Sham-controlled Crossover Trial Research Articles

The effect of the EXOPULSE Mollii Suit on pain and fibromyalgia-related symptoms-A randomized sham-controlled crossover trial.

Fibromyalgia pain and related symptoms are poorly managed by approved pharmacological and alternative interventions. This trial aimed to evaluate the effects of the EXOPULSE Mollii Suit-a multisite transcutaneous electrical nerve stimulation device-on fibromyalgia pain, fatigue, affective symptoms, disease impact, and quality of life. Adult patients with fibromyalgia were enrolled. Phase 1 implied a randomized, sham-controlled, cross-over, double-blind trial, applying daily 1 h sessions of active or sham intervention, over 2 weeks (2-week washout). In the open-label phase 2, all patients received daily active intervention for 4 weeks. Comparisons on pain, fatigue, disease impact, affective symptoms, quality of life, clinical impression, and comfort ratings were performed using Friedman, Wilcoxon signed rank, and Chi2 tests. Thirty-three patients completed the study (93.9% female, mean age: 51.3 years). Pain (primary endpoint assessed via a visual analog scale) was significantly reduced after the active (pre-active: 6.9 ± 1.4, post-active: 5.9 ± 1.8, pre-sham: 6.8 ± 1.4, post-sham: 6.6 ± 1.5) versus the sham intervention (X2 = 10.60, p = 0.014). This was also the case of other secondary endpoints (i.e., fatigue, anxiety, and disease impact), except depression and quality of life. The Clinical Global Impression of Change (CGI-C) was significantly different between the active and sham intervention periods (X2 p = 0.035), and the different proportions of categories were as follows: 'worsening' (sham: 18.2% vs. active: 0.0%), 'improvement' (sham: 48.5% vs. active 63.6%) or 'no change (sham: 33.3% vs. active 36.4%) respectively. After phase 2, significant positive effects were observed for most of the outcomes, and 78.8% of patients reported improvement according to CGI-C. This study suggests the clinical benefits of the EXOPULSE Mollii Suit in alleviating pain and fibromyalgia-related fatigue, emotional symptoms, and disease impact. It is worth noting that the study has several limitations related to the low number of participants, the short-term analysis of effects in the first blinded and controlled phase, and the open-label nature of phase 2. Future studies with a larger cohort and longer protocol treatment are needed, to further confirm the current results, and evaluate the long-term effects of this technique. Patients with fibromyalgia suffer from pain as well as fatigue, sleep impairment, emotional disturbances, and altered quality of life. Transcutaneous electrical nerve stimulation might help manage those symptoms, but the available systems are limited by the fact that they could be applied at best over two sites. This randomized controlled study is the first to apply a multi-site transcutaneous electrical nerve stimulation device, the EXOPULSE Mollii Suit, with significant effects on fibromyalgia pain and related symptoms.

Assessment of Effects of Carbon Dioxide Exposure on Sleep Stability in Insomnia Using the Envelope Analysis

Objectives: Insomnia is a common sleep disorder, and various strategies have been explored for its treatment. One of the methods involves the administration of carbon dioxide (CO<sub>2</sub>) at bedtime, as the CO<sub>2</sub> increment exerts a sedative effect on the central nervous system. We aimed to assess the effect of CO<sub>2</sub> on sleep quality in patients with insomnia using the coefficient of variation of the envelope (CVE) analysis, a novel analytical method. Methods: In this randomized, double-blind, sham-controlled crossover trial, 24 adults with sleeping difficulties underwent level 1 polysomnography. Two interventions involved exposure to either 2% low-concentration CO<sub>2</sub> gas or room air. CVE analysis was performed to assess the stability of the delta band. Morphological variations in delta waves can be quantitatively monitored using the envelope analysis, which assesses the effect of manipulations on sleep that may otherwise elude detection. Results: Exposure to CO<sub>2</sub> improved the total sleep time (TST) (<i>p</i>=0.010) and total arousal index (TAI) (<i>p</i>=0.011). The CVE analysis showed a distinct distribution between the experimental and sham-controlled groups. Moreover, correlations between the TST and CVE (r=0.41) and those between the TAI and CVE (r=0.40) were observed. Conclusions: This study is the first to evaluate the effects of CO<sub>2</sub> exposure on sleep stability in patients with insomnia. The CVE analysis implies the possibility of sleep stabilization by CO<sub>2</sub> administration and suggests a link between enhanced sleep maintenance and sleep stability.

Short-term effects of positive expiratory pressure mask on ventilation inhomogeneity in children with cystic fibrosis: A randomized, sham-controlled crossover study.

Can physiotherapy with a positive expiratory pressure (PEP) mask improve peripheral ventilation inhomogeneity, a typical feature of children with cystic fibrosis (cwCF)? To answer this question, we used the nitrogen multiple-breath washout (N2MBW) test to measure diffusion-convection-dependent inhomogeneity arising within the intracinar compartment (Sacin*VT). For this randomized, sham-controlled crossover trial, two N2MBW tests were performed near the hospital discharge date: one before and the other after PEP mask therapy (1 min of breathing through a flow-dependent PEP device attached to a face mask, followed by three huffs and one cough repeated 10 times) by either a standard (10-15 cmH20) or a sham (<5 cmH20) procedure on two consecutive mornings. Deception entailed misinforming the subjects about the nature of the study; also the N2MBW operators were blinded to treatment allocation. Study outcomes were assessed with mixed-effect models. The study sample was 19 cwCF (ten girls), aged 11.4 (2.7) years. The adjusted Sacin*VT mean difference between the standard and the sham procedure was -0.015 (90% confidence interval [CI]: -∞ to 0.025) L-1. There was no statistically significant difference in Scond*VT and lung clearance index between the two procedures: -0.005 (95% CI: -0.019 to 0.01) L-1 and 0.49 (95% CI: -0.05 to 1.03) turnovers, respectively. Our findings do not support evidence for an immediate effect of PEP mask physiotherapy on Sacin*VT with pressure range 10-15 cmH20. Measurement with the N2MBW and the crossover design were found to be time-consuming and unsuitable for a short-term study of airway clearance techniques.

Can transcranial direct current stimulation (tDCS) over the motor cortex increase endurance running performance? a randomized crossover-controlled trial.

Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique, has been shown to increase exercise performance in strength and cycling studies but its effects on running endurance remain unclear. The objectives of this randomized sham-controlled crossover trial were to assess tDCS efficacy on submaximal treadmill running time to exhaustion (TTE). Forty-five healthy male runners aged between 18 and 32 years (mean maximal oxygen consumption: 46.6 mL/min/kg) performed two constant-load tests at 90% of their maximal aerobic speed preceded by 20 minutes of active or sham multichannel (5 anodes, 3 cathodes) tDCS applied over the bilateral motor cortex with a total intensity of 4 mA. Ratings of perceived exertion (RPE), blood lactate, VO2, and heart rate were monitored every five minutes until volitional exhaustion. The median [IQR] TTE was similar following active (12.2 [10.5, 16.1] minutes) or sham (12.5 [10.2, 15.1] minutes) tDCS (p = 0.96). Likewise, there were no significant differences between active and sham conditions for RPE, blood lactate, final VO2, and final heart rate (all p ≥0.05). No difference in TTE was found when stratifying groups according to their VO2max (i.e., VO2max ≥ 45 mL/min/Kg, p = 0.53; VO2max < 45 mL/min/Kg, p = 0.45) but there was a trend for a significant correlation between VO2max and change in TTE (p = 0.06). TDCS applied over the bilateral motor cortex did not improve endurance performance in a large sample of trained runners. Characterization of individual tDCS responsiveness deserves further consideration. In our experimental conditions, tDCS had no ergogenic effect on endurance running performance. Trial registration: Clinical trial registration: NCT04005846.

Low-intensity shockwave therapy improves baseline erectile function: a randomized sham-controlled crossover trial

Abstract Background Low-intensity shockwave therapy for erectile dysfunction is emerging as a promising treatment option. Aim This randomized sham-controlled crossover trial assessed the efficacy of low-intensity shockwave therapy in the treatment of erectile dysfunction. Methods Thirty-three participants with organic erectile dysfunction were enrolled and randomized to shockwave therapy (n = 17) or sham (n = 16). The sham group was allowed to cross over to receive shockwave therapy after 1 month. Outcomes Primary outcomes were the changes in Sexual Health Inventory for Men (SHIM) score and Erection Hardness Score at 1 month following shockwave therapy vs sham, and secondary outcomes were erectile function measurements at 1, 3, and 6 months following shockwave therapy. Results At 1 month, mean SHIM scores were significantly increased in the shockwave therapy arm as compared with the sham arm (+3.0 vs −0.7, P = .024). Participants at 6 months posttreatment (n = 33) showed a mean increase of 5.5 points vs baseline (P &amp;lt; .001), with 20 (54.6%) having an increase ≥5. Of the 25 men with an initial Erection Hardness Score &amp;lt;3, 68% improved to a score ≥3 at 6 months. When compared with baseline, the entire cohort demonstrated significant increases in erectile function outcomes at 1, 3, and 6 months after treatment. Clinical Implications In this randomized sham-controlled crossover trial, we showed that 54.6% of participants with organic erectile dysfunction met the minimal clinically important difference in SHIM scores after treatment with low-intensity shockwave therapy. Strengths and Limitations Strengths of this study include a sham-controlled group that crossed over to treatment. Limitations include a modest sample size at a single institution. Conclusions Low-intensity shockwave therapy improves erectile function in men with erectile dysfunction as compared with sham treatment, which persists even 6 months after treatment. Clinical Trial Registration ClinicalTrials.gov NCT04434352.

Effects of 10 Hz individualized repetitive transcranial magnetic stimulation on patients with disorders of consciousness: a study protocol for an exploratory double-blind crossover randomized sham-controlled trial

BackgroundRepetitive transcranial magnetic stimulation (rTMS), as a non-invasive brain stimulation technique, has shown potentials for consciousness recovery of patients with disorders of consciousness (DoC), as, to a certain extent, it is effective in regulating the excitability of central nervous system. However, it is difficult to achieve satisfactory effect with “one size fits all” rTMS treatment due to different clinical conditions of patients. There is an urgent need to develop individualized strategy to improve the effectiveness of rTMS on patients with DoC.MethodsOur protocol is a randomized double-blind sham-controlled crossover trial that includes 30 DoC patients. Each patient will received 20 sessions, in which 10 sessions will be rTMS-active stimulus, and the other 10 sessions will be sham stimulus, separated by no less than 10 days’ washout period. The rTMS-active will include 10 Hz rTMS over the individualized-targeted selection area for each patient according to the different insult regions of the brain. Coma Recovery Scale-Revised (CRS-R) will be used as primary outcome at baseline, after the first stage of stimulation, at the end of the washout period, and after the second stage of stimulation. Secondary outcomes will be measured at the same time, including efficiency, relative spectral power, and functional connectivity of high-density electroencephalograph (EEG). Adverse events will be recorded during the study.DiscussionrTMS has obtained grade A evidence in treating patients with several central nervous system diseases, and there has been some evidence showing partial improvement on level of consciousness in DoC patients. However, the effectiveness of rTMS in DoC is only 30~36%, mostly due to the non-specific target selection. In this protocol, we present a double-blind crossover randomized sham-controlled trial based on the individualized-targeted selection strategy that aims to study the effectiveness of rTMS therapy for DoC, and the result may provide new insights to non-invasive brain stimulation.Trial registrationClinicalTrials.gov: NCT05187000. Registered on January 10, 2022.

Effect of acupuncture on heart rate variability in individuals with multiple sclerosis: a protocol for a double-blinded randomized controlled trial

Backgroung: the growing of patients with multiple sclerosis seeking acupuncture treatment is based on clinical reports of improvements in symptoms. Considering that autonomic impairment, including cardiovascular autonomic dysfunction, is not uncommon in patients with MS, neuromodulation with acupuncture could be an interesting tool to change heart rate variability in this population. Objective: to evaluate heart rate variability in patients with multiple sclerosis, during the application of acupuncture, in order to analyze the behavior of the autonomic nervous system before, during and after therapy and changes in condition after a longitudinal intervention. Methods: a double-blinded randomized sham-controlled crossover trial with a 1:1 allocation ratio will be conducted, with 40 individuals without a previous illness, who will constitute the control group, and 40 individuals with Multiple Sclerosis, who will constitute the experimental group, paired by age and sex. All participants will undertake active or sham acupuncture sessions. Discussion: according to the studies found, cardiovascular autonomic dysfunction is expected, with alterations in heart rate variability. Although neuromodulation with acupuncture can control pain and inflammation, there are still difficulties in affirming whether the balance between the sympathetic and parasympathetic systems can be changed by acupuncture. Trial registration: We registered this trial on ClinicalTrials.gov, ID: NCT05523466

Inter-individual differences in baseline dynamic functional connectivity are linked to cognitive aftereffects of tDCS

Transcranial direct current stimulation (tDCS) has the potential to modulate cognitive training in healthy aging; however, results from various studies have been inconsistent. We hypothesized that inter-individual differences in baseline brain state may contribute to the varied results. We aimed to explore whether baseline resting-state dynamic functional connectivity (rs-dFC) and/or conventional resting-state static functional connectivity (rs-sFC) may be related to the magnitude of cognitive aftereffects of tDCS. To achieve this aim, we used data from our double-blind randomized sham-controlled cross-over tDCS trial in 25 healthy seniors in which bifrontal tDCS combined with cognitive training had induced significant behavioral aftereffects. We performed a backward regression analysis including rs-sFC/rs-dFC measures to explain the variability in the magnitude of tDCS-induced improvements in visual object-matching task (VOMT) accuracy. Rs-dFC analysis revealed four rs-dFC states. The occurrence rate of a rs-dFC state 4, characterized by a high correlation between the left fronto-parietal control network and the language network, was significantly associated with tDCS-induced VOMT accuracy changes. The rs-sFC measure was not significantly associated with the cognitive outcome. We show that flexibility of the brain state representing readiness for top-down control of object identification implicated in the studied task is linked to the tDCS-enhanced task accuracy.

Crossover Patient Outcomes for Targeted Lung Denervation in Moderate to Severe Chronic Obstructive Pulmonary Disease: AIRFLOW-2

Background: Targeted Lung Denervation (TLD) is a potential new therapy for COPD. Radiofrequency energy is bronchoscopically delivered to the airways to disrupt pulmonary parasympathetic nerves, to reduce bronchoconstriction, mucus hypersecretion, and bronchial hyperreactivity. Objectives: This work assesses the effect of TLD on COPD exacerbations (AECOPD) in crossover subjects in the AIRFLOW-2 trial. Method: The AIRFLOW-2 trial is a multicentre, randomized, double-blind, sham-controlled crossover trial of TLD in COPD. Patients with symptomatic COPD on optimal medical therapy with an FEV1 of 30–60% predicted received either TLD or sham bronchoscopy in a 1:1 randomization. Those in the sham arm had the opportunity to cross into the treatment arm after 12 months. The primary end point was rate of respiratory adverse events. Secondary end points included adverse events, changes in lung function and health-related quality of life and symptom scores. Results: Twenty patients were treated with TLD in the crossover phase and were subsequently followed up for 12 months (50% female, mean age 64.1 ± 6.9 years). After TLD, there was a trend towards a reduction in time to first AECOPD (hazard ratio 0.65, p = 0.28, not statistically significant) in comparison to sham follow-up period. There was also a reduction in time to first severe AECOPD in the crossover period (hazard ratio 0.38, p = 0.227, not statistically significant). Symptom scores and lung function showed stability. Conclusions: AIRFLOW-2 crossover data support that of the randomization phase, showing trends towards reduction in COPD exacerbations with TLD.

Device-guided slow breathing alters postprandial oxidative stress in young adult males: A randomized sham-controlled crossover trial

Background and aimsSlow, deep breathing (SDB) lowers blood pressure (BP) though the underlying mechanisms are unknown. Redox improvements could facilitate hemodynamic adjustments with SDB though this has not been investigated. The purpose of this randomized, sham-controlled trial was to examine the acute effects of SDB on oxidative stress and endothelial function during a physiological perturbation (high-fat meal) known to induce oxidative stress. Methods and resultsSeventeen males (ages 18–35 years) were enrolled, and anthropometric measurements and 7-day physical activity monitoring were completed. Testing sessions consisted of 24-h diet recalls (ASA24), blood sample collection for superoxide dismutase (SOD) and thiobarbituric acid reactive substances (TBARS) analysis, and flow-mediated dilation (FMD). High-fat meals were ingested and 2-min breathing exercises (SDB or sham control breathing) were completed every 15 min during the 4-h postprandial phase. Blood sample collection and FMD were repeated 1-, 2-, and 4-h post meal consumption. Mean body mass index and step counts were 25.6 ± 4.3 kg/m2 and 8165 ± 4405 steps per day, respectively. Systolic and diastolic BP and nutrient intake 24 h prior were similar between conditions. No time or time by condition interaction effects were observed for FMD. The total area under the curve (AUC) for SOD was significantly lower during SDB compared to the sham breathing condition (p < 0.01). No differences were observed in TBARS AUC (p = 0.538). ConclusionsFindings from the current investigation suggest that SDB alters postprandial redox in the absence of changes in endothelial function in young, healthy males. Clinical trial registration number: NCT04864184. Clinical trials identifierNCT04864184.

A randomized sham-controlled trial on the effects of dual-tDCS \u201cduring\u201d physical therapy on lower limb performance in sub-acute stroke and a comparison to the previous study using a \u201cbefore\u201d stimulation protocol

BackgroundDual-transcranial direct current stimulation (tDCS) has been used to rebalance the cortical excitability of both hemispheres following unilateral-stroke. Our previous study showed a positive effect from a single-session of dual-tDCS applied before physical therapy (PT) on lower limb performance. However, it is still undetermined if other timings of brain stimulation (i.e., during motor practice) induce better effects. The objective of this study was to examine the effect of a single-session of dual-tDCS “during” PT on lower limb performance in sub-acute stroke and then compare the results with our previous data using a “before” stimulation paradigm.MethodFor the current “during” protocol, 19 participants were participated in a randomized sham-controlled crossover trial. Dual-tDCS over the M1 of both cortices (2 mA) was applied during the first 20 min of PT. The Timed Up and Go and Five-Times-Sit-To-Stand tests were assessed at pre- and post-intervention and 1-week follow-up. Then, data from the current study were compared with those of the previous “before” study performed in a different group of 19 subjects. Both studies were compared by the difference of mean changes from the baseline.ResultsDual-tDCS “during” PT and the sham group did not significantly improve lower limb performance. By comparing with the previous data, performance in the “before” group was significantly greater than in the “during” and sham groups at post-intervention, while at follow-up the “before” group had better improvement than sham, but not greater than the “during” group.ConclusionA single-session of dual-tDCS during PT induced no additional advantage on lower limb performance. The “before” group seemed to induce better acute effects; however, the benefits of the after-effects on motor learning for both stimulation protocols were probably not different.Trial registration Current randomized controlled trials was prospectively registered at the clinicaltrials.gov, registration number: NCT04051671. The date of registration was 09/08/2019.

Two-Week Cervical Vagus Nerve Stimulation in Chronic Pancreatitis Patients Induces Functional Connectivity Changes of Limbic Structures

ObjectivesNoninvasive vagus nerve stimulation (nVNS) has not only shown antinociceptive effects, but also demonstrated anti-inflammatory and antidepressant effects. These effects could be beneficial in chronic pancreatitis (CP) patients suffering from chronic abdominal pain, even though the underlying central mechanisms remain unclear. The aim was to investigate the effect of cervical nVNS in patients with painful CP on brain functional connectivity and cerebral metabolites. Materials and MethodsIn a randomized double-blind, sham-controlled crossover trial, we used resting-state functional magnetic resonance imaging to investigate functional connectivity changes of limbic structures (seed-based analysis) after two weeks cervical nVNS treatment (GammaCore) as compared with two weeks sham treatment. Similarly, magnetic resonance spectroscopy was performed in the anterior cingulate cortex (ACC) with assessment of glutamate/creatine (Glu/cre) and N-acetylaspartate/creatine (NAA/cre). ResultsSixteen CP patients (mean age 56.6 ± 9.4 years) completed the trial. nVNS induced reduced functional connectivity compared to sham treatment between 1) bilateral thalamus and bilateral superior frontal gyrus, 2) ACC and putamen, and 3) posterior cingulate cortex and right thalamus (all p < 0.05). No changes were observed in Glu/cre (p = 0.96) and NAA/cre (p = 0.43) levels between the nVNS and sham treatments. ConclusionIn our population of CP patients, cervical nVNS compared with sham treatment induced reduced functional connectivity of limbic structures, as also observed in other patient groups. The findings are relevant, since we have previously demonstrated an effect on pain scores in CP patients for both nVNS and sham treatment. Our results elucidate the effects in the central nervous system following nVNS treatment of CP patients, pointing at potential beneficial effects in this patient group.

The second brain in Parkinson's disease: fact or fantasy?

The second brain in Parkinson's disease: fact or fantasy?

Paired Acute Invasive/Non-invasive Stimulation (PAINS) study: A phase I/II randomized, sham-controlled crossover trial in chronic neuropathic pain

BackgroundDorsal root ganglion (DRG) stimulation, an invasive method of neuromodulation, and transcranial direct current stimulation (tDCS), a non-invasive method of altering cortical excitability, have both proven effective in relieving chronic pain. ObjectiveWe employed a randomized, sham-controlled crossover study design to investigate whether single-session tDCS would have an additive therapeutic effect alongside DRG stimulation (DRGS) in the treatment of chronic pain. MethodsSixteen neuropathic pain patients who were previously implanted with DRG stimulators were recruited. Baseline pain scores were established with DRGS-OFF. Pain scores were then recorded with DRGS-ON, after paired sham tDCS stimulation, and after paired active anodal tDCS (a-tDCS) stimulation. For active tDCS, patients were randomized to ‘MEG (magnetoencephalography) localized’ tDCS or contralateral motor cortex (M1) tDCS for 30 min. EEG recordings and evaluations of tDCS adverse effects were also collected. ResultsAll participants reported the interventions to be tolerable with no significant adverse effects during the session. Paired DRGS/active tDCS resulted in a significant reduction in pain scores compared to paired DRGS-ON/sham tDCS or DRGS alone. There was no difference in the additive effect of M1 vs. MEG-localized tDCS. Significant augmentation of beta activity was observed between DRGS-OFF and DRGS-ON conditions, as well as between paired DRGS-ON/sham tDCS and paired DRGS-ON/active tDCS. ConclusionOur results indicate that a single session of tDCS alongside DRGS is safe and can significantly reduce pain acutely in neuropathic pain patients. Paired invasive/non-invasive neuromodulation is a promising new treatment strategy for pain management and should be evaluated further to assess long-term benefits.

5-day multi-session intermittent theta burst stimulation over bilateral posterior superior temporal sulci in adults with autism-a pilot study

BackgroundTheta burst stimulation (TBS), a patterned repetitive transcranial magnetic stimulation (rTMS) protocol with shorter simulation duration and lower stimulus intensity, could be a better protocol for individuals with autism spectrum disorder (ASD). Our study aimed to explore the impacts of intermittent TBS (iTBS) over the bilateral posterior superior temporal sulcus (pSTS) on intellectually able adults with ASD. MethodsIn this randomized, single-blinded, sham-controlled crossover trial, 13 adults with ASD completed iTBS for 5 consecutive days over the bilateral pSTS and inion (as a sham control) in a 16-weeks interval and in a randomly assigned order. The neuropsychological function was measured with the Wisconsin Card Sorting Test (WCST) for cognitive flexibility while the clinical outcomes were measured with both self-rate and parents-rate Autism Spectrum Quotient (AQ) before and after 5-day iTBS interventions. ResultsThe results revealed significantly immediate effects of multi-session iTBS over the bilateral pSTS on parent-rate autistic symptoms in adults with ASD. The post-hoc analysis revealed the impacts of multi-session iTBS on cognitive flexibility were affected by baseline social-communicative impairment and baseline cognitive performance. Besides, the impacts of multi-session iTBS on clinical symptoms was affected by the concurrent psychotropic medication use and baseline autistic symptoms. ConclusionsGiven the caveat of the small sample size and discrepancy of multiple informants, this pilot study suggests the therapeutic potential of 5-day multi-session iTBS over the pSTS in adults with ASD. Individual factors modulating the response to rTMS should be explicitly considered in the future trial.

RETRACTED ARTICLE: Non-invasive vagus nerve stimulation improves clinical and molecular biomarkers of Parkinson’s disease in patients with freezing of gait

Non-invasive vagus nerve stimulation (nVNS) is an established neurostimulation therapy used in the treatment of epilepsy, migraine and cluster headache. In this randomized, double-blind, sham-controlled crossover trial we explored the role of nVNS in the treatment of gait and other motor symptoms in Parkinson’s disease (PD) patients. In a subgroup of patients, we measured selected neurotrophin levels and markers of inflammation and oxidative stress in serum, before and after the experimental intervention. Thirty-three PD patients with associated freezing of gait were randomised to either nVNS or sham. After baseline assessments, patients were instructed to deliver 6 two-minute stimulations (total 12 min/day) of the nVNS/sham device (electroCore, Inc. USA) for one month at home. Patients were then re-assessed. After a washout period of one month, the same patients were allocated to the alternate treatment arm and the same process was followed. Significant improvements in key gait parameters were observed with nVNS, including walking speed, stance time and step length, compared to sham. Similarly, overall motor function (MDS-UPDRS III) also improved significantly following nVNS stimulation. Serum Tumor Necrosis Factor (TNF)-α and glutathione levels decreased and brain-derived neurotrophic factor (BDNF) levels increased significantly (p < 0.05) after treatment with nVNS. Here we present the first double-blind sham-controlled trial evidence of the efficacy and safety of nVNS in the treatment of gait and motor function in patients with PD.

Challenging control over emotions in borderline personality disorder - a tDCS study

BackgroundDeficient cognitive control (CC) over emotional distraction is a central characteristic of borderline personality disorder (BPD). Reduced activation of the left dorsolateral prefrontal cortex (dlPFC) has been linked to this deficit. This study investigates whether it is possible to ameliorate CC deficits via anodal tDCS over the left dlPFC in BPD. Furthermore, we investigate whether the extent of CC impairment influences how well one responds to tDCS. MethodsThe effect of a single-session tDCS (1 mA for 20 min, reference electrode on the contralateral mastoid bone) to the left dlPFC (F3) on the CC of patients with BPD (N = 20) and healthy control participants (HCs, N = 20) was examined in a double-blinded, balanced randomized, sham-controlled crossover trial. A delayed response working memory task with negative, neutral and positive pictures presented during the delay period was conducted to assess CC. Stimulation was applied simultaneously with the task. ResultsNegative pictures caused prolonged response times as compared to a control condition in patients with BPD and HCs. Anodal tDCS to the left dlPFC did not significantly reduce this interference effect in the overall sample. Further analyses showed, however, that participants with impaired CC profited the most from anodal tDCS. In the subgroup of participants who actually showed an interference effect we found the expected significant amelioration of CC under tDCS. ConclusionsThe present study demonstrates that anodal tDCS applied to the left dlPFC improves deficient CC. Thereby, base-level performance moderates tDCS effects. Hence, tDCS might be suitable to support behavioral trainings to enhance CC specifically in people whose impairments in CC are comparably high.

Effects of a short, intensive, multi-session tDCS treatment in developmental dyslexia: Preliminary results of a sham-controlled randomized clinical trial.

Developmental Dyslexia (DD) significantly interferes with academic, personal, social and emotional functioning. Nevertheless, established therapeutic options are still scarce. Research has begun to emerge studying the potential action of transcranial direct current stimulation (tDCS) for ameliorating reading. However, there are still open questions regarding the most suitable tDCS protocol in young with DD. The current study tested the effectiveness of a short, intensive and multi-session tDCS protocol and presented preliminary data from a randomized sham-controlled crossover trial. Twenty-seven children and adolescents with DD were randomly assigned to active tDCS or sham tDCS. Active tDCS group received five daily-consecutive sessions of left anodal/right cathodal set at 1mA for 20min over parieto-occipital regions. Reading measures, including text, high frequency word, low frequency word and non-word lists, were recorded before, immediately after the treatment and 1-week later. We found that only the active tDCS group ameliorated non-word reading speed immediately after and 1-week later the end of the treatment compared to the baseline. Some suggestions for the development of future tDCS protocols in children and adolescents with DD are given.

Neuromodulation of premotor and posterior parietal cortices for enhancing explicit motor sequence learning in healthy individuals: a randomized, sham-controlled crossover trial

Background: Anodal transcranial Direct Current Stimulation (tDCS) has been shown to be effective in improving human motor learning when applied over the contralateral primary motor cortex (M1). However, the stimulation of other cortical areas, such as the posterior parietal (PPC) and premotor (PMC) cortices, may be also beneficial. Methods: The present study (crossover design) investigated the effects of tDCS applied over PPC, PMC, and M1 on the acquisition and retention of a new motor skill, and on the generalization of such learned skill in healthy individuals. During a sequential finger-tapping task (FTT), performed with the non-dominant (left) hand, participants received real or sham anodal tDCS (1.5 mA, 20 min) over PPC, PMC, and the M1 of the right hemisphere. Explicit motor sequence learning was measured online (during the training with tDCS; primary outcome) and 24 hours after tDCS (retention, secondary outcome). A new, untrained, sequence was used to assess generalization effects (secondary outcome). Results: Anodal tDCS of M1 improved both online learning and retention. PMC tDCS facilitated the generalization of the learning effect to the untrained motor sequence. In contrast, neuromodulation of the PPC does not influence motor sequence learning. Conclusions: These findings show that, in addition to M1, higher-order associative cortical regions (PMC and PPC) are involved in explicit online motor sequence learning, retention and generalization playing different roles, as indicated by the differential modulatory effects of anodal tDCS.

Effect of Combined Therapy of Virtual Reality and Transcranial Direct Current Stimulation in Children and Adolescents With Cerebral Palsy: A Study Protocol for a Triple-Blinded Randomized Controlled Crossover Trial.

Background: Transcranial direct current stimulation (tDCS) and therapy-based virtual reality (VR) have been investigated separately. They have shown promise as efficient and engaging new tools in the neurological rehabilitation of individuals with cerebral palsy (CP). However, the recent literature encourages investigation of the combination of therapy tools in order to potentiate clinic effects and its mechanisms.Methods: A triple-blinded randomised sham-controlled crossover trial will be performed. Thirty-six individuals with gross motor function of levels I to IV (aged 4–14 years old) will be recruited. Individuals will be randomly assigned to Group A (active first) or S (sham first): Group A will start with ten sessions of active tDSC combined with VR tasks. After a 1-month washout, this group will be reallocated to another ten sessions with sham tDCS combined with VR tasks. In contrast, Group S will carry out the opposite protocol, starting with sham tDCS. For the active tDCS the protocol will use low frequency tDCS [intensity of 1 milliampere (mA)] over the primary cortex (M1) area on the dominant side of the brain. Clinical evaluations (reaction times and coincident timing through VR, functional scales: Abilhand-Kids, ACTIVLIM-CP, Paediatric Evaluation of Disability Inventory-PEDI- and heart rate variability-HRV) will be performed at baseline, during, and after active and sham tDCS.Conclusion: tDCS has produced positive results in treating individuals with CP; thus, its combination with new technologies shows promise as a potential mechanism for improving neurological functioning. The results of this study may provide new insights into motor rehabilitation, thereby contributing to the better use of combined tDCS and VR in people with CP.Trial Registration: ClinicalTrials.gov, NCT04044677. Registered on 05 August 2019.