Sham-controlled Study Research Articles

Clinical efficacy and neurobiological correlates of electroconvulsive therapy in patients with clozapine-resistant/intolerant schizophrenia: study protocol of multi-site parallel arm double-blind randomized sham-controlled study.

Background: A substantial proportion of patients with treatment resistant schizophrenia do not respond well or partially to clozapine, with a subset that does not tolerate an adequate trial of clozapine. Electroconvulsive therapy (ECT) is regarded as one of the augmenting options, but there is a lack of high-quality evidence for this practice. This protocol describes a double-blind randomised sham-controlled modified-ECT trial to evaluate its efficacy in patients with clozapine resistant/intolerant schizophrenia. The study also involves multimodal investigations to identify the response predictors and the mechanistic basis of modified ECT in this population. Methods: One hundred consenting schizophrenia patients with resistance/intolerance to clozapine referred by clinicians for ECT would be randomly assigned to receive true ECT or sham ECT at three study centers. Sham ECT would mimic all the procedures of modified ECT including anaesthesia and muscle relaxation, except the electrical stimulation. After a blinded course, non-responders to sham ECT would be offered open-label true ECT. Clinical assessments, neurocognitive assessments and multimodal investigations (magnetic resonance imaging [MRI], electroencephalography, heart rate variability, investigative transcranial magnetic stimulation-transcranial direct current stimulation, gene polymorphism) would be conducted at baseline and repeated after the end of the trial, as well as open-label ECT course. The trial would evaluate the improvement in positive symptoms (scale for assessment of positive symptoms) of schizophrenia as the primary outcome measure with prediction of this change by resting-state functional-MRI based brain-connectivity as the second primary objective. Registration: Clinical Trial Registry of India (Reg no: CTRI/2021/05/033775) on 24 th May 2021.

Effects of Cerebellar Transcranial Alternating Current Stimulation on Gait and Balance in Healthy Subjects

Transcranial Alternating Current Stimulation (tACS) is a non-invasive brain stimulation technique [1] able to modulate neural oscillatory activities, including those linked to the cortico-cerebello-thalamo- cortical network [2,3]. In this double-blind sham-controlled study, we aimed to investigate the effects of cerebellar tACS delivered at theta and gamma frequencies on gait and balance in healthy subjects, as assessed by kinematic techniques. In a group of young healthy subjects, we applied tACS over the dominant cerebellar hemisphere during the execution of three different motor tasks: 1) standing (both with eyes open and closed); 2) gait initiation (assessed both for the dominant and non-dominant lower limb); 3) 5-meter walk test (5MWT) (Fig. 1). tACS was delivered in a random order at the theta (5 Hz, theta-tACS) and gamma (50 Hz, gamma-tACS) frequencies, and sham-tACS was used as a control condition. The stimulation intensity was set at 1,5 mA and the stimulation duration lasted as long as the motor task was accomplished. Kinematic data were obtained using a force platform and an optoelectronic system. The data analysis was conducted using a dedicated software. Theta-tACS induced a significant reduction of the Centre Of Pressure (COP) displacement during standing with eyes closed compared to sham- and gamma-tACS (mean radius displacement: theta- tACS 4.65±0.74 mm, gamma-tACS 5.58±1.26 mm, sham-tACS 5.99±2.12 mm). A similar, though weaker, trend was present in the eyes open condition. Furthermore, stride width during 5MWT resulted tighter during theta-tACS compared to sham- and gamma tACS. Boosting theta oscillations in the cerebellum through tACS improves balance during standing and gait in healthy subjects. This effect may rely on the modulation of the activity of cerebellar neurons resonant to the theta rhythm. This non-invasive neuromodulation approach could be applied in neurological conditions characterized by ataxia to possibly ameliorate the imbalance and reduce the risk of falling.

Study protocol for evaluating the clinical efficacy and neurobiological correlates of sequential treatment with tDCS primed iTBS and ECT in treatment-resistant depression

Background: Treatment-resistant depression is a burdensome condition. Intermittent theta burst stimulation (iTBS) of the left dorsolateral prefrontal cortex is considered a treatment option in early course of resistance with a proportion of such patients responding to it. Preliminary evidence suggests a role of priming iTBS stimulation with preconditioning using cathodal transcranial direct current stimulation (tDCS). This protocol describes a double-blind randomized sham-controlled study to evaluate the clinical efficacy and tolerability of tDCS-primed iTBS in the treatment of resistant depression. Non-responders to this trial will be offered open-label electroconvulsive therapy. All participants will undergo neurobiological investigations that will enable the identification of potential response predictors and mechanisms. Methods: Three hundred and fifty consenting patients with treatment resistant depression will be randomly assigned to receive 20–30 daily sessions of true-tDCS or sham-tDCS primed iTBS over left dorsolateral prefrontal cortex at three study centers. After this blinded sham-controlled trial, non-responders to the intervention will be offered open-label true ECT. Clinical assessments, neurocognitive assessments and multimodal investigations (magnetic resonance imaging, electroencephalography, heart rate variability, investigative transcranial magnetic stimulation-transcranial direct current stimulation, gene polymorphisms) will be conducted at baseline and repeated after the end of the trial, as well as open-label ECT course. The trial will evaluate the improvement in depressive symptoms (Hamilton depression rating scale) between the two groups as the primary outcome measure.

A Single Session of Bifrontal tDCS Can Improve Facial Emotion Recognition in Major Depressive Disorder: An Exploratory Pilot Study.

Emotional processing deficits are key features in major depressive disorder (MDD). Neuroimaging studies indicate that the dorsolateral prefrontal cortex (DLPFC) plays a pivotal role in both depressive symptoms and emotional processing. Recently, transcranial Direct Current Stimulations (tDCS) applied over the DLPFCs have held the promise to alleviate the symptoms in patients with MDD, but the effect on emotional processing in the patients is unclear. Here, we investigated the effect of a single session of tDCS over the DLPFCs on the emotional processing in patients with treatment-resistant MDD. In a randomized sham-controlled study, 35 patients received a single 30 min session of either active (2 mA, n = 18) or sham tDCS (n = 17). The anode was placed over the left and the cathode over the right DLPFC. Emotional processing accuracy was measured by a facial emotion recognition (FER) task. We observed an overall improvement in FER performance after the active tDCS, but not the sham tDCS. These exploratory results suggest that a single session of tDCS over the DLPFCs may improve FER in MDD, a crucial function of social cognition. Further studies are needed to investigate whether this acute improvement of FER in response to a single tDCS session could translate into clinical benefits or predict remission following repeated sessions of stimulation.

Effects of bilateral, bipolar-nonbalanced, frontal transcranial Direct Current Stimulation (tDCS) on negative symptoms and neurocognition in a sample of patients living with schizophrenia: Results of a randomized double-blind sham-controlled trial

Negative symptoms (NS), conceived as Avolition-Apathy (AA) and Expressive Deficit (EXP) domains, and neurocognitive impairments represent unmet therapeutic needs for patients with schizophrenia. The present study investigated if bilateral bipolar-nonbalanced frontal transcranial Direct Current Stimulation (tDCS) could improve these psychopathological dimensions.This randomized, double-blind, sham-controlled study (active-tDCS versus sham-tDCS, both, n = 25) included 50 outpatients diagnosed with schizophrenia clinically stabilized. Patients received 20-min 2 mA active-tDCS or sham-tDCS (anode: left Dorsolateral Prefrontal Cortex; cathode: right orbitofrontal region). Primary outcomes included: PANSS-Negative subscale, Negative Factor (Neg-PANSS), AA and EXP domains; neurocognitive performance at Brief Assessment of Cognition in Schizophrenia. Secondary outcomes included: PANSS subscales and total score, Disorganized/Concrete (DiscC-PANSS) and Positive Factors, Clinical Global Impression (CGI) scores, clinical insight at Scale to Assess Unawareness of Mental Disorder (SUMD). Analysis of covariance (ANCOVA) was performed evaluating between-group changes over time.Significant improvements following active-tDCS were observed for all NS measures (all, p < 0.001; d > 0.8) and for working memory (p = 0.025, d = 0.31). Greater variations following to active treatment emerged also for PANSS-General Psychopathology subscale (p < 0.001; d = 0.54), PANSS total score (p < 0.001; d = 0.69), CGI indexes (all, p < 0.001; d > 0.6), DiscC-PANSS (p < 0.001; d = 0.80) and SUMD-general Unawareness index (p = 0.005; d = 0.15) but not for positive symptoms and others insight measures. Good safety/tolerability profiles were found.Bilateral bipolar-nonbalanced frontal-tDCS is a non-pharmacological approach in schizophrenia effectively improving NS, particularly the AA and EXP domains, probably acting by modulating dysfunctional cortical-subcortical networks. Preliminary results also suggest working memory improvements following tDCS. Further studies are needed to confirm the neurobiological basis of these results.

Evidence for modulation of planning and working memory capacities by transcranial direct current stimulation in a sample of adults with attention deficit hyperactivity disorder

Background and ObjectiveAttention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder that affects up to 2.8% of the adult population. Albeit pharmacological and behavioral therapies alleviate some core symptoms of ADHD, they do not avail cognitive dysfunction adequately. Executive dysfunction has been considered to have a principal role in ADHD and has previously been linked to activity alterations in the prefrontal cortex. Transcranial Direct Current Stimulation (tDCS) is a noninvasive brain stimulation technique that may modulate prefrontal cortex activity and induce neuroplasticity, with preliminary results in ADHD. The aim of the present study is to assess the effect of repeated tDCS on measures of executive functions in adults with ADHD. MethodIn this randomized double-blind sham-controlled study, 22 adults with ADHD were allocated into two groups and were administered five consecutive sessions of 2 mA active/sham tDCS over the dorsolateral prefrontal cortex (right anodal/left cathodal). A neuropsychological test battery was administered before the first session and immediately after the last session. ResultsThe maximum number of digits and the total number of correct trials in the Digit Span Backward test increased in the active group (p = 0.017). The total move score in the Tower of London test decreased (p = 0.033), suggesting better planning ability. However, no significant differences were observed on Stroop Test and Trail Making Test after tDCS. DiscussionThe present study corroborates the modulating effects of tDCS on planning and working memory in a small group of adults with ADHD. Our results highlighted that cognitive functions are modulable using tDCS in adults with ADHD.

Safety and effects of transcranial direct current stimulation on hand function in preschool children with hemiplegic cerebral palsy: A pilot study.

Transcranial direct current stimulation (tDCS) has shown a promising prospect in improving function and spasticity in school-aged children with cerebral palsy, but little is known in preschool children. The aim of this study was to explore the safety and effects of tDCS on hand function in preschool children (aged 3–6 years) with hemiplegic cerebral palsy (HCP). We designed a crossover, single-blind, sham-controlled study in 30 preschool children with HCP, who were recruited to receive one session of sham and one session of active anodal tDCS (1.5 mA, 20 min) on the primary motor cortex of the affected hemisphere, with a 24-h interval between the two sessions. Questionnaire was completed by each participant and their attendants immediately, 90 min, and 24 h after each session to monitor common adverse events of tDCS, such as skin irritation, skin erythema, burning sensation, headache, dizziness, etc. Box and Block Test, Selective Control of the Upper Extremity Scale, Modified Ashworth Scale, and Melbourne Assessment 2 were conducted at baseline, immediately, and 90 min after each session. No severe adverse event occurred during the study and only a few of them felt transient and slight discomfort. Results also showed that all participants performed better at Box and Block Test of the hemiplegic hand immediately after a single anodal tDCS (P < 0.05) and this improvement lasted at least 90 min and more than 24 h. However, there was no significant improvement in Selective Control of the Upper Extremity Scale of both hands, Box and Block Test of the non-hemiplegic hand, Modified Ashworth Scale, and Melbourne Assessment 2 of the hemiplegic upper limb (P > 0.05). Shortly, this study supported the safety and effects of a single anodal tDCS on improving the manual dexterity of the hemiplegic hand for preschool children with HCP. Further researches with larger samples about the optimal dose and treatment cycle of tDCS for preschool children with HCP are warranted. This study gained the approval of ethics committee of the organization and was registered at chictr.org (ChiCTR2000031141).

Adjunctive neuronavigated accelerated continuous theta-burst stimulation in obsessive-compulsive disorder: a randomized sham-controlled study.

Approximately 40% of patients treated for obsessive-compulsive disorder (OCD) do not respond to standard and second-line augmentation treatments leading to the exploration of alternate biological treatments. Continuous theta burst stimulation (cTBS) is a form of repetitive transcranial magnetic stimulation inducing more rapid and longer-lasting effects on synaptic plasticity than the latter. To the best of our knowledge, only one recent study and a case report investigated the effect of cTBS at the supplementary motor area (SMA) in OCD. This study aimed to examine the effect of accelerated robotized neuronavigated cTBS over SMA in patients with OCD. A total of 32 patients with OCD were enrolled and randomized into active and sham cTBS groups. For active cTBS stimulation, an accelerated protocol was used. Bursts of three stimuli at 50Hz, at 80% of MT, repeated at 5Hz were used. Daily 2 sessions of 900 pulses each, for a total of 30 sessions over 3wk (weekly 10 sessions), were given. Yale-Brown Obsessive-Compulsive Rating Scale (YBOCS), Clinical Global Impressions scale (CGI), Hamilton Depression Rating Scale (HAM-D), and Hamilton Anxiety Rating Scale (HAM-A) were administered at baseline and at end of weeks 3 and 8. A total of 26 patients completed the study. Active cTBS group showed significant group × time effect in YBOCS obsession (P<.001, η2=0.288), compulsion (P=.004, η2=0.207), YBOCS total (P<.001, η2=0.288), CGI-S (P=.010, η2=0.248), CGI-C (P=.010, η2=0.248), HAM-D (P=.014, η2=0.224) than sham cTBS group. Findings from our study suggest that adjunctive accelerated cTBS significantly improves psychopathology, severity of illness, and depression among patients with OCD. Future studies with larger sample sizes will add to our knowledge.

Effects of Preceding Transcranial Direct Current Stimulation on Movement Velocity and EMG Signal during the Back Squat Exercise.

This study aimed to evaluate the effects of preceding anodal transcranial direct stimulation (a-tDCS) over the dorsolateral prefrontal cortex (DLPFC) during the back squat exercise on movement velocity and surface electromyographic (sEMG) activity. Thirteen healthy, well-trained, male firefighters (34.72 ± 3.33 years; 178 ± 7.61 cm; 76.85 ± 11.21 kg; 26.8 ± 4.2 kg·m−2; back squat 1-repetition maximum 141.5 ± 16.3 kg) completed this randomised double-blinded sham-controlled crossover study. After familiarisation and basal measurements, participants attended the laboratory on two occasions separated by 72 h to receive either Sham or a-tDCS (current intensity of 2 mA for 20 min). Immediately after stimulation, participants completed three sets of 12 repetitions (70% of 1-RM) with three minutes of recovery between sets monitored with a linear position transducer. The sEMG of the rectus femoris (RF) and vastus lateralis (VL) of both legs were recorded. No significant differences were observed between a-tDCS and Sham interventions on mean concentric velocity at any set (p > 0.05). Velocity loss and effort index were significantly higher (p < 0.05) in set 3 compared to set 1 only in the a-tDCS group. The right-leg RM and right-leg VL elicited the greatest muscle activation during set 1 after a-tDCS and Sham, respectively (p < 0.05). Our results revealed that a-tDCS over the DLPFC might impact movement velocity or fatigue tolerance in well-trained individuals. Notwithstanding, significant differences in dominant-leg muscle activity were found both in a-tDCS and Sham.

Transcranial Direct Current Stimulation (tDCS) in children with ADHD: A randomized, sham-controlled pilot study

BackgroundADHD is a common neurodevelopmental disorder with a pediatric prevalence of 5.2%.While medication treatment for ADHD is effective, it does not address all symptoms and a small but notable subgroup does not respond to medications. Adverse effects limit its use and some parents and participants resist use of medication. Thus, limitations of medication treatment for ADHD motivate searching for other therapeutic options. Transcranial Direct Current Stimulation (tDCS) has been suggested as a treatment for children with ADHD, with mixed results to date. Protocol variables employed, including combined use of cognitive training (CT) and scheduling of sessions, may explain diverse findings to date. The aim of this study was to examine safety, feasibility and efficacy of tDCS combined with CT provided three-times-per week for one-month to treat children with ADHD. MethodsIn a double blind, randomized, sham-controlled pilot study, 25 children with ADHD were randomized to receive 12 sessions of either anodal tDCS or sham-tDCS for 20 min combined with CT three-times-per-week for four weeks. The tDCS anode was over left dorsolateral prefrontal cortex (DLPFC) and cathode over vertex. Assessments were obtained prior to, after 6 sessions, 12 sessions and one-month after intervention. ResultsNo significant post-intervention differences were found between those receiving tDCS or sham-tDCS. Both groups demonstrated significant improvement on questionnaire measures of ADHD and executive function with mixed results seen on computerized performance measures. Overall, adverse effects were mild with no significant difference between groups. However, three children, all from the tDCS group, experienced headaches with two requiring temporary cessation and one requiring removal from the study. ConclusionsAnodal tDCS to the DLPFC using the above protocol in children with ADHD did not demonstrate additional treatment benefits beyond that of CT.

A Randomized, Clinical Trial Comparing the Efficacy of a Fascia Release Technique for the Treatment of Acute Ankle Sprains

Acute ankle sprains are treated with ice, elevation, immobilization, and non-steroidal anti-inflammatory drugs. Resolution typically takes days. Osteopathic physicians utilize manipulation for a variety of joint disorders and injuries. Few have been studied in randomized controlled trials and many allopathic physicians are unaware of their utility. One manipulation, a modified muscle energy release technique, appears to offer promise for the treatment of acute ankle injuries, potentially returning patients to function more quickly than standard treatment alone. This study involved a comparison of a modified muscle energy release technique with standard treatment to standard treatment alone in the emergency department (ED) setting for patients with acute ankle injuries. This is an IRB approved, randomized single-blind sham-controlled study on a convenience sample of ED patients with pain from acute inversion injury. The study was set in a suburban ED with a 3-year Emergency Medicine Residency and an annual volume of 80,000. Inclusion criteria were patients aged 18-55 years; a Grade I or II acute ankle sprain less than 48 hours old; initial VAS scores ≥ 35; and being able to take 4 steps in the ED. We excluded fractures and Grade III injuries. The experimental manipulation technique involved placing the ankle into position of injury (inversion) for over 90 seconds and then bringing the ankle back to a neutral position over 90 seconds against mild hand resistance. The sham manipulation was similar but with plantar-flexion manipulation instead Patients were evaluated pre and 5 minutes after manipulation and 2 days later with a 100mm VAS pain scale completed by the patient after taking 4 steps. 17 patients were enrolled, 7 in the experimental (E) and 10 in the sham (S) group; 7 (41%) were female. There was no difference between groups for age (E=32; S=32 years p=0.9), gender (p=0.9), time from injury (E=7 vs S=11 hours; p=0.4) or initial VAS (E= 51 mm (SD 27); S= 57 mm (SD 20) (p=0.7). Both groups had similar distributions of pain (see schematic). There was no difference in mean pain relief between groups immediately after manipulation E=2.4mm (-11.0-15.88, 95%CI) vs S= 7.2mm (0.08-14.8, 95%CI) (p=0.4) or 2 days later E=29.1mm 1mm (8.5-49.7, 95%CI) S=26 (7.7 95%CI (p=0.8). Muscle energy release for acute ankle sprain does not improve pain immediately or in 2 days compared to standard treatment.

Effects of Low-Concentration Carbon Dioxide Exposure at Bedtime on Sleep in Adults With Insomnia Symptoms

Objectives: Carbon dioxide (CO2) accumulation in an enclosed space might cause drowsiness. This study aimed to assess the effect of bedtime exposure to low concentrations of CO2 gas on the sleep quality of adults with insomnia.Methods: In this double-blind, randomized, sham-controlled cross-over study, we consecutively recruited 24 adults (9 men; age, 55.4±6.3 y) complaining of sleep disturbances (Pittsburgh Sleep Quality Index ≥5). The following two interventions were used in the study: exposure to 2% low-concentration edible CO2 gas (experimental intervention) and exposure to room air (sham-controlled intervention). A sleep air device (Gosleep®, NYX), which atomizes CO2 gas, was used in both experimental and sham-controlled interventions. For the sham session, room air was generated for 18 min, and then, gradually reduced by degrees in the next 5 min with the device finally being turned off.Results: The group exposed to CO2 gas had longer time in bed (361.3±55.2 min vs. 347.2±35.7 min, p=0.034) and total sleep time (311.0±74.3 min vs. 287.2±69.4 min, p=0.010) than the group exposed to room air. Meanwhile, the total arousal (19.7±9.5/h vs. 24.0±13.7/h, p=0.011) and non-REM arousal (20.9±11.3/h vs. 25.1±14.9/h, p=0.008) indices were lower in the group exposed to CO2 gas than in the group exposed to room air. However, perceived total sleep time or sleep latency and Karolinska Sleepiness Scale scores were not significantly different between the two groups.Conclusion: Exposure to low concentrations of CO2 improved the total sleep time and arousal index in adults with insomnia. Unexpectedly, CO2 administration was found to be effective for sleep maintenance.

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.

The Efficacy and Safety of Thrice vs Twice per Week Low-Intensity Pulsed Ultrasound Therapy for Erectile Dysfunction: A Randomized Clinical Trial

A recent sham-controlled clinical study has shown that low-intensity pulsed ultrasound twice per week can safely and effectively treat patients with mild-to-moderate erectile dysfunction (ED). However, large-scale clinical trials are needed to verify its efficacy and safety and determine a reasonable treatment interval. To study whether low-intensity pulsed ultrasound therapy thrice per week is non-inferior to twice per week in patients with mild-to-moderate ED. A randomized, open-label, parallel-group, non-inferiority clinical trial was conducted in 7 hospitals in China. A total of 323 patients with mild-to-moderate ED were randomized (1:1) into thrice per week (3/W) and twice per week (2/W) groups. Low-intensity pulsed ultrasound was applied on each side of the penis for 16 sessions. The primary outcome was response rate using the minimal clinically important difference in the International Index of Erectile Function (IIEF-EF) score at week 12. Secondary outcomes included Erection Hardness Score (EHS), Sexual Encounter Profile, Global Assessment Question, and Self Esteem and Relationship Questionnaire. Response rates in 3/W and 2/W groups were 62.0% and 62.5%, respectively. Treatment effect in the 3/W group was noninferior to that of the 2/W group, with rate difference lower bound of -0.01% [95% confidence interval -0.11 to 0.10%] within the acceptable margin (-14.0%). No significant difference was found among secondary outcomes. IIEF-EF score showed a significant increase from baseline in the 3/W group (16.8 to 20.7) and 2/W group (17.8 to 21.7), and the percentage of patients with EHS ≥3 increased in the 3/W (54.9% to 84.0%) and 2/W (59.5% to 83.5%) groups. There was no significant difference in response rate between the 2 groups after controlling for strata factors and homogeneous tests. No treatment-related adverse events were reported. Low-intensity pulsed ultrasound therapy displays similar efficacy and safety for mild-to-moderate ED when administered thrice or twice per week for 16 sessions. This study provides two options to suit patients' needs. This is a large-sample, randomized, controlled, noninferiority trial study. Short-term follow-up and mostly younger patients are the main limitations. Low-intensity pulsed ultrasound therapy thrice and twice per week showed equivalent therapeutic effects and safety for mild-to-moderate ED in a young and generally healthy population. This therapy warrants further investigation of its potential value in rehabilitation of ED.

The effects of concurrent bilateral anodal tDCS of primary motor cortex and cerebellum on corticospinal excitability: a randomized, double-blind sham-controlled study

Transcranial direct current stimulation (tDCS) applied to the primary motor cortex (M1), and cerebellum (CB) can change the level of M1 corticospinal excitability (CSE). A randomized double-blinded crossover, the sham-controlled study design was used to investigate the effects of concurrent bilateral anodal tDCS of M1 and CB (concurrent bilateral a-tDCSM1+CB) on the CSE. Twenty-one healthy participants were recruited in this study. Each participant received anodal-tDCS (a-tDCS) of 2 mA, 20 min in four pseudo-randomized, counterbalanced sessions, separated by at least 7 days (7.11 days ± 0.65). These sessions were bilateral M1 stimulation (bilateral a-tDCSM1), bilateral cerebellar stimulation (bilateral a-tDCSCB), concurrent bilateral a-tDCSM1+CB, and sham stimulation (bilateral a-tDCSSham). Transcranial magnetic stimulation (TMS) was delivered over the left M1, and motor evoked potentials (MEPs) of a contralateral hand muscle were recorded before and immediately after the intervention to measure CSE changes. Short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long interval intracortical inhibition (LICI) were assessed with paired-pulse TMS protocols. Anodal-tDCS significantly increased CSE after concurrent bilateral a-tDCSM1+CB and bilateral a-tDCSCB. Interestingly, CSE was decreased after bilateral a-tDCSM1. Respective alterations in SICI, LICI, and ICF were seen, including increased SICI and decreased ICF, which indicate the involvement of glutamatergic and GABAergic systems in these effects. These results confirm that the concurrent bilateral a-tDCSM1+CB have a facilitatory effect on CSE, whereas bilateral a-tDCSM1 exert some inhibitory effects. Moreover, the effects of the 2 mA, 20 min a-tDCS on the CB were consistent with its effects on the M1.

Effects of virtual reality-based feedback on neurofeedback training performance-A sham-controlled study.

Electroencephalography-neurofeedback (EEG-NF) has become a valuable tool in the field of psychology, e.g., to improve cognitive function. Nevertheless, a large percentage of NF users seem to be unable to control their own brain activation. Therefore, the aim of this study was to examine whether a different kind of visual feedback could positively influence NF performance after one training session. Virtual reality (VR) seems to have beneficial training effects and has already been reported to increase motivational training aspects. In the present study, we tested 61 young healthy adults (mean age: 23.48 years; 28 female) to investigate, whether 3D VR-based NF training has a more beneficial effect on the sensorimotor rhythm (SMR, 12–15 Hz) power increase than a mere 2D conventional NF paradigm. In the 3D group, participants had to roll a ball along a predefined path in an immersive virtual environment, whereas the 2D group had to increase the height of a bar. Both paradigms were presented using VR goggles. Participants completed one baseline and six feedback runs with 3 min each, in which they should try to increase SMR power over Cz. Half of the participants received real feedback whereas the other half received sham feedback. Participants receiving 3D VR-based feedback showed a linear increase in SMR power over the feedback runs within one training session. This was the case for the real as well as for the sham 3D feedback group and might be related to more general VR-related effects. The 2D group receiving the conventional bar feedback showed no changes in SMR power over the feedback runs. The present study underlines that the visual feedback modality has differential effects on the NF training performance and that 3D VR-based feedback has advantages over conventional 2D feedback.

Long-Term Prophylactic Transcranial Direct Current Stimulation Ameliorates Allodynia and Improves Clinical Outcomes in Individuals With Migraine

ObjectivesMigraine is a common and substantially debilitating disorder that may associate with allodynia, a marker of central sensitization in the pain circuits. Several unmet needs, like limited adherence to drugs due to adverse events and cost-effectivity, still occur in the prophylactic treatment of migraine. Transcranial direct current stimulation (tDCS) has recently been indicated to be beneficial in individuals with migraine with and without allodynia. However, to our knowledge, there are no studies evaluating the efficacy of six-month tDCS in migraine. Materials and MethodsThis study was a randomized double-blind parallel-group sham-controlled five-month extension study after a one-month lead-in trial of tDCS in individuals with migraine. A total of 23 individuals with migraine with allodynia who completed the lead-in trial were recruited after their consent and were administered three consecutive sessions of 2-mA anodal 20-minute tDCS over the left primary motor cortex every month for an additional five months. Pain-related outcomes were determined using monthly headache diaries. Allodynia, depression, anxiety, and disability because of migraine also were assessed throughout the study. ResultsImprovements in allodynia levels, attack frequency, number of rescue medications, and attack duration were higher, and mostly gradual during the trial, in the active group. Migraine Disability Scale grades also were lower in the active group, whereas no between-group differences were found in depression and anxiety scores. Higher responder rates of migraine attack frequency (56.8% vs 25%), number of headache days (56% vs 16.7%), and migraine attack duration (90.9% vs 8.3%) were observed after six-month tDCS in the active group than in the sham group. ConclusionsLong-term extended tDCS is shown to be a safe, efficacious, and plausible modality for prophylactic treatment in individuals with migraine with allodynia. SignificanceLong-term extended tDCS can alleviate allodynia, which is an indicator of drug resistance and chronicity, and meet the goals of prophylactic treatment in individuals with migraine with allodynia.

Clinical efficacy and neurobiological correlates of electroconvulsive therapy in patients with clozapine-resistant/intolerant schizophrenia: study protocol of multi-site parallel arm double-blind randomized sham-controlled study

Background: A substantial proportion of patients with treatment resistant schizophrenia do not respond well or partially to clozapine, with a subset that does not tolerate an adequate trial of clozapine. Electroconvulsive therapy (ECT) is regarded as one of the augmenting options, but there is a lack of high-quality evidence for this practice. This protocol describes a double-blind randomised sham-controlled modified-ECT trial to evaluate its efficacy in patients with clozapine resistant/intolerant schizophrenia. The study also involves multimodal investigations to identify the response predictors and the mechanistic basis of modified ECT in this population. Methods: One hundred consenting schizophrenia patients with resistance/intolerance to clozapine referred by clinicians for ECT would be randomly assigned to receive true ECT or sham ECT at three study centers. Sham ECT would mimic all the procedures of modified ECT including anaesthesia and muscle relaxation, except the electrical stimulation. After a blinded course, non-responders to sham ECT would be offered open-label true ECT. Clinical assessments, neurocognitive assessments and multimodal investigations (magnetic resonance imaging [MRI], electroencephalography, heart rate variability, investigative transcranial magnetic stimulation-transcranial direct current stimulation, gene polymorphism) would be conducted at baseline and repeated after the end of the trial, as well as open-label ECT course. The trial would evaluate the improvement in positive symptoms (scale for assessment of positive symptoms) of schizophrenia as the primary outcome measure with prediction of this change by resting-state functional-MRI based brain-connectivity as the second primary objective. Registration: Clinical Trial Registry of India (Reg no: CTRI/2021/05/033775) on 24th May 2021.

Genetic profile for dopamine signaling predicts brain functional reactivity to repetitive transcranial magnetic stimulation.

Research integrating molecular and imaging data provides important insights into how the genetic profile associated with dopamine signaling influences inter-individual differences in brain functions. However, the effects of genetic variations in dopamine signaling on the heterogeneity of brain changes induced by repetitive transcranial magnetic stimulation (rTMS) still remain unclear. The current study examined the composite effects of genetic variations in dopamine-related genes on rTMS-induced brain responses in terms of the functional network connectivity and working memory performance. Healthy individuals (n = 30) participated in a randomized, double-blind, sham-controlled study with a crossover design of five consecutive days where active rTMS or sham stimulation sessions were administered over the left dorsolateral prefrontal cortex (DLPFC) of the brain. Participants were mostly women (n = 29) and genotyped for polymorphisms in the catechol-O-methyltransferase and D2 dopamine receptor genes and categorized according to their genetic composite scores: high vs. low dopamine signaling groups. Pre- and post-intervention data of resting-state functional magnetic resonance imaging and working memory performance were obtained from 27 individuals with active rTMS and 30 with sham stimulation sessions. The mean functional connectivity within the resting-state networks centered on the DLPFC increased in the high dopamine signaling group. Working memory performance also improved with rTMS in the high dopamine signaling group compared to that in the low dopamine signaling group. The present results suggest that genetic predisposition to higher dopamine signaling may be a promising neurobiological predictor for rTMS effects on cognitive enhancement.Trial registration: ClinicalTrials.gov (NCT02932085).

Very Low-Level Transcranial Photobiomodulation for Major Depressive Disorder: The ELATED-3 Multicenter, Randomized, Sham-Controlled Trial.

Background: Transcranial photobiomodulation (t-PBM) with near-infrared (NIR) light might represent a treatment for major depressive disorder (MDD). However, the dosimetry of administered t-PBM varies widely. We tested the efficacy of t-PBM with low irradiance, low energy per session, and low number of sessions in individuals with MDD.Methods: A 2-site, double-blind, sham-controlled study was conducted of adjunct t-PBM NIR (830 nm; continuous wave; 35.8 cm2 treatment area; 54.8 mW/cm2 irradiance; 65.8 J/cm2 fluence, 20 min/session; ~2 W total power; 2.3 kJ total energy per session), delivered to the prefrontal cortex, bilaterally, twice a week for 6 weeks, in subjects diagnosed with MDD per the DSM-IV criteria. Subjects were recruited between August 2016 and May 2018. A sequential parallel comparison design was used: 18 nonresponders to sham in phase 1 (6 weeks) were re-randomized in phase 2. The primary outcome was reduction in depression severity (Hamilton Depression Rating Scale [HDRS-17] and Quick Inventory of Depressive Symptomatology-Clinician Rating [QIDS-C] scores) from baseline. Statistical analyses used R package SPCDAnalyze2, including all subjects with ≥ 1 post-randomization evaluation.Results: Of the 54 subjects recruited, we included 49 MDD subjects in the analysis (71% female, mean ± SD age 40.8 ± 16.1 years). There were no significant differences between t-PBM and sham with respect to the change in HDRS-17 (t = -0.319, P = .751) or QIDS-C (t = -0.499, P = .620) scores. The sham effect was reasonably low.Conclusions: Mostly uncontrolled studies suggest the efficacy of t-PBM for MDD; however, its optimal dose is still to be defined. A minimal dose threshold is likely necessary, similarly to other neuromodulation techniques in MDD (electroconvulsive therapy, transcranial magnetic stimulation). We established a threshold of inefficacy of t-PBM for MDD, based on combined low irradiance, low energy per session, and low number of sessions.Trial Registration: ClinicalTrials.gov identifier: NCT02959307.