Sham tDCS: A hidden source of variability? Reflections for further blinded,controlled trials

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique increasingly used to modulate neural activity in the living brain. In order to establish the neurophysiological, cognitive or clinical effects of tDCS, most studies compare the effects of active tDCS to those observed with a sham tDCS intervention. In most cases, sham tDCS consists in delivering an active stimulation for a few seconds to mimic the sensations observed with active tDCS and keep participants blind to the intervention. However, to date, sham-controlled tDCS studies yield inconsistent results, which might arise in part from sham inconsistencies. Indeed, a multiplicity of sham stimulation protocols is being used in the tDCS research field and might have different biological effects beyond the intended transient sensations. Here, we seek to enlighten the scientific community to this possible confounding factor in order to increase reproducibility of neurophysiological, cognitive and clinical tDCS studies.     

Efficacy of semantic–phonological treatment combined with tDCS for verb retrieval in a patient with aphasia

Recent studies reported enhanced performance on language tasks induced by transcranial direct current stimulation (tDCS) in patients with aphasia. One chronic patient with non-fluent aphasia received 20 sessions of a verb anomia training combined with off-line bihemispheric tDCS applied to the dorsolateral prefrontal cortex (DLPFC) – anodal tDCS over left DLPFC plus cathodal tDCS over right DLPFC. A significant improvement in verb naming was observed at all testing times (4, 12, 24, and 48 weeks from post-entry/baseline testing) for treated and untreated verbs. Our findings show beneficial effects of verb anomia training in combination with tDCS in chronic aphasic patient, suggesting a long-lasting effect of this treatment.     

Effects of tDCS on reward responsiveness and valuation in Parkinson’s patients with impulse control disorders

Journal of Neurology - Parkinson’s disease (PD) patients with impulse control disorders (ICD) frequently report hypersensitivity to rewards. However, a few studies have explored the...     

Can transcranial direct current stimulation (tDCS) alleviate symptoms and improve cognition in psychiatric disorders?

Objectives. Since the discovery of psychopharmacological treatments in the early 1950s, followed by the development of second-generation antidepressants and antipsychotics, biological psychiatry has not achieved much progress. Recent technological advances in the field of non-invasive brain stimulation open new perspectives in the treatment of psychiatric disorders. Amongst them, transcranial direct current stimulation (tDCS) modulates cortical excitability and induces long-lasting effects. Here, we aimed at evaluating whether tDCS has potential to be developed as an innovative treatment in psychiatry. Methods. We conducted a systematic review of the current state of development and application of tDCS in psychiatric disorders, exploring clinical and cognitive effects, especially in major depressive disorder (MDD), schizophrenia and substance use disorder. Results. Systematic literature search yielded 40 publications: 22 in MDD, nine in schizophrenia, seven in substance use disorder, one in obsessive–compulsive disorder and one in mania. Our findings indicated beneficial clinical effects of tDCS for MDD and a promising literature in schizophrenia and substance use disorder. Conclusions. Despite methodological differences, the data published to date are promising and supports the use of tDCS as a treatment for psychiatric disorders. However, its place regarding other treatments still has to be determined before becoming a routine clinical treatment.     

美多芭联合tDCS治疗PD的疗效及对UPDRS评分的影响分析

目的探讨美多芭联合经颅直流电刺激(t DCS)治疗帕金森(PD)的疗效及对PD综合评分量表(UPDRS)评分的影响。方法将本院2016年3月至2017年3月期间收治的94例PD患者根据随机数字法分为试验组和对照组,试验组给予美多芭联合t DCS治疗,对照组给予美多芭治疗,分别于治疗前、治疗后7d及1个月对UPDRS评分、治疗效果以及不良反应等进行综合评价。结果治疗1个月后,试验组患者的治疗总有效率为82.98%显著高于对照组的72.34%,组间比较差异有统计学意义(P0.05)。对照组失眠2例,便秘2例,头晕3例,体位性低血压2例,不良反应发生率为23.40%。试验组失眠4例,便秘1例,头晕5例,体位性低血压1例,不良反应发生率为19.15%,两组的不良反应发生率(P0.05);治疗7d及1个月后,试验组UPDRSⅠ、Ⅱ、Ⅲ及总的评分均低于对照组,组间差异有统计学意义(P0.05)。结论对PD患者采用美多芭联合t DCS治疗方案,能显著改善患者的UPDRS评分,且该法具有较高的临床安全性,今后可能成为有潜力的PD治疗方法。     

Age- and task-dependent effects of cerebellar tDCS on manual dexterity and motor learning–A preliminary study

ObjectivesThe role of the cerebellum in motor learning of dexterous control and interaction with aging remains incompletely understood. We compared the effect of age and cerebellar transcranial direct current stimulation (CRB-tDCS) on motor learning in two different manual dexterity tasks, visuomotor force control vs. effector selection (independent finger movements).MethodsTwenty younger and 20 older adults were randomized (double-blinded) to anodal or sham CRB-tDCS during dexterity training over three consecutive days, and followed-up at day 10. Motor learning was measured as (i) overall learning (across 10 days), (ii) within-day (short-term) learning, (iii) between-day learning (consolidation), and (iv) retention (long-term learning; day 3 to day 10).ResultsYounger and older subjects showed significant overall learning in both tasks. Subjects with poor initial performance showed stronger learning. No effects of CRB-tDCS were observed in younger adults. A significant Age*CRB-tDCS interaction showed that CRB-tDCS improved within-day learning in finger independence (improved reaction time in effector selection) in older adults. However, a significant Age*CRB-tDCS interaction showed that CRB-tDCS impacted consolidation negatively in older subjects. No stimulation effects were found on retention. Finally, we found that degree of within-day learning in finger independence (change in reaction times) correlated with baseline (pre-training) reaction times in both young and old subjects.DiscussionThe results suggest that CRB-tDCS may improve short-term learning of manual dexterity in older adults in a task-dependent manner, specifically in difficult tasks requiring effector (action) selection. However, cerebellar tDCS stimulation may also interfere with consolidation in older subjects. These results need confirmation in a larger sample.     

Modulation of verbal fluency networks by transcranial direct current stimulation (tDCS) in Parkinson’s disease

BackgroundVerbal fluency relies on the coordinated activity between left frontal and temporal areas. Patients with Parkinson’s disease (PD) present phonemic and semantic fluency deficits. Recent studies suggest that transcranial direct current stimulation (tDCS) enhances adaptative patterns of brain activity between functionally connected areas.ObjectiveThe aim of this study was to assess the differences in the effects induced by tDCS applied to frontal and temporo-parietal areas on phonemic and semantic fluency functional networks in patients with PD.MethodSixteen patients were randomized to receive tDCS to left dorsolateral prefrontal cortex (DLPFC) and left temporo-parietal cortex (TPC) in a counterbalanced order. Immediately following stimulation, patients underwent a verbal fluency paradigm inside a fMRI scanner. Changes induced by tDCS in activation and deactivation task-related pattern networks were studied using free-model independent component analyses (ICA).ResultsFunctional connectivity in verbal fluency and deactivation task-related networks was significantly more enhanced by tDCS to DLPFC than to TPC. In addition, DLPFC tDCS increased performance on the phonemic fluency task, after adjusting for baseline phonemic performance.ConclusionsThese findings provide evidence that tDCS to specific brain regions induces changes in large scale functional networks that underlay behavioural effects, and suggest that tDCS might be useful to enhance phonemic fluency in PD.     

The effects of 1 Hz rTMS preconditioned by tDCS on gait kinematics in Parkinson’s disease

Hypokinetic gait is a common and very disabling symptom of Parkinson’s disease (PD). Repetitive transcranial magnetic stimulation (rTMS) over the motor cortex has been used with variable effectiveness to treat hypokinesia in PD. Preconditioning rTMS by transcranial direct current stimulation (tDCS) may enhance its effectiveness to treat hypokinetic gait in PD. Three-dimensional kinematic gait analysis was performed (1) prior to, (2) immediately after and (3) 30 min after low-frequency rTMS (1 Hz, 900 pulses, 80 % of resting motor threshold) over M1 contralateral to the more affected body side preconditioned by (1) cathodal, (2) anodal or (3) sham tDCS (amperage: 1 mA, duration: 10 min) in ten subjects with PD (7 females, mean age 63 ± 9 years) and ten healthy subjects (four females, mean age 50 ± 11 years). The effects of tDCS-preconditioned rTMS on gait kinematics were assessed by the following parameters: number of steps, step length, stride length, double support time, cadence, swing and stance phases. Our data suggest a bilateral improvement of hypokinetic gait in PD after 1 Hz rTMS over M1 of the more affected body side preceded by anodal tDCS. In contrast, 1 Hz rTMS alone (preceded by sham tDCS) and 1 Hz rTMS preceded by cathodal tDCS were ineffective to improve gait kinematics in PD. In healthy subjects, gait kinematics was unaffected by either intervention. Preconditioning motor cortex rTMS by tDCS is a promising approach to treat hypokinetic gait in PD.     

Comparing Cortical Plasticity Induced by Conventional and High-Definition 4 × 1 Ring tDCS: A Neurophysiological Study

BackgroundTranscranial direct current stimulation (tDCS) induces long-lasting NMDA receptor-dependent cortical plasticity via persistent subthreshold polarization of neuronal membranes. Conventional bipolar tDCS is applied with two large (35 cm²) rectangular electrodes, resulting in directional modulation of neuronal excitability. Recently a newly designed 4 × 1 high-definition (HD) tDCS protocol was proposed for more focal stimulation according to the results of computational modeling. HD tDCS utilizes small disc electrodes deployed in 4 × 1 ring configuration whereby the physiological effects of the induced electric field are thought to be grossly constrained to the cortical area circumscribed by the ring.ObjectiveWe aim to compare the physiological effects of both tDCS electrode arrangements on motor cortex excitability.MethodstDCS was applied with 2 mA for 10 min. Fourteen healthy subjects participated, and motor cortex excitability was monitored by transcranial magnetic stimulation (TMS) before and after tDCS.ResultsExcitability enhancement following anodal and a respective reduction after cathodal stimulation occurred in both, conventional and HD tDCS. However, the plastic changes showed a more delayed peak at 30 min and longer lasting after-effects for more than 2 h after HD tDCS for both polarities, as compared to conventional tDCS.ConclusionThe results show that this new electrode arrangement is efficient for the induction of neuroplasticity in the primary motor cortex. The pattern of aftereffects might be compatible with the concept of GABA-mediated surround inhibition, which should be explored in future studies directly.     

Do tDCS and TMS influence tinnitus transiently via a direct cortical and indirect somatosensory modulating effect? A combined TMS-tDCS and TENS study

Tinnitus is usually defined as an intrinsic sound percept that cannot be attributed to an external sound source that tinnitus can be suppressed by neuromodulation techniques such as transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), and transcranial electrical nerve stimulation (TENS). It is thought that TMS and tDCS modulate tinnitus directly by targeting the frontal and/or auditory cortex of the brain, whereas TENS most likely influences tinnitus indirectly via cervical nerve-cochlear nucleus interactions. It is unknown whether part of the tinnitus modulating effect of tDCS and TMS also depends on a somatosensory modulating effect analogous to TENS, via the trigeminal and cervical nerves. We aimed to investigate this question by analyzing to which extent response to one neuromodulation technique predicts the response to another neuromodulation technique. We analyzed 153 patients with chronic tinnitus (> 1 year) who underwent all three neuromodulation techniques (C2 nerve TENS, auditory cortex TMS, and bifrontal tDCS). Our results show that TENS predicts tDCS and TMS better than the opposite, and tDCS predicts TMS response and vice versa. On the basis of these results, it is it is argued that TENS only modulates the tinnitus brain circuit indirectly, whereas TMS and tDCS have a dual working mechanism, a TENS-like mechanism plus a direct brain modulating mechanism.     

Bifrontal and bioccipital transcranial direct current stimulation (tDCS) does not induce mood changes in healthy volunteers: A placebo controlled study

Transcranial direct current stimulation (tDCS) is the application of a weak electrical direct current (1.5?mA), which has the ability to modulate spontaneous firing rates of the cortical neurons by depolarizing or hyperpolarizing the neural resting membrane potential. tDCS in patients with depressive disorders has been proven to be an interesting therapeutic method potentially influencing pathologic mood states. Except one study, no alterations in mood could be confirmed applying tDCS in healthy participants. In this study, bifrontal or bioccipital stimulation was applied in 17 healthy subjects during 20 minutes with 1.5 mA in a placebo-controlled manner. Bifrontal stimulation consisted of both anodal and cathodal placement on right and left dorsolateral prefrontal cortex (DLPFC) in two separate sessions. Using a set of self-reported moodscales (SUDS, POMS-32, PANAS, BISBAS) no significant mood changes could be observed, neither with bifrontal nor bioccipital tDCS. As already demonstrated by previous studies, we confirmed the minimal side effects and the safety of this neuromodulation technique.     

1 Hz rTMS preconditioned by tDCS over the primary motor cortex in Parkinson’s disease: effects on bradykinesia of arm and hand

To investigate whether a period of 1 Hz repetitive transcranial magnetic stimulation (rTMS) over M1 preconditioned by tDCS improves bradykinesia of the upper limb in Parkinson’s disease (PD). Fifteen patients with PD performed index finger, hand tapping and horizontal pointing movements as well as reach-to-grasp movements with either hand before (baseline conditions) and after a period of 1 Hz rTMS preconditioned by (1) sham, (2) anodal or (3) cathodal tDCS over the primary motor cortex contralateral to the more affected body side. Movement kinematics was analysed using an ultrasound-based motion analyser at baseline, immediately after and 30 min after each stimulation session. Dopaminergic medication was continued. Compared to baseline, 1 Hz rTMS significantly increased the frequency of index finger and hand tapping as well as horizontal pointing movements performed with the contralateral hand. Movement frequency increased up to 40% over 30 min after cessation of the stimulation. Preconditioning with cathodal tDCS, but not with anodal tDCS, reduced the effectiveness of 1 Hz rTMS to improve tapping and pointing movements. There was no significant increase of movement frequencies of the ipsilateral hand induced by 1 Hz rTMS preconditioned by either tDCS session. Movement kinematics of reach-to-grasp movements were not significantly influenced by either stimulation session. In PD the beneficial effects of 1 Hz rTMS over the primary motor cortex on bradykinesia of simple finger, hand and pointing movements is reduced by preconditioning with cathodal tDCS, but not with anodal tDCS. Preconditioning with tDCS is a powerful tool to modulate the behavioural effect of 1 Hz rTMS over the primary motor cortex in PD.     

The fade-in - Short stimulation - Fade out approach to sham tDCS - Reliable at 1 mA for naïve and experienced subjects, but not investigators

ObjectiveSlowly ramping down initial current intensity after a minimal interval of stimulation is the de facto standard for sham stimulation in transcranial electrical stimulation research. The aim of this study is to further investigate the effectiveness of this method of blinding.MethodsWe have investigated the time course of the cutaneous perception during 10 min of anodal, cathodal, and sham transcranial direct current stimulation, probing the perceived strength and site of the perceived sensation. We have also utilized post-stimulation assessment and measurements of sleepiness prior to and after the intervention. Previous exposure to tDCS has also been taken into account: the experiment has been repeated in naïve and experienced subject groups, and a group consisting of investigators who use tDCS as a research tool.ResultsAlthough we have observed a general reduction in the perceived strength of the stimulation with time, we have not found the complete disappearance of the cutaneous perception during either the verum or the sham conditions. Experienced subjects were more likely to be able to differentiate between trials with stimulation and non-stimulation trials and to correctly identify sham and verum stimulation conditions.ConclusionWhen taking only naïve and experienced subjects into account, there was no significant difference between the strength of the perceived stimulation in the verum and sham conditions. The fade-in – short stimulation – fade-out sham stimulation can be indistinguishable from verum stimulation, but not because it mimics the disappearance of the cutaneous sensations associated with the verum stimulation, but because these sensations persist also in the sham stimulation. The significance of this finding with potential confounding factors and limitations are discussed.     

Efficacy and safety of simultaneous rTMS–tDCS over bilateral angular gyrus on neuropsychiatric symptoms in patients with moderate Alzheimer's disease: A prospective,randomized, sham-controlled pilot study

BackgroundTreating neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) remains highly challenging. Noninvasive brain stimulation using repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) is of considerable interest in this context.ObjectiveTo investigate the efficacy and safety of a novel technique involving simultaneous application of rTMS and tDCS (rTMS–tDCS) over bilateral angular gyrus (AG, P5/P6 electrode site) for AD-related NPS.MethodsEighty-four AD patients were randomized to receive rTMS–tDCS, single-rTMS, single-tDCS, or sham stimulation for 4 weeks, with evaluation at week-4 (W4, immediately after treatment) and week-12 (W12, follow-up period) after initial examination. Primary outcome comprising Neuropsychiatric Inventory (NPI) score and secondary outcomes comprising mini-mental state examination (MMSE), AD assessment scale-cognitive subscale (ADAS-cog), and Pittsburgh sleep quality index (PSQI) scores were collected and analyzed by a two-factor (time and treatment), mixed-design ANOVA.ResultsrTMS–tDCS produced greater improvement in NPI scores than single-tDCS and sham at W4 and W12 (both P < 0.017) and trended better than single-rTMS (W4: P = 0.058, W12: P = 0.034). rTMS–tDCS improved MMSE scores compared with single-tDCS at W4 (P = 0.011) and sham at W4 and W12 (both P < 0.017). rTMS–tDCS also significantly improved PSQI compared with single-rTMS and sham (both P < 0.017). Interestingly, rTMS–tDCS-induced NPI/PSQI improvement was significantly associated with MMSE/ADAS-cog improvement. tDCS- and/or rTMS-related adverse events appeared slightly and briefly.ConclusionsrTMS–tDCS application to bilateral AG can effectively improve AD-related NPS, cognitive function, and sleep quality with considerable safety.