Contribution of transcranial magnetic stimulation in restless legs syndrome: pathophysiological insights and therapeutical approaches

Transcranial magnetic stimulation (TMS) may offer a reliable means to characterize significant pathophysiologic and neurochemical aspects of restless legs syndrome (RLS). Namely, TMS has revealed specific patterns of changes in cortical excitability and plasticity, in particular dysfunctional inhibitory mechanisms and sensorimotor integration, which are thought to be part of the pathophysiological mechanisms of RLS rather than reflect a non-specific consequence of sleep architecture alteration.If delivered repetitively, TMS is able to transiently modulate the neural activity of the stimulated and connected areas. Some studies have begun to therapeutically use repetitive TMS (rTMS) to improve sensory and motor disturbances in RLS. High-frequency rTMS applied over the primary motor cortex or the supplementary motor cortex, as well as low-frequency rTMS over the primary somatosensory cortex, seem to have transient beneficial effects. However, further studies with larger patient samples, repeated sessions, an optimized rTMS setup, and clinical follow-up are needed in order to corroborate preliminary results.Thus, we performed a systematic search of all the studies that have used TMS and rTMS techniques in patients with RLS.     

A novel tDCS sham approach based on model-driven controlled shunting

BackgroundTranscranial direct current stimulation (tDCS), a non-invasive brain stimulation technique able to transiently modulate brain activity, is surging as one of the most promising therapeutic solutions in many neurological and psychiatric disorders. However, profound limitations exist in current placebo (sham) protocols that limit single- and double-blinding, especially in non-naïve subjects.ObjectiveTo ensure better blinding and strengthen reliability of tDCS studies and trials, we tested a new optimization algorithm aimed at creating an “active” sham tDCS condition (ActiSham hereafter) capable of inducing the same scalp sensations perceived during real stimulation while preventing currents from reaching the cortex and cause changes in brain excitability.MethodsA novel model-based multielectrode technique — optimizing the location and currents of a set of small electrodes placed on the scalp — was used to control the relative amount of current delivered transcranially in real and placebo multichannel tDCS conditions. The presence, intensity and localization of scalp sensations during tDCS was evaluated by means of a specifically designed questionnaire administered to the participants. We compared blinding ratings by directly addressing subjects’ ability to discriminate across conditions for both traditional (Bifocal-tDCS and Sham, using sponge electrodes) and our novel multifocal approach (both real Multifocal-tDCS and ActiSham). Changes in corticospinal excitability were monitored based on Motor Evoked Potentials (MEPs) recorded via concurrent Transcranial Magnetic Stimulation (TMS) and electromyography (EMG).ResultsParticipants perceived Multifocal-tDCS and ActiSham similarly in terms of both localization and intensity of scalp sensations, whereas traditional Bifocal stimulation was rated as more painful and annoying compared to its Sham counterpart. Additionally, differences in scalp localization were reported for active/sham Bifocal-tDCS, with Sham tDCS inducing more widespread itching and burning sensations. As for MEPs amplitude, a main effect of stimulation was found when comparing Bifocal-Sham and ActiSham (F_(1,13) = 6.67, p = .023), with higher MEPs amplitudes after the application of Bifocal-Sham.ConclusionsCompared to traditional Bifocal-tDCS, ActiSham offers better participants’ blinding by inducing very similar scalp sensations to those of real Multifocal tDCS both in terms of intensity and localization, while not affecting corticospinal excitability.     

How structural and functional MRI can inform dual-site tACS parameters: A case study in a clinical population and its pragmatic implications

BackgroundAbnormalities in frontoparietal network (FPN) were observed in many neuropsychiatric diseases including substance use disorders. A growing number of studies are using dual-site-tACS with frontoparietal synchronization to engage this network. However, a computational pathway to inform and optimize parameter space for frontoparietal synchronization is still lacking. In this case study, in a group of participants with methamphetamine use disorders, we proposed a computational pathway to extract optimal electrode montage while accounting for stimulation intensity using structural and functional MRI.MethodsSixty methamphetamine users completed an fMRI drug cue-reactivity task. Four main steps were taken to define electrode montage and adjust stimulation intensity using 4x1 high-definition (HD) electrodes for a dual-site-tACS; (1) Frontal seed was defined based on the maximum electric fields (EF) predicted by simulation of HD montage over DLPFC (F3/F4 in EEG 10–10), (2) frontal seed-to-whole brain context-dependent correlation was calculated to determine connected regions to frontal seeds, (3) center of connected cluster in parietal cortex was selected as a location for placing the second set of HD electrodes to shape the informed montage, (4) individualized head models were used to determine optimal stimulation intensity considering underlying brain structure. The informed montage was compared to montages with large electrodes and classic frontoparietal HD montages (F3-P3/F4-P4) in terms of tACS-induced EF and ROI-to-ROI task-based/resting-state connectivity.ResultsCompared to the large electrodes, HD frontoparietal montages allow for a finer control of the spatial peak fields in the main nodes of the FPN at the cost of lower maximum EF (large-pad/HD: max EF[V/m] = 0.37/0.11, number of cortical sub-regions that EF exceeds 50% of the max = 77/13). For defining stimulation targets based on EF patterns, using group-level head models compared to a single standard head model results in comparable but significantly different seed locations (6.43 mm Euclidean distance between the locations of the frontal maximum EF in standard-space). As expected, significant task-based/resting-state connections were only found between frontal-parietal locations in the informed montage. Cue-induced craving score was correlated with frontoparietal connectivity only in the informed montage (r = ?0.24). Stimulation intensity in the informed montage, and not in the classic HD montage, needs 40% reduction in the parietal site to reduce the disparity in EF between stimulation sites.ConclusionThis study provides some empirical insights to montage and dose selection in dual-site-tACS using individual brain structures and functions and proposes a computational pathway to use head models and functional MRI to define (1) optimum electrode montage for targeting FPN in a context of interest (drug-cue-reactivity) and (2) proper transcranial stimulation intensity.     

Meta-analysis of the effects of transcranial direct current stimulation on inhibitory control

BackgroundInhibitory control refers to a central cognitive capacity involved in the interruption and correction of actions. Dysfunctions in these cognitive control processes have been identified as major maintaining mechanisms in a range of mental disorders such as ADHD, binge eating disorder, obesity, and addiction. Improving inhibitory control by transcranial direct current stimulation (tDCS) could ameliorate symptoms in a broad range of mental disorders.ObjectiveThe primary aim of this pre-registered meta-analysis was to investigate whether inhibitory control can be improved by tDCS in healthy and clinical samples. Additionally, several moderator variables were investigated.MethodsA comprehensive literature search was performed on PubMed/MEDLINE database, Web of Science, and Scopus. To achieve a homogenous sample, only studies that assessed inhibitory control in the go-/no-go (GNG) or stop-signal task (SST) were included, yielding a total of 75 effect sizes from 45 studies.ResultsResults of the meta-analysis indicate a small but significant overall effect of tDCS on inhibitory control (g = 0.21) which was moderated by target and return electrode placement as well as by the task. The small effect size was further reduced after correction for publication bias.ConclusionBased on the studies included, our meta-analytic approach substantiates previously observed differences between brain regions, i.e., involvement of the right inferior frontal gyrus (rIFG) vs. the right dorsolateral prefrontal cortex (rDLPFC) in inhibitory control. Results indicate a small moderating effect of tDCS on inhibitory control in single-session studies and highlight the relevance of technical and behavioral parameters.     

Sensory evoked potentials in patients with Rett syndrome through the lens of animal studies: Systematic review

ObjectiveSystematically review the abnormalities in event related potential (ERP) recorded in Rett Syndrome (RTT) patients and animals in search of translational biomarkers of deficits related to the particular neurophysiological processes of known genetic origin (MECP2 mutations).MethodsPubmed, ISI Web of Knowledge and BIORXIV were searched for the relevant articles according to PRISMA standards.ResultsERP components are generally delayed across all sensory modalities both in RTT patients and its animal model, while findings on ERPs amplitude strongly depend on stimulus properties and presentation rate. Studies on RTT animal models uncovered the abnormalities in the excitatory and inhibitory transmission as critical mechanisms underlying the ERPs changes, but showed that even similar ERP alterations in auditory and visual domains have a diverse neural basis. A range of novel approaches has been developed in animal studies bringing along the meaningful neurophysiological interpretation of ERP measures in RTT patients.ConclusionsWhile there is a clear evidence for sensory ERPs abnormalities in RTT, to further advance the field there is a need in a large-scale ERP studies with the functionally-relevant experimental paradigms.SignificanceThe review provides insights into domain-specific neural basis of the ERP abnormalities and promotes clinical application of the ERP measures as the non-invasive functional biomarkers of RTT pathophysiology.     

Derivation of Power M-Mode Transcranial Doppler Criteria for Angiographic Proven MCA Occlusion

BACKGROUND: Stringent transcranial Doppler (TCD) criteria for diagnosing occlusion are needed for more reliable TCD performance at bedside in the acute stroke setting. SUBJECTS AND METHODS: At three academic stroke centers, we performed TCD examination for patients with symptoms of cerebral ischemia who underwent digital subtraction angiography (DSA). We used a standard insonation protocol with power M-mode Doppler (PMD) TCD (TCD 100 M, Spencer Technologies Inc., Seattle, WA). We collected mean flow velocity (MFV), pulsatility indices (PI), and power M-mode resistance signature (absent, high, or low) in symptomatic middle (MCA), anterior (ACA), posterior (PCA), and in affected (a), ipsilateral (i), and contralateral (c-lat) cerebral arteries. Ratios of aMCA/c-lat MCA, aMCA/iACA, and aMCA/iPCA MFV were subsequently calculated. PMD-TCD flow findings were evaluated with a receiver-operating characteristic (ROC) analysis for angiographically proven MCA occlusion. RESULTS: We studied 120 patients with acute cerebral ischemia with PMD-TCD examinations prior to or immediately after DSA. Lower aMCA velocities pointed to higher probability of occlusion (P= .055). The aMCA/iPCA MFV ratio was superior to the aMCA/iACA ratio and strongly predictive of occlusion at a threshold ratio of 0.5 (RR 2.31 CI(95) 2.13-2.51). High resistance or absent M-mode flow signatures in the proximal MCA were present in 87% of M1 and M2 MCA occlusions (probability 87%). In the presence of a low-resistance PMD signature, obtaining the aMCA/iPCA MFV ratio <0.5 increases probability of occlusion to 87%. Normal MFV ratios and low-resistance M-mode signatures are highly predictive of a negative angiogram for MCA occlusion. CONCLUSION: In acute cerebral ischemia, reliable criteria for proximal MCA occlusion have been developed based on combination of MFV ratios and M-mode flow resistance signatures. Validation of these criteria will require multicenter studies.