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.

Transcranial current stimulation in epilepsy: A systematic review of the fundamental and clinical aspects.

Purpose: Transcranial electrical current stimulation (tES or tCS, as it is sometimes referred to) has been proposed as non-invasive therapy for pharmacoresistant epilepsy. This technique, which includes direct current (tDCS) and alternating current (tACS) stimulation involves the application of weak currents across the cortex to change cortical excitability. Although clinical trials have demonstrated the therapeutic efficacy of tES, its specific effects on epileptic brain activity are poorly understood. We sought to summarize the clinical and fundamental effects underlying the application of tES in epilepsy. Methods: A systematic review was performed in accordance with the PRISMA guidelines. A database search was performed in PUBMED, MEDLINE, Web of Science and Cochrane CENTRAL for articles corresponding to the keywords "epilepsy AND (transcranial current stimulation OR transcranial electrical stimulation)". Results: A total of 56 studies were included in this review. Through these records, we show that tDCS and tACS epileptic patients are safe and clinically relevant techniques for epilepsy. Recent articles reported changes of functional connectivity in epileptic patients after tDCS. We argue that tDCS may act by affecting brain networks, rather than simply modifying local activity in the targeted area. To explain the mechanisms of tES, various cellular effects have been identified. Among them, reduced cell loss, mossy fiber sprouting, and hippocampal BDNF protein levels. Brain modeling and human studies highlight the influence of individual brain anatomy and physiology on the electric field distribution. Computational models may optimize the stimulation parameters and bring new therapeutic perspectives. Conclusion: Both tDCS and tACS are promising techniques for epilepsy patients. Although the clinical effects of tDCS have been repeatedly assessed, only one clinical trial has involved a consistent number of epileptic patients and little knowledge is present about the clinical outcome of tACS. To fill this gap, multicenter studies on tES in epileptic patients are needed involving novel methods such as personalized stimulation protocols based on computational modeling. Furthermore, there is a need for more in vivo studies replicating the tES parameters applied in patients. Finally, there is a lack of clinical studies investigating changes in intracranial epileptiform discharges during tES application, which could clarify the nature of tES-related local and network dynamics in epilepsy.

Network-Based Transcranial Direct Current Stimulation May Modulate Gait Variability in Young Healthy Adults.

Purpose: Previous studies have linked gait variability to resting-state functional connectivity between the dorsal attention network (DAN) and the default network (DN) in the brain. The purpose of this study was to examine the effects of a novel transcranial direct current stimulation (tDCS) paradigm designed to simultaneously facilitate the excitability of the DAN and suppress the excitability of the DN (i.e., DAN+/DN-tDCS) on gait variability and other gait characteristics in young healthy adults. Methods: In this double-blinded randomized and sham-controlled study, 48 healthy adults aged 22 ± 2 years received one 20-min session of DAN+/DN-tDCS (n = 24) or no stimulation (the Sham group, n = 24). Immediately before and after stimulation, participants completed a gait assessment under three conditions: walking at self-selected speed (i.e., normal walking), walking as fast as possible (i.e., fast walking), and walking while counting backward (i.e., dual-task walking). Primary outcomes included gait stride time variability and gait stride length variability in normal walking conditions. Secondary outcomes include gait stride time and length variability in fast and dual-task conditions, and other gait metrics derived from the three walking conditions. Results: Compared to the Sham group, DAN+/DN-tDCS reduced stride length variability in normal and fast walking conditions, double-limb support time variability in fast and dual-task walking conditions, and step width variability in fast walking conditions. In contrast, DAN+/DN-tDCS did not alter average gait speed or the average value of any other gait metrics as compared to the sham group. Conclusion: In healthy young adults, a single exposure to tDCS designed to simultaneously modulate DAN and DN excitability reduced gait variability, yet did not alter gait speed or other average gait metrics, when tested just after stimulation. These results suggest that gait variability may be uniquely regulated by these spatially-distinct yet functionally-connected cortical networks. These results warrant additional research on the short- and longer-term effects of this type of network-based tDCS on the cortical control of walking in younger and older populations.

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.

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.

Patient-Tailored, Home-Based Non-invasive Brain Stimulation for Memory Deficits in Dementia Due to Alzheimer's Disease.

Alzheimer's disease (AD) is an irreversible, progressive brain disorder that can cause dementia (Alzheimer's disease-related dementia, ADRD) with growing cognitive disability and vast physical, emotional, and financial pressures not only on the patients but also on caregivers and families. Loss of memory is an early and very debilitating symptom in AD patients and a relevant predictor of disease progression. Data from rodents, as well as human studies, suggest that dysregulation of specific brain oscillations, particularly in the hippocampus, is linked to memory deficits. Animal and human studies demonstrate that non-invasive brain stimulation (NIBS) in the form of transcranial alternating current stimulation (tACS) allows to reliably and safely interact with ongoing oscillatory patterns in the brain in specific frequencies. We developed a protocol for patient-tailored home-based tACS with an instruction program to train a caregiver to deliver daily sessions of tACS that can be remotely monitored by the study team. We provide a discussion of the neurobiological rationale to modulate oscillations and a description of the study protocol. Data of two patients with ADRD who have completed this protocol illustrate the feasibility of the approach and provide pilot evidence on the safety of the remotely-monitored, caregiver-administered, home-based tACS intervention. These findings encourage the pursuit of a large, adequately powered, randomized controlled trial of home-based tACS for memory dysfunction in ADRD.

External induction and stabilization of brain oscillations in the human.

BACKGROUND: Neural oscillations in the cerebral cortex are associated with a range of cognitive processes and neuropsychiatric disorders. However, non-invasively modulating oscillatory activity remains technically challenging, due to limited strength, duration, or non-synchronization of stimulation waveforms with endogenous rhythms. OBJECTIVE: We hypothesized that applying controllable phase-synchronized repetitive transcranial magnetic stimulation pulses (rTMS) with alternating currents (tACS) may induce and stabilize neuro-oscillatory resting-state activity at targeted frequencies. METHODS: Using a novel circuit to precisely synchronize rTMS pulses with phase of tACS, we empirically tested whether combined, 10-Hz prefrontal bilateral stimulation could induce and stabilize 10-Hz oscillations in the bilateral prefrontal cortex (PFC). 25 healthy participants took part in a repeated-measures design. Whole-brain resting-state EEG in eyes-open (EO) and eyes-closed (EC) was recorded before (baseline), immediately (1-min), and 15- and 30-min after stimulation. Bilateral, phase-synchronized rTMS aligned to the positive tACS peak was compared with rTMS at tACS trough, with bilateral tACS or rTMS on its own, and to sham. RESULTS: 10-Hz resting-state PFC power increased significantly with peak-synchronized rTMS + tACS (EO: 44.64%, EC: 46.30%, p < 0.05) compared to each stimulation protocol on its own, and sham, with effects spanning between prefrontal and parietal regions and sustaining throughout 30-min. No effects were observed with the sham protocol. Moreover, rTMS timed to the negative tACS trough did not induce local or global changes in oscillations. CONCLUSION: Phase-synchronizing rTMS with tACS may be a viable approach for inducing and stabilizing neuro-oscillatory activity, particularly in scenarios where endogenous oscillatory tone is attenuated, such as disorders of consciousness or major depression.

Safety and Feasibility of Tele-Supervised Home-Based Transcranial Direct Current Stimulation for Major Depressive Disorder.

Major depressive disorder (MDD) is a worldwide cause of disability in older age, especially during the covid pandemic. Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that has shown encouraging efficacy for treatment of depression. Here, we investigate the feasibility of an innovative protocol where tDCS is administered within the homes of older adults with MDD (patient participants) with the help of a study companion (i.e. caregiver). We further analyze the feasibility of a remotely-hosted training program that provides the knowledge and skills to administer tDCS at home, without requiring them to visit the lab. We also employed a newly developed multi-channel tDCS system with real-time monitoring designed to guarantee the safety and efficacy of home-based tDCS. Patient participants underwent a total of 37 home-based tDCS sessions distributed over 12 weeks. The protocol consisted of three phases each lasting four weeks: an acute phase, containing 28 home-based tDCS sessions, a taper phase containing nine home-based tDCS sessions, and a follow up phase, with no stimulation sessions. We found that the home-based, remotely-supervised, study companion administered, multi-channel tDCS protocol for older adults with MDD was feasible and safe. Further, the study introduces a novel training program for remote instruction of study companions in the administration of tDCS. Future research is required to determine the translatability of these findings to a larger sample. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04799405?term=NCT04799405&draw=2&rank=1, identifier NCT04799405.

Network Mapping of Connectivity Alterations in Disorder of Consciousness: Towards Targeted Neuromodulation.

Disorder of consciousness (DoC) refers to a group of clinical conditions that may emerge after brain injury, characterized by a varying decrease in the level of consciousness that can last from days to years. An understanding of its neural correlates is crucial for the conceptualization and application of effective therapeutic interventions. Here we propose a quantitative meta-analysis of the neural substrate of DoC emerging from functional magnetic resonance (fMRI) and positron emission tomography (PET) studies. We also map the relevant networks of resulting areas to highlight similarities with Resting State Networks (RSNs) and hypothesize potential therapeutic solutions leveraging network-targeted noninvasive brain stimulation. Available literature was reviewed and analyzed through the activation likelihood estimate (ALE) statistical framework to describe resting-state or task-dependent brain activation patterns in DoC patients. Results show that task-related activity is limited to temporal regions resembling the auditory cortex, whereas resting-state fMRI data reveal a diffuse decreased activation affecting two subgroups of cortical (angular gyrus, middle frontal gyrus) and subcortical (thalamus, cingulate cortex, caudate nucleus) regions. Clustering of their cortical functional connectivity projections identify two main altered functional networks, related to decreased activity of (i) the default mode and frontoparietal networks, as well as (ii) the anterior salience and visual/auditory networks. Based on the strength and topography of their connectivity profile, biophysical modeling of potential brain stimulation solutions suggests the first network as the most feasible target for tES, tDCS neuromodulation in DoC patients.

Direct mapping of the electric permittivity of heterogeneous non-planar thin films at gigahertz frequencies by scanning microwave microscopy.

We obtained maps of electric permittivity at ∼19 GHz frequencies on non-planar thin film heterogeneous samples by means of combined atomic force-scanning microwave microscopy (AFM-SMM). We show that the electric permittivity maps can be obtained directly from the capacitance images acquired in contact mode, after removing the topographic cross-talk effects. This result demonstrates the possibility of identifying the electric permittivity of different materials in a thin film sample irrespectively of their thickness by just direct imaging and processing. We show, in addition, that quantitative maps of the electric permittivity can be obtained with no need for any theoretical calculation or complex quantification procedures when the electric permittivity of one of the materials is known. To achieve these results the use of contact mode imaging is a key factor. For non-contact imaging modes the effects of local sample thickness and of the imaging distance make the interpretation of the capacitance images in terms of the electric permittivity properties of the materials much more complex. The present results represent a substantial contribution to the field of nanoscale microwave dielectric characterization of thin film materials with important implications for the characterization of novel 3D electronic devices and 3D nanomaterials.

Nanoscale Electric Permittivity of Single Bacterial Cells at Gigahertz Frequencies by Scanning Microwave Microscopy.

We quantified the electric permittivity of single bacterial cells at microwave frequencies and nanoscale spatial resolution by means of near-field scanning microwave microscopy. To this end, calibrated complex admittance images have been obtained at ∼19 GHz and analyzed with a methodology that removes the nonlocal topographic cross-talk contributions and thus provides quantifiable intrinsic dielectric images of the bacterial cells. Results for single Escherichia coli cells provide a relative electric permittivity of ∼4 in dry conditions and ∼20 in humid conditions, with no significant loss contributions. Present findings, together with the ability of microwaves to penetrate the cell membrane, open an important avenue in the microwave label-free imaging of single cells with nanoscale spatial resolution.