Network-targeted transcranial direct current stimulation of the hypothalamus appetite-control network: a feasibility study.

The hypothalamus is the key regulator for energy homeostasis and is functionally connected to striatal and cortical regions vital for the inhibitory control of appetite. Hence, the ability to non-invasively modulate the hypothalamus network could open new ways for the treatment of metabolic diseases. Here, we tested a novel method for network-targeted transcranial direct current stimulation (net-tDCS) to influence the excitability of brain regions involved in the control of appetite. Based on the resting-state functional connectivity map of the hypothalamus, a 12-channel net-tDCS protocol was generated (Neuroelectrics Starstim system), which included anodal, cathodal and sham stimulation. Ten participants with overweight or obesity were enrolled in a sham-controlled, crossover study. During stimulation or sham control, participants completed a stop-signal task to measure inhibitory control. Overall, stimulation was well tolerated. Anodal net-tDCS resulted in faster stop signal reaction time (SSRT) compared to sham (p = 0.039) and cathodal net-tDCS (p = 0.042). Baseline functional connectivity of the target network correlated with SSRT after anodal compared to sham stimulation (p = 0.016). These preliminary data indicate that modulating hypothalamus functional network connectivity via net-tDCS may result in improved inhibitory control. Further studies need to evaluate the effects on eating behavior and metabolism.

Multichannel tDCS with Advanced Targeting for Major Depressive Disorder: A Tele-Supervised At-Home Pilot Study.

Introduction: Proof-of-principle human studies suggest that transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) may improve depression severity. This open-label multicenter study tested remotely supervised multichannel tDCS delivered at home in patients (N=35) with major depressive disorder (MDD). The primary aim was to assess the feasibility and safety of our protocol. As an exploratory aim, we evaluated therapeutic efficacy: the primary efficacy measure was the median percent change from baseline to the end of the 4-week post-treatment follow-up period in the observer-rated Montgomery-Asberg Depression Mood Rating Scale (MADRS). Methods: Participants received 37 at-home stimulation sessions (30 minutes each) of specifically designed multichannel tDCS targeting the left DLPFC administered over eight weeks (4 weeks of daily treatments plus 4 weeks of taper), with a follow-up period of 4 weeks following the final stimulation session. The stimulation montage (electrode positions and currents) was optimized by employing computational models of the electric field generated by multichannel tDCS using available structural data from a similar population (group optimization). Conducted entirely remotely, the study employed the MADRS for assessment at baseline, at weeks 4 and 8 during treatment, and at 4-week follow-up visits. Results: 34 patients (85.3% women) with a mean age of 59 years, a diagnosis of MDD according to DSM-5 criteria, and a MADRS score ≥20 at the time of study enrolment completed all study visits. At baseline, the mean time since MDD diagnosis was 24.0 (SD 19.1) months. Concerning compliance, 85% of the participants (n=29) completed the complete course of 37 stimulation sessions at home, while 97% completed at least 36 sessions. No detrimental effects were observed, including suicidal ideation and/or behavior. The study observed a median MADRS score reduction of 64.5% (48.6, 72.4) 4 weeks post-treatment (Hedge's g = -3.1). We observed a response rate (≥ 50% improvement in MADRS scores) of 72.7% (n=24) from baseline to the last visit 4 weeks post-treatment. Secondary measures reflected similar improvements. Conclusions: These results suggest that remotely supervised and supported multichannel home-based tDCS is safe and feasible, and antidepressant efficacy motivates further appropriately controlled clinical studies.

Neuroanatomical predictors of transcranial direct current stimulation (tDCS)-induced modifications in neurocognitive task performance in typically developing individuals.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique gaining more attention in neurodevelopmental disorders (NDDs). Due to the phenotypic heterogeneity of NDDs, tDCS is unlikely to be equally effective in all individuals. The present study aimed to establish neuroanatomical markers in typical developing (TD) individuals that may be used for the prediction of individual responses to tDCS. 57 TD male and female children received 2mA anodal and sham tDCS, targeting the left dorsolateral prefrontal cortex (DLPFCleft), right inferior frontal gyrus, and bilateral temporo-parietal junction. Response to tDCS was assessed based on task performance differences between anodal and sham tDCS in different neurocognitive tasks (N-back, Flanker, Mooney Faces Detection, Attentional Emotional Recognition task). Measures of cortical thickness (CT) and surface area (SA) were derived from 3-Tesla structural MRI scans. Associations between neuroanatomy and task performance were assessed using a general linear model. Machine learning (ML) algorithms were employed to predict responses to tDCS. Overall, vertex-wise estimates of SA were more closely linked to differences in task performance than measures of CT. Across ML algorithms, highest accuracies were observed for the prediction of N-back task performance differences following stimulation of the DLPFCleft, where 65% of behavioural variance was explained by variability in SA. Lower accuracies were observed for all other tasks and stimulated regions. This suggests that it may be possible to predict individual responses to tDCS for some behavioural measures and target regions. In the future, these models might be extended to predict treatment outcome in individuals with NDDs.Significance statement Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that has recently gained more attention in neurodevelopmental disorders (NDDs), such as autism and attention-deficit/hyperactivity disorder. However, due to the phenotypic heterogeneity of NDDs, tDCS is unlikely to be equally effective in all individuals. The present study aimed to establish neuroanatomical biomarkers in typical developing individuals that may be used for the prediction of individual responses to tDCS. Our findings suggest that it may be possible to accurately predict individual responses to tDCS for some behavioural measures using measures of neuroanatomy. In the future, our models might be extended to predict treatment outcome in individuals with clinical diagnoses, and may allow for more individualized, person-centred interventions.

Effects of Mixed Baculovirus Infections in Biological Control: A Comprehensive Historical and Technical Analysis.

Baculoviruses are insect-specific DNA viruses that have been exploited as bioinsecticides for the control of agricultural and forest pests around the world. Mixed infections with two different baculoviruses have been found in nature, infecting the same host. They have been studied to understand the biology of virus interactions, their effects on susceptible insects, and their insecticidal implications. In this work, we summarize and analyze the in vivo baculovirus co-infections reported in the literature, mainly focusing on pest biocontrol applications. We discuss the most common terms used to describe the effects of mixed infections, such as synergism, neutralism, and antagonism, and how to determine them based on host mortality. Frequently, baculovirus co-infections found in nature are caused by a combination of a nucleopolyhedrovirus and a granulovirus. Studies performed with mixed infections indicated that viral dose, larval stage, or the presence of synergistic factors in baculovirus occlusion bodies are important for the type of virus interaction. We also enumerate and discuss technical aspects to take into account in studies on mixed infections, such as statistical procedures, quantification of viral inocula, the selection of instars, and molecular methodologies for an appropriate analysis of baculovirus interaction. Several experimental infections using two different baculoviruses demonstrated increased viral mortality or a synergistic effect on the target larvae compared to single infections. This can be exploited to improve the baculovirus-killing properties of commercial formulations. In this work, we offer a current overview of baculovirus interactions in vivo and discuss their potential applications in pest control strategies.

Biophysical modeling of the electric field magnitude and distribution induced by electrical stimulation with intracerebral electrodes.

Intracranial electrodes are used clinically for diagnostic or therapeutic purposes, notably in drug-refractory epilepsy (DRE) among others. Visualization and quantification of the energy delivered through such electrodes is key to understanding how the resulting electric fields modulate neuronal excitability, i.e. the ratio between excitation and inhibition. Quantifying the electric field induced by electrical stimulation in a patient-specific manner is challenging, because these electric fields depend on a number of factors: electrode trajectory with respect to folded brain anatomy, biophysical (electrical conductivity / permittivity) properties of brain tissue and stimulation parameters such as electrode contacts position and intensity. Here, we aimed to evaluate various biophysical models for characterizing the electric fields induced by electrical stimulation in DRE patients undergoing stereoelectroencephalography (SEEG) recordings in the context of pre-surgical evaluation. This stimulation was performed with multiple-contact intracranial electrodes used in routine clinical practice. We introduced realistic 3D models of electrode geometry and trajectory in the neocortex. For the electrodes, we compared point (0D) and line (1D) sources approximations. For brain tissue, we considered three configurations of increasing complexity: a 6-layer spherical model, a toy model with a sulcus representation, replicating results from previous approaches; and went beyond the state-of-the-art by using a realistic head model geometry. Electrode geometry influenced the electric field distribution at close distances (∼3 mm) from the electrode axis. For larger distances, the volume conductor geometry and electrical conductivity dominated electric field distribution. These results are the first step towards accurate and computationally tractable patient-specific models of electric fields induced by neuromodulation and neurostimulation procedures.

Spherical harmonics representation of the steady-state membrane potential shift induced by tDCS in realistic neuron models.

Objective.We provide a systematic framework for quantifying the effect of externally applied weak electric fields on realistic neuron compartment models as captured by physiologically relevant quantities such as the membrane potential or transmembrane current as a function of the orientation of the field.Approach.We define a response function as the steady-state change of the membrane potential induced by a canonical external field of 1 V m-1as a function of its orientation. We estimate the function values through simulations employing reconstructions of the rat somatosensory cortex from the Blue Brain Project. The response of different cell types is simulated using the NEURON simulation environment. We represent and analyze the angular response as an expansion in spherical harmonics.Main results.We report membrane perturbation values comparable to those in the literature, extend them to different cell types, and provide their profiles as spherical harmonic coefficients. We show that at rest, responses are dominated by their dipole terms (ℓ=1), in agreement with experimental findings and compartment theory. Indeed, we show analytically that for a passive cell, only the dipole term is nonzero. However, while minor, other terms are relevant for states different from resting. In particular, we show howℓ=0andℓ=2terms can modify the function to induce asymmetries in the response.Significance.This work provides a practical framework for the representation of the effects of weak electric fields on different neuron types and their main regions-an important milestone for developing micro- and mesoscale models and optimizing brain stimulation solutions.

Towards a mesoscale physical modeling framework for stereotactic-EEG recordings.

Objective.Stereotactic-electroencephalography (SEEG) and scalp EEG recordings can be modeled using mesoscale neural mass population models (NMMs). However, the relationship between those mathematical models and the physics of the measurements is unclear. In addition, it is challenging to represent SEEG data by combining NMMs and volume conductor models due to the intermediate spatial scale represented by these measurements.Approach.We provide a framework combining the multi-compartmental modeling formalism and a detailed geometrical model to simulate the transmembrane currents that appear in layer 3, 5 and 6 pyramidal cells due to a synaptic input. With this approach, it is possible to realistically simulate the current source density (CSD) depth profile inside a cortical patch due to inputs localized into a single cortical layer and the induced voltage measured by two SEEG contacts using a volume conductor model. Based on this approach, we built a framework to connect the activity of a NMM with a volume conductor model and we simulated an example of SEEG signal as a proof of concept.Main results.CSD depends strongly on the distribution of the synaptic inputs onto the different cortical layers and the equivalent current dipole strengths display substantial differences (of up to a factor of four in magnitude in our example). Thus, the inputs coming from different neural populations do not contribute equally to the electrophysiological recordings. A direct consequence of this is that the raw output of NMMs is not a good proxy for electrical recordings. We also show that the simplest CSD model that can accurately reproduce SEEG measurements can be constructed from discrete monopolar sources (one per cortical layer).Significance.Our results highlight the importance of including a physical model in NMMs to represent measurements. We provide a framework connecting microscale neuron models with the neural mass formalism and with physical models of the measurement process that can improve the accuracy of predicted electrophysiological recordings.

Personalized, Multisession, Multichannel Transcranial Direct Current Stimulation in Medication-Refractory Focal Epilepsy: An Open-Label Study.

PURPOSE: Animal and proof-of-principle human studies suggest that cathodal transcranial direct current stimulation may suppress seizures in drug-resistant focal epilepsy. The present study tests the safety, tolerability, and effect size of repeated daily cathodal transcranial direct current stimulation in epilepsy have not been established, limiting development of clinically meaningful interventions. METHODS: We conducted a 2-center, open-label study on 20 participants with medically refractory, focal epilepsy, aged 9 to 56 years (11 women and 9 children younger than18 years). Each participant underwent 10 sessions of 20 minutes of cathodal transcranial direct current stimulation over 2 weeks. Multielectrode montages were designed using a realistic head model-driven approach to conduct an inhibitory electric field to the target cortical seizure foci and surrounding cortex to suppress excitability and reduce seizure rates. Patients recorded daily seizures using a seizure diary 8 weeks prior, 2 weeks during, and 8 to 12 weeks after the stimulation period. RESULTS: The median seizure reduction was 44% relative to baseline and did not differ between adult and pediatric patients. Three patients experienced an increase in seizure frequency of >50% during the stimulation period; in one, a 36% increase in seizure frequency persisted through 12 weeks of follow-up. Otherwise, participants experienced only minor adverse events-the most common being scalp discomfort during transcranial direct current stimulation. CONCLUSIONS: This pilot study supports the safety and efficacy of multifocal, personalized, multichannel, cathodal transcranial direct current stimulation for adult and pediatric patients with medication-refractory focal epilepsy, although identifies a possibility of seizure exacerbation in some. The data also provide insight into the effect size to inform the design of a randomized, sham-stimulation controlled trial.

A personalizable autonomous neural mass model of epileptic seizures.

Work in the last two decades has shown that neural mass models (NMM) can realistically reproduce and explain epileptic seizure transitions as recorded by electrophysiological methods (EEG, SEEG). In previous work, advances were achieved by increasing excitation and heuristically varying network inhibitory coupling parameters in the models. Based on these early studies, we provide a laminar NMM capable of realistically reproducing the electrical activity recorded by SEEG in the epileptogenic zone during interictal to ictal states. With the exception of the external noise input into the pyramidal cell population, the model dynamics are autonomous. By setting the system at a point close to bifurcation, seizure-like transitions are generated, including pre-ictal spikes, low voltage fast activity, and ictal rhythmic activity. A novel element in the model is a physiologically motivated algorithm for chloride dynamics: the gain of GABAergic post-synaptic potentials is modulated by the pathological accumulation of chloride in pyramidal cells due to high inhibitory input and/or dysfunctional chloride transport. In addition, in order to simulate SEEG signals for comparison with real seizure recordings, the NMM is embedded first in a layered model of the neocortex and then in a realistic physical model. We compare modeling results with data from four epilepsy patient cases. By including key pathophysiological mechanisms, the proposed framework captures succinctly the electrophysiological phenomenology observed in ictal states, paving the way for robust personalization methods based on NMMs.

Local and Distributed fMRI Changes Induced by 40 Hz Gamma tACS of the Bilateral Dorsolateral Prefrontal Cortex: A Pilot Study.

Over the past few years, the possibility of modulating fast brain oscillatory activity in the gamma (γ) band through transcranial alternating current stimulation (tACS) has been discussed in the context of both cognitive enhancement and therapeutic scenarios. However, the effects of tACS targeting regions outside the motor cortex, as well as its spatial specificity, are still unclear. Here, we present a concurrent tACS-fMRI block design study to characterize the impact of 40 Hz tACS applied over the left and right dorsolateral prefrontal cortex (DLPFC) in healthy subjects. Results suggest an increase in blood oxygenation level-dependent (BOLD) activity in the targeted bilateral DLPFCs, as well as in surrounding brain areas affected by stimulation according to biophysical modeling, i.e., the premotor cortex and anterior cingulate cortex (ACC). However, off-target effects were also observed, primarily involving the visual cortices, with further effects on the supplementary motor areas (SMA), left subgenual cingulate, and right superior temporal gyrus. The specificity of 40 Hz tACS over bilateral DLPFC and the possibility for network-level effects should be considered in future studies, especially in the context of recently promoted gamma-induction therapeutic protocols for neurodegenerative disorders.

Stereo-EEG based personalized multichannel transcranial direct current stimulation in drug-resistant epilepsy.

OBJECTIVE: In epilepsy, multichannel transcranial direct electrical stimulation (tDCS) is applied to decrease cortical activity through the delivery of weak currents using several scalp electrodes. We investigated the long-term effects of personalized, multisession, stereotactic-EEG (SEEG)-targeted multichannel tDCS on seizure frequency (SF) and functional connectivity (Fc) as measured by EEG in patients with drug-resistant epilepsy (DRE). METHODS: Ten patients suffering from DRE were recruited. Multichannel tDCS (Starstim, Neuroelectrics) was applied during three cycles (one cycle every 2 months) of stimulation. Each cycle consisted of five consecutive days where patients received tDCS daily in two 20 min sessions separated by 20 min. The montages were personalized to target epileptogenic area of each patient as defined by SEEG recordings. SF during and after treatment was compared with baseline. Fc changes were analysed using scalp EEG recordings. RESULTS: After the last tDCS session, five patients experienced a SF decrease of 50% or more compared with baseline (R: responders, average SF decrease of 74%). We estimated Fc changes between cycles and across R and non-responder (NR) patients. R presented a significant decrease in Fc (p < 0.05) at the third session in alpha and beta frequency bands compared to the first one. CONCLUSIONS: Multichannel tDCS guided by SEEG is a promising therapeutic approach. Significant response was associated with a decrease of Fc after three stimulation cycles. SIGNIFICANCE: Such results suggest that tDCS-induced functional plasticity changes that may underlie the clinical response.

Modeling implanted metals in electrical stimulation applications.

Objective. Metal implants impact the dosimetry assessment in electrical stimulation techniques. Therefore, they need to be included in numerical models. While currents in the body are ionic, metals only allow electron transport. In fact, charge transfer between tissues and metals requires electric fields to drive electrochemical reactions at the interface. Thus, metal implants may act as insulators or as conductors depending on the scenario. The aim of this paper is to provide a theoretical argument that guides the choice of the correct representation of metal implants in electrical models while considering the electrochemical nature of the problemApproach.We built a simple model of a metal implant exposed to a homogeneous electric field of various magnitudes. The same geometry was solved using two different models: a purely electric one (with different conductivities for the implant), and an electrochemical one. As an example of application, we also modeled a transcranial electrical stimulation (tES) treatment in a realistic head model with a skull plate using a high and low conductivity value for the plate.Main results. Metal implants generally act as electric insulators when exposed to electric fields up to around 100 V m-1and they only resemble a perfect conductor for fields in the order of 1000 V m-1and above. The results are independent of the implant's metal, but they depend on its geometry. tES modeling with implants incorrectly treated as conductors can lead to errors of 50% or more in the estimation of the induced fieldsSignificance.Metal implants can be accurately represented by a simple electrical model of constant conductivity, but an incorrect model choice can lead to large errors in the dosimetry assessment. Our results can be used to guide the selection of the most appropriate model in each scenario.

RNAi Expression in Cotton for Control of Herbivorous Insects.

Cultivated cotton (Gossypium hirsutum) is heavily attacked by various species of insects worldwide and breeding of new varieties resistant to pests is still a hard battle to win. RNAi technology is an important reverse genetics tool to induce gene silencing in eukaryotic organisms and produce phenotypic modifications. In cotton, RNAi was applied to investigate gene function and enhance resistance to insects and pathogens. Different methods and techniques can be used to synthetize double stranded RNA (dsRNA) into plant cells. The Agrobacterium-mediated transformation is a common method to introduce RNAi binary plasmids into cotton genome and obtain stable transgenics plants. This methodology includes the coculture of cotton tissues with Agrobacterium cultures, selection of transgenic cells and induction of somatic embryogenesis to finally obtain transgenic plants after a relatively long period of time. The transient synthesis of dsRNA mediated by virus-induced gene silencing (VIGS) in cotton is an alternative to anticipate the silencing effect of a specific RNA sequence, prior to the development of a stable transgenic plant. VIGS vectors are incorporated into the plant by agroinfiltration technique. During VIGS replication inside plant cells, synthetized dsRNA allows the study on specific heterologous gene expression including the phenotypic effect on herbivorous target pests, thus facilitating a rapid evaluation of dsRNA expressed in cotton plants against individual insect target genes. Here we describe the complementation of these two techniques to evaluate RNAi-based cotton plant protection against insect pests.

Multifocal Transcranial Direct Current Stimulation Modulates Resting-State Functional Connectivity in Older Adults Depending on the Induced Current Density.

Combining non-invasive brain stimulation (NIBS) with resting-state functional magnetic resonance imaging (rs-fMRI) is a promising approach to characterize and potentially optimize the brain networks subtending cognition that changes as a function of age. However, whether multifocal NIBS approaches are able to modulate rs-fMRI brain dynamics in aged populations, and if these NIBS-induced changes are consistent with the simulated electric current distribution on the brain remains largely unknown. In the present investigation, thirty-one cognitively healthy older adults underwent two different multifocal real transcranial direct current stimulation (tDCS) conditions (C1 and C2) and a sham condition in a crossover design during a rs-fMRI acquisition. The real tDCS conditions were designed to electrically induce two distinct complex neural patterns, either targeting generalized frontoparietal cortical overactivity (C1) or a detachment between the frontal areas and the posteromedial cortex (C2). Data revealed that the two tDCS conditions modulated rs-fMRI differently. C1 increased the coactivation of multiple functional couplings as compared to sham, while a smaller number of connections increased in C1 as compared to C2. At the group level, C1-induced changes were topographically consistent with the calculated electric current density distribution. At the individual level, the extent of tDCS-induced rs-fMRI modulation in C1 was related with the magnitude of the simulated electric current density estimates. These results highlight that multifocal tDCS procedures can effectively change rs-fMRI neural functioning in advancing age, being the induced modulation consistent with the spatial distribution of the simulated electric current on the brain. Moreover, our data supports that individually tailoring NIBS-based interventions grounded on subject-specific structural data might be crucial to increase tDCS potential in future studies amongst older adults.

Impact of multisession 40Hz tACS on hippocampal perfusion in patients with Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is associated with alterations in cortical perfusion that correlate with cognitive impairment. Recently, neural activity in the gamma band has been identified as a driver of arteriolar vasomotion while, on the other hand, gamma activity induction on preclinical models of AD has been shown to promote protein clearance and cognitive protection. METHODS: In two open-label studies, we assessed the possibility to modulate cerebral perfusion in 15 mild to moderate AD participants via 40Hz (gamma) transcranial alternating current stimulation (tACS) administered 1 h daily for 2 or 4 weeks, primarily targeting the temporal lobe. Perfusion-sensitive MRI scans were acquired at baseline and right after the intervention, along with electrophysiological recording and cognitive assessments. RESULTS: No serious adverse effects were reported by any of the participants. Arterial spin labeling MRI revealed a significant increase in blood perfusion in the bilateral temporal lobes after the tACS treatment. Moreover, perfusion changes displayed a positive correlation with changes in episodic memory and spectral power changes in the gamma band. CONCLUSIONS: Results suggest 40Hz tACS should be further investigated in larger placebo-controlled trials as a safe, non-invasive countermeasure to increase fast brain oscillatory activity and increase perfusion in critical brain areas in AD patients. TRIAL REGISTRATION: Studies were registered separately on ClinicalTrials.gov ( NCT03290326 , registered on September 21, 2017; NCT03412604 , registered on January 26, 2018).

Multichannel anodal tDCS over the left dorsolateral prefrontal cortex in a paediatric population.

Methodological studies investigating transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (lDLPFC) in paediatric populations are limited. Therefore, we investigated in a paediatric population whether stimulation success of multichannel tDCS over the lDLPFC depends on concurrent task performance and individual head anatomy. In a randomised, sham-controlled, double-blind crossover study 22 healthy participants (10-17 years) received 2 mA multichannel anodal tDCS (atDCS) over the lDLPFC with and without a 2-back working memory (WM) task. After stimulation, the 2-back task and a Flanker task were performed. Resting state and task-related EEG were recorded. In 16 participants we calculated the individual electric field (E-field) distribution. Performance and neurophysiological activity in the 2-back task were not affected by atDCS. atDCS reduced reaction times in the Flanker task, independent of whether atDCS had been combined with the 2-back task. Flanker task related beta oscillation increased following stimulation without 2-back task performance. atDCS effects were not correlated with the E-field. We found no effect of multichannel atDCS over the lDLPFC on WM in children/adolescents but a transfer effect on interference control. While this effect on behaviour was independent of concurrent task performance, neurophysiological activity might be more sensitive to cognitive activation during stimulation. However, our results are limited by the small sample size, the lack of an active control group and variations in WM performance.

Targeted tDCS Mitigates Dual-Task Costs to Gait and Balance in Older Adults.

OBJECTIVE: Among older adults, the ability to stand or walk while performing cognitive tasks (ie, dual-tasking) requires coordinated activation of several brain networks. In this multicenter, double-blinded, randomized, and sham-controlled study, we examined the effects of modulating the excitability of the left dorsolateral prefrontal cortex (L-DLPFC) and the primary sensorimotor cortex (SM1) on dual-task performance "costs" to standing and walking. METHODS: Fifty-seven older adults without overt illness or disease completed 4 separate study visits during which they received 20 minutes of transcranial direct current stimulation (tDCS) optimized to facilitate the excitability of the L-DLPFC and SM1 simultaneously, or each region separately, or neither region (sham). Before and immediately after stimulation, participants completed a dual-task paradigm in which they were asked to stand and walk with and without concurrent performance of a serial-subtraction task. RESULTS: tDCS simultaneously targeting the L-DLPFC and SM1, as well as tDCS targeting the L-DLPFC alone, mitigated dual-task costs to standing and walking to a greater extent than tDCS targeting SM1 alone or sham (p < 0.02). Blinding efficacy was excellent and participant subjective belief in the type of stimulation received (real or sham) did not contribute to the observed functional benefits of tDCS. INTERPRETATION: These results demonstrate that in older adults, dual-task decrements may be amenable to change and implicate L-DPFC excitability as a modifiable component of the control system that enables dual-task standing and walking. tDCS may be used to improve resilience and the ability of older results to walk and stand under challenging conditions, potentially enhancing everyday functioning and reducing fall risks. ANN NEUROL 2021;90:428-439.

A novel closed-loop EEG-tDCS approach to promote responsiveness of patients in minimally conscious state: A study protocol.

Transcranial direct current stimulation (tDCS) applied over the prefrontal cortex has been shown to improve behavioral responsiveness in patients with disorders of consciousness following severe brain injury, especially those in minimally conscious state (MCS). However, one potential barrier of clinical response to tDCS is the timing of stimulation with regard to the fluctuations of vigilance that characterize this population. Indeed, a previous study showed that the vigilance of MCS patients has periodic average cycles of 70 min (range 57-80 min), potentially preventing them to be in an optimal neural state to benefit from tDCS when applied randomly. To tackle this issue, we propose a new protocol to optimize the application of tDCS by selectively stimulating at high and low vigilance states. Electroencephalography (EEG) real-time spectral entropy will be used as a marker of vigilance and to trigger tDCS, in a closed-loop fashion. We will conduct a randomized controlled crossover clinical trial on 16 patients in prolonged MCS who will undergo three EEG-tDCS sessions 5 days apart (1. tDCS applied at high vigilance; 2. tDCS applied at low vigilance; 3. tDCS applied at a random moment). Behavioral effects will be assessed using the Coma Recovery Scale-Revised at baseline and right after the stimulations. EEG will be recorded throughout the session and for 30 min after the end of the stimulation. This unique and novel approach will provide patients' tailored treatment options, currently lacking in the field of disorders of consciousness.

Phase-IIa randomized, double-blind, sham-controlled, parallel group trial on anodal transcranial direct current stimulation (tDCS) over the left and right tempo-parietal junction in autism spectrum disorder-StimAT: study protocol for a clinical trial.

BACKGROUND: Autism spectrum disorder (ASD) is characterized by impaired social communication and interaction, and stereotyped, repetitive behaviour and sensory interests. To date, there is no effective medication that can improve social communication and interaction in ASD, and effect sizes of behaviour-based psychotherapy remain in the low to medium range. Consequently, there is a clear need for new treatment options. ASD is associated with altered activation and connectivity patterns in brain areas which process social information. Transcranial direct current stimulation (tDCS) is a technique that applies a weak electrical current to the brain in order to modulate neural excitability and alter connectivity. Combined with specific cognitive tasks, it allows to facilitate and consolidate the respective training effects. Therefore, application of tDCS in brain areas relevant to social cognition in combination with a specific cognitive training is a promising treatment approach for ASD. METHODS: A phase-IIa pilot randomized, double-blind, sham-controlled, parallel-group clinical study is presented, which aims at investigating if 10 days of 20-min multi-channel tDCS stimulation of the bilateral tempo-parietal junction (TPJ) at 2.0 mA in combination with a computer-based cognitive training on perspective taking, intention and emotion understanding, can improve social cognitive abilities in children and adolescents with ASD. The main objectives are to describe the change in parent-rated social responsiveness from baseline (within 1 week before first stimulation) to post-intervention (within 7 days after last stimulation) and to monitor safety and tolerability of the intervention. Secondary objectives include the evaluation of change in parent-rated social responsiveness at follow-up (4 weeks after end of intervention), change in other ASD core symptoms and psychopathology, social cognitive abilities and neural functioning post-intervention and at follow-up in order to explore underlying neural and cognitive mechanisms. DISCUSSION: If shown, positive results regarding change in parent-rated social cognition and favourable safety and tolerability of the intervention will confirm tDCS as a promising treatment for ASD core-symptoms. This may be a first step in establishing a new and cost-efficient intervention for individuals with ASD. TRIAL REGISTRATION: The trial is registered with the German Clinical Trials Register (DRKS), DRKS00014732 . Registered on 15 August 2018. PROTOCOL VERSION: This study protocol refers to protocol version 1.2 from 24 May 2019.