Noninvasive Electromagnetic Neuromodulation of the Central and Peripheral Nervous System for Upper-Limb Motor Strength and Functionality in Individuals with Cervical Spinal Cord Injury: A Systematic Review and Meta-Analysis.

(1) Background: Restoring arm and hand function is one of the priorities of people with cervical spinal cord injury (cSCI). Noninvasive electromagnetic neuromodulation is a current approach that aims to improve upper-limb function in individuals with SCI. The aim of this study is to review updated information on the different applications of noninvasive electromagnetic neuromodulation techniques that focus on restoring upper-limb functionality and motor function in people with cSCI. (2) Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were used to structure the search protocol. A systematic review of the literature was performed in three databases: the Cochrane Library, PubMed, and Physiotherapy Evidence Database (PEDro). (3) Results: Twenty-five studies were included: four were on transcranial magnetic stimulation (TMS), four on transcranial direct current stimulation (tDCS), two on transcutaneous spinal cord stimulation (tSCS), ten on functional electrical stimulation (FES), four on transcutaneous electrical nerve stimulation (TENS), and one on neuromuscular stimulation (NMS). The meta-analysis could not be completed due to a lack of common motor or functional evaluations. Finally, we realized a narrative review of the results, which reported that noninvasive electromagnetic neuromodulation combined with rehabilitation at the cerebral or spinal cord level significantly improved upper-limb functionality and motor function in cSCI subjects. Results were significant compared with the control group when tSCS, FES, TENS, and NMS was applied. (4) Conclusions: To perform a meta-analysis and contribute to more evidence, randomized controlled trials with standardized outcome measures for the upper extremities in cSCI are needed, even though significant improvement was reported in each non-invasive electromagnetic neuromodulation study.

Improvement in Motor and Walking Capacity during Multisegmental Transcutaneous Spinal Stimulation in Individuals with Incomplete Spinal Cord Injury.

Transcutaneous multisegmental spinal cord stimulation (tSCS) has shown superior efficacy in modulating spinal locomotor circuits compared to single-site stimulation in individuals with spinal cord injury (SCI). Building on these findings, we hypothesized that administering a single session of tSCS at multiple spinal segments may yield greater enhancements in muscle strength and gait function during stimulation compared to tSCS at only one or two segments. In our study, tSCS was applied at single segments (C5, L1, and Coc1), two segments (C5-L1, C5-Coc1, and L1-Coc1), or multisegments (C5-L1-Coc1) in a randomized order. We evaluated the 6-m walking test (6MWT) and maximum voluntary contraction (MVC) and assessed the Hmax/Mmax ratio during stimulation in ten individuals with incomplete motor SCI. Our findings indicate that multisegmental tSCS improved walking time and reduced spinal cord excitability, as measured by the Hmax/Mmax ratio, similar to some single or two-site tSCS interventions. However, only multisegmental tSCS resulted in increased tibialis anterior (TA) muscle strength. These results suggest that multisegmental tSCS holds promise for enhancing walking capacity, increasing muscle strength, and altering spinal cord excitability in individuals with incomplete SCI.

Clinical effects of intrathecal administration of expanded Wharton jelly mesenchymal stromal cells in patients with chronic complete spinal cord injury: a randomized controlled study.

BACKGROUND AIMS: Spinal cord injury (SCI) represents a devastating condition leading to severe disability related to motor, sensory and autonomic dysfunction. Stem cell transplantation is considered a potential emerging therapy to stimulate neuroplastic and neuroregenerative processes after SCI. In this clinical trial, the authors investigated the safety and clinical recovery effects of intrathecal infusion of expanded Wharton jelly mesenchymal stromal cells (WJ-MSCs) in chronic complete SCI patients. METHODS: The authors designed a randomized, double-blind, crossover, placebo-controlled, phase 1/2a clinical trial (NCT03003364). Participants were 10 patients (7 males, 3 females, age range, 25-47 years) with chronic complete SCI (American Spinal Injury Association A) at dorsal level (T3-11). Patients were randomly assigned to receive a single dose of intrathecal ex vivo-expanded WJ-MSCs (10 × 106 cells) from human umbilical cord or placebo and were then switched to the other arm at 6 months. Clinical evaluation (American Spinal Injury Association impairment scale motor and sensory score, spasticity, neuropathic pain, electrical perception and pain thresholds), lower limb motor evoked potentials (MEPs) and sensory evoked potentials (SEPs), Spinal Cord Independence Measure and World Health Organization Quality of Life Brief Version were assessed at baseline, 1 month, 3 months and 6 months after each intervention. Urodynamic studies and urinary-specific quality of life (Qualiveen questionnaire) as well as anorectal manometry, functional assessment of bowel dysfunction (Rome III diagnostic questionnaire) and severity of fecal incontinence (Wexner score) were conducted at baseline and at 6 months after each intervention. RESULTS: Intrathecal transplantation of WJ-MSCs was considered safe, with no significant side effects. Following MSC infusion, the authors found significant improvement in pinprick sensation in the dermatomes below the level of injury compared with placebo. Other clinically relevant effects, such as an increase in bladder maximum capacity and compliance and a decrease in bladder neurogenic hyperactivity and external sphincter dyssynergy, were observed only at the individual level. No changes in motor function, spasticity, MEPs, SEPs, bowel function, quality of life or independence measures were observed. CONCLUSIONS: Intrathecal transplantation of human umbilical cord-derived WJ-MSCs is a safe intervention. A single intrathecal infusion of WJ-MSCs in patients with chronic complete SCI induced sensory improvement in the segments adjacent to the injury site.

Botulinum toxin type-A infiltration of the external anal sphincter to treat outlet constipation in motor incomplete spinal cord injury: pilot cohort study.

BACKGROUND: Outlet constipation is a major problem in spinal cord injury (SCI) patients. We aimed to study the efficacy of external anal sphincter (EAS) infiltration with type-A botulinum toxin (BTX-A) in motor incomplete SCI patients with outlet constipation. METHODS: Double blind, randomized, placebo controlled, comparative study in 16 motor incomplete SCI subjects. Patients were randomly assigned toreceive100 UI of BTX-A (n = 9) or physiologic serum infiltration (n = 7) in the EAS under electromyographic guidance. Outcome measures included a questionnaire for clinical bowel function evaluation, colonic transit time and anorectal manometry. All assessments were done at baseline, 1 and 3 months after treatment. RESULTS: Fourteen patients completed the study. In the BTX-A group we observed an improvement of subjective perception of bowel function (p = 0.01), constipation (p = 0.02) and neurogenic bowel dysfunction score (p = 0.02). The anorectal manometry revealed are duction of EAS voluntary contraction pressure (p = 0.01). No changes were observed in the placebo group. No significant side effects were observed in none of the groups. CONCLUSION: BTX-A infiltration of the EAS is a safe technique that in motor incomplete SCI, decreases the EAS contraction and the anal canal pressure during straining, and improves outlet constipation symptoms. Future studies in larger populations are needed.

Effects of different vibration frequencies on spinal cord reflex circuits and thermoalgesic perception.

OBJECTIVES: We studied the effect of different vibration frequencies on spinal cord excitability and heat pain perception. We hypothesized that the effects of vibration on spinal cord reflexes, and, also those on heat pain perception, depend on vibration frequency. METHODS: In 9 healthy subjects, we applied vibration over the tibialis anterior muscle at three different frequencies (50, 150, or 250 Hz) on spinal cord reflex excitably, tested with the H reflex and the T wave in the soleus muscle, as well as on sensory and pain perception, tested by measuring warm perception (WT) and heat pain perception thresholds, (HPT) in sites rostral and caudal to vibration. Exams were carried out before, during, and after vibration. RESULTS: The amplitude of the H reflex and T wave significantly decreased during vibration in comparison to baseline. Low frequencies (50 and 150Hz) induced greater reflex suppression than high frequency (250Hz). No significant changes were observed on WT and HPT. CONCLUSIONS: The effects of vibratory stimulation can be summarized as frequency-related suppression of the spinal cord excitability without an effect on warm and heat pain perception. The present results may help to design vibration-related interventions intended to diminish spinal cord reflex excitability in spastic patients.

Detection of Sleep-Disordered Breathing in Patients with Spinal Cord Injury Using a Smartphone.

Patients with spinal cord injury (SCI) have an increased risk of sleep-disordered breathing (SDB), which can lead to serious comorbidities and impact patients' recovery and quality of life. However, sleep tests are rarely performed on SCI patients, given their multiple health needs and the cost and complexity of diagnostic equipment. The objective of this study was to use a novel smartphone system as a simple non-invasive tool to monitor SDB in SCI patients. We recorded pulse oximetry, acoustic, and accelerometer data using a smartphone during overnight tests in 19 SCI patients and 19 able-bodied controls. Then, we analyzed these signals with automatic algorithms to detect desaturation, apnea, and hypopnea events and monitor sleep position. The apnea-hypopnea index (AHI) was significantly higher in SCI patients than controls (25 ± 15 vs. 9 ± 7, p < 0.001). We found that 63% of SCI patients had moderate-to-severe SDB (AHI ≥ 15) in contrast to 21% of control subjects. Most SCI patients slept predominantly in supine position, but an increased occurrence of events in supine position was only observed for eight patients. This study highlights the problem of SDB in SCI and provides simple cost-effective sleep monitoring tools to facilitate the detection, understanding, and management of SDB in SCI patients.

Noninvasive Brain Stimulation and Noninvasive Peripheral Stimulation for Neglect Syndrome Following Acquired Brain Injury.

OBJECTIVE: Hemispatial neglect is a frequent condition usually following nondominant hemispheric brain injury. It strongly affects rehabilitation strategies and everyday life activities. It is associated with behavioral and cognitive disability with a strong impact on patient's life. METHODS: We reviewed the published literature on the use of noninvasive brain stimulation, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), and of noninvasive peripheral muscle stimulation, as therapeutic strategies for rehabilitation of neglect after acquired brain injury, such as in stroke or in traumatic injuries. The studies were grouped as controlled or uncontrolled studies in each stimulation techniques. RESULTS: Thirty-four studies were identified and 16 on rTMS, 10 on tDCS, and 8 on vibration. All studies were conducted in adult patients who suffered a stroke, except for one that was conducted in a patient suffering traumatic acquired brain injury and another that was conducted in a patient with brain tumor. In spite of significant variability in treatment protocols, patients' features and assessment of neglect, improvement was reported in almost all studies with no side-effects. CONCLUSIONS: Noninvasive brain stimulation and neuromuscular vibration are promising therapeutic neuromodulatory approaches for neglect. Further randomized-controlled studies are needed to corroborate their effectiveness as separate and combined techniques.

Jendrassik maneuver effect on spinal and brainstem reflexes.

The effect of Jendrassik Maneuver (JM) has been extensively studied on monosynaptic reflexes in numerous muscles below the level at which the maneuver was performed. Here we hypothesize that the effect of JM could be observed also on other reflexes, indicating a widespread influence of performing a motor act such as the JM. We examined polysynaptic reflexes caudal (i.e., the withdrawal reflex of the lower extremities) and rostral (i.e., the blink reflex to supraorbital nerve stimulation) to the level of JM contraction. We have assessed soleus tendon (T) reflex; withdrawal reflex in tibialis anterior and soleus muscle; blink reflex (BR), blink reflex excitability recovery curve (BR-ER) and prepulse inhibition of the blink reflex. Our results showed that (1) T-reflex amplitude increased during JM and decreased just after and 15 min after JM; (2) no change in the withdrawal reflex; (3) R2 area of BR reduced significantly just after or 15 min after JM; (4) Prepulse inhibition in BR reduced significantly during JM; (5) no change in BR-ER. Our results indicate that JM leads to generalized effects on neural excitability at both caudal and rostral levels. Furthermore, JM has a selective effect on excitability of reflex circuitries.

Placebo-controlled study of rTMS combined with Lokomat® gait training for treatment in subjects with motor incomplete spinal cord injury.

High-frequency rTMS combined with gait training improves lower extremity motor score (LEMS) and gait velocity in SCI subjects who are able to walk over ground. The aim of this study was to optimize the functional outcome in early phases of gait rehabilitation in SCI using rTMS as an additional treatment to physical therapy. The present study included 31 motor incomplete SCI subjects randomized to receive real or sham rTMS, just before Lokomat gait training (15 subjects for real, 16 for sham rTMS). rTMS consisted of one daily session for 20 days over vertex (at 20 Hz). The subjects were evaluated using modified Ashworth scale (MAS) for spasticity, upper and lower extremity motor score (UEMS and LEMS, respectively), ten meters walking test (10MWT) and Walking Index for SCI (WISCI-II) for gait at baseline, after last rTMS session, and during follow-up. UEMS and LEMS improved significantly after last session in both groups and during follow-up period. The improvement was greater in real than in sham rTMS group. At follow-up, 71.4 % of the subjects after real rTMS and 40 % of the subjects after sham rTMS could perform 10MWT without significant differences in gait velocity, cadence, step length and WISCI-II between both groups. We conclude that 20 sessions of daily high-frequency rTMS combined with Lokomat gait training can lead to clinical improvement of gait in motor incomplete SCI. Such combined treatment improved motor strength in lower extremity in incomplete SCI subjects and in upper extremity in those with cervical SCI.

Motor Cortex Plasticity during Unilateral Finger Movement with Mirror Visual Feedback.

Plasticity is one of the most important physiological mechanisms underlying motor recovery from brain lesions. Rehabilitation methods, such as mirror visual feedback therapy, which are based on multisensory integration of motor, cognitive, and perceptual processes, are considered effective methods to induce cortical reorganization. The present study investigated 3 different types of visual feedback (direct, mirrored, and blocked visual feedback: DVF, MVF, and BVF, resp.) on M1 cortex excitability and intracortical inhibition/facilitation at rest and during phasic unimanual motor task in 11 healthy individuals. The excitability of the ipsilateral M1 cortex and the intracortical facilitation increased during motor task performance in the DVF and MVF but not in the BVF condition. In addition, MVF induced cortical disinhibition of the ipsilateral hemisphere to the index finger performing the motor task, which was greater when compared to the BVF and restricted to the homologue first dorsal interosseous muscle. The visual feedback is relevant to M1 cortex excitability modulation but the MVF plays a crucial role in promoting changes in intracortical inhibition in comparison to BVF. Altogether, it can be concluded that a combination of motor training with MVF therapy may induce more robust neuroplastic changes through multisensory integration that is relevant to motor rehabilitation.

Influence of spinal cord lesion level and severity on H-reflex excitability and recovery curve.

INTRODUCTION: Changes in spinal reflexes can result from alterations in the spinal cord and descending pathways. We studied whether H-reflex excitability and its recovery depend on the level and/or severity of spinal cord injury (SCI). METHODS: The soleus Hmax and Mmax responses and the H-reflex recovery curve (HRC) at interstimulus intervals (ISIs) ranging from 50 to 1,000 ms were recorded in 38 SCI individuals and 18 healthy subjects. RESULTS: Amplitude of Mmax correlated with level and severity of lesion (smaller amplitude correlated with more severe SCI or with more caudal lesion). Hmax/Mmax correlated only with age in the SCI group. HRC was increased significantly in complete SCI at ISIs < 500 ms and in incomplete SCI at ISIs > 200 ms with respect to healthy subjects. CONCLUSIONS: The changes in spinal reflexes as measured by the H-reflex and its recovery curve after SCI depend on the severity, but not on the level of the lesion.

Long-term use of intrathecal baclofen reduces neuropathic pain and its interference with general activity in spinal cord injury individuals.

INTRODUCTION: Long-term analgesic effect of intrathecal baclofen was reported in individuals with spinal cord injury. We conducted a prospective study to evaluate the effect of intrathecal baclofen on subtypes of neuropathic pain and its interference with general activity. MATERIALS AND METHODS: Nine spinal cord injury individuals who presented with severe spasticity and moderate to severe neuropathic pain received intrathecal baclofen via an implanted pump. We applied the ASIA Impairment Scale to assess spinal cord injury severity. Neuropathic pain was evaluated by numerical rating scale, Neuropathic Pain Symptom Inventory, and Brief Pain Inventory. Evaluations were performed at baseline and after at least 6 months of continuous intrathecal baclofen treatment. RESULTS: Intrathecal baclofen led to significant pain reduction as measured by numerical rating scale, Neuropathic Pain Symptom Inventory, and Brief Pain Inventory (p < 0.05). Improvements were significant for paroxysmal pain and dysesthesia and for pain interference with general activity, as assessed by the Brief Pain Inventory (p < 0.05). There was a significant relationship between the time since spinal cord injury and changes in paroxysmal pain as well as in the total Neuropathic Pain Symptom Inventory score (p < 0.05). The baclofen dose correlated also to the percentage changes in neuropathic pain improvement and sleep (p < 0.003). CONCLUSIONS: The present results provide evidence that intrathecal baclofen effectively reduces neuropathic pain, particularly paroxysmal pain and dysesthesia, and improves pain interference and overall well-being in individuals with spinal cord injury. Clinicians should be aware of this less well-known beneficial effect of intrathecal baclofen and should consider such a treatment option for better control of neuropathic pain in individuals with spinal cord injury.

Diagnostic challenges of functional neurological disorders after covid-19 disease or vaccination: case series and review of the literature.

BACKGROUND: Functional neurological disorders have rarely been described in patients recovering from Covid-19 or after vaccination but they are probably under diagnosed. MATERIAL AND METHODS: Six patients referred for rehabilitation of persistent symptoms and/or sequelae of Coronavirus disease 2019 (COVID-19) were diagnosed with functional neurological disorders. A literature review was conducted to identify reported cases of functional neurological disorders after Covid-19 infection or vaccination. RESULTS: In the current case series, patients diagnosed with functional neurological disorders presented high variability of clinical symptoms including hemiplegia, lower limb unilateral or bilateral paralysis, myoclonus, dystonia, tremor and sensory impairment. Four patients were young females with mild Covid-19 infection without hospital admission. Their neurological symptoms developed over the course of 4 weeks after the beginning of Covid-19 symptoms or vaccine administration with normal ancillary exams. One patient presented overlapping functional neurological symptoms and mild impairment of the left common peroneal nerve after prolonged ICU stay. In addition, all patients in our case series reported other non-motor symptoms such as fatigue, cognitive impairment and diffuse pain or dysesthesia, which are compatible with post Covid-19 condition. CONCLUSIONS: It is important that clinicians recognize functional neurological symptoms and consider it as a differential diagnosis in patients with neurological complications of Covid-19 infection and vaccination.

Transcutaneous Spinal Cord Stimulation Improves Respiratory Muscle Strength and Function in Subjects with Cervical Spinal Cord Injury: Original Research.

(1) Background: Respiratory muscle weakness is common following cervical spinal cord injury (cSCI). Transcutaneous spinal cord stimulation (tSCS) promotes the motor recovery of the upper and lower limbs. tSCS improved breathing and coughing abilities in one subject with tetraplegia. Objective: We therefore hypothesized that tSCS applied at the cervical and thoracic levels could improve respiratory function in cSCI subjects; (2) Methods: This study was a randomized controlled trial. Eleven cSCI subjects received inspiratory muscle training (IMT) alone. Eleven cSCI subjects received tSCS combined with IMT (six of these subjects underwent IMT alone first and then they were given the opportunity to receive tSCS + IMT). The subjects evaluated their sensation of breathlessness/dyspnea and hypophonia compared to pre-SCI using a numerical rating scale. The thoracic muscle strength was assessed by maximum inspiratory (MIP), expiratory pressure (MEP), and spirometric measures. All assessments were conducted at baseline and after the last session. tSCS was applied at C3-4 and Th9-10 at a frequency of 30 Hz for 30 min on 5 consecutive days; (3) Results: Following tSCS + IMT, the subjects reported a significant improvement in breathlessness/dyspnea and hypophonia (p < 0.05). There was also a significant improvement in MIP, MEP, and forced vital capacity (p < 0.05). Following IMT alone, there were no significant changes in any measurement; (4) Conclusions: Current evidence supports the potential of tSCS as an adjunctive therapy to accelerate and enhance the rehabilitation process for respiratory impairments following SCI. However, further research is needed to validate these results and establish the long-term benefits of tSCS in this population.

Effects of Bihemispheric Transcranial Direct Current Stimulation Combined With Repetitive Peripheral Nerve Stimulation in Acute Stroke Patients.

PURPOSE: Transcranial direct current stimulation (tDCS) can change the excitability of the central nervous system and contribute to motor recovery of stroke patients. The aim of our study was to examine the short- and long-term effects of real versus sham bihemispheric tDCS combined with repetitive peripheral nerve stimulation in patients with acute stroke and a severe motor impairment. METHODS: The study was prospective, randomized, double blind, and placebo controlled. Nineteen acute stroke patients (ischemic and hemorrhagic) with upper limb Fugl-Meyer mean score of <19 were randomized in two groups: one group received five consecutive daily sessions of anodal tDCS over the affected hemisphere and cathodal over unaffected hemisphere combined with repetitive peripheral nerve stimulation and the other received sham tDCS associated to repetitive peripheral nerve stimulation. Clinical and neurophysiological assessment was applied before tDCS, 5 days after tDCS, and 3, 6, and 12 months after tDCS. RESULTS: There were significant time-related changes in both groups of patients in motor evoked potentials, somatosensory evoked potentials, Hmax:Mmax ratio, upper limb Fugl-Meyer scores, and Modified Ashworth scales scores ( P < 0.05). However, no significant differences between groups were present at any time ( P > 0.05). CONCLUSIONS: Bihemispheric tDCS and repetitive peripheral nerve stimulation with the parameters of our study did not add significant short- or long-term clinical improvement or change in neurophysiological data in severe acute stroke patients in comparison to sham stimulation. The severity of motor impairment in stroke patients may influence a possible response to an interventional tDCS treatment.

Transcutaneous Cervical Spinal Cord Stimulation Combined with Robotic Exoskeleton Rehabilitation for the Upper Limbs in Subjects with Cervical SCI: Clinical Trial.

(1) Background: Restoring arm and hand function is a priority for individuals with cervical spinal cord injury (cSCI) for independence and quality of life. Transcutaneous spinal cord stimulation (tSCS) promotes the upper extremity (UE) motor function when applied at the cervical region. The aim of the study was to determine the effects of cervical tSCS, combined with an exoskeleton, on motor strength and functionality of UE in subjects with cSCI. (2) Methods: twenty-two subjects participated in the randomized mix of parallel-group and crossover clinical trial, consisting of an intervention group (n = 15; tSCS exoskeleton) and a control group (n = 14; exoskeleton). The assessment was carried out at baseline, after the last session, and two weeks after the last session. We assessed graded redefined assessment of strength, sensibility, and prehension (GRASSP), box and block test (BBT), spinal cord independence measure III (SCIM-III), maximal voluntary contraction (MVC), ASIA impairment scale (AIS), and WhoQol-Bref; (3) Results: GRASSP, BBT, SCIM III, cylindrical grip force and AIS motor score showed significant improvement in both groups (p ≤ 0.05), however, it was significantly higher in the intervention group than the control group for GRASSP strength, and GRASSP prehension ability (p ≤ 0.05); (4) Conclusion: our findings show potential advantages of the combination of cervical tSCS with an exoskeleton to optimize the outcome for UE.

Multidisciplinary outpatient rehabilitation of physical and neurological sequelae and persistent symptoms of covid-19: a prospective, observational cohort study.

PURPOSE: This prospective, observational cohort study investigated the effects of multidisciplinary rehabilitation of post Covid-19 sequelae and persistent symptoms and their impact on patients' functioning and quality of life. METHODS: From 58 patients referred for neurorehabilitation, 43 were eligible for and participated in the present study. Before and after 8 weeks of rehabilitation, patients underwent physical, neuropsychological and respiratory evaluations and assessment of functional independence, impact of fatigue and quality of life. RESULTS: Forty of 43 individuals (52 ± 11.4 years, 24 male) completed the rehabilitation program. Fatigue (87.5%), dyspnea and/or shortness of breath (62.5%), and cognitive impairment (37.5%) were reported by both previously hospitalized and home-confined patients. Neurological sequelae (35.5%) were present only in hospitalized patients. After 8 weeks of rehabilitation, patients reported significant improvements in motor functional independence, upper and lower limb functionality, impact of fatigue on daily activities, respiratory muscle strength, cognitive performance, and quality of life. CONCLUSIONS: Post Covid-19 patients present with heterogeneous neurological, physical, and respiratory impairments requiring a multidisciplinary rehabilitation approach to reduce disability and improve functionality and quality of life. A comprehensive assessment of clinical profiles and responses to rehabilitation may facilitate the identification of rehabilitation candidates and help to design effective rehabilitation interventions.Implication for rehabilitationPost Covid-19 patients present multiple, heterogeneous neurological, physical and respiratory impairments that are observed in both previously hospitalized and home-confined patients.Eight weeks of multidisciplinary rehabilitation may significantly reduce disability and improve functionality and quality of life.A comprehensive assessment of their clinical profile and response to rehabilitation may facilitate the identification of rehabilitation candidates and help to design more effective rehabilitation interventions.

Preclinical Development of a Therapy for Chronic Traumatic Spinal Cord Injury in Rats Using Human Wharton's Jelly Mesenchymal Stromal Cells: Proof of Concept and Regulatory Compliance.

(1) Background: the use of Mesenchymal Stromal Cells (MSC) in emerging therapies for spinal cord injury (SCI) hold the potential to improve functional recovery. However, the development of cell-based medicines is challenging and preclinical studies addressing quality, safety and efficacy must be conducted prior to clinical testing; (2) Methods: herein we present (i) the characterization of the quality attributes of MSC from the Wharton's jelly (WJ) of the umbilical cord, (ii) safety of intrathecal infusion in a 3-month subchronic toxicity assessment study, and (iii) efficacy in a rat SCI model by controlled impaction (100 kdynes) after single (day 7 post-injury) and repeated dose of 1 × 106 MSC,WJ (days 7 and 14 post-injury) with 70-day monitoring by electrophysiological testing, motor function assessment and histology evaluation; (3) Results: no toxicity associated to MSC,WJ infusion was observed. Regarding efficacy, recovery of locomotion was promoted at early time points. Persistence of MSC,WJ was detected early after administration (day 2 post-injection) but not at days 14 and 63 post-injection. (4) Conclusions: the safety profile and signs of efficacy substantiate the suitability of the presented data for inclusion in the Investigational Medicinal Product Dossier for further consideration by the competent Regulatory Authority to proceed with clinical trials.

Effectiveness of transcranial direct current stimulation and visual illusion on neuropathic pain in spinal cord injury.

The aim of this study was to evaluate the analgesic effect of transcranial direct current stimulation of the motor cortex and techniques of visual illusion, applied isolated or combined, in patients with neuropathic pain following spinal cord injury. In a sham controlled, double-blind, parallel group design, 39 patients were randomized into four groups receiving transcranial direct current stimulation with walking visual illusion or with control illusion and sham stimulation with visual illusion or with control illusion. For transcranial direct current stimulation, the anode was placed over the primary motor cortex. Each patient received ten treatment sessions during two consecutive weeks. Clinical assessment was performed before, after the last day of treatment, after 2 and 4 weeks follow-up and after 12 weeks. Clinical assessment included overall pain intensity perception, Neuropathic Pain Symptom Inventory and Brief Pain Inventory. The combination of transcranial direct current stimulation and visual illusion reduced the intensity of neuropathic pain significantly more than any of the single interventions. Patients receiving transcranial direct current stimulation and visual illusion experienced a significant improvement in all pain subtypes, while patients in the transcranial direct current stimulation group showed improvement in continuous and paroxysmal pain, and those in the visual illusion group improved only in continuous pain and dysaesthesias. At 12 weeks after treatment, the combined treatment group still presented significant improvement on the overall pain intensity perception, whereas no improvements were reported in the other three groups. Our results demonstrate that transcranial direct current stimulation and visual illusion can be effective in the management of neuropathic pain following spinal cord injury, with minimal side effects and with good tolerability.

Transcranial Direct Current Stimulation and Visual Illusion Effect According to Sensory Phenotypes in Patients With Spinal Cord Injury and Neuropathic Pain.

Treatment of neuropathic pain (NP) in patients with spinal cord injury (SCI) remains a major challenge. The aim of the present study is to investigate if the effect of transcranial direct current stimulation combined with visual illusion, following a previously published protocol, has differential effects on pain-related sensory symptoms according to sensory phenotypes profiles. One hundred and thirty SCI patients with NP participated in this open-label trial. Sixty-five patients were given a daily 20-minutes combined treatment of transcranial direct current stimulation and visual illusion for 2 weeks. Sixty-five patients served as a control group. Clinical assessment was performed before and 2 weeks later, by using Neuropathic Pain Symptom Inventory (NPSI), Brief Pain Inventory, and Patient Health Questionnaire-9. There was significant improvement in the combined treatment group according to NPSI, Brief Pain Inventory, and Patient Health Questionnaire-9, but no changes in the control group. Following a cluster analysis of NPSI items at baseline assessment, 5 subgroups of patients with different pain-related characteristics were identified among the treated group, although differences between clusters were not significant. There was also improvement in mood, sleep quality, and enjoyment of life in the treated group. Despite a reduction of NP with the combined treatment, the analysis of sensory phenotype pain profiles does not provide a predictive value regarding the analgesic results of this combined neuromodulatory treatment. PERSPECTIVE: In this article we confirm the analgesic effect of a combined neuromodulatory therapy, transcranial direct current stimulation associated with visual illusion in patients with NP after an SCI. We have identified 5 clusters of NP with distinct sensory phenotypes, but there was not any specific sensory phenotype cluster that significantly responded to the combined therapy better than the other.