Self-administered non-invasive vagus nerve stimulation therapy for severe pharmacoresistant restless legs syndrome: outcomes at 6 months.

Severe pharmacoresistant restless legs syndrome (RLS) is difficult to manage and a source of suffering to patients. We studied the effectiveness at 6 months of an innovative treatment: transauricular vagus nerve stimulation (taVNS) in the left cymba concha in a case series of 15 patients, 53% male, mean (SD) age 62.7 (12.3) years with severe pharmacoresistant RLS (mean [SD] International Restless Legs Rating Scale [IRLS] score of 31.9 [2.9]) at baseline. Following an 8-week non-randomised hospital-based study with eight 1-h sessions of taVNS, patients were trained to administer taVNS at home and were followed up for 6 months. The primary outcome measure was the IRLS score, secondary outcome measures were quality of life, mood disorders using the Hospital Anxiety and Depression scale (HAD) subscales for depression (HADD) and anxiety (HADA). At the 6-month follow-up 13/15 patients continued to use weekly taVNS. Symptom severity decreased (mean [SD] IRLS score 22.2 [9.32] at 6 months, p = 0.0005). Four of the 15 patients had an IRLS score of <20 at 6 months and two an IRLS score of 5. Quality of life significantly improved compared to baseline (mean [SD] score at baseline 49.3 [18.1] versus 65.66 [22.58] at 6 months, p = 0.0005) as did anxiety and depression symptoms (mean [SD] HADA score at baseline 8.9 [5.4] versus 7.53 [4.42] at 6 months, p = 0.029; and HADD score at baseline 5.2 [4.5] versus 4.73 [4.44] at 6 months, p = 0.03). Treatment was well tolerated, and no adverse events were reported. Our case series shows a potential role for self-administered taVNS in patients with severe pharmacoresistant RLS. Randomised controlled trials are needed to confirm the utility of taVNS.

Noninvasive Vagus Nerve Stimulation: A New Therapeutic Approach for Pharmacoresistant Restless Legs Syndrome.

AIMS: This work aimed to study the effect of noninvasive vagus nerve stimulation on severe restless legs syndrome (RLS) resistant to pharmacotherapy. MATERIALS AND METHODS: Patients with severe pharmacoresistant RLS were recruited from a tertiary care sleep center. Intervention was one-hour weekly sessions of transauricular vagus nerve stimulation (tVNS) in the left cymba concha, for eight weeks. The primary outcome measure was the score on the International Restless Legs Rating Scale (IRLS); secondary outcome measures were quality of life (Restless Legs Syndrome Quality of Life scale [RLSQOL]), mood disorders using the Hospital Anxiety and Depression scale subscale for depression (HADD) and Hospital Anxiety and Depression scale subscale for anxiety (HADA), and objective sleep latency, sleep duration, efficiency, and leg movement time measured by actigraphy. RESULTS: Fifteen patients, 53% male, aged mean 62.7 ± 12.3 years with severe RLS, reduced quality of life, and symptoms of anxiety and depression, were included. The IRLS improved from baseline to session eight: IRLS 31.9 ± 2.9 vs 24.6 ± 5.9 p = 0.0003. Of these participants, 27% (4/15) had a total response with a decrease below an IRLS score of 20; 40% (6/15) a partial response with an improvement in the IRLS > 5 but an IRLS above 20; and 33% (5/15) were nonresponders. After tVNS, quality of life improved (RLSQOL 49.3 ± 18.1 vs 80.0 ± 19.6 p = 0.0005), as did anxiety (HADA 8.9 ± 5.4 vs 6.2 ± 5.0 p = 0.001) and depression (HADD 5.2 ± 4.5 vs 4.0 ± 4.0 p = 0.01). No significant change was found in actigraphic outcome measures. CONCLUSIONS: In this pilot study, tVNS improved the symptoms of RLS in 66% of participants (10/15) with severe pharmacoresistant RLS, with concomitant improvements in quality of life and mood. Randomized controlled trials evaluating therapeutic efficacy of tVNS in RLS are needed to confirm these promising findings.

Training with noninvasive brain-machine interface, tactile feedback, and locomotion to enhance neurological recovery in individuals with complete paraplegia: a randomized pilot study.

In recent years, our group and others have reported multiple cases of consistent neurological recovery in people with spinal cord injury (SCI) following a protocol that integrates locomotion training with brain machine interfaces (BMI). The primary objective of this pilot study was to compare the neurological outcomes (motor, tactile, nociception, proprioception, and vibration) in both an intensive assisted locomotion training (LOC) and a neurorehabilitation protocol integrating assisted locomotion with a noninvasive brain-machine interface (L + BMI), virtual reality, and tactile feedback. We also investigated whether individuals with chronic-complete SCI could learn to perform leg motor imagery. We ran a parallel two-arm randomized pilot study; the experiments took place in São Paulo, Brazil. Eight adults sensorimotor-complete (AIS A) (all male) with chronic (> 6 months) traumatic spinal SCI participated in the protocol that was organized in two blocks of 14 weeks of training and an 8-week follow-up. The participants were allocated to either the LOC group (n = 4) or L + BMI group (n = 4) using block randomization (blinded outcome assessment). We show three important results: (i) locomotion training alone can induce some level of neurological recovery in sensorimotor-complete SCI, and (ii) the recovery rate is enhanced when such locomotion training is associated with BMI and tactile feedback (∆Mean Lower Extremity Motor score improvement for LOC = + 2.5, L + B = + 3.5; ∆Pinprick score: LOC = + 3.75, L + B = + 4.75 and ∆Tactile score LOC = + 4.75, L + B = + 9.5). (iii) Furthermore, we report that the BMI classifier accuracy was significantly above the chance level for all participants in L + B group. Our study shows potential for sensory and motor improvement in individuals with chronic complete SCI following a protocol with BMIs and locomotion therapy. We report no dropouts nor adverse events in both subgroups participating in the study, opening the possibility for a more definitive clinical trial with a larger cohort of people with SCI.Trial registration: http://www.ensaiosclinicos.gov.br/ identifier RBR-2pb8gq.

Randomized Cross Over Study Assessing the Efficacy of Non-invasive Stimulation of the Vagus Nerve in Patients With Axial Spondyloarthritis Resistant to Biotherapies: The ESNV-SPA Study Protocol.

Axial spondyloarthritis (SpA), is a major cause of chronic pain and disability that profoundly alters the quality of life of patients. Nearly half of patients with SpA usually develop drug resistance. Non-pharmacological treatments targeting inflammation are an attractive alternative to drug administration. Vagus nerve stimulation (VNS), by promoting a cholinergic anti-inflammatory reflex holds promise for treating inflammatory disease. Inflammatory reflex signaling, which is enhanced by electrically stimulating the vagus nerve, significantly reduces cytokine production and attenuates disease severity in animal models of endotoxemia, sepsis, colitis, and other preclinical models of inflammatory diseases. It has been proposed that vagal efferent fibers release acetylcholine (Ach), which can interact with α7-subunit-containing nicotinic receptors expressed by tissue macrophages and other immune cells to rapidly inhibit the synthesis/release of pro-inflammatory cytokines such as TNFα, IL-1ß, IL-6, and IL-18. External vagal nerve stimulation devices are now available that do not require surgery nor implantation to non-invasively stimulate the vagal nerve. This double-blind randomized cross-over clinical trial aims to study the change in SpA disease activity, according to Assessment in Ankylosing Spondylitis 20 (ASAS20) definition, after 12 weeks of non-invasive VNS treatment vs. non-specific dummy stimulation (control group). One hundred and twenty adult patients with drug resistant SpA, meeting the ASAS classification criteria, will be included in the study. Patients will be randomized into two parallel groups according to a cross over design: either active VNS for 12 weeks, then dummy stimulation for 12 weeks, or dummy stimulation for 12 weeks, then active VNS for 12 weeks. The two stimulation periods will be separated by a 4 weeks wash-out period. A transcutaneous auricular vagus nerve stimulator Tens Eco Plus SCHWA MEDICOTM France will be used in this study. The active VNS stimulation will be applied in the cymba conchae of the left ear upon the auricular branch of the vagus nerve, using low intensity (2-5 mA), once à week, during 1 h. Dummy stimulation will be performed under the same conditions and parameters as active VNS stimulation, but at an irrelevant anatomical site: the left ear lobule. This multicenter study was registered on ClinicalTrials.gov: NCT04286373.

Vagus Nerve Stimulation: A Potential Adjunct Therapy for COVID-19.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) through excessive end organ inflammation. Despite improved understanding of the pathophysiology, management, and the great efforts worldwide to produce effective drugs, death rates of COVID-19 patients remain unacceptably high, and effective treatment is unfortunately lacking. Pharmacological strategies aimed at modulating inflammation in COVID-19 are being evaluated worldwide. Several drug therapies targeting this excessive inflammation, such as tocilizumab, an interleukin (IL)-6 inhibitor, corticosteroids, programmed cell death protein (PD)-1/PD-L1 checkpoint inhibition, cytokine-adsorption devices, and intravenous immunoglobulin have been identified as potentially useful and reliable approaches to counteract the cytokine storm. However, little attention is currently paid for non-drug therapeutic strategies targeting inflammatory and immunological processes that may be useful for reducing COVID-19-induced complications and improving patient outcome. Vagus nerve stimulation attenuates inflammation both in experimental models and preliminary data in human. Modulating the activity of cholinergic anti-inflammatory pathways (CAPs) described by the group of KJ Tracey has indeed become an important target of therapeutic research strategies for inflammatory diseases and sepsis. Non-invasive transcutaneous vagal nerve stimulation (t-VNS), as a non-pharmacological adjuvant, may help reduce the burden of COVID-19 and deserve to be investigated. VNS as an adjunct therapy in COVID-19 patients should be investigated in clinical trials. Two clinical trials on this topic are currently underway (NCT04382391 and NCT04368156). The results of these trials will be informative, but additional larger studies are needed.

Randomized Controlled Study Evaluating Efficiency of Low Intensity Transcranial Direct Current Stimulation (tDCS) for Dyspnea Relief in Mechanically Ventilated COVID-19 Patients in ICU: The tDCS-DYSP-COVID Protocol.

The severe respiratory distress syndrome linked to the new coronavirus disease (COVID-19) includes unbearable dyspneic suffering which contributes to the deterioration of the prognosis of patients in intensive care unit (ICU). Patients are put on mechanical ventilation to reduce respiratory suffering and preserve life. Despite this mechanical ventilation, most patients continue to suffer from dyspnea. Dyspnea is a major source of suffering in intensive care and one of the main factors that affect the prognosis of patients. The development of innovative methods for its management, especially non-drug management is more than necessary. In recent years, numerous studies have shown that transcranial direct current stimulation (tDCS) could modulate the perception of acute or chronic pain. In the other hand, it has been shown that the brain zones activated during pain and dyspnea are close and/or superimposed, suggesting that brain structures involved in the integration of aversive emotional component are shared by these two complex sensory experiences. Therefore, it can be hypothesized that stimulation by tDCS with regard to the areas which, in the case of pain have activated one or more of these brain structures, may also have an effect on dyspnea. In addition, our team recently demonstrated that the application of tDCS on the primary cortical motor area can modulate the excitability of the respiratory neurological pathways. Indeed, tDCS in anodal or cathodal modality reduced the excitability of the diaphragmatic cortico-spinal pathways in healthy subjects. We therefore hypothesized that tDCS could relieve dyspnea in COVID-19 patients under mechanical ventilation in ICU. This study was designed to evaluate effects of two modalities of tDCS (anodal and cathodal) vs. placebo, on the relief of dyspnea in COVID-19 patients requiring mechanical ventilation in ICU. Trial Registration: This protocol is derived from the tDCS-DYSP-REA project registered on ClinicalTrials.gov NCT03640455. It will however be registered under its own NCT number.

SMR/Theta Neurofeedback Training Improves Cognitive Performance and EEG Activity in Elderly With Mild Cognitive Impairment: A Pilot Study.

Background: Neurofeedback (NF) training, as a method of self-regulation of brain activity, may be beneficial in elderly patients with mild cognitive impairment (MCI). In this pilot study, we investigated whether a sensorimotor (SMR)/theta NF training could improve cognitive performance and brain electrical activity in elderly patients with MCI. Methods: Twenty elderly patients with MCI were assigned to 20 consecutive sessions of sensorimotor (SMR)/theta NF training, during 10 weeks, on a basis of two sessions each week. Neuropsychological assessments and questionnaires, as well as electroencephalogram (EEG), were performed and compared between baseline (T0), after the last NF training session at 10 weeks (T1), and 1-month follow-up (T2). Results: Repeated measures ANOVA revealed that from baseline to post-intervention, participants showed significant improvement in the Montreal cognitive assessment (MoCa, F = 4.78; p = 0.012), the delayed recall of the Rey auditory verbal learning test (RAVLT, F = 3.675; p = 0.032), the Forward digit span (F = 13.82; p < 0.0001), the Anxiety Goldberg Scale (F = 4.54; p = 0.015), the Wechsler Adult Intelligence Score-Fourth Edition (WAIS-IV; F = 24.75; p < 0.0001), and the Mac Nair score (F = 4.47; p = 0.016). EEG theta power (F = 4.44; p = 0.016) and alpha power (F = 3.84; p = 0.027) during eyes-closed resting-state significantly increased after the NF training and showed sustained improvement at a 1-month follow-up. Conclusion: Our results suggest that NF training could be effective to reduce cognitive deficits in elderly patients with MCI and improve their EEG activity. If these findings are confirmed by randomized controlled studies with larger samples of patients, NF could be seen as a useful non-invasive, non-pharmacological tool for preventing further decline, rehabilitation of cognitive function in the elderly. Clinical Trial Registration: This pilot study was a preliminary step before the trial registered in www.ClinicalTrials.gov, under the number of NCT03526692.

Training with brain-machine interfaces, visuo-tactile feedback and assisted locomotion improves sensorimotor, visceral, and psychological signs in chronic paraplegic patients.

Spinal cord injury (SCI) induces severe deficiencies in sensory-motor and autonomic functions and has a significant negative impact on patients' quality of life. There is currently no systematic rehabilitation technique assuring recovery of the neurological impairments caused by a complete SCI. Here, we report significant clinical improvement in a group of seven chronic SCI patients (six AIS A, one AIS B) following a 28-month, multi-step protocol that combined training with non-invasive brain-machine interfaces, visuo-tactile feedback and assisted locomotion. All patients recovered significant levels of nociceptive sensation below their original SCI (up to 16 dermatomes, average 11 dermatomes), voluntary motor functions (lower-limbs muscle contractions plus multi-joint movements) and partial sensory function for several modalities (proprioception, tactile, pressure, vibration). Patients also recovered partial intestinal, urinary and sexual functions. By the end of the protocol, all patients had their AIS classification upgraded (six from AIS A to C, one from B to C). These improvements translated into significant changes in the patients' quality of life as measured by standardized psychological instruments. Reexamination of one patient that discontinued the protocol after 12 months of training showed that the 16-month break resulted in neurological stagnation and no reclassification. We suggest that our neurorehabilitation protocol, based uniquely on non-invasive technology (therefore necessitating no surgical operation), can become a promising therapy for patients diagnosed with severe paraplegia (AIS A, B), even at the chronic phase of their lesion.