Intensified electrical stimulation targeting lateral and medial prefrontal cortices for the treatment of social anxiety disorder: A randomized,double-blind,parallel-group,dose-comparison study

BackgroundSocial Anxiety Disorder (SAD) is the most common anxiety disorder while remains largely untreated. Disturbed amygdala-frontal network functions are central to the pathophysiology of SAD, marked by hypoactivity of the lateral prefrontal cortex (PFC), and hypersensitivity of the medial PFC and the amygdala. The objective of this study was to determine whether modulation of the dorsolateral and medial PFC activity with a novel intensified stimulation protocol reduces SAD core symptoms, improves treatment-related variables, and reduces attention bias to threatening stimuli.MethodsIn this randomized, sham-controlled, double-blind trial, we assessed the efficacy of an intensified stimulation protocol (20 min, twice-daily sessions with 20 min intervals, 5 consecutive days) in two intensities (1 vs 2 mA) compared to sham stimulations. 45 patients with SAD were randomized in three tDCS arms (1-mA, 2-mA, sham). SAD symptoms, treatment-related variables (worries, depressive state, emotion regulation, quality of life), and attention bias to threatening stimuli (dot-probe paradigm) were assessed before and right after the intervention. SAD symptoms were also assessed at 2-month follow-up.ResultsBoth 1-mA and 2-mA protocols significantly reduced fear/avoidance symptoms, worries and improved, emotion regulation and quality of life after the intervention compared to the sham group. Improving effect of the 2-mA protocol on avoidance symptoms, worries and depressive state was significantly larger than the 1-mA group. Only the 2-mA protocol reduced attention bias to threat-related stimuli, the avoidance symptom at follow-up, and depressive states, as compared to the sham group.ConclusionsModulation of lateral-medial PFC activity with intensified stimulation can improve cognitive control, motivation and emotion networks in SAD and might thereby result in therapeutic effects. These effects can be larger with 2-mA vs 1-mA intensities, though a linear relationship between intensity and efficacy should not be concluded. Our results need replication in larger trials.     

External trigeminal nerve stimulation for drug resistant epilepsy: A randomized controlled trial

BackgroundExternal trigeminal nerve stimulation (ETNS) is an emergent, non-invasive neurostimulation therapy delivered bilaterally with adhesive skin electrodes. In previous studies, ETNS was associated to a decrease in seizure frequency in patients with focal drug-resistant epilepsy (DRE).ObjectiveTo determine the long-term efficacy and tolerability of ETNS in patients with focal DRE. Moreover, to explore whether its efficacy depends on the epileptogenic zone (frontal or temporal), and its impact on mood, cognitive function, quality of life, and trigeminal nerve excitability.MethodsForty consecutive patients with frontal or temporal DRE, unsuitable for surgery, were randomized to ETNS or usual medical treatment. Participants were evaluated at 3, 6 and 12 months for efficacy, side effects, mood scales, neuropsychological tests and trigeminal nerve excitability.ResultsSubjects had a median of 15 seizures per month and had tried a median of 12.5 antiepileptic drugs. At 12 months, percentage of responders was 50% in ETNS group and 0% in control group. Seizure frequency in ETNS group decreased by −43.5% from baseline. Temporal epilepsy subgroup responded better than frontal epilepsy subgroup (55.56% vs. 45.45%, respectively). Median stimulation intensity was 6.2 mA. ETNS improved quality of life, but not anxiety or depression. Long-term ETNS affected neither neuropsychological function, nor trigeminal nerve excitability. No relevant adverse events were observed.ConclusionsETNS is an effective and well-tolerated therapy for focal DRE. Patients with temporal epilepsy showed a better response than those with frontal epilepsy. Future studies with larger populations may define its role compared to other neurostimulation techniques.Classification of evidenceThis study provides Class II evidence that ETNS reduces seizure frequency in patients with focal DRE.     

Navigated repetitive transcranial magnetic stimulation improves the outcome of postsurgical paresis in glioma patients – A randomized,double-blinded trial

BackgroundNavigated repetitive transcranial magnetic stimulation (nrTMS) is effective therapy for stroke patients. Neurorehabilitation could be supported by low-frequency stimulation of the non-damaged hemisphere to reduce transcallosal inhibition.ObjectiveThe present study examines the effect of postoperative nrTMS therapy of the unaffected hemisphere in glioma patients suffering from acute surgery-related paresis of the upper extremity (UE) due to subcortical ischemia.MethodsWe performed a randomized, sham-controlled, double-blinded trial on patients suffering from acute surgery-related paresis of the UE after glioma resection. Patients were randomly assigned to receive either low frequency nrTMS (1 Hz, 15 min) or sham stimulation directly before physical therapy for 7 consecutive days. We performed primary and secondary outcome measures on day 1, on day 7, and at a 3-month follow-up (FU). The primary endpoint was the change in Fugl-Meyer Assessment (FMA) at FU compared to day 1 after surgery.ResultsCompared to the sham stimulation, nrTMS significantly improved outcomes between day 1 and FU based on the FMA (mean [95% CI] +31.9 [22.6, 41.3] vs. +4.2 [-4.1, 12.5]; P = .001) and the National Institutes of Health Stroke Scale (NIHSS) (−5.6 [-7.5, −3.6] vs. −2.4 [-3.6, −1.2]; P = .02). To achieve a minimal clinically important difference of 10 points on the FMA scale, the number needed to treat is 2.19.ConclusionThe present results show that patients suffering from acute surgery-related paresis of the UE due to subcortical ischemia after glioma resection significantly benefit from low-frequency nrTMS stimulation therapy of the unaffected hemisphere.Clinical trial registrationLocal institutional registration: 12/15; ClinicalTrials.gov number: NCT03982329     

Anodal transcranial direct current stimulation in chronic migraine and medication overuse headache: A pilot double-blind randomized sham-controlled trial

ObjectivesLittle evidence is available on the role of transcranial direct current stimulation (tDCS) in patients affected by chronic migraine (CM) and medication overuse headache (MOH). We aim to investigate the effects of tDCS in patients with CM and MOH as well as its role on brain activity.MethodsTwenty patients with CM and MOH were hospitalized for a 7-day detoxification treatment. Upon admission, patients were randomly assigned to anodal tDCS or sham stimulation delivered over the primary motor cortex contralateral to the prevalent migraine pain side every day for 5 days. Clinical data were recorded at baseline (T0), after 1 month (T2) and 6 months (T3). EEG recording was performed at T0, at the end of the tDCS/Sham treatment, and at T2.ResultsAt T2 and T3, we found a significant reduction in monthly migraine days (p = 0.001), which were more pronounced in the tDCS group when compared to the sham group (p = 0.016).At T2, we found a significant increase of alpha rhythm in occipital leads, which was significantly higher in tDCS group when compared to sham group.ConclusionstDCS showed adjuvant effects to detoxification in the management of patients with CM and MOH. The EEG recording showed a significant potentiation of alpha rhythm, which may represent a correlate of the underlying changes in cortico-thalamic connections.SignificanceThis study suggests a possible role for tDCS in the treatment of CM and MOH. The observed clinical improvement is coupled with a potentiation of EEG alpha rhythm.     

Motor cortex transcranial direct current stimulation effects on knee osteoarthritis pain in elderly subjects with dysfunctional descending pain inhibitory system: A randomized controlled trial

BackgroundAlthough evidence has indicated a positive effect of transcranial direct current stimulation (tDCS) on reducing pain, few studies have focused on the elderly population with knee osteoarthritis (KOA).ObjectiveTo evaluate whether tDCS reduces KOA pain in elderly individuals with a dysfunctional descending pain inhibitory system (DPIS).MethodsIn a double-blind trial, individuals ≥ 60 years with KOA pain and a dysfunctional DPIS, we randomly assigned patients to receive 15 daily sessions of 2 mA tDCS over the primary motor cortex (anode) and contralateral supraorbital area (cathode) (M1-SO) for 20 min or sham tDCS. Change in pain perception indexed by the Brief Pain Inventory (BPI) at the end of intervention was the primary outcome. Secondary outcomes included: disability, quantitative sensory testing, pain pressure threshold and conditioned pain modulation (CPM). Subjects were followed-up for 2 months.ResultsOf the 104 enrolled subjects, with mean (SD) age of 73.9 (8.01) years and 88 (84.6%) female, 102 finished the trial. In the intention-to-treat analysis, the active tDCS group had a significantly greater reduction in BPI compared to the sham group (difference, 1.59; 95% CI, 0.95 to 2.23; P < 0.001; Cohen’s d, 0.58); and, also a significantly greater improvement in CPM-pressure in the knee (P = 0.01) and CPM-pain in the hand (P = 0.01). These effects were not sustained at follow-up. The intervention was well tolerated, with no severe adverse effects.ConclusionM1-SO tDCS is associated with a moderate effect size in reducing pain in elderly patients with KOA after 15 daily sessions of stimulation. This intervention has also shown to modulate the DPIS.     

Self-administered transcranial direct current stimulation for pain in older adults with knee osteoarthritis: A randomized controlled study

BackgroundKnee osteoarthritis (OA) is a leading cause of pain in older adults. Previous studies indicated clinic-based transcranial direct current stimulation (tDCS) was effective to reduce pain in various populations, but no published studies have reported the efficacy of home-based self-administered tDCS in older adults with knee OA using a randomized clinical study.ObjectiveThe purpose of this study was to evaluate the efficacy and feasibility of tDCS on clinical pain intensity in adults with knee OA pain.MethodsOne hundred twenty participants aged 50–85 years with knee OA pain were randomly assigned to receive fifteen daily sessions of 2 mA tDCS for 20 min (n = 60) or sham tDCS (n = 60) over 3 weeks with remote supervision via telehealth. Clinical pain intensity was measured by the Numeric Rating Scale and Western Ontario and McMaster Universities Osteoarthritis Index. Also, we collected data on the tDCS experience via a questionnaire.ResultsParticipants (68% female) had a mean age of 66 years. Active tDCS significantly reduced pain intensity compared to sham tDCS after completion of the fifteen daily sessions (Cohen's d = 1.20; p-value < 0.0001). Participants showed high levels of satisfaction with their tDCS experience, and there have been no adverse events.ConclusionWe demonstrated that home-based self-administered tDCS was feasible and reduced clinical pain intensity in older adults with knee OA, which can increase its accessibility. Future studies with multi-site randomized controlled trials are needed to validate our findings.Trial registrationClinicalTrials.gov Identifier NCT04016272.     

Transcutaneous auricular vagus nerve stimulation reduces cytokine production in sepsis: An open double-blind,sham-controlled,pilot study

BackgroundStudies have shown that vagus nerve-mediated inflammatory reflex could inhibit cytokine production and inflammation in sepsis animals.ObjectivesThis study aimed to explore the efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) on inflammation and disease severity of sepsis patients.MethodsA randomized, double-blind, sham-controlled pilot study was performed. Twenty sepsis patients were randomly assigned to receive taVNS or sham stimulation for five consecutive days. Stimulation effect was assessed with serum cytokine levels, Acute Physiology and Chronic Health Evaluation (APACHE) Ⅱ score, and Sequential Organ Failure Assessment (SOFA) score at baseline and on Day 3, Day 5, and Day 7.ResultsTaVNS was well tolerated in the study population. Patients receiving taVNS experienced significant reductions in serum TNF-α and IL-1β levels and increases in IL-4 and IL-10 levels. SOFA scores decreased on Day 5 and Day 7 compared with baseline in the taVNS group. However, no changes were found in sham stimulation group. The changes of cytokine from Day 7 to Day 1 were greater with taVNS than sham stimulation. No differences in the APACHE Ⅱ score and SOFA score were observed between the two groups.ConclusionsTaVNS resulted in significantly lower serum pro-inflammatory cytokines and higher serum anti-inflammatory cytokines in sepsis patients.     

Probing EEG activity in the targeted cortex after focal transcranial electrical stimulation

BackgroundRecording electroencephalography (EEG) from the targeted cortex immediately before and after focal transcranial electrical stimulation (TES) remains a challenge.MethodsWe introduce a hybrid stimulation-recording approach where a single EEG electrode is inserted into the inner electrode of a double-ring montage for focal TES. The new combined electrode was placed at the C3 position of the EEG 10–20 system. Neuronal activity was recorded in two volunteers before and after 20 Hz alternating-current TES at peak-to-peak intensities of 1 and 2 mA. TES-induced electric field distributions were simulated with SIMNIBS software.ResultsUsing the hybrid stimulation-recording set-up, EEG activity was successfully recorded directly before and after TES. Simulations revealed comparable electrical fields in the stimulated cortex for the pseudomonopolar montage with and without embedded EEG electrode.ConclusionThe hybrid TES-EEG approach can be used to probe after-effects of focal TES on neuronal activity in the targeted cortex.     

Transcutaneous cervical vagus nerve stimulation reduces behavioral and physiological manifestations of withdrawal in patients with opioid use disorder: A double-blind,randomized, sham-controlled pilot study

BackgroundOpioid Use Disorder (OUD) is a serious public health problem, and the behavioral and physiological effects of opioid withdrawal can be a major impediment to recovery. Medication for OUD is currently the mainstay of treatment; however, it has limitations and alternative approaches are needed.ObjectiveThe purpose of this study was to assess the effects of transcutaneous cervical vagus nerve stimulation (tcVNS) on behavioral and physiological manifestations of acute opioid withdrawal.MethodsPatients with OUD undergoing acute opioid withdrawal were randomly assigned to receive double blind active tcVNS (N = 10) or sham stimulation (N = 11) while watching neutral and opioid cue videos. Subjective opioid withdrawal, opioid craving, and anxiety were measured using a Visual Analogue Scale (VAS). Distress was measured using the Subjective Units of Distress Scale (SUDS), and pain was measured using the Numerical Rating Scale (NRS) for pain. Electrocardiogram signals were measured to compute heart rate. The primary outcomes of this initial phase of the clinical trial (ClinicalTrials.gov NCT04556552) were heart rate and craving.ResultstcVNS compared to sham resulted in statistically significant reductions in subjective opioid withdrawal (p = .047), pain (p = .045), and distress (p = .004). In addition, tcVNS was associated with lower heart rate compared to sham (p = .026). Craving did not significantly differ between groups (p = .11).ConclusionstcVNS reduces behavioral and physiological manifestations of opioid withdrawal, and should be evaluated in future studies as a possible non-pharmacologic, easily implemented approach for adjunctive OUD treatment.     

Thalamic deep brain stimulation for Tourette Syndrome: A naturalistic trial with brief randomized,double-blinded sham-controlled periods

BackgroundThere is still a lack of controlled studies to prove efficacy of thalamic deep brain stimulation for Tourette's Syndrome.ObjectivesIn this controlled trial, we investigated the course of tic severity, comorbidities and quality of life during thalamic stimulation and whether changes in tic severity can be assigned to ongoing compared to sham stimulation.MethodsWe included eight adult patients with medically refractory Tourette's syndrome. Bilateral electrodes were implanted in the centromedian-parafascicular-complex and the nucleus ventro-oralis internus. Tic severity, quality of life and comorbidities were assessed before surgery as well as six and twelve months after. Short randomized, double-blinded sham-controlled crossover sequences with either active or sham stimulation were implemented at both six- and twelve-months’ assessments. The primary outcome measurement was the difference in the Yale Global Tic Severity Scale tic score between active and sham stimulation. Adverse events were systematically surveyed for all patients to evaluate safety.ResultsActive stimulation resulted in significantly higher tic reductions than sham stimulation (F = 79.5; p = 0.001). Overall quality of life and comorbidities improved significantly in the open-label-phase. Over the course of the trial two severe adverse events occurred that were resolved without sequelae.ConclusionOur results provide evidence that thalamic stimulation is effective in improving tic severity and overall quality of life. Crucially, the reduction of tic severity was primarily driven by active stimulation. Further research may focus on improving stimulation protocols and refining patient selection to improve efficacy and safety of deep brain stimulation for Tourette's Syndrome.     

Subthalamic nucleus deep brain stimulation improves sleep in Parkinson's disease patients: a retrospective study and a meta-analysis

BackgroundMost Parkinson's patients suffered from sleep problems. There is increasing evidence that Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) has a positive effect on several sleep parameters, improving overall sleep quality in patients with PD. However, the results are controversial.MethodsWe performed a retrospective study and meta-analysis to assess the Parkinson's disease sleep scale (PDSS) in Parkinson's patients.ResultsWe reviewed our data of patients who underwent STN-DBS, and then extracted five other trials to perform a meta-analysis. The pooled results showed an advantage on post-operative PDSS in both our medical center and pooled results (MD = 20.41, 95% CI = [13.03, 27.79], I² = 61%, P < 0.001). There was a significant difference in Unified Parkinson's Disease Rating Scale (UPDRS)-Ⅲ score between pre and post-operation (MD = −12.59, 95% CI = [−14.70, −10.49], I² = 90%, P < 0.001). What's more, Parkinsonian medication was significantly lower in the post-operative groups after DBS (MD = −314.71, 95% CI = [−468.13, −161.28], I² = 53%, P < 0.001).ConclusionIn the retrospective study and meta-analysis of 6 trials, we found that DBS can significantly increase sleep quality. Furthermore, motor function improved and Parkinsonian medication was significantly decreased postoperatively. The sample size was enough and no further investigations would change the conclusion.     

Early transcranial direct current stimulation with modified constraint-induced movement therapy for motor and functional upper limb recovery in hospitalized patients with stroke: A randomized,multicentre, double-blind,clinical trial

BackgroundConstraint-induced movement therapy (CIMT) and transcranial direct current stimulation (tDCS) are used to reduce interhemispheric imbalance after stroke, which is why the combination of these therapies has been used for neurological recovery, but not in the acute phase.ObjectivesTo evaluate the effectiveness of combining active or sham bihemispheric tDCS with modified CIMT (mCIMT) for the recovery of the Upper Limb (UL) in hospitalized patients with acute and subacute stroke.MethodsThis randomized controlled, double-blind, placebo-controlled, parallel group clinical trial was executed between September 2018 to March 2021 recruited 70 patients. The patients were randomized to one of two groups to receive treatment for 7 consecutive days, which included 20 min of active or sham bihemispheric tDCS daily (anodal ipsilesional and cathodal contralesional), with an mCIMT protocol. The primary outcome was the difference in the evolution of motor and functional upper limb recovery with assessment on days 0, 5, 7, 10 and 90. The secondary outcomes were independence in activities of daily living (ADL) and quality of life.ResultsThe active group presented a statistically significant gap compared to the simulated group throughout the trend in the scores of the FMA (motor function and joint pain) and WMFT (functional ability and weight to box) (p < 0.05) and showed a minimal clinically important difference (FMA: difference between groups of 4.9 points [CI: 0.007- 9.799]; WMFT: difference between groups of 6.54 points [CI: 1.10-14.15]). In the secondary outcomes, there was a significant difference between the groups in ADL independence (Functional Independence Measure: difference of 8.63 [CI: 1.37-18.64]) and perceived recovery of quality of life evaluated at 90 days (p = 0.0176).ConclusionsCombining mCIMT with bihemispheric tDCS in patients hospitalized with acute-subacute stroke allows us to maximize the motor and functional recovery of the paretic upper limb in the early stages and independence in ADL, maintaining the effects over time.     

Region-dependent bidirectional plasticity in M1 following quadripulse transcranial magnetic stimulation in the inferior parietal cortex

BackgroundThe ability to manipulate the excitability of the network between the inferior parietal lobule (IPL) and primary motor cortex (M1) may have clinical value.ObjectiveTo investigate the possibility of inducing long-lasting changes in M1 excitability by applying quadripulse transcranial magnetic stimulation (QPS) to the IPL, and to ascertain stimulus condition- and site-dependent differences in the effects.MethodsQPS was applied to M1, the primary somatosensory cortex (S1), the supramarginal gyrus (SMG) and angular gyrus (AG) IPL areas, with the inter-stimulus interval (ISI) in the train of pulses set to either 5 ms (QPS-5) or 50 ms (QPS-50). QPS was repeated at 0.2 Hz for 30 min, or not presented (sham condition). Excitability changes in the target site were examined by means of single-pulse transcranial magnetic stimulation (TMS).ResultsQPS-5 and QPS-50 at M1 increased and decreased M1 excitability, respectively. QPS at S1 induced no obvious change in M1 excitability. However, QPS at the SMG induced mainly suppressive effects in M1 for at least 30 min, regardless of the ISI length. Both QPS ISIs at the AG yielded significantly different MEP compared to those at the SMG. Thus, the direction of the plastic effect of QPS differed depending on the site, even under the same stimulation conditions.ConclusionsQPS at the IPL produced long-lasting changes in M1 excitability, which differed depending on the precise stimulation site within the IPL. These results raise the possibility of noninvasive induction of functional plasticity in M1 via input from the IPL.     

Sleep modulates effective connectivity: A study using intracranial stimulation and recording

ObjectiveSleep is an active process with an important role in memory. Epilepsy patients often display a disturbed sleep architecture, with consequences on cognition. We aimed to investigate the effect of sleep on cortical networks’ organization.MethodsWe analyzed cortico-cortical evoked responses elicited by single pulse electrical stimulation (SPES) using intracranial depth electrodes in 25 patients with drug-resistant focal epilepsy explored using stereo-EEG. We applied the SPES protocol during wakefulness and NREM – N2 sleep. We analyzed 31,710 significant responses elicited by 799 stimulations covering most brain structures, epileptogenic or non-epileptogenic. We analyzed effective connectivity between structures using a graph-theory approach.ResultsSleep increases excitability in the brain, regardless of epileptogenicity. Local and distant connections are differently modulated by sleep, depending on the tissue epileptogenicity.In non-epileptogenic areas, frontal lobe connectivity is enhanced during sleep. There is increased connectivity between the hippocampus and temporal neocortex, while perisylvian structures are disconnected from the temporal lobe. In epileptogenic areas, we found a clear interhemispheric difference, with decreased connectivity in the right hemisphere during sleep.ConclusionsSleep modulates brain excitability and reconfigures functional brain networks, depending on tissue epileptogenicity.SignificanceWe found specific patterns of information flow during sleep in physiologic and pathologic structures, with possible implications for cognition.     

Exploring and optimizing the neuroplastic effects of anodal transcranial direct current stimulation over the primary motor cortex of older humans

BackgroundtDCS modulates cortical plasticity and has shown potential to improve cognitive/motor functions in healthy young humans. However, age-related alterations of brain structure and functions might require an adaptation of tDCS-parameters to achieve a targeted plasticity effect in older humans and conclusions obtained from young adults might not be directly transferable to older adults. Thus, our study aimed to systematically explore the association between tDCS-parameters and induced aftereffects on motor cortical excitability to determine optimal stimulation protocols for older individuals, as well as to investigate age-related differences of motor cortex plasticity in two different age groups of older adults.Methods32 healthy, volunteers from two different age groups of Young-Old (50–65 years, n = 16) and Old-Old (66–80 years, n = 16) participated in this study. Anodal tDCS was applied over the primary motor cortex, with respective combinations of three intensities (1, 2, and 3 mA) and durations (15, 20, and 30 min), in a sham-controlled cross-over design. Cortical excitability alterations were monitored by single-pulse TMS-induced MEPs until the next day morning after stimulation.ResultsAll active stimulation conditions resulted in a significant enhancement of motor cortical excitability in both age groups. The facilitatory aftereffects of anodal tDCS did not significantly differ between age groups. We observed prolonged plasticity in the late-phase range for two protocols with the highest stimulation intensity (i.e., 3 mA-20 min, 3 mA-30 min).ConclusionsOur study highlights the role of stimulation dosage in tDCS-induced neuroplastic aftereffects in the motor cortex of healthy older adults and delivers crucial information about optimized tDCS protocols in the domain of the primary motor cortex. Our findings might set the grounds for the development of optimal stimulation protocols to reinstate neuroplasticity in different cortical areas and induce long-lasting, functionally relevant plasticity in normal aging and in pathological conditions, which would require however systematic tDCS titration studies over respective target areas.     

Difference in background factors between responders to gabapentin enacarbil treatment and responders to placebo: pooled analyses of two randomized,double-blind,placebo-controlled studies in Japanese patients with restless legs syndrome

ObjectiveRestless legs syndrome (RLS) is a sensorimotor disorder that is characterized by uncomfortable and unpleasant sensations mainly in the legs. Two placebo-controlled studies (Phase II/III and post-marketing) in Japanese patients with RLS failed to demonstrate the efficacy of gabapentin enacarbil (GE) 600 mg in the change from baseline in International Restless Legs Syndrome Rating Scale (IRLS) score at the end of the treatment period. The high response to placebo is thought to be a possible reason why the post-marketing study failed. The objectives of these post hoc analyses were to determine potential predictive factors associated with improvement in IRLS score with GE treatment and to identify subgroups with higher placebo responses.MethodsWe combined data from the two Japanese studies and analyzed change from baseline in IRLS score in the pooled population and subgroups defined by several patient characteristics. Moreover, we calculated the variable importance of each factor and performed predictive enrichment analysis to identify an enrichable subpopulation with greater improvement by GE treatment.ResultsThe post hoc analyses suggested that higher baseline IRLS score (≥21) and higher body mass index (≥25 kg/m²) were associated with higher placebo responses. On the other hand, positive family history of RLS, prior use of dopaminergic receptor agonists, and higher baseline ferritin level (≥50 ng/mL) were associated with higher responses to GE.ConclusionsOur results suggest that patients with typical idiopathic RLS characteristics, including positive family history and no low ferritin level, would be expected to derive the greatest benefits from GE treatment.     

Cortical modulation of nociception by galvanic vestibular stimulation: A potential clinical tool?

ObjectiveVestibular afferents converge with nociceptive ones within the posterior insula, and can therefore modulate nociception. Consistent with this hypothesis, caloric vestibular stimulation (CVS) has been shown to reduce experimental and clinical pain. Since CVS can induce undesirable effects in a proportion of patients, here we explored an alternative means to activate non-invasively the vestibular pathways using innocuous bi-mastoid galvanic stimulation (GVS), and assessed its effects on experimental pain.MethodsSixteen healthy volunteers participated in this study. Experimental pain was induced by noxious laser-heat stimuli to the left hand while recording pain ratings and related brain potentials (LEPs). We evaluated changes of these indices during left- or right-anodal GVS (cathode on contralateral mastoid), and contrasted them with those during sham GVS, optokinetic vestibular stimulation (OKS) using virtual reality, and attentional distraction to ascertain the vestibular-specific analgesic effects of GVS.ResultsGVS elicited brief sensations of head/trunk deviation, inoffensive to all participants. Both active GVS conditions showed analgesic effects, greater for the right anodal stimulation. OKS was helpful to attain significant LEP reductions during the left-anodal stimulation. Neither sham-GVS nor the distraction task were able to modulate significantly pain ratings or LEPs.ConclusionsGVS appeared as a well-tolerated and powerful procedure for the relief of experimental pain, probably through physiological interaction within insular nociceptive networks. Either isolated or in combination with other types of vestibular activation (e.g., optokinetic stimuli), GVS deserves being tested in clinical settings.