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Mechanisms and Therapeutic Strategies of Brain and Spinal Cord Injury

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (31 May 2026) | Viewed by 14458

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Editors

Dr. Hatice Kumru

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Guest Editor

Institut Guttmann, Badalona, Spain
Interests: neuromodulation; neuroplasticity; neurology; neurorehabilitation; spinal cord
Special Issues, Collections and Topics in MDPI journals

Dr. Xabier Urra

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Guest Editor

Department of Neurology, Hospital Clínic, Barcelona, Spain
Interests: stroke; immunology; neuroimaging; acute ischemic stroke

Special Issue Information

Dear Colleagues,

Brain and spinal cord injuries are devastating conditions that can lead to serious long-term disability or even death. Understanding the mechanisms behind these injuries and developing effective therapeutic strategies is crucial to improving outcomes for affected individuals. These injuries involve complex primary and secondary injury mechanisms that require multifaceted therapeutic strategies. Advances in surgical techniques, pharmacotherapy, rehabilitation, and experimental treatments hold promise for improving the quality of life of those affected. Ongoing research into innovative therapies such as neuroprotectants, stem cells, gene therapy, invasive and non-invasive neuromodulation techniques, and biomaterials continues to provide hope for more effective treatments in the future.

Dr. Hatice Kumru
Dr. Xabier Urra
Guest Editors

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Keywords

brain injury
spinal cord injury
stem cells
gene therapy
neuromodulation techniques

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Published Papers (8 papers)

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Research

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22 pages, 1300 KB

Open AccessArticle

Mesenchymal Stromal/Stem Cells in Chronic Incomplete Traumatic Spinal Cord Injury: A Phase I/II Double-Blind Placebo-Controlled Multicentre Trial

by Fernando Martins Braga, Hatice Kumru, Jesús Benito-Penalva, Joaquim Vives, Ruth Coll Bonet, Wanbao Ge, Luciano Rodríguez, Margarita Codinach, Aurora de la Iglesia-López, Antonio Gómez-Rodríguez, José Javier Cid-Fernández, Antonio Montoto-Marqués and Joan Vidal Samsó

Biomedicines 2026, 14(4), 762; https://doi.org/10.3390/biomedicines14040762 - 26 Mar 2026

Viewed by 1174

Abstract

Background/Objectives: Chronic traumatic spinal cord injury (SCI) causes persistent neurological deficits for which no clinically effective regenerative therapy is currently available. Mesenchymal stromal/stem cells (MSCs), particularly Wharton’s jelly-derived MSCs (WJ-MSCs), demonstrate immunomodulatory and neurotrophic potential. This phase I/II study evaluated the safety and efficacy of intrathecal allogeneic WJ-MSC administration in individuals with chronic incomplete cervical SCI. Methods: In this multicentre, randomised, double-blind, placebo-controlled trial (NCT05054803, EudraCT 2021-000346-18), 18 participants with chronic (1–5 years post-injury) incomplete cervical SCI (AIS B–D) received two intrathecal injections of WJ-MSCs (0.7–1.3 × 10⁶ viable cells/kg) or a placebo at baseline and 3 months. Seventeen participants completed the 12-month follow-up. Primary outcomes assessed safety, and secondary endpoints included International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) motor and sensory scores, spasticity, neuropathic pain, functional independence, neurophysiological measures, and quality of life. Results: Intrathecal WJ-MSC administration was safe and well tolerated. Eighty adverse events occurred (placebo: 26; WJ-MSC: 54), predominantly mild or moderate; four severe events were unrelated to treatment. Both groups demonstrated significant within-group improvements in total motor scores at 12 months, with no between-group difference. No treatment effects were observed for sensory scores, electrophysiological measures, functional independence, spasticity, pain, or patient-reported outcomes. Conclusions: In this first randomised, placebo-controlled trial evaluating intrathecal WJ-MSCs in chronic incomplete cervical SCI, WJ-MSC administration demonstrated a favourable safety profile; however, no significant between-group differences were detected relative to the placebo. Given the limited sample size and early-phase design, the efficacy findings should be interpreted cautiously. Future research should explore enhanced cell products, intensified dosing schedules, optimised delivery strategies, early intervention, and multimodal therapeutic combinations. Full article

(This article belongs to the Special Issue Mechanisms and Therapeutic Strategies of Brain and Spinal Cord Injury)

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21 pages, 20432 KB

Open AccessArticle

Assessment of Chronic Multi-Electrode Spinal Cord Electrical Stimulation and Electromyography Platform in Non-Human Primates

by Alena D. Militskova, Vyacheslav. V. Andrianov, Artur R. Biktimirov, Evgeny. V. Gulaev, Tatiana. B. Alfimova, Matthew. O. Shkap, Larisa A. Burachek, Roman V. Panfilov, Dmitry. V. Bulgin, Sergey. V. Zhirnov, Alexander. P. Trashkov, Igor A. Lavrov and Vladimir P. Baklaushev

Biomedicines 2026, 14(1), 166; https://doi.org/10.3390/biomedicines14010166 - 13 Jan 2026

Cited by 1 | Viewed by 1305

Abstract

Background/Objectives: Traumatic spinal cord (SC) injury (SCI) is a debilitating neurological condition. Minimally invasive approaches to monitor in real time the functional state of the neuromotor apparatus in animal models of SCI (at rest and movement) to assess effectiveness of therapy are needed in preclinical studies. We aimed to develop such a bioethically acceptable platform for SCI studies on non-human primates (Rhesus macaques). Methods: Epidural and myographic electrode implantation (EI) (wireless and wired, connected via a head plug) was performed. After EI, motor responses caused by electrical stimulation of the SC at the level of the cervical and lumbar thickening were recorded; electromyography of the limb muscles was recorded during quadrupedal movement of the animal on a treadmill with simultaneous assessment of movements’ kinematic parameters. Five weeks after EI, three animals underwent lateral hemisection of the SC in the C4–C5 segment under the control of a surgical microscope and intraoperative recording of motor- and sensory-evoked potentials. Results: Within 30 days after SCI, during treadmill testing, a decrease in electromyographic activity of the limb muscles and the volume of angular movement in the joints on the side of the injury was detected. Electrical stimulation at the L2–S1 segments of the SC at a frequency of 30 Hz led to the appearance of a locomotor pattern in the muscles of the hind limbs and an increase in the range of motion. Conclusions: Our platform can be used for pathophysiological studies of various neuromodulation modes and as a basis for the development of control neurointerfaces. Full article

(This article belongs to the Special Issue Mechanisms and Therapeutic Strategies of Brain and Spinal Cord Injury)

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13 pages, 1008 KB

Open AccessArticle

Significance of Initial Serum Phosphate Imbalance in Traumatic Brain Injury with and Without Concomitant Spinal Injuries: Retrospective Analysis

by Ayman El-Menyar, Ahammed Mekkodathil, Naushad A. Khan, Mohammad Asim, Bellal Joseph and Hassan Al-Thani

Biomedicines 2025, 13(12), 2858; https://doi.org/10.3390/biomedicines13122858 - 24 Nov 2025

Cited by 1 | Viewed by 801

Abstract

Objectives: On-admission phosphate imbalance (OAPI) in traumatic brain injury (TBI) is scarce in the literature, either alone or with concomitant spinal injuries (CSI). We aimed to explore the OAPI in TBI and hypothesized that OAPI has unfavorable outcomes in TBI as well as spinal injury. Methods: In this retrospective study, all hospitalized patients with TBI were reviewed, and their serum phosphate levels were measured upon admission. Outcomes included in-hospital mortality and neurological deficit. Results: Among 912 TBI patients, 13% had hyperphosphatemia (n = 118/912) and 30% had associated CSI (n = 272/912). Hypophosphatemia was found in two-thirds of TBI patients (n = 607/912). Thirteen patients of CSI group developed neurological deficits (4.8%) with hypophosphatemia. Serum phosphate levels were significantly correlated with serum potassium, magnesium, and lactate levels, as well as Injury Severity Score (ISS). The serum glucose-phosphate ratio was higher in patients with severe Glasgow Coma Scale (GCS). The overall mortality was 21.3% (47% had hyperphosphatemia, 17% had hypophosphatemia, and 18% had normophosphatemia). Multivariable analysis showed that hyperphosphatemia, high serum lactate, sodium, and potassium levels, high head Abbreviated Injury Scale (AIS), and low GCS were significantly associated with increased mortality. Conclusions: Hypophosphatemia was common in TBI patients regardless of the presence of spinal injuries and was observed in all patients with neurological deficits. Routine phosphate monitoring may help in early risk stratification and targeted management of TBI. Full article

(This article belongs to the Special Issue Mechanisms and Therapeutic Strategies of Brain and Spinal Cord Injury)

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17 pages, 1585 KB

Open AccessArticle

Short-Term Cyclosporin A Treatment Reduced Serum Neurofilament-Light Levels in Diffuse but Not Focal Traumatic Brain Injury in a Piglet Model

by Colin M. Huber, Akshara D. Thakore, Anna Oeur and Susan S. Margulies

Biomedicines 2025, 13(10), 2547; https://doi.org/10.3390/biomedicines13102547 - 18 Oct 2025

Cited by 1 | Viewed by 1070

Abstract

Background/Objectives: Traumatic brain injury (TBI) in the pediatric patient results in acute neurophysiological deficits and can have potential long-term sequelae, impacting neurodevelopment. Serum biomarkers are an active area of study for TBI prognosis and diagnosis. Cyclosporin A (CsA), an immunosuppressant drug with neuroprotective qualities, targets mitochondria to stabilize the neurometabolic energy crisis following TBI. The objective of this study was to determine the acute effect of CsA treatment following focal and diffuse TBI on piglet serum biomarkers associated with glial neurofilaments, axonal dysfunction, and neuronal injury. Methods: Biomarker concentrations of GFAP, Nf-L, and UCH-L1 were quantified retrospectively from porcine serum samples (n = 488) at multiple timepoints from three experimental groups: anesthetized sham (n = 10), controlled cortical impact (CCI, n = 49), or rapid, non-impact rotations (RNR, n = 151) of the head. Injured animals received 24 h post-injury intravenous administration of saline or one of four CsA treatment doses (10, 20, 40, or 60 mg/kg/day), and then, were sacrificed. Results: After RNR, GFAP levels significantly increased from baseline at 1 h and recovered by 1 day to healthy reference ranges, while Nf-L increased at 1 day. Multiple CsA treatment doses (10, 40 mg/kg/day) significantly reduced Nf-L levels at 1 day compared to the untreated group. After CCI, GFAP and Nf-L increased at 1 day; there were no significant treatment effects. Conclusions: Focal and diffuse brain injury mechanisms resulted in distinct biomarker timelines. CsA reduced Nf-L levels at 1 day after diffuse TBI, showing promise of acute therapeutic benefit and warranting further investigation in extended timelines. Full article

(This article belongs to the Special Issue Mechanisms and Therapeutic Strategies of Brain and Spinal Cord Injury)

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22 pages, 1258 KB

Open AccessArticle

Transcutaneous Spinal Stimulation Modulates Spinal Reflex Circuit Excitability in Persons with Spinal Cord Injury

by Evan B. Sandler, Jennifer Ann Iddings, Karen Minassian and Edelle C. Field-Fote

Biomedicines 2025, 13(9), 2195; https://doi.org/10.3390/biomedicines13092195 - 8 Sep 2025

Cited by 1 | Viewed by 2134

Abstract

Background: Transcutaneous spinal stimulation (TSS) is a noninvasive stimulation approach to modulate spinal reflex circuit excitability after spinal cord injury (SCI) Posterior root muscle (PRM) reflexes can be used to characterize the change in excitability of spinal reflex circuits after TSS; these responses are likely influenced by stimulus parameters. Methods: We compared PRM reflex responses to 3 TSS conditions: single-site continuous (SS-CONT), single-site burst (SS-BURST), and dual-site continuous (DS-CONT). Stimulation (frequency: 50 Hz, intensity: 80% soleus reflex threshold[RT]) was delivered for 30 min. The cathode was placed over the thoracic spine (T11–T12) and anodes placed paraumbilically; a second cathode over the lumbar spine (L1/2 or L2/3) was used for DS-CONT. PRM reflex responses in the soleus were elicited by paired 1 ms monophasic conditioning–test stimuli at a 50 ms interstimulus interval via the T11–12 cathode and paraumbilical anodes. Soleus PRM reflex indices included RT, response amplitude at 1.2xRT (RA_1.2xRT), slope, area under the input–output curve (AUC). Paired-pulse indices were collected, including paired-pulse depression (PPD) and depression of the area under the curve (AUC_dep). To assess the correlation between biomechanical and electrophysiologic measures of soleus spasticity, the ankle clonus drop test first drop excursion (FDE) was measured. All indices were measured at baseline and immediately post-intervention. Results: In whole-group analyses, PPD and AUC_dep were significantly decreased. Significant decreases in PPD and AUC_dep were identified only after the SS-CONT condition. No significant changes were identified in other PRM reflex indices after any of the 3 TSS conditions. No relationships between baseline FDE and any PRM reflex parameter were identified at baseline. Conclusions: With stimulation intensity of 80% soleus RT, modulation of targeted spinal reflex circuits was observed only in the SS-CONT condition when the response of the conditioning and test stimuli were considered. In addition, stretch-induced spasticity of the soleus may not be consistent with electrophysiologic testing. Full article

(This article belongs to the Special Issue Mechanisms and Therapeutic Strategies of Brain and Spinal Cord Injury)

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15 pages, 579 KB

Open AccessArticle

Performance of the Baseline Sport Concussion Assessment Tool in Male and Female Spanish Amateur Rugby Players

by Cristian Solís-Mencía, Juan José Ramos-Álvarez, José Luis Maté-Muñoz, Juan José Montoya-Miñano, Laura Martín, Pablo García-Horcajo, Carlota Requeno-Conde, Elena Oliva-Iglesias, Luis De Sousa-De Sousa and Pablo García-Fernández

Biomedicines 2025, 13(2), 419; https://doi.org/10.3390/biomedicines13020419 - 10 Feb 2025

Cited by 1 | Viewed by 3153

Abstract

Background/Objectives: The Sport Concussion Assessment Tool (SCAT) is a test used to screen for suspected concussions, with the results compared to baseline values. If current baseline values are unavailable, they can be compared to baseline values obtained from professional rugby players. The aim of this study was to evaluate the baseline SCAT values in Hispanic community rugby players of both sexes. This cohort study used an observational, prospective, and descriptive design. Methods: Participants: A total of 81 female (age: 23.3 ± 3.3 years) and 138 male (age: 23.7 ± 4.3 years) Spanish rugby players who participated in national-level competitions. Interventions (or assessment of risk factors of independent variables): The SCAT was administered as part of the pre-season medical testing, including symptoms endorsed, cognitive submode performance, and balance performance. Results: Most of the Spanish community rugby players presented some symptom in the SCAT (male = 75.4%; female = 91.4%). The number and severity of the symptoms reported by the male players were lower than those reported by the female players (p = 0.001). The time to complete the tandem gait test and balance test showed differences between sexes (p < 0.001). Conclusions: The baseline SCAT values of Spanish community rugby players differ from those of professional players, leading to the recommendation of conducting the SCAT for all players before the beginning of the season. If baseline evaluations cannot be performed, the results obtained could serve as a basis for developing reference values for community rugby in the Hispanic population. Recording the menstrual cycle phase during which the SCAT is performed may help improve its interpretation. Full article

(This article belongs to the Special Issue Mechanisms and Therapeutic Strategies of Brain and Spinal Cord Injury)

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Review

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28 pages, 1340 KB

Open AccessReview

Spasticity and Abnormal Tone Regulation After Spinal Cord Injury: Mechanisms and the Effects of Neuromodulation

by Joshua Ceisler, Nilanjana Datta, Pedro P. Saraiva and James D. Guest

Biomedicines 2026, 14(6), 1348; https://doi.org/10.3390/biomedicines14061348 - 15 Jun 2026

Viewed by 712

Abstract

Spinal cord injury (SCI) is frequently accompanied by abnormal muscle tone and spasticity, which impair voluntary motor control, mobility, and quality of life. Although classically defined as velocity-dependent hyperreflexia, tone abnormalities after SCI encompass a broader spectrum, including sustained muscle activation, co-contraction, clonus, and non–velocity-dependent resistance to movement. These manifestations arise from distributed changes across spinal and supraspinal motor systems. At the segmental level, SCI induces maladaptive plasticity involving motoneurons, interneurons, sensory afferents, and muscle, including dysregulated persistent inward currents, altered inhibitory neurotransmission, afferent hyperexcitability, synaptic reorganization, and structural muscle remodeling. In parallel, supraspinal adaptations—including cortical motor map reorganization, reduced intracortical inhibition, corticospinal–reticulospinal imbalance, loss of monoaminergic modulation, and altered brainstem and cerebellar regulation—further amplify spinal circuit gain and impair inhibitory control of tone. Current pharmacologic treatments largely suppress symptoms without addressing these underlying circuit changes, while invasive neuromodulatory strategies are limited by surgical risk or state-dependent effects. This review synthesizes emerging insights into the multilevel mechanisms regulating abnormal tone after SCI and examines neuromodulatory approaches targeting spinal and supraspinal networks. Particular attention is given to transcutaneous spinal cord stimulation (TcSCS), a non-invasive method capable of modulating segmental reflex circuits and descending control pathways. Advances in transcriptomic and epigenetic profiling may further enable mechanism-based therapies and biomarker-guided strategies for treating spasticity. Full article

(This article belongs to the Special Issue Mechanisms and Therapeutic Strategies of Brain and Spinal Cord Injury)

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21 pages, 674 KB

Open AccessReview

What Is New in Spinal Cord Injury Management: A Narrative Review on the Emerging Role of Nanotechnology

by Loredana Raciti, Gianfranco Raciti and Rocco Salvatore Calabrò

Biomedicines 2025, 13(9), 2176; https://doi.org/10.3390/biomedicines13092176 - 5 Sep 2025

Cited by 5 | Viewed by 2624

Abstract

Traumatic injuries to the brain and spinal cord remain among the most challenging conditions in clinical neuroscience due to the complexity of repair mechanisms and the limited regenerative capacity of neural tissues. Nanotechnology has emerged as a transformative field, offering precise diagnostic tools, targeted therapeutic delivery systems, and advanced scaffolding platforms that are capable of overcoming the biological barriers to regeneration. This review summarizes the recent advances in nanoscale diagnostic markers, functionalized nanoparticles for drug delivery, and nanostructured scaffolds designed to modulate the injured microenvironment and support axonal regrowth and remyelination. Emerging evidence indicates that nanotechnology enables real-time, minimally invasive detection of inflammation, oxidative stress, and cellular damage, while improving therapeutic efficacy and reducing systemic side effects through targeted delivery. Electroconductive scaffolds and hybrid strategies that integrate electrical stimulation, gene therapy, and artificial intelligence further expand opportunities for personalized neuroregeneration. Despite these advances, significant challenges remain, including long-term safety, immune compatibility, the scalability of large-scale production, and translational barriers, such as small sample sizes, heterogeneous preclinical models, and limited follow-up in existing studies. Addressing these issues will be critical to realize the full potential of nanotechnology in traumatic brain and spinal cord injury and to accelerate the transition from promising preclinical findings to effective clinical therapies. Full article

(This article belongs to the Special Issue Mechanisms and Therapeutic Strategies of Brain and Spinal Cord Injury)

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