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Background High frequency alternating current (HFAC) stimulation have been shown to produce a peripheral nerve conduction block. Currently, all the studies applying HFAC stimulation in clinical studies, have employed frequencies below 10 kHz. The main aim of this work was to investigate the neuromodulatory effect of transcutaneous 20 kHz stimulation on somatosensory and pain thresholds, and maximal handgrip strength. Methods A randomized, crossover, single-blinded, placebo-controlled trial was conducted following recruitment of fourteen healthy volunteers. Transcutaneous stimulation at 20 kHz and sham stimulation were applied over the ulnar and median nerves of fourteen healthy volunteers for 20 min. Maximal handgrip strength (MHS), mechanical detection threshold (MDT) and pressure pain threshold (PPT) were registered prior to, during (15 min), immediately after the end (20 min), and 10 min following stimulation. Results The 20 kHz stimulation showed a lower MHS during the stimulation at the 15 min (30.1 kgs SE 2.8) and at 20 min (31.8 kgs, SE 2.8) when compared to sham stimulation (35.1 kgs, SE 3.4; p p = 0.03, respectively). The 20 kHz stimulation resulted in a slight increase in MDT at 15 min (0.25 mN; 0.25–2.00) when compared to the sham stimulation (0.25 mN; 0.25–0.25; p = 0.02), and no effects were showed for PPT. Conclusions High-frequency stimulation at 20 kHz suggests a partial block of nerve activity. Studies in subjects with neurological disorders characterized by nerve hyperactivity are needed to confirm the clinical impact of this non-invasive electrical stimulation technique. Trial registration NCT, NCT02837458. Registered on 12 April 2017.

Background. Epidural spinal electrical stimulation at the lumbar spinal level evokes rhythmic muscle activation of lower-limb antagonists, attributed to the central pattern generator. However, the efficacy of noninvasive spinal stimulation for the activation of lower-limb muscles is not yet clear. This review aimed to analyze the feasibility and efficacy of noninvasive transcutaneous spinal cord stimulation (tSCS) on motor function in individuals with spinal cord injury. Methods. A search for tSCS studies was made of the following databases: PubMed; Cochrane Registry; and Physiotherapy Evidence Database (PEDro). In addition, an inverse manual search of the references cited by the identified articles was carried out. The keywords transcutaneous, non-invasive, electrical stimulation, spinal cord stimulation [Mesh term], and spinal cord injury were used. Results. A total of 352 articles were initially screened, of which 13 studies met the inclusion criteria for systematic review. The total participant sample comprised 55 persons with spinal cord injury. All studies with tSCS provided evidence of induced muscle activation in the lower and upper limbs, and applied stimulation at the level of the T11-T12 and C4-C7 interspinous space, respectively. All studies reported an increase in motor response measured by recording surface electromyography, voluntary movement, muscle strength, or function. Conclusions. Although this review highlights tSCS as a feasible therapeutic neuromodulatory strategy to enhance voluntary movement, muscle strength, and function in patients with chronic spinal cord injury, the clinical impact and efficacy of electrode location and current intensity need to be characterized in statistically powered and controlled clinical trials.

Resumen: Objetivo: Determinar si la estimulación eléctrica nerviosa transcutánea (TENS) tiene un efecto analgésico superior al placebo o a otros tratamientos en pacientes con fibromialgia. Además, se pretendía analizar los parámetros de aplicación óptimos para conseguir una mayor reducción del dolor. Diseño: Revisión sistemática. Fuentes de datos: Ensayos clínicos aleatorizados sobre el efecto del TENS en la fibromialgia en las bases de datos Pubmed, Cochrane y PEDro hasta noviembre de 2016. Selección de estudios: Se seleccionaron 8 estudios de un total de 62. Se incluyeron ensayos clínicos controlados en los que se aplicase TENS a personas con fibromialgia. Extracción de datos: Se analizó el dolor como variable principal, aunque también se incluyeron otras variables como fatiga, calidad de vida e impacto de la enfermedad, recorrido articular y depresión. Resultados: Seis de 8 trabajos obtuvieron una disminución significativa del dolor. En 2 estudios se aplicó el TENS como tratamiento complementario al ejercicio terapéutico con resultados evidenciando una disminución del dolor. El resto de variables estudiadas presentaron gran variabilidad y no se pudieron establecer resultados concluyentes. Conclusiones: El tratamiento con TENS resulta efectivo para la disminución del dolor en personas con fibromialgia. Además, la inclusión del TENS en programas de ejercicio terapéutico parece tener un efecto superior a la realización del ejercicio terapéutico de forma aislada. Sin embargo, no se ha demostrado eficacia en otras variables diferentes al dolor. Son necesarios más estudios que indaguen en la optimización de los parámetros del TENS y un mayor consenso entre las variables utilizadas. Abstract: Objective: To determine whether transcutaneous electrical nerve stimulation (TENS) has an analgesic effect greater than placebo or other treatments in patients with fibromyalgia. Furthermore, it was intended to analyze the optimal application parameters to achieve a greater reduction of pain. Design: A systematic review. Data source: Randomized clinical trials on the effect of TENS on fibromyalgia in the databases Pubmed, Cochrane and PEDro until November 2016. Selection of studies: 8 studies out of a total of 62 were selected. Controlled clinical trials in which TENS was applied in patients with fibromyalgia were included. Data extraction: Pain was analyzed as the main variable, although other variables such as fatigue, quality of life and impact, range of motion and depression were also included. Results: 6 out of 8 studies obtained a significant decrease of pain. In 2 studies, TENS was applied as complementary treatment to therapeutic exercise with results evidencing a decrease in pain. The rest of the variables studied presented a great variability and conclusive results could not be established. Conclusions: Treatment with TENS is effective for reducing pain in people with fibromyalgia. In addition, the inclusion of TENS in therapeutic exercise programs seems to have a greater effect than practicing therapeutic exercise in isolation. However, no efficacy has been demonstrated in other variables different to pain. Further studies are needed to investigate the optimization of the parameters of the TENS and a greater consensus among the variables used. Palabras clave: Fibromialgia, Estimulación eléctrica nerviosa transcutánea, Sensibilización central, Dolor crónico, Keywords: Fibromyalgia, Transcutaneous electric nerve stimulation, Central sensitization, Chronic pain

The main aim of this work was to investigate the difference in the excitability of the soleus H-reflex in healthy volunteers following spinal transcutaneous electrical nerve stimulation (TENS) and high-frequency alternating current (HFAC) at a frequency of 10 kHz applied at the lower thoracic spinal level (T10-T12). A double-blind, randomized, crossover, controlled clinical trial was designed. Participants received three randomized interventions (TENS, 10 kHz, and sham stimulation) during 40 min. The amplitude and latency of the soleus H-reflex were registered prior to, during, and 10 min following stimulation. Twenty-four participants completed the study. A significant inhibition of H-reflex amplitude was observed following transcutaneous spinal TENS (12.7%; 95% CI 1.5-22.2%) when compared with sham stimulation (5.5%; 95% CI 3.6-14.5%; p = 0.03). An increase in H-reflex latency was also observed following transcutaneous spinal stimulation at 10 kHz (2%; 95% CI 1.4-2.5%) as compared with sham stimulation (0.7%; 95% CI 0.07-1.3%; p 0.01). No differences were found between TENS and 10 kHz for H-reflex modulation. Transcutaneous spinal TENS and HFAC at a frequency of 10 kHz had a modulatory effect on the soleus H-reflex when compared to sham stimulation; however, no differences were found between these two interventions.

Objective The purpose of this study was to develop and validate a Spanish version of the Whiplash Disability Questionnaire (WDQ) for the Spanish population with acute whiplash-associated disorder (WAD). Methods This was a cross-sectional questionnaire validation study. Adults with acute WAD (grade I to III) were enrolled within 3 weeks of their injury. A blinded forward and back translation of the WDQ was made from English to Spanish, and the resulting back-translation version was compared with the original. Patients with WAD completed the Spanish version of the 13-item WDQ. The developed questionnaire was assessed using psychometric statistical analysis including correlation with the numerical rating score for pain, Northwick Park Neck Pain Questionnaire, Neck Disability Index, and 36-item Short Form Health Survey. Results Fifty-six patients completed the questionnaire, the mean age was 33.9 years (standard deviation [SD] = 10.5), and 76.8% were women. Participants were enrolled 13.9 days (SD 4.9) after the injury, with 14.3% presenting with WAD grade I and 85.7% with WAD grade II. The mean WDQ score was 62 (SD = 31). Two factors were detected, and the factor structure remained stable after translation. Positive correlations were identified between the total WDQ score and the numerical rating score, Neck Pain Questionnaire, and Neck Disability Index results, with a strong negative correlation with the 36-item Short Form Health Survey. Conclusion The Spanish version of WDQ is psychometrically reliable and a valid instrument to measure the disability status in patients with acute WAD within the clinic.

Sunitinib and pazopanib are standard first-line treatments for patients with metastatic renal cell carcinoma (mRCC). Nonetheless, as the number of treatment options increases, there is a need to identify biomarkers that can predict drug efficacy and toxicity. In this prospective study we evaluated a set of biomarkers that had been previously identified within a secretory signature in mRCC patients. This set includes tumor expression of c-Met and serum levels of HGF, IL-6, IL-8, CXCL9, CXCL10 and CXCL11. Our cohort included 60 patients with mRCC from 10 different Spanish hospitals who received sunitinib (n = 51), pazopanib (n = 4) or both (n = 5). Levels of biomarkers were studied in relation to response rate, progression-free survival (PFS) and overall survival (OS). High tumor expression of c-Met and high basal serum levels of HGF, IL-6, CXCL11 and CXCL10 were significantly associated with reduced PFS and/or OS. In multivariable Cox regression analysis, CXCL11 was identified as an independent biomarker predictive of shorter PFS and OS, and HGF was an independent predictor of reduced PFS. Correlation analyses using our cohort of patients and patients from TCGA showed that HGF levels were significantly correlated with those of IL-6, CXCL11 and CXCL10. Bioinformatic protein–protein network analysis revealed a significant interaction between these proteins, all this suggesting a coordinated expression and secretion. We also developed a prognostic index that considers this group of biomarkers, where high values in mRCC patients can predict higher risk of relapse (HR 5.28 [2.32–12.0], p &lt, 0.0001). In conclusion, high plasma HGF, CXCL11, CXCL10 and IL-6 levels are associated with worse outcome in mRCC patients treated with sunitinib or pazopanib. Our findings also suggest that these factors may constitute a secretory cluster that acts coordinately to promote tumor growth and resistance to antiangiogenic therapy.

Objective The aim of this study was to assess whether anodal DCS applied to the suboccipital (SO) target area could potentiate antinociception assessed primarily with conditioned pain modulation of tonic thermal test stimuli. Design Randomized double-blinded control trial. Setting Rehabilitation hospital. Subjects Healthy participants. Methods Forty healthy participants were randomized to receive either SO-DCS or M1-DCS. The 20-minute 1.5 mA anodal or sham DCS intervention were applied to each participant in randomized order during two test sessions. The primary outcome measure included heterotopic cold-pressor conditioned pain modulation (CPM) of tonic heat pain. Secondary measures included pressure pain threshold and tonic thermal pain intensity. Results Heterotopic CPM of tonic heat pain intensity was unaffected by either SO-DCS or active M1, including the secondary measures of pressure pain threshold and tonic thermal pain intensity. Although low-power non-significant interactions were identified for DCS intervention (active versus sham) and time (before and after), a significant within-group inhibition of tonic cold pain was identified following SO-DCS (P = .011, mean [SD]: −0.76 ± 0.88 points) and M1-DCS (P Conclusions Although heterotopic CPM was not facilitated with either SO-DCS or M1-DCS, a general significant inhibition of tonic cold pain intensity was demonstrated following both interventions. The general effects of active DCS compared to sham on tonic cold pain—irrespective of the M1 or SO target—need to be confirmed using standard quantitative sensory testing.

This work has been funded by the Foundation for Applied Medical Research, ISCIII-Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional 'Una manera de hacer Europa' (PI19/00230 to AC, PI19/00098 to LMM, PI17/00411 to RP and DA, PI19/00560 to JMGP; CIBERONC CB16/12/00443 to LMM and CB16/12/00390 to JMGP), AECC and Ramón Areces Foundations (both to LMM), 'Instituto de Investigación Sanitaria del Principado de Asturias to JMGP and BMS (to JA and LMM)., Redin, E., Garmendia, I., Lozano, T., Serrano, D., Senent, Y., Redrado, M., Villalba, M., De Andrea, C.E., Exposito, F., Ajona, D., Ortiz-Espinosa, S., Remirez, A., Bertolo, C., Sainz, C., Garcia-Pedrero, J., Pio, R., Lasarte, J., Agorreta, J., Montuenga, L.M., Calvo, A.

Simple Summary Apart from genetic changes, cancer is characterized by epigenetic alterations, which indicate modifications in the DNA (such as DNA methylation) and histones (such as methylation and acetylation), as well as gene expression regulation by non-coding (nc)RNAs. These changes can be used in biological fluids (liquid biopsies) for diagnosis, prognosis and prediction of cancer drug response. Although these alterations are not widely used as biomarkers in the clinical practice yet, increasing number of commercial kits and clinical trials are expected to prove that epigenetic changes are able to offer valuable information for cancer patients. Abstract Early alterations in cancer include the deregulation of epigenetic events such as changes in DNA methylation and abnormal levels of non-coding (nc)RNAs. Although these changes can be identified in tumors, alternative sources of samples may offer advantages over tissue biopsies. Because tumors shed DNA, RNA, and proteins, biological fluids containing these molecules can accurately reflect alterations found in cancer cells, not only coming from the primary tumor, but also from metastasis and from the tumor microenvironment (TME). Depending on the type of cancer, biological fluids encompass blood, urine, cerebrospinal fluid, and saliva, among others. Such samples are named with the general term “liquid biopsy” (LB). With the advent of ultrasensitive technologies during the last decade, the identification of actionable genetic alterations (i.e., mutations) in LB is a common practice to decide whether or not targeted therapy should be applied. Likewise, the analysis of global or specific epigenetic alterations may also be important as biomarkers for diagnosis, prognosis, and even for cancer drug response. Several commercial kits that assess the DNA promoter methylation of single genes or gene sets are available, with some of them being tested as biomarkers for diagnosis in clinical trials. From the tumors with highest incidence, we can stress the relevance of DNA methylation changes in the following genes found in LB: SHOX2 (for lung cancer); RASSF1A, RARB2, and GSTP1 (for lung, breast, genitourinary and colon cancers); and SEPT9 (for colon cancer). Moreover, multi-cancer high-throughput methylation-based tests are now commercially available. Increased levels of the microRNA miR21 and several miRNA- and long ncRNA-signatures can also be indicative biomarkers in LB. Therefore, epigenetic biomarkers are attractive and may have a clinical value in cancer. Nonetheless, validation, standardization, and demonstration of an added value over the common clinical practice are issues needed to be addressed in the transfer of this knowledge from “bench to bedside”.

The structural organization of chromosomes is a crucial feature that defines the functional state of genes and genomes. The extent of structural changes experienced by genomes of eukaryotic cells can be dramatic and spans several orders of magnitude. At the core of these changes lies a unique group of ATPases –the SMC proteins– that act as major effectors of chromosome behavior in cells. The Smc5/6 proteins play essential roles in the maintenance of genome stability, yet their mode of action is not fully understood. Here we show that the human Smc5/6 complex recognizes unusual DNA configurations and uses the energy of ATP hydrolysis to promote their compaction. Structural analyses reveal subunit interfaces responsible for the functionality of the Smc5/6 complex and how mutations in these regions may lead to chromosome breakage syndromes in humans. Collectively, our results suggest that the Smc5/6 complex promotes genome stability as a DNA micro-compaction machine.

Transcutaneous electrical spinal cord stimulation (tSCS) is a non-invasive technique for neuromodulation and has therapeutic potential for motor rehabilitation following spinal cord injury. The main aim of the present study is to quantify the effect of a single session of tSCS on lower limb motor evoked potentials (MEPs) in healthy participants. A double-blind, sham-controlled, randomized, crossover, clinical trial was carried out in 15 participants. Two 10-min sessions of tSCS (active-tSCS and sham-tSCS) were applied at the T11-T12 vertebral level. Quadriceps (Q) and tibialis anterior (TA) muscle MEPs were recorded at baseline, during and after tSCS. Q and TA isometric maximal voluntary contraction was also recorded. A significant increase of the Q-MEP amplitude was observed during active-tSCS (1.96 &plusmn, 0.3 mV) when compared from baseline (1.40 &plusmn, 0.2 mV, p = 0.01) and when compared to sham-tSCS at the same time-point (1.13 &plusmn, 0.3 mV, p = 0.03). No significant modulation was identified for TA-MEP amplitude or for Q and TA isometric maximal voluntary isometric strength. In conclusion, tSCS applied over the T11-T12 vertebral level increased Q-MEP but not TA-MEP compared to sham stimulation. The specific neuromodulatory effect of tSCS on Q-MEP may reflect optimal excitation of this motor response at the interneuronal or motoneuronal level.

Numerous neurological dysfunctions are accompanied by an undesirable increase of nerve activity, such as neuropathic pain or spasticity. There have been several studies over the last years on peripheral nerve block using high-frequency alternating currents, which could become a therapeutic alternative for such nerve hyperactivity. The main aim of this systematic review was to determine the optimal parameters of the electrical currents for producing peripheral nerve conduction block, the underlying neurophysiological mechanisms, and their possible adverse effects. Of the 49 included studies, 30 were animal experiments, 13 were computer simulations, and six were clinical trials. High-frequency alternating currents using frequencies of >4–5 kHz effectively block nerve conduction. However, depending on the type of axon or nerve diameter, the minimum frequency required to produce the nerve block could be >20kHz. Electrodes design, electrode-axon distance, and temperature are variables that affect the block threshold. There is no consensus about the block mechanism, although it has been showed that the frequency is a key factor to produce K+ channels activation or Na+ channels inactivation. The nerve block produced by currents quickly reverts without causing further damage to the nerve. Studies in humans are necessary to further validate what preclinical studies have already shown.

Transcranial direct current stimulation (tDCS) is a non-invasive, easy to administer, well-tolerated, and safe technique capable of affecting brain excitability, both at the cortical and cerebellum levels. However, its effectiveness has not been sufficiently assessed in all population segments or clinical applications. This systematic review aimed at compiling and summarizing the currently available scientific evidence about the effect of tDCS on functionality in older adults over 60 years of age. A search of databases was conducted to find randomized clinical trials that applied tDCS versus sham stimulation in the above-mentioned population. No limits were established in terms of date of publication. A total of 237 trials were found, of which 24 met the inclusion criteria. Finally, nine studies were analyzed, including 260 healthy subjects with average age between 61.0 and 85.8 years. Seven of the nine included studies reported superior improvements in functionality variables following the application of tDCS compared to sham stimulation. Anodal tDCS applied over the motor cortex may be an effective technique for improving balance and posture control in healthy older adults. However, further high-quality randomized controlled trials are required to determine the most effective protocols and to clarify potential benefits for older adults.

Omega-3 polyunsaturated fatty acids (PUFAs), such as docosaexaenoic acid (DHA) and eicosapentaenoic acid (EPA), mediate neuroactive effects in experimental models of traumatic peripheral nerve and spinal cord injury. Cellular mechanisms of PUFAs include reduced neuroinflammation and oxidative stress, enhanced neurotrophic support, and activation of cell survival pathways. Bioactive Omega-9 monounsaturated fatty acids, such as oleic acid (OA) and 2-hydroxy oleic acid (2-OHOA), also show therapeutic effects in neurotrauma models. These FAs reduces noxious hyperreflexia and pain-related anxiety behavior following peripheral nerve injury and improves sensorimotor function following spinal cord injury (SCI), including facilitation of descending inhibitory antinociception. The relative safe profile of neuroactive fatty acids (FAs) holds promise for the future clinical development of these molecules as analgesic agents. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá.

Background Transcranial direct-current stimulation (tDCS) is an easy-to-apply, cheap, and safe technique capable of affecting cortical brain activity. However, its effectiveness has not been proven for many clinical applications. Objective The aim of this systematic review was to determine whether the effect of different strategies for gait training in patients with neurological disorders can be enhanced by the combined application of tDCS compared to sham stimulation. Additionally, we attempted to record and analyze tDCS parameters to optimize its efficacy. Methods A search in Pubmed, PEDro, and Cochrane databases was performed to find randomized clinical trials that combined tDCS with gait training. A chronological filter from 2010 to 2018 was applied and only studies with variables that quantified the gait function were included. Results A total of 274 studies were found, of which 25 met the inclusion criteria. Of them, 17 were rejected based on exclusion criteria. Finally, 8 trials were evaluated that included 91 subjects with stroke, 57 suffering from Parkinson’s disease, and 39 with spinal cord injury. Four of the eight assessed studies did not report improved outcomes for any of its variables compared to the placebo treatment. Conclusions There are no conclusive results that confirm that tDCS can enhance the effect of the different strategies for gait training. Further research for specific pathologies, with larger sample sizes and adequate follow-up periods, are required to optimize the existing protocols for applying tDCS.

OBJECTIVES This study examined predictive correlations between periaqueductal gray (PAG) and anterior cingulate cortex (ACC) metabolite levels with deficient inhibitory endogenous pain modulation (EPM), including sensory and affective measures of pain during chronic whiplash injury (WHI). MATERIALS AND METHODS Healthy patients, and participants with chronic WHI, without (WHI-noP) or with pain (WHI-P), were screened with the Douleur Neuropathique 4 tool (DN4). EPM was assessed with C6 tonic heat pain stimuli with a Conditioned Pain Modulation (CPM) protocol. Magnetic resonance spectroscopy quantified ACC and PAG metabolite levels. RESULTS WHI-P participants were characterized with high pain intensity and interference, and lower quality of life scores, compared with WHI-noP. Inhibitory CPM at 30 seconds was identified in the healthy noninjured (-45±16%; P

Objectives: To evaluate the effectiveness of high-intensity laser therapy on shoulder pain and function in subacromial impingement syndrome. Design: Clinical controlled trial with alternate allocation. Setting: Hospital Department of Rehabilitation. Subjects: A total of 46 participants with subacromial impingement syndrome. Intervention: Participants were sequence allocated to an intervention group (high-intensity laser therapy + exercise therapy) and control group (sham-laser + exercise therapy) and received 15 sessions (five days a week during three weeks). Main measures: Patiens were evaluated at baseline, after 15 sessions, and at one month and at three months after completing the intervention. The main outcome variables were pain and functionality as measured by visual analogue scale; pressure pain threshold; Shoulder Pain and Disability Index; Constant-Murley Score; and QuickDASH. Secondary outcomes were number of sessions at discharge and drug use. Results: A total of 21 patients in high-intensity laser therapy group (56.7 ± 8.9 years) and 22 patients in sham-laser group (61.3 ± 8.9 years) concluded the study. Visual analogue scale (cm) at baseline, one-month, and three-months were 6.2 ± 0.5, 3 ± 2.6, and 2.6 ± 2.4 for the control group and 5.4 ± 1.5, 3.6 ± 1.3, and 1.8 ± 1.7 for experimental group, respectively. Shoulder Pain and Disability Index (points) at baseline, one-month, and three-monts were 51.8 ± 16.1, 16.3 ± 16.1, and 13.6 ± 17.1 in the control group and 41.8 ± 20.6, 20.5 ± 19.7, 11 ± 14.5 in experimental group, respectively. No differences were found between groups ( P > 0.05). Conclusion: The effect of high-intensity laser therapy plus exercise is not higher than exercise alone to reduce pain and improve functionality in patients with subacromial syndrome.

BACKGROUND: High-frequency alternating currents of greater than 1 kHz applied on peripheral nerves has been used in animal studies to produce a motor nerve block. It has been evidenced that frequencies higher than 5 kHz are necessary to produce a complete peripheral nerve block in primates, whose nerve thickness is more similar to humans. The aim of the study was to determine the effect on muscle strength after the application of a high-frequency stimulation at 5 and 10 kHz compared to sham stimulation in healthy volunteers. FINDINGS: Transcutaneous stimulation at 5 kHz, 10 kHz and sham stimulation were applied to eleven healthy volunteers over the ulnar and median nerves for 20 min. Maximal handgrip strength was measured before, during, immediately after the intervention, and 10 min after the end of intervention. The 10 kHz stimulation showed a lower handgrip strength during the intervention (28.1 N, SEM 3.9) when compared to 5 kHz (31.1 N, SEM 3.6; p

BACKGROUND Tibialis Anterior (TA) cutaneous reflex (CR) activity evoked following cutaneous stimulation of the plantar (Pl) surface (Pl-TA CR) has demonstrated hyperreflexia and damage of inhibitory mechanisms in subjects with spinal cord injury (SCI) and spasticity. OBJECTIVES To modulate Pl-TA CR and Soleus H-reflex activity with transcutaneous electrical nerve stimulation (TENS) and vibratory stimulation of the plantar pad during rest and controlled isometric plantarflexion. METHODS Non-injured subjects (n = 11) and individuals with incomplete SCI with (n = 14) and without spasticity (n = 14) were recruited. The effect of TENS and vibratory stimuli on Pl-TA CR and soleus H-reflex activity were assessed during rest and controlled ramp-and-hold plantarflexion. RESULTS Vibration failed to inhibit H-reflex activity during rest or plantarflexoin following SCI compared to healthy subjects. In contrast, vibration-induced inhibition of Pl-TA CR was specifically detected in SCI spastic subjects during both rest and the hold phase of plantarflexion. TENS inhibited Pl-TA CR activity in the SCI spasticity group only during hold plantarflexion. CONCLUSIONS Plantar vibratory stimuli inhibited the pl-TA CR, but not the H reflex, during rest and controlled movement in SCI spastic subjects. Assessment of Pl-TA CR modulation should contribute to the development of modality-specific sensory stimuli programmes for the neurorehabilitation of SCI spasticity.

OBJECTIVE Appropriate afferent feedback delivery during the execution of motor tasks is important for rehabilitation after incomplete spinal cord injury (iSCI). However, during leg-cycling therapy, the plantar afferent feedback is minimal. We hypothesize that the augmentation of sensory input by combining cycling with a locomotor-like stimulation of plantar cutaneous innervations (ES-cycling), might help to restore proper spinal processing of sensorimotor function. METHODS Thirteen non-injured subjects and 10 subjects with iSCI performed 10 minutes of cycling and, on another session, of ES-cycling. To assess spinal processing of sensorimotor function, soleus H-reflex response was tested following a conditioning plantar electrical stimulation applied at 25-100 ms inter-stimulus intervals (ISI's), measured before and after the execution of the tasks. RESULTS Before tasks execution, the conditioned H-reflex response was modulated in non-injured subjects, and absent in subjects with iSCI; after cycling, modulation profiles were unchanged. However, after ES-cycling a significant increase in H-reflex excitability was observed in the non-injured group at 100 ms ISI (p

Several studies have examined spinal reflex modulation during leg cycling in healthy and spinal cord injury (SCI) subjects. However, the effect of cutaneous plantar afferent input on spinal excitability during leg cycling after SCI has not been characterised. The aim of the study was to test the feasibility of using controlled leg cycling in combination with plantar cutaneous electrical stimulation (ES) cycling to assess lower limb spinal sensorimotor excitability in subjects with motor complete or incomplete SCI. Spinal sensorimotor excitability was estimated by measuring cutaneomuscular-conditioned soleus H-reflex activity. Reflex excitability was tested before and after a 10-min ES cycling session in 13 non-injured subjects, 6 subjects with motor incomplete SCI (iSCI) who had moderately impaired gait function, 4 subjects with motor iSCI who had severely impaired gait function, and 5 subjects with motor complete SCI (cSCI). No modulation of soleus H-reflex with plantar cutaneous stimuli was observed after either iSCI or cSCI when compared to non-injured subjects. However, after ES cycling, reflex excitability significantly increased in subjects with iSCI and moderately impaired gait function. ES cycling facilitated spinal sensorimotor excitability only in subjects with motor iSCI with residual gait function. Increased spinal excitability induced with a combination of exercise and afferent stimulation could be adopted with diagnostic and prognostic purposes to reveal the activity-based neurorehabilitation profile of individual subjects with motor iSCI. Trial registration: ISRCTN 26172500 ; retrospectively registered on 15 July 2016

Nowadays, exoskeletons have been introduced for empowering walking in military, industrial and rehabilitation settings. Several companies are commercializing these devices, but there is a lack of understanding of their effects on muscle activations and coordination. The objective of this article is to investigate the impact on muscle activation and user effort during ambulatory, robotic-assisted walking. Compared with free walking, our results suggest that robotic assistance with the Exo-H2 lower limb exoskeleton may result in increased muscle activation. Muscular timing experienced unspecific changes with respect to unassisted walking. Further research is needed to unveil the mechanical interaction between the robot and the lower limbs and the underlying motor adaptations in response to robot-assisted walking.

Gait rehabilitation robots are of increasing importance in neurorehabilitation. The aim of this study is to assess the effects of Exo-H2 on metabolic cost in patients with incomplete SCI while walking with two control modes, compared with unassisted walking. Three patients with incomplete SCI participated in the study and three walking tests were conducted in randomized order with two control modes and unassisted gait while recording the oxygen consumption and prior and after blood pressure, heart rate, VAS of pain and fatigue was obtained. As conclusion, our results suggest that the gait robotic assistance with Exo-H2 is more physiological when is selected compliant mode.

Cutaneomuscular afferent information is essential for voluntary motor tasks such as gait and balance. After spinal cord injury (SCI) changes in sensorimotor activity are involved in recovery of limited motor function. Here we present a review of clinical neurophysiological measures that quantify sensorimotor dysfunction and which have the potential to benchmark the therapeutic effect of cutaneous stimulation during SCI neurorehabilitation. Specifically we will show that long-latency cutaneous reflex and cutaneomuscular conditioned H-reflex techniques can quantify spinal neuronal activity and the presence of either adaptive or maladaptive motor control mechanisms after incomplete SCI. In conclusion, the development of neurorehabilitation programs in combination with cutaneomuscular stimulation protocols is a viable strategy not only to promote motor recovery but to prevent maladaptive neuroplasticity such as spasticity after SCI.

Resumen: Introducción: Aunque tradicionalmente la estimulación eléctrica nerviosa transcutánea (TENS) se ha utilizado como tratamiento del dolor, algunos estudios han evidenciado una reducción de la espasticidad tras la aplicación de TENS. Sin embargo, su uso en la clínica aún está muy poco extendido. El objetivo de este estudio consiste en determinar si la estimulación TENS aplicada en pacientes con afectación neurológica resulta efectiva para tratar la espasticidad o alguno de sus síntomas asociados. Además, se pretende determinar los parámetros de estimulación que mayor efecto producen sobre las diferentes variables asociadas a la espasticidad. Desarrollo: Se buscaron ensayos clínicos aleatorizados relacionados con TENS y espasticidad encontrados en las bases de datos PubMed, PEDro y Cochrane con anterioridad al 12 de mayo del 2015. Dos revisores independientes realizaron las búsquedas y seleccionaron los estudios en función de los criterios de inclusión previamente establecidos. En la búsqueda inicial se encontraron un total de 96 artículos, de los cuales 86 fueron excluidos y 10 fueron seleccionados para analizar en esta revisión. Se presentan resultados en 207 sujetos con accidente cerebrovascular, 84 con esclerosis múltiple y 39 con lesión medular. Conclusiones: Debido a los resultados observados, su bajo coste, facilidad de aplicación y ausencia de efectos adversos, se recomienda la estimulación mediante TENS como tratamiento de la espasticidad. Sin embargo, la gran variabilidad existente entre las formas de estimulación, los parámetros utilizados y las variables analizadas, dificultan el análisis y la comparación de resultados que puedan determinar la eficacia objetiva de la técnica y la optimización de parámetros. Abstract: Introduction: Although transcutaneous electrical nerve stimulation (TENS) has traditionally been used to treat pain, some studies have observed decreased spasticity after use of this technique. However, its use in clinical practice is still limited. Our purpose was twofold: to determine whether TENS is effective for treating spasticity or associated symptoms in patients with neurological involvement, and to determine which stimulation parameters exert the greatest effect on variables associated with spasticity. Development: Two independent reviewers used PubMed, PEDro, and Cochrane databases to search for randomised clinical trials addressing TENS and spasticity published before 12 May 2015, and selected the articles that met the inclusion criteria. Of the initial 96 articles, 86 were excluded. The remaining 10 articles present results from 207 patients with a cerebrovascular accident, 84 with multiple sclerosis, and 39 with spinal cord lesions. Conclusions: In light of our results, we recommend TENS as a treatment for spasticity due to its low cost, ease of use, and absence of adverse reactions. However, the great variability in the types of stimulation used in the studies, and the differences in parameters and variables, make it difficult to assess and compare any results that might objectively determine the effectiveness of this technique and show how to optimise parameters. Palabras clave: Espasticidad, Estimulación eléctrica terapéutica, Hipertonía, Patología neurológica, Síndrome de la motoneurona superior, Estimulación eléctrica nerviosa transcutánea, Keywords: Spasticity, Transcutaneous electrical nerve stimulation, Hypertonia, Neurological disease, Upper motor neuron syndrome, Transcutaneous electrical nerve stimulation

The intensity used during transcutaneous electrical nerve stimulation (TENS) in both, clinical practice and research studies, is often based on subjective commands such as "strong but comfortable sensation". There is no consensus regarding the effectiveness dose of TENS. The objective was to determine the difference in the effect of spinal TENS on soleus H-reflex modulation when applied by two therapists instructed to apply the stimulation at a "strong but comfortable" intensity. Twenty healthy volunteers divided into two groups: Therapist 1 (n = 10) and Therapist 2 (n = 10). Both therapist applied spinal TENS and sham stimulation at the T10-12 spinal level for 40min in random order to each subject, at an intensity designed to produce a "strong but comfortable" sensation. To avoid habituation, the intensity was adjusted every 2min. Soleus H-reflex was recorded before, during, and 10min after TENS by an observer blinded to the stimulus applied. Despite the instruction to apply TENS at a "strong comfortable" level, a significant difference in current density was identified: Therapist 1 (0.67mA/cm2, SD 0.54) applied more than Therapist 2 (0.53mA/cm2, SD 0.57; p