Repetitive transcranial magnetic stimulation promotes motor function recovery in mice after spinal cord injury via regulation of the Cx43-autophagy loop.

Spinal cord injury (SCI) is a severe condition with an extremely high disability rate. It is mainly manifested as the loss of motor, sensory and autonomic nerve functions below the injury site. High-frequency transcranial magnetic stimulation, a recently developed neuromodulation method, can increase motor function in mice with spinal cord injury. This study aimed to explore the possible mechanism by which transcranial magnetic stimulation (TMS) restores motor function after SCI. A complete T8 transection model of the spinal cord was established in mice, and the mice were treated daily with 15 Hz high-frequency transcranial magnetic stimulation. The BMS was used to evaluate the motor function of the mice after SCI. Western blotting and immunofluorescence were used to detect the expression of Connexin43 (CX43) and autophagy-related proteins in vivo and in vitro, and correlation analysis was performed to study the relationships among autophagy, CX43 and motor function recovery after SCI in mice. Western blotting was used to observe the effect of magnetic stimulation on the expression of mTOR pathway members. In the control group, the expression of CX43 was significantly decreased, and the expression of microtubule-associated protein 1 A/1b light chain 3 (LC3II) and P62 was significantly increased after 4 weeks of spinal cord transection. After high-frequency magnetic stimulation, the level of CX43 decreased, and the levels of LC3II and P62 increased in primary astrocytes. The BMS of the magnetic stimulation group was greater than that of the control group. High-frequency magnetic stimulation can inhibit the expression of CX43, which negatively regulates autophagic flux. HF-rTMS increased the expression levels of mTOR, p-mTOR and p-S6. Our experiments showed that rTMS can restore hindlimb motor function in mice after spinal cord injury via regulation of the Cx43-autophagy loop and activation of the mTOR signalling pathway.

Research progress and prospects of benefit-risk assessment methods for umbilical cord mesenchymal stem cell transplantation in the clinical treatment of spinal cord injury.

Over the past decade, we have witnessed the development of cell transplantation as a new strategy for repairing spinal cord injury (SCI). However, due to the complexity of the central nervous system (CNS), achieving successful clinical translation remains a significant challenge. Human umbilical cord mesenchymal stem cells (hUMSCs) possess distinct advantages, such as easy collection, lack of ethical concerns, high self-renewal ability, multilineage differentiation potential, and immunomodulatory properties. hUMSCs are promising for regenerating the injured spinal cord to a significant extent. At the same time, for advancing SCI treatment, the appropriate benefit and risk evaluation methods play a pivotal role in determining the clinical applicability of treatment plans. Hence, this study discusses the advantages and risks of hUMSCs in SCI treatment across four dimensions-comprehensive evaluation of motor and sensory function, imaging, electrophysiology, and autonomic nervous system (ANS) function-aiming to improve the rationality of relevant clinical research and the feasibility of clinical translation.

The Development of Principles for Patient and Public Involvement (PPI) in Preclinical Spinal Cord Research: A Modified Delphi Study.

INTRODUCTION: There is currently limited guidance for researchers on Patient and Public Involvement (PPI) for preclinical spinal cord research, leading to uncertainty about design and implementation. This study aimed to develop evidence-informed principles to support preclinical spinal cord researchers to incorporate PPI into their research. METHODS: This study used a modified Delphi method with the aim of establishing consensus on a set of principles for PPI in spinal cord research. Thirty-eight stakeholders including researchers, clinicians and people living with spinal cord injury took part in the expert panel. Participants were asked to rate their agreement with a series of statements relating to PPI in preclinical spinal cord research over two rounds. As part of Round 2, they were also asked to rate statements as essential or desirable. RESULTS: Thirty-eight statements were included in Round 1, after which five statements were amended and two additional statements were added. After Round 2, consensus (> 75% agreement) was reached for a total of 27 principles, with 13 rated as essential and 14 rated as desirable. The principles with highest agreement related to diversity in representation among PPI contributors, clarity of the purpose of PPI and effective communication. CONCLUSION: This research developed a previously unavailable set of evidence-informed principles to inform PPI in preclinical spinal cord research. These principles provide guidance for researchers seeking to conduct PPI in preclinical spinal cord research and may also inform PPI in other preclinical disciplines. PATIENT AND PUBLIC INVOLVEMENT STATEMENT: This study was conducted as part of a project aiming to develop PPI in preclinical spinal cord injury research associated with an ongoing research collaboration funded by the Irish Rugby Football Union Charitable Trust (IRFU CT) and the Science Foundation Ireland Centre for Advanced Materials and BioEngineering Research (SFI AMBER), with research conducted by the Tissue Engineering Research Group (TERG) at the RCSI University of Medicine and Health Sciences. The project aims to develop an advanced biomaterials platform for spinal cord repair and includes a PPI Advisory Panel comprising researchers, clinicians and seriously injured rugby players to oversee the work of the project. PPI is included in this study through the involvement of members of the PPI Advisory Panel in the conceptualisation of this research, review of findings, identification of key points for discussion and preparation of the study manuscript as co-authors.

[Specialized Concepts for the Management of Severe Neurotrauma]. / Spezielle Behandlungskonzepte bei schwerem Neurotrauma.

Neurotrauma results from violence on structures of the central or peripheral nervous system and is a clinically common disease entity with high relevance for patients' long-term outcome. The application of evidence-based diagnostic and therapeutic concepts aims to minimize secondary injury and thus to improve treatment outcome. This article describes the current management of the two main injury patterns of neurotrauma - traumatic brain and spinal cord injury.

Traumatic Brain Injury and Traumatic Spinal Cord Injury.

OBJECTIVE: This article reviews the mechanisms of primary traumatic injury to the brain and spinal cord, with an emphasis on grading severity, identifying surgical indications, anticipating complications, and managing secondary injury. LATEST DEVELOPMENTS: Serum biomarkers have emerged for clinical decision making and prognosis after traumatic injury. Cortical spreading depolarization has been identified as a potentially modifiable mechanism of secondary injury after traumatic brain injury. Innovative methods to detect covert consciousness may inform prognosis and enrich future studies of coma recovery. The time-sensitive nature of spinal decompression is being elucidated. ESSENTIAL POINTS: Proven management strategies for patients with severe neurotrauma in the intensive care unit include surgical decompression when appropriate, the optimization of perfusion, and the anticipation and treatment of complications. Despite validated models, predicting outcomes after traumatic brain injury remains challenging, requiring prognostic humility and a model of shared decision making with surrogate decision makers to establish care goals. Penetrating injuries, especially gunshot wounds, are often devastating and require public health and policy approaches that target prevention.

Optical Devices for the Diagnosis and Management of Spinal Cord Injuries: A Review.

Throughout the central nervous system, the spinal cord plays a very important role, namely, transmitting sensory and motor information inwardly so that it can be processed by the brain. There are many different ways this structure can be damaged, such as through traumatic injury or surgery, such as scoliosis correction, for instance. Consequently, damage may be caused to the nervous system as a result of this. There is no doubt that optical devices such as microscopes and cameras can have a significant impact on research, diagnosis, and treatment planning for patients with spinal cord injuries (SCIs). Additionally, these technologies contribute a great deal to our understanding of these injuries, and they are also essential in enhancing the quality of life of individuals with spinal cord injuries. Through increasingly powerful, accurate, and minimally invasive technologies that have been developed over the last decade or so, several new optical devices have been introduced that are capable of improving the accuracy of SCI diagnosis and treatment and promoting a better quality of life after surgery. We aim in this paper to present a timely overview of the various research fields that have been conducted on optical devices that can be used to diagnose spinal cord injuries as well as to manage the associated health complications that affected individuals may experience.

mHealth-Based Just-in-Time Adaptive Intervention to Improve the Physical Activity Levels of Individuals With Spinal Cord Injury: Protocol for a Randomized Controlled Trial.

BACKGROUND: The lack of regular physical activity (PA) in individuals with spinal cord injury (SCI) in the United States is an ongoing health crisis. Regular PA and exercise-based interventions have been linked with improved outcomes and healthier lifestyles among those with SCI. Providing people with an accurate estimate of their everyday PA level can promote PA. Furthermore, PA tracking can be combined with mobile health technology such as smartphones and smartwatches to provide a just-in-time adaptive intervention (JITAI) for individuals with SCI as they go about everyday life. A JITAI can prompt an individual to set a PA goal or provide feedback about their PA levels. OBJECTIVE: The primary aim of this study is to investigate whether minutes of moderate-intensity PA among individuals with SCI can be increased by integrating a JITAI with a web-based PA intervention (WI) program. The WI program is a 14-week web-based PA program widely recommended for individuals with disabilities. A secondary aim is to investigate the benefit of a JITAI on proximal PA, defined as minutes of moderate-intensity PA within 120 minutes of a PA feedback prompt. METHODS: Individuals with SCI (N=196) will be randomized to a WI arm or a WI+JITAI arm. Within the WI+JITAI arm, a microrandomized trial will be used to randomize participants several times a day to different tailored feedback and PA recommendations. Participants will take part in the 24-week study from their home environment in the community. The study has three phases: (1) baseline, (2) WI program with or without JITAI, and (3) PA sustainability. Participants will provide survey-based information at the initial meeting and at the end of weeks 2, 8, 16, and 24. Participants will be asked to wear a smartwatch every day for ≥12 hours for the duration of the study. RESULTS: Recruitment and enrollment began in May 2023. Data analysis is expected to be completed within 6 months of finishing participant data collection. CONCLUSIONS: The JITAI has the potential to achieve long-term PA performance by delivering tailored, just-in-time feedback based on the person's actual PA behavior rather than a generic PA recommendation. New insights from this study may guide intervention designers to develop engaging PA interventions for individuals with disability. TRIAL REGISTRATION: ClinicalTrials.gov NCT05317832; https://clinicaltrials.gov/study/NCT05317832. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/57699.

Pyroptosis in Spinal Cord Injury: Implications for Pathogenesis and Therapeutic Approaches.

Traumatic spinal cord injury (SCI) is a serious disease of the central nervous system. Aside from the limited intrinsic regenerative capacity of neurons, complex microenvironmental disturbances can also lead to further cellular damage and growth inhibition. Programmed cell death regulated by pyroptosis has an important role in the pathogenesis of SCI. While there has been a wealth of new knowledge regarding cellular pyroptosis, a detailed understanding of its role in SCI and possible therapeutic strategies is still lacking. This review summarizes current advances in the regulatory role of pyroptosis-regulated cell death and inflammasome components in the inhibitory microenvironment following SCI, as well as recent therapeutic advances.

Decellularized porcine peripheral nerve based injectable hydrogels as a Schwann cell carrier for injured spinal cord regeneration.

Objective.To develop a clinically relevant injectable hydrogel derived from decellularized porcine peripheral nerves and with mechanical properties comparable to native central nervous system (CNS) tissue to be used as a delivery vehicle for Schwann cell transplantation to treat spinal cord injury (SCI).Approach.Porcine peripheral nerves (sciatic and peroneal) were decellularized by chemical decellularization using a sodium deoxycholate and DNase (SDD) method previously developed by our group. The decellularized nerves were delipidated using dichloromethane and ethanol solvent and then digested using pepsin enzyme to form injectable hydrogel formulations. Genipin was used as a crosslinker to enhance mechanical properties. The injectability, mechanical properties, and gelation kinetics of the hydrogels were further analyzed using rheology. Schwann cells encapsulated within the injectable hydrogel formulations were passed through a 25-gauge needle and cell viability was assessed using live/dead staining. The ability of the hydrogel to maintain Schwann cell viability against an inflammatory milieu was assessedin vitrousing inflamed astrocytes co-cultured with Schwann cells.Mainresults. The SDD method effectively removes cells and retains extracellular matrix in decellularized tissues. Using rheological studies, we found that delipidation of decellularized porcine peripheral nerves using dichloromethane and ethanol solvent improves gelation kinetics and mechanical strength of hydrogels. The delipidated and decellularized hydrogels crosslinked using genipin mimicked the mechanical strength of CNS tissue. The hydrogels were found to have shear thinning properties desirable for injectable formulations and they also maintained higher Schwann cell viability during injection compared to saline controls. Usingin vitroco-culture experiments, we found that the genipin-crosslinked hydrogels also protected Schwann cells from astrocyte-mediated inflammation.Significance. Injectable hydrogels developed using delipidated and decellularized porcine peripheral nerves are a potential clinically relevant solution to deliver Schwann cells, and possibly other therapeutic cells, at the SCI site by maintaining higher cellular viability and increasing therapeutic efficacy for SCI treatment.

Development of Combinatorial Therapeutics for Spinal Cord Injury using Stem Cell Delivery.

Traumatic spinal cord injury (SCI) induces permanent sensorimotor deficit below the site of injury. It affects approximately a quarter million people in the US, and it represents an immeasurable public health concern. Research has been conducted to provide effective therapy; however, SCI is still considered incurable due to the complex nature of the injury site. A variety of strategies, including drug delivery, cell transplantation, and injectable biomaterials, are investigated, but one strategy alone limits their efficacy for regeneration. As such, combinatorial therapies have recently gained attention that can target multifaceted features of the injury. It has been shown that extracellular matrices (ECM) may increase the efficacy of cell transplantation for SCI. To this end, 3D hydrogels consisting of decellularized spinal cords (dSCs) and sciatic nerves (dSNs) were developed at different ratios and characterized. Histological analysis of dSCs and dSNs confirmed the removal of cellular and nuclear components, and native tissue architectures were retained after decellularization. Afterward, composite hydrogels were created at different volumetric ratios and subjected to analyses of turbidity gelation kinetics, mechanical properties, and embedded human adipose-derived stem cell (hASC) viability. No significant differences in mechanical properties were found among the different ratios of hydrogels and decellularized spinal cord matrices. Human ASCs embedded in the gels remained viable throughout the 14-day culture. This study provides a means of generating tissue-engineered combinatorial hydrogels that present nerve-specific ECM and pro-regenerative mesenchymal stem cells. This platform can provide new insights into neuro-regenerative strategies after SCI with future investigations.

Correlation of bilateral M1 hand area excitability and overall functional recovery after spinal cord injury: protocol for a prospective cohort study.

BACKGROUND: After spinal cord injury (SCI), a large number of survivors suffer from severe motor dysfunction (MD). Although the injury site is in the spinal cord, excitability significantly decreases in the primary motor cortex (M1), especially in the lower extremity (LE) area. Unfortunately, M1 LE area-targeted repetitive transcranial magnetic stimulation (rTMS) has not achieved significant motor improvement in individuals with SCI. A recent study reported that the M1 hand area in individuals with SCl contains a compositional code (the movement-coding component of neural activity) that links matching movements from the upper extremities (UE) and the LE. However, the correlation between bilateral M1 hand area excitability and overall functional recovery is unknown. OBJECTIVE: To clarify the changes in the excitability of the bilateral M1 hand area after SCI and its correlation with motor recovery, we aim to specify the therapeutic parameters of rTMS for SCI motor rehabilitation. METHODS: This study is a 12-month prospective cohort study. The neurophysiological and overall functional status of the participants will be assessed. The primary outcomes included single-pulse and paired-pulse TMS. The second outcome included functional near-infrared spectroscopy (fNIRS) measurements. Overall functional status included total motor score, modified Ashworth scale score, ASIA Impairment Scale grade, spinal cord independence measure and modified Barthel index. The data will be recorded for individuals with SCI at disease durations of 1 month, 2 months, 4 months, 6 months and 12 months. The matched healthy controls will be measured during the same period of time after recruitment. DISCUSSION: The present study is the first to analyze the role of bilateral M1 hand area excitability changes in the evaluation and prediction of overall functional recovery (including motor function and activities of daily living) after SCI, which will further expand the traditional theory of the predominant role of M1, optimize the current rTMS treatment, and explore the brain-computer interface design for individuals with SCI. TRIAL REGISTRATION NUMBER: ChiCTR2300068831.

Mesenchymal Stem Cells for the Treatment of Spinal Cord Injury in Rat Models: A Systematic Review and Network Meta-Analysis.

Transplantation of mesenchymal stem cells (MSCs) is one of the hopeful treatments for spinal cord injury (SCI). Most current studies are in animals, and less in humans, and the optimal transplantation strategy for MSCs is still controversial. In this article, we explore the optimal transplantation strategy of MSCs through a network meta-analysis of the effects of MSCs on SCI in animal models. PubMed, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Wanfang Database, China Science and Technology Journal Database (VIP), and Chinese Biomedical Literature Service System (SinoMed) databases were searched by computer for randomized controlled studies on MSCs for SCI. Two investigators independently completed the literature screening and data extraction based on the inclusion and exclusion criteria. RevMan 5.4 software was used to assess the quality of the included literature. Stata 16.0 software was used for standard meta-analysis and network meta-analysis. Standardized mean difference (SMD) was used for continuous variables to combine the statistics and calculate 95% confidence interval (95% CI). P < 0.05 was considered a statistically significant difference. Cochrane's Q test and the I2 value were used to indicate the magnitude of heterogeneity. A random-effects model was used if I2 > 50% and P < 0.10 indicated significant heterogeneity between studies, and conversely, a fixed-effects model was used. Evidence network diagrams were drawn based on direct comparisons between various interventions. The surface under the cumulative ranking curve area (SUCRA) was used to predict the ranking of the treatment effects of each intervention. A total of 32 animal studies were included in this article for analysis. The results of the standard meta-analysis showed that MSCs improved motor ability after SCI. The network meta-analysis showed that the best treatment effect was achieved for adipose tissue-derived mesenchymal stromal cells (ADMSCs) in terms of cell source and intrathecal (IT) in terms of transplantation modality. For transplantation timing, the best treatment effect was achieved when transplantation was performed in the subacute phase. The available literature suggests that IT transplantation using ADMSCs in the subacute phase may be the best transplantation strategy to improve functional impairment after SCI. Future high-quality studies are still needed to further validate the results of this study to ensure the reliability of the results.

Enhancing regenerative potential: A comprehensive review of stem cell transplantation for sports-related neuronal injuries, with a focus on spinal cord injuries and peripheral nervous system damage.

Neuronal injuries, as one of the consequences of sports-related incidents, exert a profound influence on the athletes' future, potentially leading to complete immobility and impeding their athletic pursuits. In cases of severe damage inflicted upon the spinal cord (SC) and peripheral nervous systems (PNS), the regenerative process is notably compromised, rendering it essentially inefficient. Among the pivotal therapeutic approaches for the enhancement and prevention of secondary SC injuries (SCI), stem cell transplantation (SCT) stands out prominently. Stem cells, whether directly involved in replacement and reconstruction or indirectly through modification and secretion of crucial bioenvironmental factors, engage in the intricate process of tissue regeneration. Stem cells, through the secretion of neurotrophic factors (NTFs) (aiming to modulate the immune system), reduction of inflammation, axonal growth stimulation, and myelin formation, endeavor to facilitate the regeneration of damaged SC tissue. The fundamental challenges of this approach encompass the proper selection of suitable stem cell candidates for transplantation and the establishment of an appropriate microenvironment conducive to SC repair. In this article, an attempt has been made to explore sports-related injuries, particularly SCI, to comprehensively review innovative methods for treating SCI, and to address the existing challenges. Additionally, some of the stem cells used in neural injuries and the process of their utilization have been discussed.

Advances of the MAPK pathway in the treatment of spinal cord injury.

Spinal cord injury (SCI) represents a complex pathology within the central nervous system (CNS), leading to severe sensory and motor impairments. It activates various signaling pathways, notably the mitogen-activated protein kinase (MAPK) pathway. Present treatment approaches primarily focus on symptomatic relief, lacking efficacy in addressing the underlying pathophysiological mechanisms. Emerging research underscores the significance of the MAPK pathway in neuronal differentiation, growth, survival, axonal regeneration, and inflammatory responses post-SCI. Modulating this pathway post-injury has shown promise in attenuating inflammation, minimizing apoptosis, alleviating neuropathic pain, and fostering neural regeneration. Given its pivotal role, the MAPK pathway emerges as a potential therapeutic target in SCI management. This review synthesizes current knowledge on SCI pathology, delineates the MAPK pathway's characteristics, and explores its dual roles in SCI pathology and therapeutic interventions. Furthermore, it addresses the existing challenges in MAPK research in the context of SCI, proposing solutions to overcome these hurdles. Our aim is to offer a comprehensive reference for future research on the MAPK pathway and SCI, laying the groundwork for targeted therapeutic strategies.

Exosomes Derived from Mesenchymal Stem Cells: Therapeutic Opportunities for Spinal Cord Injury.

Spinal cord injury (SCI) is a serious neurological condition comprising primary and secondary injury and causing severe neurological impairments. The effect of the conventional treatment is limited, including supportive therapy and emergency surgery. Exosomes derived from mesenchymal stem cells (MSCs-Exos) were previously reported to exert its potential therapeutic effects on SCI. Compared with mesenchymal stem cells (MSCs) transplantation for SCI, MSC-Exos showed several superiorities. In the present review, we summarized the revealed data of mechanisms underlying MSC-Exos repairing of SCI and discussed the issues of MSC-Exos use. Thus, in this review we summarized the latest studies on MSCs-Exos in the therapy of SCI and discussed whether MSCs-Exos can be applied to SCI and the prospects of transformation application.

Combination of induced pluripotent stem cell-derived motor neuron progenitor cells with irradiated brain-derived neurotrophic factor over-expressing engineered mesenchymal stem cells enhanced restoration of axonal regeneration in a chronic spinal cord injury rat model.

BACKGROUND: Spinal cord injury (SCI) is a disease that causes permanent impairment of motor, sensory, and autonomic nervous system functions. Stem cell transplantation for neuron regeneration is a promising strategic treatment for SCI. However, selecting stem cell sources and cell transplantation based on experimental evidence is required. Therefore, this study aimed to investigate the efficacy of combination cell transplantation using the brain-derived neurotrophic factor (BDNF) over-expressing engineered mesenchymal stem cell (BDNF-eMSC) and induced pluripotent stem cell-derived motor neuron progenitor cell (iMNP) in a chronic SCI rat model. METHOD: A contusive chronic SCI was induced in Sprague-Dawley rats. At 6 weeks post-injury, BDNF-eMSC and iMNP were transplanted into the lesion site via the intralesional route. At 12 weeks post-injury, differentiation and growth factors were evaluated through immunofluorescence staining and western blot analysis. Motor neuron differentiation and neurite outgrowth were evaluated by co-culturing BDNF-eMSC and iMNP in vitro in 2-dimensional and 3-dimensional. RESULTS: Combination cell transplantation in the chronic SCI model improved behavioral recovery more than single-cell transplantation. Additionally, combination cell transplantation enhanced mature motor neuron differentiation and axonal regeneration at the injured spinal cord. Both BDNF-eMSC and iMNP played a critical role in neurite outgrowth and motor neuron maturation via BDNF expression. CONCLUSIONS: Our results suggest that the combined transplantation of BDNF- eMSC and iMNP in chronic SCI results in a significant clinical recovery. The transplanted iMNP cells predominantly differentiated into mature motor neurons. Additionally, BDNF-eMSC exerts a paracrine effect on neuron regeneration through BDNF expression in the injured spinal cord.

A physiatrist's role in managing unique challenges in pregnancy and delivery in a patient with incomplete lumbar SCI: a case report.

INTRODUCTION: Women of childbearing age make up around 5-10% of individuals with spinal cord injury (SCI) and may face unique medical and functional complications during pregnancy, including prolonged hospitalization and increased risk of early rehospitalization due to falls. CASE PRESENTATION: Here, we discuss a case of a young ambulatory woman with a lumbar motor incomplete spinal cord injury who underwent successful delivery via cesarean section and the role of the physiatrist in the management of the patient's antepartum, intrapartum, and postpartum complications. The patient faced significant antepartum challenges secondary to her neurogenic bladder and pelvic floor weakness, resulting in increased use of her manual wheelchair. The physiatry team assisted with the co-development of a multidisciplinary bladder plan for increased urinary frequency and urinary tract infection prevention with the patient's obstetrics physician (OB). In addition, the physiatry team assisted with the procurement of a new wheelchair suited for the patient's pregnancy and childcare needs in anticipation of decreased mobility during this time. Regarding intrapartum challenges, the physiatry team worked with the patient and her OB to develop a safe birth plan considering the method of delivery, epidural usage, and the need for pelvic floor therapy before and after childbirth. DISCUSSION: The patient had a successful cesarean section delivery, with return to independent mobility soon after childbirth. In summary, this case demonstrates that there is a need for a multidisciplinary approach to patients with SCI during pregnancy and that the role of physiatry is critical to optimizing medical and functional outcomes.

Neuromuscular electrical stimulation to combat cognitive aging in people with spinal cord injury: protocol for a single case experimental design study.

INTRODUCTION: Individuals with spinal cord injury (SCI) can experience accelerated cognitive aging. Myokines (factors released from muscle cells during contractions), such as brain-derived neurotrophic factor (BDNF), are thought to have beneficial effects on cognition. Neuromuscular electrical stimulation (NMES) was shown to elicit a large release of myokines. However, the effects of NMES on cognitive function have not been studied. OBJECTIVE: To present the study protocol for a clinical trial evaluating the effects of NMES aimed at improving cognition and BDNF. METHODS: A replicated randomized three-phases single-case experimental design (SCED) with sequential multiple baseline time series and a single-armed prospective trial will be conducted with 15 adults with chronic SCI (> 12 months after injury) above L1 neurological level undergoing 30-min quadriceps NMES, 3 days per week for 12 weeks. MAIN STUDY ENDPOINTS: Primary endpoint is cognitive performance (assessed by a smartphone test) conducted three times per week during the baseline phase with random duration of 3 to 8 weeks, the intervention phase of 12 weeks, and the follow-up phase of 3 weeks after a no measurement rest period of 12 weeks. Secondary endpoints are changes in BDNF levels and cognitive performance measured before the baseline period, before and after intervention and after a 12 weeks follow-up. CONCLUSION: This will be the first study investigating the effects of 12 weeks NMES on both cognition and BDNF levels in individuals with SCI. The SCED results provide information on individual treatment effect courses which may direct future research. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05822297, 12/01/2023).