia. These results elucidate that selectively eliminating resident astrocytes attenuated neuropathic pain associated with type I IFNs signal activation in microglia. Targeting type I IFNs signals is proven to be an effective strategy for neuropathic pain treatment after SCI.

Targeting resident astrocytes attenuates neuropathic pain after spinal cord injury

Astrocytes derive from different lineages and play a critical role in neuropathic pain after spinal cord injury (SCI). Whether selectively eliminating these main origins of astrocytes in lumbar enlargement could attenuate SCI-induced neuropathic pain remains unclear. Through transgenic mice injected with an adeno-associated virus vector and diphtheria toxin, astrocytes in lumbar enlargement were lineage traced, targeted, and selectively eliminated. Pain-related behaviors were measured with an electronic von Frey apparatus and a cold/hot plate after SCI. RNA sequencing, bioinformatics analysis, molecular experiment, and immunohistochemistry were used to explore the potential mechanisms after astrocyte elimination. Lineage tracing revealed that the resident astrocytes but not ependymal cells were the main origins of astrocytes-induced neuropathic pain. SCI-induced mice to obtain significant pain symptoms and astrocyte activation in lumbar enlargement. Selective resident astrocyte elimination in lumbar enlargement could attenuate neuropathic pain and activate microglia. Interestingly, the type I interferons (IFNs) signal was significantly activated after astrocytes elimination, and the most activated Gene Ontology terms and pathways were associated with the type I IFNs signal which was mainly activated in microglia and further verified in vitro and in vivo. Furthermore, different concentrations of interferon and Stimulator of interferon genes (STING) agonist could activate the type I IFNs signal in microglia. These results elucidate that selectively eliminating resident astrocytes attenuated neuropathic pain associated with type I IFNs signal activation in microglia. Targeting type I IFNs signals is proven to be an effective strategy for neuropathic pain treatment after SCI.

Silencing of SH3BP2 Inhibits Microglia Activation Via the JAK/STAT Signaling in Spinal Cord Injury Models.

The purpose of our study was to investigate the expression of SH3 domain-binding protein 2 (SH3BP2) in spinal cord injury (SCI) rats and lipopolysaccharide (LPS)-induced microglia, and explored its impact as well as potential mechanism. We examined the level of SH3BP2 in SCI rats using GEO data, immunofluorescence co-staining, qRT-PCR and western blotting. Next, we constructed a rat model with SH3BP2 silencing by injecting LV-shSH3BP2 into the injury site of SCI rats, and then evaluated its neurological outcome, functional recovery, M1 polarization and neuroinflammation by Basso-Beattie-Bresnahan (BBB) score, inclined plane test, Nissl staining and hematoxylin-eosin (H&E). The SH3BP2-related signaling pathway was predicted by KEGG analysis in GSE45006 dataset. BV2 microglial cells and primary microglia were incubated with LPS, and then measured its activation and inflammation by qRT-PCR, western blotting and immunofluorescence. Further complement experiments were performed to explore the molecular mechanisms of SH3BP2. The expression of SH3BP2 was increased in the spinal dorsal horn tissues of SCI rats and LPS-induced microglia. Silencing of SH3BP2 improved neurological outcomes and functional recovery, attenuated neuroinflammation and microglia polarization in SCI rats. Additionally, the JAK/STAT pathway was regulated by SH3BP2. Silencing of SH3BP2 inhibited LPS-induced microglia inflammation and activation, decreased the phosphorylation levels of JAK and STAT. Silencing of SH3BP2 attenuated SCI by regulating the JAK/STAT pathway to inhibit the activation of microglia.

Macrophage Polarization-Based Biomaterials for Repairing Spinal Cord Injury

Macrophage Polarization-Based Biomaterials for Repairing Spinal Cord Injury

Photo-responsive Carboxymethyl Chitosan/Laponite Hydrogel as a Potential Spinal Cord Injury Scaffold: Characterization and Cytocompatibility Study

Photo-responsive Carboxymethyl Chitosan/Laponite Hydrogel as a Potential Spinal Cord Injury Scaffold: Characterization and Cytocompatibility Study

Therapeutic potential of melatonin-pretreated human dental pulp stem cells (hDPSCs) in an animal model of spinal cord injury.

Dental pulp stem cells (DPSCs) show potential for treating neurodegenerative and traumatic diseases due to their neural crest origin. Melatonin (MT), an endogenous neurohormone with well-documented anti-inflammatory and antioxidant properties, has shown promising results with MSCs in terms of engraftment, proliferation, and neuronal differentiation in animal SCI models. However, the effects of melatonin preconditioning on human dental pulp stem cells (hDPSCs) for SCI treatment remain unclear. This study investigates the impact of melatonin preconditioning on hDPSCs engraftment, neural differentiation, and neurological function in rats with SCI. Forty-two male Sprague-Dawley rats were divided into six groups: Control, Sham, Model, Vehicle, Lesion Treatment A(SCI + hDPSCs), and Lesion Treatment B(SCI + MT-hDPSCs). After obtaining hDPSCs, stem cells were evaluated using flow cytometry. Cell viability was assessed using the MTT assay. SCI was induced in the Model, Vehicle, Lesion Treatment A, and Lesion Treatment B groups. The Lesion Treatment A and B groups received hDPSCs and hDPSCs pretreated with melatonin, respectively, 1 week after SCI, while the Vehicle group received only an intravenous injection of DMEM to simulate treatment. The other groups were used for behavioral testing. Immunohistochemistry (IHC) was employed to assess hDPSCs engraftment and differentiation at the SCI site. Motor function across the six groups was evaluated using the Basso, Beattie, and Bresnahan (BBB) score. Histological studies and cell counts confirmed hDPSCs implantation at the injury site, with a significantly higher presence in the MT-hDPSCs compared to hDPSCs(p < 0.01). IHC revealed that hDPSCs and MT-hDPSCs differentiated into neurons and astrocytes, with greater differentiation observed in the MT-hDPSCs compared to the hDPSCs (p < 0.01 and p < 0.05, respectively). Functional improvement was noted in both SCI + hDPSCs and SCI + MT-hDPSCs groups compared to SCI and Vehicle groups from Week 4 onward (p < 0.001). Significant differences were also observed between the SCI + hDPSCs and SCI + MT-hDPSCs groups starting from Week 7 (p < 0.01). Preconditioning hDPSCs with melatonin enhances engraftment, neuronal differentiation, and greater performance improvement compared to hDPSCs alone in the SCI animal model.

Spinal cord neural stem cells derived from human embryonic stem cells promote synapse regeneration and remyelination in spinal cord injury model rats.

Spinal cord injury (SCI) is a devastating injury that significantly impairs patients' quality of life. To date, there is no effective treatment to mitigate nerve tissue damage and restore neurological function. Neural stem cells (NSCs) derived from human embryonic stem cells (hESCs) are considered an important cell source for reconstructing damaged neural circuits and enabling axonal regeneration. Recent preclinical studies have shown that NSCs are potential therapeutic cell sources for neuroprotection and neuroregeneration in SCI animal models. NSCs can be derived from different sources and the spinal cord-specific NSCs have a higher potential for the regeneration of SCI. However, the long-term therapeutic efficacy of spinal cord-specific NSCs remains unproven. Here, we generated human spinal cord NSCs (hSCNSCs) and investigated the effects of transplanted hSCNSCs on the repair of the SCI model rats for 60 days. The transplanted hSCNSCs improved BBB scores, reduced the lesion area and promoted an increase in the number of Nestin-positive cells in the spinal cord compared to the model rats. Meanwhile, hSCNSC transplantation promoted the expression of synaptophysin, a synaptic signature protein and MBP, a protein associated with remyelination. Interestingly, BAF45D, a chromatin remodelling factor that contributes to the induction of hSCNSCs with region-specific spinal cord identity, were increased by the hSCNSC transplantation. In addition, conditioned medium derived from the hSCNSCs also promoted regenerative repair of the injured spinal cord. These results demonstrate that hSCNSCs may play a critical role in the regenerative repair of SCI.

Neurological Surgery Manpower Training and Density in Islamic Republic of Iran: A Population Study

BACKGROUND AND OBJECTIVES: Significant disparities in worldwide neurosurgical training and workforce distribution are prominent primarily in low-income and middle-income countries. Although Iran is considered a lower middle–income country, neurosurgical density and distribution in Iran has surpassed the recommended ratio of 1 neurosurgeon for every 100 000 population. The objective was to determine neurological surgery density and distribution in Iran and the factors significant in the relative success in training and allocation of neurosurgeons in Iran. METHODS: Review of PubMed and administration of site surveys of multiple data sources including Neurosurgical Society of Iran, Iranian Board of Neurological Surgery, Medical Council of Islamic Republic of Iran, Universities of Medical Sciences in Iran, and Ministry of Health and Higher Education of Iran. RESULTS: Over the 72-year period from 1952 to 2024, 1200 neurosurgeons have been trained and distributed in 31 provinces in Iran, attaining a ratio of 1.4/100 000 population. All but 40 neurosurgeons were trained after 1981, which coincided with the Iran-Iraq War. Decentralization of medical and neurosurgical residency training programs, resolving the immediate need for neurosurgeons managing penetrating traumatic brain and spinal cord injuries during the 1980 to 1988 Iran-Iraq War, and active participation of legislative and executive branches of government in solving health care disparities were major factors in meeting the needs of the country. At the present time, more than 555 neurosurgeons are practicing in Tehran Province, a proportion of 3.8 neurosurgeons for every 100 000 population, which indicates an element of disparity in density distribution across Iranian land. CONCLUSION: Legislative initiatives and government support of public health care delivery and decentralization of medical and residency training programs after the Iran-Iraq War and introduction of the Ministry of Health and Medical Education are considered the main reasons for the relative success in meeting the neurosurgical demand and manpower density. Still, further adjustment of distribution of manpower is needed.

Bioactive Three-Dimensional Chitosan-Based Scaffolds Modified with Poly(dopamine)/CBD@Pt/Au/PVP Nanoparticles as Potential NGCs Applicable in Nervous Tissue Regeneration—Preparation and Characterization

Tissue engineering of nervous tissue is a promising direction in the treatment of neurological diseases such as spinal cord injuries or neuropathies. Thanks to technological progress and scientific achievements; the use of cells; artificial scaffolds; and growth factors are becoming increasingly common. Despite challenges such as the complex structure of this tissue, regenerative medicine appears as a promising future approach to improve the quality of life of patients with nervous injuries. Until now; most functional biomaterials used for this purpose were based on decellularized extra cellular matrix (ECM) or nanofibrous materials, whereas current clinically verified ones in most cases do not exhibit bioactivity or the possibility for external stimulation. The aim of this research was to develop a new type of bioactive, chitosan-based 3D materials applicable as nerve guide conduits (NGCs) modified with poly(dopamine), Au/Pt coated with PVP nanoparticles, and cannabidiol. The NGCs were prepared under microwave-assisted conditions and their chemical structure was studied using the FT-IR method. Next, this study will discuss novel biomaterials for morphology and swelling abilities as well as susceptibility to biodegradation in the presence of collagenase and lysozyme. Finally, their potential in the field of nervous tissue engineering has been verified via a cytotoxicity study using the 1321N1 human astrocytoma cell line, which confirmed their biocompatibility in direct contact studies.

Procaine regulates the STAT3/CCL5 axis and inhibits microglia M1 polarization to alleviate CFA rats pain behavior.

Neuropathic pain (NP) caused by sciatic nerve injury can significantly impact the quality of life of patients. The M1 phenotype of microglia has been reported to promote the progression of NP. Procaine is a lipid-soluble local anesthetic drug that exerts narcotic analgesic effects. Nevertheless, the detailed effect of procaine in NP is not clear. In order to explore the role of procaine in the polarization of NP microglia, HAPI cells were exposed to LPS to polarize into M1 type. In addition, the number of the M1 phenotype of HAPI cells was assessed using flow cytometry. The binding site between CCL5 and STAT3 was explored using the dual luciferase assay. Furthermore, in vivo experiments were applied for testing the impact of procaine on NP.LPS significantly inhibited HAPI cell viability, which was reversed by procaine. Consistently, procaine alleviated LPS-induced upregulation of inflammatory factors. Additionally, it significantly inhibited HAPI cells M1 polarization induced by LPS. Meanwhile, overexpression of STAT3 was able to promote HAPI cells M1 polarization through binding with the CCL5 promoter region and activating the PI3K/Akt signaling. Procaine could alleviate the painful behavior of complete Freund's adjuvant (CFA) rats by modulating the STAT3/CCL5 axis and inhibiting microglia M1 polarization. In conclusion, procaine alleviated the painful behavior of CFA rats via regulating the STAT3/CCL5 axis and inhibiting microglia M1 polarization. Hence, the research might provide a novel agent for NP treatment.Significance statement Neuropathic pain (NP) refers to pain caused by damage to the somatosensory system, which can be caused by brain or spinal cord injury and have a serious impact on the patient's quality of life. The M1 phenotype of microglia plays a crucial role in promoting the progression of NP. In this study, we investigated the specific mechanism of local anesthetic procaine in improving NP by inhibiting microglia polarization towards M1 type. Our findings may provide a new drug for NP treatment.

Acute intermittent hypoxia elicits sympathetic neuroplasticity independent of peripheral chemoreflex activation and spinal cord tissue hypoxia in a rodent model of high-thoracic spinal cord injury.

The loss of medullary control of spinal circuits controlling the heart and blood vessels is a unifying mechanism linking both hemodynamic instability and the risk for cardiovascular diseases (CVD) following spinal cord injury (SCI). As such, new avenues to regulate sympathetic activity are essential to mitigate CVD in this population. Acute intermittent hypoxia (AIH) induces a type of neuroplasticity known as long-term facilitation (LTF), a persistent increase in nerve activity post-AIH in spinal motor circuits. Whether LTF occurs within the sympathetic circuit following SCI is largely unknown. We aimed to test whether AIH elicits sympathetic LTF (i.e., sLTF) and attenuates hypoactivity in sub-lesional splanchnic sympathetic circuits in a male rat model of SCI. In 3 experimental series, we tested whether 1) high-thoracic contusion SCI induces hypoactivity in splanchnic sympathetic nerve activity, 2) AIH elicits sLTF following SCI, and 3) sLTF requires carotid chemoreflex or spinal cord tissue hypoxia. Our results indicate that a single-session of AIH therapy (10 × 1 min of FiO2 = 0.1, interspersed with 2 min of FiO2 = 1.0) delivered at 2 weeks following SCI attenuates SCI-induced sympathetic hypoactivity by eliciting sLTF 90 min post-treatment that is independent of peripheral chemoreflex activation and/or spinal cord hypoxia. These findings advance our mechanistic understanding of AIH in the field and yield new insights into factors underpinning AIH-induced sLTF following SCI in a rat model. Our findings also set the stage for the chronic application of AIH to alleviate secondary complications resulting from sympathetic hypoactivity following SCI.

Molecular signaling predicts corticospinal axon growth state and muscle response plasticity induced by neuromodulation

Electrical motor cortex stimulation can produce corticospinal system plasticity and enhance motor function after injury. We investigate molecular mechanisms of structural and physiological plasticity following electrical neuromodulation, focusing on identifying molecular predictors, or biomarkers, for durable plasticity. We used two neuromodulation protocols, repetitive multipulse stimulation (rMPS) and patterned intermittent theta burst stimulation (iTBS), incorporating different stimulation durations and follow-up periods. We compared neuromodulation efficacy in promoting corticospinal tract (CST) sprouting, motor cortex muscle evoked potential (MEP) LTP-like plasticity, and their associated molecular underpinnings. Only iTBS produced CST sprouting after short-term neuromodulation (1 d of stimulation; 9-d survival for sprouting expression); both iTBS and rMPS produced sprouting with long-term (10-d) neuromodulation. Significant mTOR signaling activation and phosphatase and tensin homolog (PTEN) protein deactivation predicted axon growth across all neuromodulation conditions that produced significant sprouting. Both neuromodulation protocols, regardless of duration, were effective in producing MEP enhancement. However, persistent LTP-like enhancement of MEPs at 30 d was only produced by long-term iTBS. Statistical modeling suggests that Stat3 signaling is the key mediator of MEP enhancement. Cervical spinal cord injury (SCI) alone did not affect baseline molecular signaling. Whereas iTBS and rMPS after SCI produced strong mTOR activation and PTEN deactivation, only iTBS produced Stat3 activation. Our findings support differential molecular biomarkers for neuromodulation-dependent structural and physiological plasticity and show that motor cortex epidural neuromodulation produces molecular changes in neurons that support axonal growth after SCI. iTBS may be more suitable for repair after SCI because it promotes molecular signaling for both CST growth and MEP plasticity.

MRI Spinal Cord Reconstruction Provides Insights into Mapping and Migration Following Percutaneous Epidural Stimulation Implantation in Spinal Cord Injury

Background: Spinal cord epidural stimulation (SCES) has the potential to restore motor functions following spinal cord injury (SCI). Spinal cord mapping is a cornerstone step towards successfully configuring SCES to improve motor function, aiming to restore standing and stepping abilities in individuals with SCI. While some centers have advocated for the use of intraoperative mapping to anatomically target the spinal cord locomotor centers, this is a resource-intensive endeavor and may not be a feasible approach in all centers. Methods: Two participants underwent percutaneous SCES implantation as part of a clinical trial. Each participant underwent a temporary (1-week, two-lead) trial followed by a permanent, two-lead implantation. SCES configurations were matched between temporary and permanent mappings, and motor evoked potential in response to 2 Hz, for a duration of 250–1000 µs and with an amplitude of 1–14 mA, was measured using electromyography. T2 axial MRI images captured prior to implantation were used to retrospectively reconstruct the lumbosacral segments of the spinal cord. The effects of lead migration on mapping were further determined in one of the participants. Results: In both participants, there were recognized discrepancies in the recruitment curves of the motor evoked potentials across different muscle groups between temporary and permanent SCES mappings. These may be explained by retrospective MRI reconstruction of the spinal cord, which indicated that the percutaneous leads did not specifically target the entire L1-S2 segments in both participants. Minor lead migration appeared to have a minimal impact on spinal cord mapping outcomes in one of the participants but did dampen the motor activity of the hip and knee muscle groups. Conclusions: Temporary mapping coupled with MRI reconstruction has the potential to be considered as guidance for permanent implantation considering target activation of the spinal cord locomotor centers. Since lead migration may alter the synergistic coordination between different muscle groups and since lead migration of 1–2 contacts is expected and planned for in clinical practice, it can be better guided with proper spinal cord mapping and a diligent SCES lead trial beforehand.