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Fatigue is a common and often debilitating feature of multiple sclerosis (MS) that lacks reliably effective treatment options for most patients. Transcranial direct current stimulation (tDCS), a safe and well-tolerated type of noninvasive brain stimulation, is a low-cost and home-based approach with the potential to reduce fatigue in MS. We conducted a double-blind, sham-controlled, randomized clinical trial to compare active vs. low-dose (sham) tDCS paired with computer-based cognitive training, delivered as a home-based intervention, to reduce MS-related fatigue. Participants with MS-related fatigue, but without depression, were stratified by neurologic disability using the Extended Disability Status Scale (EDSS) and randomized to complete 30 daily sessions over six weeks of either active or sham tDCS paired with online cognitive training (BrainHQ). The primary outcome was the change in PROMIS Fatigue score from baseline to the end of the intervention. A total of 117 participants were randomized, with 92% completing all treatment sessions. Both groups showed significant reductions in fatigue, with no significant difference between them. This suggests that tDCS does not provide any additional benefit over cognitive training alone in reducing fatigue, but confirms the feasibility and tolerance of this home-based intervention., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Galvanic Vestibular Stimulation (GVS) is a method of manipulating the vestibular system through non-invasive electrical current. Depending on how GVS is applied, it produces specific sensations related to vestibular mediated central pathways. The method has been tested for decades for both medical and non-medical applications and has demonstrated promise in treating a variety of disorders including peripheral vestibular conditions, central vestibular pathology due to neurodegenerative diseases, and post-stroke motor rehabilitation. As GVS continues to grow in popularity and applications, the field lacks clarity on appropriate stimulation parameters, despite their importance for safe and efficacious neuromodulation. This study aims to review the parameters used in various treatment applications while also providing a concise overview of the mechanisms underlying GVS thereby offering essential context and justification for the chosen parameters. We performed a literature search on the PubMed and Embase databases for clinical trials including the term "galvanic vestibular stimulation." After removing duplicates, secondary analyses, and studies that did not use GVS for therapeutic purposes, we were left with 53 independent studies. We extracted the stimulation parameters used in each study and report them here. The results of this review suggest that while some stimulation parameters are relatively standardized for specific treatment indications, others lack universally accepted guidelines as the field of GVS continues to evolve. Based on our findings, we recommend that future GVS research include at least one sham condition, the use of individualized current intensity, and the comparison of multiple GVS parameters within the same trial., Competing Interests: YV, LV, and AD were employees of Soterix Medical, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Valter, Vataksi, Allred, Hebert, Brunyé, Clark, Serrador and Datta.)

Candida auris is an emerging multidrug-resistant fungal pathogen that preferentially colonizes and persists in skin tissue, yet the host immune factors that regulate the skin colonization of C. auris in vivo are unknown. In this study, we employed unbiased single-cell transcriptomics of murine skin infected with C. auris to understand the cell type-specific immune response to C. auris. C. auris skin infection results in the accumulation of immune cells such as neutrophils, inflammatory monocytes, macrophages, dendritic cells, T cells, and NK cells at the site of infection. We identified fibroblasts as a major non-immune cell accumulated in the C. auris infected skin tissue. The comprehensive single-cell profiling revealed the transcriptomic signatures in cytokines, chemokines, host receptors (TLRs, C-type lectin receptors, NOD receptors), antimicrobial peptides, and immune signaling pathways in individual immune and non-immune cells during C. auris skin infection. Our analysis revealed that C. auris infection upregulates the expression of the IL-1RN gene (encoding IL-1R antagonist protein) in different cell types. We found IL-1Ra produced by macrophages during C. auris skin infection decreases the killing activity of neutrophils. Furthermore, C. auris uses a unique cell wall mannan outer layer to evade IL-1R-signaling mediated host defense. Collectively, our single-cell RNA seq profiling identified the transcriptomic signatures in immune and non-immune cells during C. auris skin infection. Our results demonstrate the IL-1Ra and IL-1R-mediated immune evasion mechanisms employed by C. auris to persist in the skin. These results enhance our understanding of host defense and immune evasion mechanisms during C. auris skin infection and identify potential targets for novel antifungal therapeutics., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Candida auris , a multidrug-resistant human fungal pathogen, was first identified in 2009 in Japan. Since then, systemic C. auris infections have now been reported in more than 50 countries, with mortality rates of 30%-60%. A major contributing factor to its high inter- and intrahospital clonal transmission is that C. auris, unlike most Candida species, displays unique skin tropism and can stay on human skin for a prolonged period. However, the molecular mechanisms responsible for C. auris skin colonization, intradermal persistence, and systemic virulence are poorly understood. Here, we report that C. auris Hog1 mitogen-activated protein kinase is essential for efficient skin colonization, intradermal persistence as well as systemic virulence. RNA-seq analysis of wild-type parental and hog1 Δ mutant strains revealed marked downregulation of genes involved in processes such as cell adhesion, cell wall rearrangement, and pathogenesis in hog1 Δ mutant compared to the wild-type parent. Consistent with these data, we found a prominent role for Hog1 in maintaining cell wall architecture, as the hog1 Δ mutant demonstrated a significant increase in cell-surface β-glucan exposure and a concomitant reduction in chitin content. Additionally, we observed that Hog1 was required for biofilm formation in vitro and fungal survival when challenged with primary murine macrophages and neutrophils ex vivo . Collectively, these findings have important implications for understanding the C. auris skin adherence mechanisms and penetration of skin epithelial layers preceding bloodstream infections., Importance: Candida auris is a World Health Organization fungal priority pathogen and an urgent public health threat recognized by the Centers for Disease Control and Prevention. C. auris has a unique ability to colonize human skin. It also persists on abiotic surfaces in healthcare environments for an extended period of time. These attributes facilitate the inter- and intrahospital clonal transmission of C. auris . Therefore, understanding C. auris skin colonization mechanisms is critical for infection control, especially in hospitals and nursing homes. However, despite its profound clinical relevance, the molecular and genetic basis of C. auris skin colonization mechanisms are poorly understood. Herein, we present data on the identification of the Hog1 MAP kinase as a key regulator of C. auris skin colonization. These findings lay the foundation for further characterization of unique mechanisms that promote fungal persistence on human skin., Competing Interests: The authors declare no conflict of interest.

Candida auris is an emerging multidrug-resistant fungal pathogen that preferentially colonizes and persists in skin tissue, yet the host immune factors that regulate the skin colonization of C. auris in vivo are unknown. In this study, we employed unbiased single-cell transcriptomics of murine skin infected with C. auris to understand the cell type-specific immune response to C. auris. C. auris skin infection results in the accumulation of immune cells such as neutrophils, inflammatory monocytes, macrophages, dendritic cells, T cells, and NK cells at the site of infection. We identified fibroblasts as a major non-immune cell accumulated in the C. auris infected skin tissue. The comprehensive single-cell profiling revealed the transcriptomic signatures in cytokines, chemokines, host receptors (TLRs, C-type lectin receptors, NOD receptors), antimicrobial peptides, and immune signaling pathways in individual immune and non-immune cells during C. auris skin infection. Our analysis revealed that C. auris infection upregulates the expression of the IL-1RN gene (encoding IL-1R antagonist protein) in different cell types. We found IL-1Ra produced by macrophages during C. auris skin infection decreases the killing activity of neutrophils. Furthermore, C. auris uses a unique cell wall mannan outer layer to evade IL-1R-signaling mediated host defense. Collectively, our single-cell RNA seq profiling identified the transcriptomic signatures in immune and non-immune cells during C. auris skin infection. Our results demonstrate the IL-1Ra and IL-1R-mediated immune evasion mechanisms employed by C. auris to persist in the skin. These results enhance our understanding of host defense and immune evasion mechanisms during C. auris skin infection and identify potential targets for novel antifungal therapeutics., Competing Interests: Conflict of Interest: None

Galvanic Vestibular Stimulation (GVS) has been proposed as an alternative display modality to relay information without increasing demands on the visual or auditory sensory modalities of the wearer or in environments where those modalities cannot be used (e.g., covert night operations). We further investigated this concept with four experiments designed to test: (1) thresholds at which subjects could distinguish between different GVS current amplitudes and polarities, (2) thresholds at which different bipolar (i.e., sinusoidal waveform with current oscillating between left and right directions) current frequencies were distinguishable among room temperature, hot, cold, and windy environments, (3) effects of unipolar (i.e., sinusoidal waveform with current occurring in only the left or right direction) currents on balance performance, and (4) dual-task performance among frequency and polarity modulated GVS conditions during a concordant visual search task. Subjects reliably distinguished between current amplitudes that varied from a pedestal of ± 0.6 mA by a median of 0.03 mA (range of 0.02-0.32 mA) and between unipolar currents at a median amplitude of 0.55 mA (range of 0.32-0.83 mA). GVS frequency thresholds were robust to the environment conditions tested, with no statistical differences found. Sway and balance errors were increased with unipolar currents. GVS thresholds were not impacted by the dual-task paradigm, but the visual search scores were slightly elevated when congruently performing a polarity thresholding task. Overall findings continue to support GVS use as a display modality, but some limitations are noted, such as the use of unipolar currents under scenarios where postural control is important., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Many individuals with progressive multiple sclerosis (PMS) are challenged by reduced manual dexterity and limited rehabilitation options. Transcranial direct current stimulation (tDCS) during motor training can improve rehabilitation outcomes. We developed a protocol for remotely supervising tDCS to deliver sessions of stimulation paired with training at home., Objective: This study evaluated the effectiveness of at-home tDCS paired with manual dexterity training for individuals with PMS., Methods: Sixty-five right-hand dominant participants with PMS and hand impairment were randomized to receive either active or sham M1-SO tDCS paired with manual dexterity training over 4 weeks. Clinical outcomes were measured by the changes in Nine-Hole Peg Test (9-HPT) and Dellon-Modified-Moberg-Pick-Up Test (DMMPUT)., Results: The intervention had high rates of adherence and completion (98% of participants completed at least 18 of 20 sessions). The active tDCS group demonstrated significant improvement for the left hand compared with baseline in 9-HPT (-5.85 ± 6.19 vs -4.23 ± 4.34, p = 0.049) and DMMPUT (-10.62 ± 8.46 vs -8.97 ± 6.18, p = 0.049). The active tDCS group reported improvements in multiple sclerosis (MS)-related quality of life (mean increase: 5.93 ± 13.04 vs -0.05 ± -8.27; p = 0.04)., Conclusion: At-home tDCS paired with manual dexterity training is effective for individuals with PMS, with M1-SO tDCS enhancing training outcomes and offering a promising intervention for improving and preserving hand dexterity., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: L.C. has received a speaker fee from Soterix Medical Inc. The City University of New York holds patents on brain stimulation with M.B. and A.D. as inventors. M.B. has equity in Soterix Medical Inc. A.D. is an employee of Soterix Medical Inc.

Background: Transcranial temporal interference stimulation (tTIS) is a new, emerging neurostimulation technology that utilizes two or more electric fields at specific frequencies to modulate the oscillations of neurons at a desired spatial location in the brain. The physics of tTIS offers the advantage of modulating deep brain structures in a non-invasive fashion and with minimal stimulation of the overlying cortex outside of a selected target. As such, tTIS can be effectively employed in the context of therapeutics for the psychiatric disease of disrupted brain connectivity, such as major depressive disorder (MDD). The subgenual anterior cingulate cortex (sgACC), a key brain center that regulates human emotions and influences negative emotional states, is a plausible target for tTIS in MDD based on reports of its successful neuromodulation with invasive deep brain stimulation., Methods: This pilot, single-site, double-blind, randomized, sham-controlled interventional clinical trial will be conducted at St. Michael's Hospital - Unity Health Toronto in Toronto, ON, Canada. The primary objective is to demonstrate target engagement of the sgACC with 130 Hz tTIS using resting-state magnetic resonance imaging (MRI) techniques. The secondary objective is to estimate the therapeutic potential of tTIS for MDD by evaluating the change in clinical characteristics of participants and electrophysiological outcomes and providing feasibility and tolerability estimates for a large-scale efficacy trial. Thirty participants (18-65 years) with unipolar, non-psychotic MDD will be recruited and randomized to receive 10 sessions of 130 Hz tTIS or sham stimulation ( n = 15 per arm). The trial includes a pre- vs. post-treatment 3T MRI scan of the brain, clinical evaluation, and electroencephalography (EEG) acquisition at rest and during the auditory mismatch negativity (MMN) paradigm., Discussion: This study is one of the first-ever clinical trials among patients with psychiatric disorders examining the therapeutic potential of repetitive tTIS and its neurobiological mechanisms. Data obtained from this trial will be used to optimize the tTIS approach and design a large-scale efficacy trial. Research in this area has the potential to provide a novel treatment option for individuals with MDD and circuitry-related disorders and may contribute to the process of obtaining regulatory approval for therapeutic applications of tTIS., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT05295888., Competing Interests: AD is an employee of Soterix Medical, Inc. AH was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, 424778381 – TRR 295), Deutsches Zentrum für Luft- und Raumfahrt (DynaSti grant within the EU Joint Programme Neurodegenerative Disease Research, JPND), the National Institutes of Health (R01 13478451, 1R01NS127892-01, 2R01 MH113929, and UM1NS132358) as well as the New Venture Fund (FFOR Seed Grant), and reports lecture fees for Boston Scientific and is a consultant for Functional Neuromodulation Ltd. and Abbott. SHK has received honoraria or research funds from Abbott, Alkermes, Allergan, Boehringer Ingelheim, Brain Canada, Canadian Institutes of Health Research, Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute, Ontario Research Fund, Otsuka, Pfizer, Servier, Sunovion, Sun Pharmaceuticals, and holds stock in Field Trip Health. ESB is an inventor on the Temporal Interference (TI) Stimulation patent and a co-founder of TI Solutions, a for-profit company. VB is supported by the Academic Scholar Award from the University of Toronto Department of Psychiatry and has received research support from the Canadian Institutes of Health Research, Brain & Behavior Foundation, Ontario Ministry of Health Innovation Funds, Royal College of Physicians and Surgeons of Canada, Department of National Defence (Government of Canada), New Frontiers in Research Fund, Associated Medical Services Inc. Healthcare, American Foundation for Suicide Prevention, Roche Canada, Novartis, and Eisai. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Demchenko, Rampersad, Datta, Horn, Churchill, Kennedy, Krishnan, Rueda, Schweizer, Griffiths, Boyden, Santarnecchi and Bhat.)

Background: Galvanic Vestibular Stimulation (GVS) is a non-invasive electrical stimulation technique that is typically used to probe the vestibular system. When using direct current or very low frequency sine, GVS causes postural sway or perception of illusory (virtual) motions. GVS is commonly delivered using two electrodes placed at the mastoids, however, placements involving additional electrodes / locations have been employed. Our objective was to systematically evaluate all known GVS electrode placements, compare induced current flow, and how it relates to the archetypal sway and virtual motions. The ultimate goal is to help users in having a better understanding of the effects of different placements., Methods: We simulated seven GVS electrode placements with same total injected current using an ultra-high resolution model. Induced electric field (EF) patterns at the cortical and the level of vestibular organs (left and right) were determined. A range of current flow metrics including potential factors such as inter-electrode separation, percentage of current entering the cranial cavity, and symmetricity were calculated. Finally, we relate current flow to reported GVS motions., Results: As expected, current flow patterns are electrode placement specific. Placements with two electrodes generally result in higher EF magnitude. Placements with four electrodes result in lower percentage of current entering the cranial cavity. Symmetric placements do not result in similar EF values in the left and the right organs respectively- highlighting inherent anatomical asymmetry of the human head. Asymmetric placements were found to induce as much as ~3-fold higher EF in one organ over the other. The percentage of current entering the cranial cavity varies between ~15% and ~40% depending on the placement., Conclusions: We expect our study to advance understanding of GVS and provide insight on probable mechanism of action of a certain electrode placement choice. The dataset generated across several metrics will support hypothesis testing relating empirical outcomes to current flow patterns. Further, the differences in current flow will guide stimulation strategy (what placement and how much scalp current to use) and facilitate a quantitatively informed rational / optimal decision., Competing Interests: DQT, CT, SI, YV, and AD are employees of Soterix Medical. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Truong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Candida auris, an emerging fungal pathogen, predominately colonizes human skin leading to serious invasive infections in humans. Though it is assumed that skin colonization can lead to invasive infection, dissemination potential of C. auris from skin to internal organs is still unknown. In this study, immunocompetent and immunocompromised mouse models of intradermal skin infection were used to compare the dissemination potential of C. auris to internal organs. Our results suggest that C. auris persists in the skin tissue of both immunocompetent and immunocompromised infected mice even at 30 days post-infection. Furthermore, C. auris can readily disseminate from skin tissue to internal organs such as the spleen and kidney as early as 24 h post-infection and was detected until 30 days post-infection. Taken together, our findings for the first time indicate that murine skin intradermally infected with C. auris can readily disseminate to internal organs and cause invasive infections., Importance: Candida auris is a multi-drug-resistant emerging fungal pathogen colonizes the human skin and causes life-threatening infections. However, whether C. auris can disseminate from the skin to internal organs is unclear. Understanding the dissemination potential of C. auris in both immunocompetent and immunocompromised hosts is necessary to monitor susceptible individuals and to develop novel approaches to prevent and treat this emerging fungal pathogen. Using mouse models of intradermal C. auris skin infection, our findings report a novel observation that mice skin intradermally infected with C. auris can readily disseminate to internal organs leading to systemic disease. These findings help explain the colonization, persistence, and dissemination potential of C. auris in immunocompetent and immunocompromised hosts and reveal that skin infection is a potential source of invasive infection., Competing Interests: The authors declare no conflict of interest.

Introduction: Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique with simultaneous (during stimulation) and cumulative effects (after repeated sessions) on blood flow and neuronal metabolism. These effects remain mostly unclear especially in multiple sclerosis (MS). This work aims to elucidate brain metabolic and hemodynamic underpinnings of tDCS and its potential therapeutic impact in MS patients using quantitative tDCS-MRI., Methods: MS participants (n = 20; age = 45.4 ± 12.3 years, 7 males) underwent 3 T MRI scans before and after 20 daily sessions of dorsolateral prefrontal cortex (DLFPC) tDCS (2.0 mA, left anodal) paired with adaptive cognitive training (aCT). During both visits, imaging measurements of cerebral blood flow (CBF), cerebral venous blood oxygenation (Yv) and calculated cerebral metabolic rate of oxygen (CMRO 2 ) were obtained at pre-tDCS, during-tDCS and post-tDCS., Results: At baseline, significant increase from pre- to during-tDCS was observed in CMRO 2 (7.6%; p  = 0.002), CBF (11.0%; p  < 0.0001) and Yv (1.9%; p  = 0.006). At follow up, we observed an increase in pre-tDCS CMRO 2 (140.59 ± 13.83 μmol/100 g/min) compared to baseline pre-tDCS levels (128.30 ± 14.00 μmol/100 g/min; p  = 0.006). Sustained elevations in CMRO 2 and CBF into post-tDCS were also observed (tDCS lingering effects). Cumulative tDCS effects were observed in the form of sustained elevations in CMRO 2 and CBF in pre-tDCS follow up, reaching the magnitudes measured at baseline during-tDCS., Discussion: TDCS induces an acute surge in metabolic activity persisting immediately after the stimulation is removed. Moreover, treatment composed of repeated tDCS-aCT paired sessions contributes to establishing long-lasting increases in neuronal activity., Competing Interests: Soterix Medical Inc. provided the tDCS equipment used for research use. The City University of New York holds patents on brain stimulation with MB as inventor. The City University of New York holds patents on brain stimulation with AD as inventor. AD is an employee of Soterix Medical Inc. AD has equity in Soterix Medical Inc. MB has equity in Soterix Medical Inc. MB consults, received grants, assigned inventions, and/or serves on the SAB of SafeToddles, Boston Scientific, GlaxoSmithKline, Biovisics, Mecta, Lumenis, Halo Neuroscience, Google-X, i-Lumen, Humm, Allergan (Abbvie), Apple. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Muccio, Pilloni, Walton Masters, He, Krupp, Datta, Bikson, Charvet and Ge.)

Inhibitors of the transforming growth factor-β (TGF-β) pathway are potentially promising antifibrotic therapies, but nonselective simultaneous inhibition of all three TGF-β homologs has safety liabilities. TGF-β1 is noncovalently bound to a latency-associated peptide that is, in turn, covalently bound to different presenting molecules within large latent complexes. The latent TGF-β-binding proteins (LTBPs) present TGF-β1 in the extracellular matrix, and TGF-β1 is presented on immune cells by two transmembrane proteins, glycoprotein A repetitions predominant (GARP) and leucine-rich repeat protein 33 (LRRC33). Here, we describe LTBP-49247, an antibody that selectively bound to and inhibited the activation of TGF-β1 presented by LTBPs but did not bind to TGF-β1 presented by GARP or LRRC33. Structural studies demonstrated that LTBP-49247 recognized an epitope on LTBP-presented TGF-β1 that is not accessible on GARP- or LRRC33-presented TGF-β1, explaining the antibody's selectivity for LTBP-complexed TGF-β1. In two rodent models of kidney fibrosis of different etiologies, LTBP-49247 attenuated fibrotic progression, indicating the central role of LTBP-presented TGF-β1 in renal fibrosis. In mice, LTBP-49247 did not have the toxic effects associated with less selective TGF-β inhibitors. These results establish the feasibility of selectively targeting LTBP-bound TGF-β1 as an approach for treating fibrosis.

Transcranial Photobiomodulation (tPBM) is a non-invasive procedure where light is applied to the scalp to modulate underlying brain activity. tPBM has recently attracted immense interest as a potential therapeutic option for a range of neurological and neuropsychiatric conditions. The common technological questions related to this modality are extent of light penetration and associated scalp and brain temperature increases. Limited computational efforts to quantify these aspects are restricted to simplified models. We consider here a 3D high-resolution (1 mm) and anatomically realistic model to simulate light propagation and thermal effects. We consider a dose of 100 mW /cm 2 and use a single light source targeting the F3 location based on 10-20 EEG. Our simulations reveal that while the induced irradiance distribution largely mimics the shape and extent of the source, there is a blurring effect at the brain. This diffusion is attributed to the scalp, skull, and compounded at the surface of the cerebrospinal fluid. Around 1% of the injected irradiance reaches the gray matter. As expected and aligned with previous efforts, the scalp accounts for the greatest loss (~65%). We observe a nominal 0.38 °C rise in the scalp in regions directly underneath the source. There is negligible temperature rise in the brain. Finally, irradiance reduces to 0.01 mW /cm 2 at ~13.5 cm from the scalp surface.

Introduction: Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are increasingly used for major depressive disorder (MDD). Most tDCS and rTMS studies target the left dorsolateral prefrontal cortex, either with or without neuronavigation. We examined the effect of rTMS and tDCS, and the added value of neuronavigation in the treatment of MDD., Methods: A search on PubMed, Embase, and Cochrane databases for rTMS or tDCS randomized controlled trials of MDD up to 1 February 2023, yielded 89 studies. We then performed meta-analyses comparing tDCS efficacy to non-neuronavigated rTMS, tDCS to neuronavigated rTMS, and neuronavigated rTMS to non-neuronavigated rTMS. We assessed the significance of the effect in subgroups and in the whole meta-analysis with a z-test and subgroup differences with a chi-square test., Results: We found small-to-medium effects of both tDCS and rTMS on MDD, with a slightly greater effect from rTMS. No significant difference was found between neuronavigation and non-neuronavigation., Conclusion: Although both tDCS and rTMS are effective in treating MDD, many patients do not respond. Additionally, current neuronavigation methods are not significantly improving MDD treatment. It is therefore imperative to seek personalized methods for these interventions.

Candida auris , a multidrug-resistant human fungal pathogen, was first identified in 2009 in Japan. Since then, systemic C. auris infections have now been reported in more than 50 countries, with mortality rates of 30-60%. A major contributing factor to its high inter- and intrahospital clonal transmission is that C. auris, unlike most Candida species, displays unique skin tropism and can stay on human skin for a prolonged period. However, the molecular mechanisms responsible for C. auris skin colonization, intradermal persistence, and systemic virulence are poorly understood. Here, we report that C. auris Hog1 mitogen-activated protein kinase (MAPK) is essential for efficient skin colonization, intradermal persistence, as well as systemic virulence. RNA-seq analysis of wildtype parental and hog1 Δ mutant strains revealed marked down-regulation of genes involved in processes such as cell adhesion, cell-wall rearrangement, and pathogenesis in hog1 Δ mutant compared to the wildtype parent. Consistent with these data, we found a prominent role for Hog1 in maintaining cell-wall architecture, as the hog1 Δ mutant demonstrated a significant increase in cell-surface β-glucan exposure and a concomitant reduction in chitin content. Additionally, we observed that Hog1 was required for biofilm formation in vitro and fungal survival when challenged with primary murine macrophages and neutrophils ex vivo . Collectively, these findings have important implications for understanding the C. auris skin adherence mechanisms and penetration of skin epithelial layers preceding bloodstream infections., Importance: Candida auris is a World Health Organization (WHO) fungal priority pathogen and an urgent public health threat recognized by the Centers for Disease Control and Prevention (CDC). C. auris has a unique ability to colonize human skin. It also persists on abiotic surfaces in healthcare environments for an extended period of time. These attributes facilitate the inter- and intrahospital clonal transmission of C. auris . Therefore, understanding C. auris skin colonization mechanisms are critical for infection control, especially in hospitals and nursing homes. However, despite its profound clinical relevance, the molecular and genetic basis of C. auris skin colonization mechanisms are poorly understood. Herein, we present data on the identification of the Hog1 MAP kinase as a key regulator of C. auris skin colonization. These findings lay foundation for further characterization of unique mechanisms that promote fungal persistence on human skin.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that uses low-amplitude direct currents to alter cortical excitability. Previous trials have established the safety and tolerability of tDCS, and its potential to mitigate symptoms. However, the effects are cumulative, making it more difficult to have adherence to the treatment since frequent visits to the clinic or outpatient center are required. Moreover, the time needed for transportation to the center and the related expenses limit the accessibility of the treatment for many participants. Following guidelines for remotely supervised transcranial direct current stimulation (RS-tDCS) implementation, we propose a protocol designed for remotely supervised and home-based participation that uses specific devices and materials modified for patient use, with real-time monitoring by researchers through an encrypted video conferencing platform. We have developed detailed instructional materials and structured training procedures to allow for self- or proxy-administration while supervised remotely in real time. This protocol has a specific design to have a series of checkpoints during training and execution of the visit. This protocol is currently in use in a large pragmatic study of RS-tDCS for phantom limb pain (PLP). In this article, we will discuss the operational challenges of conducting a home-based RS-tDCS session and show methods to enhance its efficacy with supervised sessions.

Converging theoretical frameworks suggest a role and a therapeutic potential for spinal interoceptive pathways in major depressive disorder (MDD). Here, we aimed to evaluate the antidepressant effects and tolerability of transcutaneous spinal direct current stimulation (tsDCS) in MDD. This was a double-blind, randomized, sham-controlled, parallel group, pilot clinical trial in unmedicated adults with moderate MDD. Twenty participants were randomly allocated (1:1 ratio) to receive "active" 2.5 mA or "sham" anodal tsDCS sessions with a thoracic (anode; T10)/right shoulder (cathode) electrode montage 3 times/week for 8 weeks. Change in depression severity (MADRS) scores (prespecified primary outcome) and secondary clinical outcomes were analyzed with ANOVA models. An E-Field model was generated using the active tsDCS parameters. Compared to sham (n = 9), the active tsDCS group (n = 10) showed a greater baseline to endpoint decrease in MADRS score with a large effect size (-14.6 ± 2.5 vs. -21.7 ± 2.3, p = 0.040, d = 0.86). Additionally, compared to sham, active tsDCS induced a greater decrease in MADRS "reported sadness" item (-1.8 ± 0.4 vs. -3.2 ± 0.4, p = 0.012), and a greater cumulative decrease in pre/post tsDCS session diastolic blood pressure change from baseline to endpoint (group difference: 7.9 ± 3.7 mmHg, p = 0.039). Statistical trends in the same direction were observed for MADRS "pessimistic thoughts" item and week-8 CGI-I scores. No group differences were observed in adverse events (AEs) and no serious AEs occurred. The current flow simulation showed electric field at strength within the neuromodulation range (max. ~0.45 V/m) reaching the thoracic spinal gray matter. The results from this pilot study suggest that tsDCS is feasible, well-tolerated, and shows therapeutic potential in MDD. This work also provides the initial framework for the cautious exploration of non-invasive spinal cord neuromodulation in the context of mental health research and therapeutics. The underlying mechanisms warrant further investigation. Clinicaltrials.gov registration: NCT03433339 URL: https://clinicaltrials.gov/ct2/show/NCT03433339 ., (© 2023. The Author(s).)

Objective: We propose and assess galvanic vestibular stimulation (GVS) as a novel means to provide information dissociated from self-orientation., Background: In modern user interfaces, visual and auditory modalities dominate information transfer so much that these "processing channels" become overloaded with information. Fortunately, the brain is capable of processing separate sensory sources in parallel enabling alternative display modalities to inform operators more effectively and without increasing cognitive strain. To date, the vestibular system, normally responsible for sensing self-orientation and helping with balance, has not been considered as a display modality., Method: Bilateral GVS was provided at 0.6 mA for 1-second intervals with moderately high-frequency sinusoidal waveforms, designed to not elicit sensations of self-motion. We assessed subjects' ability to differentiate between two cues of different frequencies., Results: We found subjects were able to reliably distinguish between cues with an average just-noticeable difference threshold of only ±12 Hz (range across subjects: 5.4-19.6 Hz) relative to a pedestal cue of 50 Hz. Further, we found the GVS sensory modality to be robust to various environments: walking, standing, sitting, passive motion, and loud background noise. Finally, the application of the GVS cues did not have significant destabilizing effects when standing or walking., Conclusion: These results show that GVS may be an effective alternative display modality, using varying frequency to encode information. It is robust to various operational environments and non-destabilizing., Application: A fully functional display can convey information to operators of vehicles and other machinery as well as high-performance operators like astronauts and soldiers.

Electroconvulsive therapy (ECT) pulse amplitude, which dictates the induced electric field (E-field) magnitude in the brain, is presently fixed at 800 or 900 milliamperes (mA) without clinical or scientific rationale. We have previously demonstrated that increased E-field strength improves ECT's antidepressant effect but worsens cognitive outcomes. Amplitude-determined seizure titration may reduce the E-field variability relative to fixed amplitude ECT. In this investigation, we assessed the relationships among amplitude-determined seizure-threshold (ST a ), E-field magnitude, and clinical outcomes in older adults (age range 50 to 80 years) with depression. Subjects received brain imaging, depression assessment, and neuropsychological assessment pre-, mid-, and post-ECT. ST a was determined during the first treatment with a Soterix Medical 4×1 High Definition ECT Multi-channel Stimulation Interface (Investigation Device Exemption: G200123). Subsequent treatments were completed with right unilateral electrode placement (RUL) and 800 mA. We calculated E brain defined as the 90th percentile of E-field magnitude in the whole brain for RUL electrode placement. Twenty-nine subjects were included in the final analyses. E brain per unit electrode current, E brain /I, was associated with ST a . ST a was associated with antidepressant outcomes at the mid-ECT assessment and bitemporal electrode placement switch. E brain /I was associated with changes in category fluency with a large effect size. The relationship between ST a and E brain /I extends work from preclinical models and provides a validation step for ECT E-field modeling. ECT with individualized amplitude based on E-field modeling or ST a has the potential to enhance neuroscience-based ECT parameter selection and improve clinical outcomes., (© 2024. The Author(s).)

Importance: Candida auris is a globally emerging fungal pathogen that transmits among individuals in hospitals and nursing home residents. Unlike other Candida species, C. auris predominantly colonizes and persists in skin tissue, resulting in outbreaks of nosocomial infections. Understanding the factors that regulate C. auris skin colonization is critical to develop novel preventive and therapeutic approaches against this emerging pathogen. We established a model of intradermal C. auris inoculation in mice and found that mice infected with C. auris elicit less potent innate and adaptive immune responses in the infected skin compared to C. albicans . These findings help explain the clinical observation of persistent C. auris colonization in skin tissue., Competing Interests: The authors declare no conflict of interest.

Background: The two-implant retained mandibular overdenture utilizing nonsplinted implants is a proven treatment modality for completely edentulous patients. However, a lacuna still exists regarding the suitability of mini dental implants for this purpose. The purpose of the study was to evaluate implant stability and crestal bone loss in single-piece mini dental implants loaded with immediate or conventional loading protocols to retain a mandibular overdenture., Method: Twenty-four completely edentulous patients were rehabilitated using conventional maxillary complete denture and a mandibular two-implant retained overdenture utilizing nonsplinted single piece mini implants. The implants were loaded with immediate or conventional loading protocols. Implant stability (with Periotest TM) and crestal bone loss (with radiovisiograph and radiographic grid) were evaluated at the time of loading and at one, two, and six months after loading. Statistical analysis was done with the Independent Samples "t" test and One-Way ANOVA., Results: Mean Periotest Values observed were significantly more negative in implants loaded with the conventional loading protocol. Crestal bone loss was significantly lesser in the immediate loading protocol but was still higher than the requisite 1.5 mm postulated by established criteria., Conclusion: Two single-piece nonsplinted mini implants may be sufficient to retain a mandibular overdenture utilizing the immediate loading protocol. Further studies with a longer duration of observation and larger sample size are required., Competing Interests: The authors have none to declare., (© 2021 Director General, Armed Forces Medical Services. Published by Elsevier, a division of RELX India Pvt. Ltd.)

Background: Amyotrophic lateral sclerosis (ALS) is a progressive disease for which no curative treatment is currently available., Objective: This study aimed to investigate whether cortico-spinal transcranial direct current stimulation (tDCS) could mitigate symptoms in ALS patients via a randomized, double-blind, sham-controlled trial, followed by an open-label phase., Methods: Thirty-one participants were randomized into two groups for the initial controlled phase. At baseline (T0), Group 1 received placebo stimulation (sham tDCS), while Group 2 received cortico-spinal stimulation (real tDCS) for five days/week for two weeks (T1), with an 8-week (T2) follow-up (randomized, double-blind, sham-controlled phase). At the 24-week follow-up (T3), all participants (Groups 1 and 2) received a second treatment of anodal bilateral motor cortex and cathodal spinal stimulation (real tDCS) for five days/week for two weeks (T4). Follow-up evaluations were performed at 32-weeks (T5) and 48-weeks (T6) (open-label phase). At each time point, clinical assessment, blood sampling, and intracortical connectivity measures using transcranial magnetic stimulation (TMS) were evaluated. Additionally, we evaluated survival rates., Results: Compared to sham stimulation, cortico-spinal tDCS significantly improved global strength, caregiver burden, and quality of life scores, which correlated with the restoration of intracortical connectivity measures. Serum neurofilament light levels decreased among patients who underwent real tDCS but not in those receiving sham tDCS. The number of completed 2-week tDCS treatments significantly influenced patient survival., Conclusions: Cortico-spinal tDCS may represent a promising therapeutic and rehabilitative approach for patients with ALS. Further larger-scale studies are necessary to evaluate whether tDCS could potentially impact patient survival., Clinical Trial Registration: NCT04293484., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Transcranial direct current stimulation (tDCS) has been shown to benefit patients with brain lesions or traumatic brain injury (TBI). These patients usually have skull defects with different sizes and electrical conductivities. There is very little data in the literature that show how to optimally stimulate these patients with the presence of skull defects., Methods: Here we leveraged high-resolution (1 mm) realistic head models to explore the best montages targeting right beneath the skull defects with different sizes and conductivities. Specifically, open-source software ROAST was used to solve for the lead field on the publicly available MIDA model. Four different skull defects/plates were modeled with the center above the right primary motor cortex: a larger defect (10 cm diameter) modeled as either titanium or acrylic plate, and a smaller defect (2.5 cm diameter) modeled as either acute state filled with cerebrospinal fluid (CSF) or chronic state with scar tissue. Optimized stimulation with maximal intensity was run using ROAST targeting the right primary motor cortex., Results: We show that optimized high-definition montages can achieve an average of 0.3 V/m higher stimulation intensities at the target compared to un-optimized montages (M1-SO or 4×1). Large skull defects with titanium or acrylic plates significantly reduce the stimulation intensity by about 80%, while small defects with acute (CSF) or chronic (scar) tissues significantly increase the stimulation intensity by about 200%. Furthermore, one can use M1-SO to achieve almost the same stimulation strength as the optimized montage if the skull has a large defect with titanium plate, and there is no significant difference in stimulation intensity between 4×1 montage and the optimized montage for small skull defects with scar tissue., Discussion: Based on this work, future modeling studies leveraging individual anatomy of skull defects may help guide tDCS practice on patients with skull defects and skull plates., Competing Interests: AG, DT, AD, and YH were employed by Research and Development, Soterix Medical, Inc., (Copyright © 2023 Guillen, Truong, Datta and Huang.)

Background: Transcutaneous auricular vagus nerve stimulation (taVNS) has potential clinical application for autism spectrum disorder (ASD). At-home sessions are necessary to allow delivery of repeated sessions, and remove burden on patients for daily visits, and reduce costs of clinic delivery. Our objective was to validate a protocol for remote supervised administration for home delivery of taVNS using specially designed equipment and platform., Methods: An open-label design was followed involving administration by caretakers to 12 patients with ASD (ages:7-16). Daily 1-h sessions over 2 weeks were administered under remote supervision. The primary outcome was feasibility, which was assessed by completion rate, stimulation tolerability, and confirmation of programmed stimulation delivery. The secondary measures were initial efficacy assessed by Childhood Anxiety Sensitivity Index-Revised (CASI-R), Parent Rated Anxiety Scale for Youth with ASD (PRAS-ASD), and Clinician Global Impression (CGI) scales. Sleep measures were also tracked using Cleveland Adolescent Sleep Questionnaire (CASQ)., Results: Across 132 sessions, we obtained an 88.5% completion rate. A total of 22 expected adverse events were reported with headache being the most common followed by transient pain, itchiness, and stinging at the electrode site. One subject dropped out of the study unrelated to the stimulation or the study. Average scores of anxiety (CASI-R, PRAS-ASD, and CGI) and sleepiness (CASQ) were all improved at the 2 week time point. While not powered to determine efficacy, benefits were suggested in this open label pilot., Conclusion: Remotely supervised, proxy-administered, at-home delivery of taVNS is feasible in patients with ASD. Initial efficacy supports pursuing larger scale trials., Competing Interests: YV and AD are employees of Soterix Medical, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Black, Hunter, Cottrell, Dar, Takahashi, Ferguson, Valter, Porges, Datta and Beversdorf.)

Transcranial direct current stimulation (tDCS) is an emerging treatment for major depression. We recruited participants with moderate-to-severe major depressive episodes for an observational clinical trial using Soterix Medical's tDCS telehealth platform as a standard of care. The acute intervention consisted of 28 sessions (5 sessions/week, 6 weeks) of the left anodal dorsolateral prefrontal cortex (DLPFC) tDCS (2.0 mA × 30 min) followed by a tapering phase of weekly sessions for 4 weeks (weeks 7-10). The n = 16 completing participants had a significant reduction in depressive symptoms by week 2 of treatment [Montgomery-Åsberg Depression Rating Scale (MADRS), Baseline : 28.00 ± 4.35 vs. Week 2: 17.12 ± 5.32, p < 0.001] with continual improvement across each biweekly timepoint. Acute intervention responder and remission rates were 75 and 63% and 88 and 81% following the taper period (week 10)., Competing Interests: The City University of New York holds patents on brain stimulation with MB and AD as inventors. MB has equity in Soterix Medical Inc., consulted, received grants, assigned inventions, and/or served on the SAB of SafeToddles, Boston Scientific, GlaxoSmithKline, Biovisics, Mecta, Lumenis, Halo Neuroscience, Google-X, i-Lumen, Humm, Allergan (Abbvie), Apple, Ybrain, Ceragem, and Remz. LC has consulted for Ybrain, Neuroelectrics, Johnson & Johnson, and Biogen. AD and KN are employees of Soterix Medical Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Charvet, George, Charlson, Lustberg, Vogel-Eyny, Eilam-Stock, Cho, Best, Fernandez, Datta, Bikson, Nazim and Pilloni.)

Background: The field of view (FOV) considered in MRI-guided forward models of electroconvulsive therapy (ECT) are, as expected, limited to the MRI volume collected. Therefore, there is variation in model extent considered across simulation efforts. This study examines the impact of FOV on the induced electric field (E-field) due to two common electrode placements: right unilateral (RUL) and bilateral (BL)., Methods: A full-body dataset was obtained and processed for modeling relevant to ECT physics. Multiple extents were derived by truncating from the head down to four levels: upper head (whole-brain), full head, neck, and torso. All relevant stimulation and focality metrics were determined. The differences in the 99th percentile peak of stimulation strength in the brain between each extent to the full-body (reference) model were considered as the relative error (RE). We also determine the FOV beyond which the difference to a full-body model would be negligible., Results: The 2D and 3D spatial plots revealed anticipated results in line with prior efforts. The RE for BL upper head was ~50% reducing to ~2% for the neck FOV. The RE for RUL upper head was ~5% reducing to subpercentage (0.28%) for the full-head FOV. As shown previously, BL was found to stimulate a larger brain volume-but restricted to the upper head and for amplitude up to ~480 mA. To some extent, RUL stimulated a larger volume. The RUL-induced volume was larger even when considering the neural activation threshold corresponding to brief pulse BL if ECT amplitude was >270 mA. This finding is explained by the BL-induced current loss through the inferior regions as more FOV is considered. Our result is a departure from prior efforts and raises questions about the focality metric as defined and/or inter-individual differences., Conclusion: Our findings highlight that BL is impacted more than RUL with respect to FOV. It is imperative to collect full-head data at a minimum for any BL simulation and possibly more. Clinical practice resorts to using BL ECT when RUL is unsuccessful. However, the notion that BL is more efficacious on the premise of stimulating more brain volume needs to be revisited., Competing Interests: AG, YH, DT, and AD were employed by the Soterix Medical, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Guillen, Abbott, Deng, Huang, Pascoal-Faria, Truong and Datta.)

Background: Currently, there are no FDA approved therapies for persistent post-traumatic headache (PPTH) secondary to traumatic brain injury (TBI). As such neither headache nor TBI specialists have an effective means to manage PPTH. Thus, the objective of the present pilot trial was to evaluate the feasibility and preliminary efficacy of a four-week at-home remotely supervised transcranial direct current stimulation (RS-tDCS) intervention for veterans with PPTH., Methods: Twenty-five ( m  = 46.6 ± 8.7 years) veterans with PPTH were randomized into two groups and received either active ( n  = 12) or sham ( n  = 13) RS-tDCS, with anodal stimulation over left dlPFC and cathodal over occipital pole. Following a four-week baseline, participants completed 20-sessions of active or sham RS-tDCS with real-time video monitoring over a period of four-weeks. Participants were assessed again at the end of the intervention and at four-weeks post-intervention. Primary outcomes were overall adherence rate (feasibility) and change in moderate-to-severe headache days per month (efficacy). Secondary outcomes were changes in total number of headache days, and PPTH-related functional outcomes., Results: Adherence rate was high with 88% of participants (active = 10/12; sham = 12/13) fully completing tDCS interventions. Importantly, there was no significant difference in adherence between active and sham groups ( p  = 0.59). Moderate-to-severe headache days were significantly reduced within the active RS-tDCS group ( p  = 0.004), compared to sham during treatment (-2.5 ± 3.5 vs. 2.3 ± 3.4), and 4-week follow-up (-3.9 ± 6.4 vs. 1.2 ± 6.5). Total number of headache days was significantly reduced within the active RS-tDCS ( p  = 0.03), compared to sham during-treatment (-4.0 ± 5.2 vs. 1.5 ± 3.8), and 4-week follow-up (-2.1 ± 7.2 vs. -0.2 ± 4.4)., Conclusion: The current results indicate our RS-tDCS paradigm provides a safe and effective means for reducing the severity and number of headache days in veterans with PPTH. High treatment adherence rate and the remote nature of our paradigm indicate RS-tDCS may be a feasible means to reduce PPTH, especially for veterans with limited access to medical facilities.Clinical Trial Registration: ClinicalTrials.gov, identifier [NCT04012853]., Competing Interests: AD was employed by Soterix Medical, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Charvet, Harrison, Mangold, Moore, Guo, Zhang, Datta and Androulakis.)

The objective and scope of this Limited Output Transcranial Electrical Stimulation 2023 (LOTES-2023) guidance is to update the previous LOTES-2017 guidance. These documents should therefore be considered together. The LOTES provides a clearly articulated and transparent framework for the design of devices providing limited output (specified low-intensity range) transcranial electrical stimulation for a variety of intended uses. These guidelines can inform trial design and regulatory decisions, but most directly inform manufacturer activities - and hence were presented in LOTES-2017 as "Voluntary industry standard for compliance controlled limited output tES devices". In LOTES-2023 we emphasize that these standards are largely aligned across international standards and national regulations (including those in USA, EU, and South Korea), and so might be better understood as "Industry standards for compliance controlled limited output tES devices". LOTES-2023 is therefore updated to reflect a consensus among emerging international standards, as well as best available scientific evidence. "Warnings" and "Precautions" are updated to align with current biomedical evidence and applications. LOTES standards applied to a constrained device dose range, but within this dose range and for different use-cases, manufacturers are responsible to conduct device-specific risk management., Competing Interests: Declaration of competing interest The City University of New York holds patents on brain stimulation with MB as inventor. MB has equity in Soterix Medical Inc. MB consults, received grants, assigned inventions, and/or served on the SAB of Safe Toddles, Boston Scientific, GlaxoSmithKline, Biovisics, Mecta, Lumenis, Halo Neuroscience, Google-X, i-Lumen, Humm, Allergan (Abbvie), Apple, Ybrain, Ceragem, Remz. MB is supported by grants from Harold Shames and the National Institutes of Health: NIH-NIDA UG3DA048502, NIH-NIGMS T34 GM137858, NIH-NINDS R01 NS112996, NIH-NINDS R01 NS101362, and NIH-G-RISE T32GM136499. AG-A serves as consultant and has non-financial/material support from Flow Neuroscience in tDCS equipment. ATS is Chief Scientific Advisor of PlatoScience and Alphasys, CEO of Neurowear Medical B.V., received equipment support from MagVenture, Deymed, and MagStim Company, and is Scientific Director of the International Clinical TMS Certification Course. ER has equity in and is an employee of Flow Neuroscience. ER is an inventor of patents related to brain stimulation. BHO has equity in and is the director of PlatoScience ApS, a company manufacturing LOTES devices. PlatoScience and BHO are listed on patents and patent applications related to LOTES devices. MGJ is an employee of PlatoScience ApS, a company manufacturing LOTES devices. PlatoScience are listed on patents and patent applications related to LOTES devices. SK, JK and KL are employees of Ybrain. AD is an employee in Soterix Medical Inc. The City University of New York holds patents on brain stimulation with AD as inventor. AD is supported by grants from NIH: NIH-NIDA-75N95020C00024, DoD: W912CG21C0014 and W81XWH22C0111, NASA: 80NSSC22CA071, ED:91990022C0043. GU consulted for Halo Neuroscience., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Galvanic vestibular stimulation (GVS) uses at least one electrode placed on the mastoid process with one or multiple placed over other head areas to stimulate the vestibular system. The exact electrode size used is not given much importance in the literature and has not been reported in several studies. In a previous study, we compared the clinical effects of using different electrode sizes (3 cm2 and 35 cm2) with placebo but with the same injected current, on postural control. We observed significant improvement using the smaller size electrode but not with the bigger size electrode. The goal of this study was to simulate the current flow patterns with the intent to shed light and potentially explain the experimental outcome., Methods: We used an ultra-high-resolution structural dataset and developed a model to simulate the application of different electrode sizes. We considered current flow in the brain and in the vestibular labyrinth., Results: Our simulation results verified the focality increase using smaller electrodes that we postulated as the main reason for our clinical effect. The use of smaller size electrodes in combination with the montage employed also result in higher induced electric field (E-field) in the brain., Conclusions: Electrode size and related current density is a critical parameter to characterize any GVS administration as the choice impacts the induced E-field. It is evident that the higher induced E-field likely contributed to the clinical outcome reported in our prior study., Competing Interests: DQT, AG, and AD are employees of Soterix Medical. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Truong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Closed-loop neuromodulation measures dynamic neural or physiological activity to optimize interventions for clinical and nonclinical behavioral, cognitive, wellness, attentional, or general task performance enhancement. Conventional closed-loop stimulation approaches can contain biased biomarker detection (decoders and error-based triggering) and stimulation-type application. We present and verify a novel deep learning framework for designing and deploying flexible, data-driven, automated closed-loop neuromodulation that is scalable using diverse datasets, agnostic to stimulation technology (supporting multi-modal stimulation: tACS, tDCS, tFUS, TMS), and without the need for personalized ground-truth performance data. Our approach is based on identified periods of responsiveness - detected states that result in a change in performance when stimulation is applied compared to no stimulation. To demonstrate our framework, we acquire, analyze, and apply a data-driven approach to our open sourced GX dataset, which includes concurrent physiological (ECG, EOG) and neuronal (EEG) measures, paired with continuous vigilance/attention-fatigue tracking, and High-Definition transcranial electrical stimulation (HD-tES). Our framework's decision process for intervention application identified 88.26% of trials as correct applications, showed potential improvement with varying stimulation types, or missed opportunities to stimulate, whereas 11.25% of trials were predicted to stimulate at inopportune times. With emerging datasets and stimulation technologies, our unifying and integrative framework; leveraging deep learning (Convolutional Neural Networks - CNNs); demonstrates the adaptability and feasibility of automated multimodal neuromodulation for both clinical and nonclinical applications., Competing Interests: Competing Interests The authors declare no competing non-financial interests but the following competing financial interests. Nigel Gebodh has consulted for HUMM and been formerly employed by Soterix Medical Inc. Vladimir Miskovic and Sarah Laszlo are current employees of Alphabet Inc. Abhishek Datta and Marom Bikson and have equity in Soterix Medical Inc. The City University of New York holds patents on brain stimulation with Marom Bikson as inventor. Marom Bikson consults, received grants, assigned inventions, and/or serves on the SAB of SafeToddles, Boston Scientific, GlaxoSmithKline, Biovisics, Mecta, Lumenis, Halo Neuroscience, Google-X, i-Lumen, Humm, Allergan (Abbvie), Apple, Ybrain, Ceragem, Remz.

Background: and purpose: Fatigue is among the most common persistent symptoms following post-acute sequelae of Sars-COV-2 infection (PASC). The current study investigated the potential therapeutic effects of High-Definition transcranial Direct Current Stimulation (HD-tDCS) associated with rehabilitation program for the management of PASC-related fatigue., Methods: Seventy patients with PASC-related fatigue were randomized to receive 3 mA or sham HD-tDCS targeting the left primary motor cortex (M1) for 30 min paired with a rehabilitation program. Each patient underwent 10 sessions (2 sessions/week) over five weeks. Fatigue was measured as the primary outcome before and after the intervention using the Modified Fatigue Impact Scale (MFIS). Pain level, anxiety severity and quality of life were secondary outcomes assessed, respectively, through the McGill Questionnaire, Hamilton Anxiety Rating Scale (HAM-A) and WHOQOL., Results: Active HD-tDCS resulted in significantly greater reduction in fatigue compared to sham HD-tDCS (mean group MFIS reduction of 22.11 points vs 10.34 points). Distinct effects of HD-tDCS were observed in fatigue domains with greater effect on cognitive (mean group difference 8.29 points; effect size 1.1; 95% CI 3.56-13.01; P < .0001) and psychosocial domains (mean group difference 2.37 points; effect size 1.2; 95% CI 1.34-3.40; P < .0001), with no significant difference between the groups in the physical subscale (mean group difference 0.71 points; effect size 0.1; 95% CI 4.47-5.90; P = .09). Compared to sham, the active HD-tDCS group also had a significant reduction in anxiety (mean group difference 4.88; effect size 0.9; 95% CI 1.93-7.84; P < .0001) and improvement in quality of life (mean group difference 14.80; effect size 0.7; 95% CI 7.87-21.73; P < .0001). There was no significant difference in pain (mean group difference -0.74; no effect size; 95% CI 3.66-5.14; P = .09)., Conclusion: An intervention with M1 targeted HD-tDCS paired with a rehabilitation program was effective in reducing fatigue and anxiety, while improving quality of life in people with PASC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The City University of New York holds patents on brain stimulation with MB as inventor.MB has equity in Soterix Medical Inc. MB consults, received grants, assigned inventions, and/or serves on the SAB of SafeToddles, Boston Scientific, GlaxoSmithKline, Biophysics, Mecta, Lumenis, Halo Neuroscience, Google-X, i-Lumen, Humm, Allergan (Abbvie), Apple. AD is an employee and has equity in Soterix Medical Inc., (Copyright © 2023. Published by Elsevier Inc.)

Background: Transcranial direct current stimulation (tDCS) is a safe and well-tolerated noninvasive technique used for cortical excitability modulation. tDCS has been extensively investigated for its clinical applications; however further understanding of its underlying in-vivo physiological mechanisms remains a fundamental focus of current research., Objectives: We investigated the simultaneous effects of tDCS on cerebral blood flow (CBF), venous blood oxygenation (Yv) and cerebral metabolic rate of oxygen (CMRO 2 ) using simultaneous MRI in healthy adults to provide a reference frame for its neurobiological mechanisms., Methods: Twenty-three healthy participants (age = 35.6 ± 15.0 years old, 10 males) completed a simultaneous tDCS-MRI session in a 3 T scanner fitted with a 64-channels head coil. A MR-compatible tDCS device was used to acquire CBF, Yv and CMRO 2 at three time points: pre-, during- and post- 15 minutes of 2.0 mA tDCS on left anodal dorsolateral prefrontal cortex., Results: During tDCS, CBF significantly increased (57.10 ± 8.33 mL/100g/min) from baseline (53.67 ± 7.75 mL/100g/min; p < 0.0001) and remained elevated in post-tDCS (56.79 ± 8.70 mL/100g/min). Venous blood oxygenation levels measured in pre-tDCS (60.71 ± 4.12 %) did not significantly change across the three timepoints. The resulting CMRO 2 significantly increased by 5.9 % during-tDCS (175.68 ± 30.78 µmol/100g/min) compared to pre-tDCS (165.84 ± 25.32 µmol/100g/min; p = 0.0015), maintaining increased levels in post-tDCS (176.86 ± 28.58 µmol/100g/min)., Conclusions: tDCS has immediate effects on neuronal excitability, as measured by increased cerebral blood supply and oxygen consumption supporting increased neuronal firing. These findings provide a standard range of CBF and CMRO 2 changes due to tDCS in healthy adults that may be incorporated in clinical studies to evaluate its therapeutic potential., Competing Interests: Declaration of Competing Interest Soterix Medical Inc. provided the tDCS equipment used for research use. The City University of New York holds patents on brain stimulation with MB as inventor. The City University of New York holds patents on brain stimulation with AD as inventor. AD is an employee of Soterix Medical Inc. AD has equity in Soterix Medical Inc. MB has equity in Soterix Medical Inc. MB consults, received grants, assigned inventions, and/or serves on the SAB of SafeToddles, Boston Scientific, GlaxoSmithKline, Biovisics, Mecta, Lumenis, Halo Neuroscience, Google-X, i-Lumen, Humm, Allergan (Abbvie), Apple., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Although relatively costly and non-scalable, non-invasive neuromodulation interventions are treatment alternatives for neuropsychiatric disorders. The recent developments of highly-deployable transcranial electric stimulation (tES) systems, combined with mobile-Health technologies, could be incorporated in digital trials to overcome methodological barriers and increase equity of access. The study aims are to discuss the implementation of tES digital trials by performing a systematic scoping review and strategic process mapping, evaluate methodological aspects of tES digital trial designs, and provide Delphi-based recommendations for implementing digital trials using tES., Methods: We convened 61 highly-productive specialists and contacted 8 tES companies to assess 71 issues related to tES digitalization readiness, and processes, barriers, advantages, and opportunities for implementing tES digital trials. Delphi-based recommendations (>60% agreement) were provided., Results: The main strengths/opportunities of tES were: (i) non-pharmacological nature (92% of agreement), safety of these techniques (80%), affordability (88%), and potential scalability (78%). As for weaknesses/threats, we listed insufficient supervision (76%) and unclear regulatory status (69%). Many issues related to methodological biases did not reach consensus. Device appraisal showed moderate digitalization readiness, with high safety and potential for trial implementation, but low connectivity., Conclusions: Panelists recognized the potential of tES for scalability, generalizability, and leverage of digital trials processes; with no consensus about aspects regarding methodological biases., Significance: We further propose and discuss a conceptual framework for exploiting shared aspects between mobile-Health tES technologies with digital trials methodology to drive future efforts for digitizing tES trials., (Copyright © 2022 International Federation of Clinical Neurophysiology. All rights reserved.)

Contralateral silent period (cSP) is a period of suppression in the background electrical muscle activity captured by electromyography (EMG) after a motor evoked potential (MEP). To obtain this, an MEP is elicited by a suprathreshold transcranial magnetic stimulation (TMS) pulse delivered to the primary motor cortex (M1) of the target muscle selected, while the participant provides a standardized voluntary target muscle contraction. The cSP is a result of inhibitory mechanisms that occur after the MEP; it provides a broad temporal assessment of spinal inhibition in its initial ~50 ms, and cortical inhibition after. Researchers have tried to better understand the neurobiological mechanism behind the cSP to validate it as a potential diagnostic, surrogate, and predictive biomarker for different neuropsychiatric diseases. Therefore, this article describes a method to measure M1 cSP of lower and upper limbs, including a selection of target muscle, electrode placement, coil positioning, method of measuring voluntary contraction stimulation, intensity setup, and data analysis to obtain a representative result. It has the educational objective of giving a visual guideline in performing a feasible, reliable, and reproducible cSP protocol for lower and upper limbs and discussing practical challenges of this technique.

Objective: This study aimed to assess whether non-invasive brain stimulation with transcranial alternating current stimulation at gamma-frequency (γ-tACS) applied over the precuneus can improve episodic memory and modulate cholinergic transmission by modulating cerebral rhythms in early Alzheimer's disease (AD)., Methods: In this randomized, double-blind, sham controlled, crossover study, 60 AD patients underwent a clinical and neurophysiological evaluation including assessment of episodic memory and cholinergic transmission pre and post 60 minutes treatment with γ-tACS targeting the precuneus or sham tACS. In a subset of 10 patients, EEG analysis and individualized modelling of electric field distribution were carried out. Predictors to γ-tACS efficacy were evaluated., Results: We observed a significant improvement in the Rey Auditory Verbal Learning (RAVL) test immediate recall (p < 0.001) and delayed recall scores (p < 0.001) after γ-tACS but not after sham tACS. Face-name associations scores improved with γ-tACS (p < 0.001) but not after sham tACS. Short latency afferent inhibition, an indirect measure of cholinergic transmission, increased only after γ-tACS (p < 0.001). ApoE genotype and baseline cognitive impairment were the best predictors of response to γ-tACS. Clinical improvement correlated with the increase in gamma frequencies in posterior regions and with the amount of predicted electric field distribution in the precuneus., Interpretation: Precuneus γ-tACS, able to increase γ-power activity on the posterior brain regions, showed a significant improvement of episodic memory performances, along with restoration of intracortical excitability measures of cholinergic transmission. Response to γ-tACS was dependent on genetic factors and disease stage. ANN NEUROL 2022;92:322-334., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Invasive Candida albicans ( CA ) infections often arise from the intestine and cause life-threatening infections in immunocompromised individuals. The role of gut commensal microbiota, metabolites, and host factors in the regulation of CA colonization in the intestine is poorly understood. Previous findings from our lab indicate that taurocholic acid ( TCA ), a major bile acid present in the intestine, promotes CA colonization and dissemination. Here, we report that oral administration of TCA to CA-infected mice significantly decreased the number of mononuclear phagocytes and CD4+ IL17A+ T helper 17 cells that play a critical role in controlling CA in the intestine. Collectively, our results indicate that TCA modulates mucosal innate and adaptive immune responses to promote CA colonization in the intestine.

Objective: The objective of the study was to investigate transcranial wave propagation through two low-intensity focused ultrasound (LIFU)-based brain stimulation techniques-transcranial focused ultrasound stimulation (tFUS) and transcranial pulse stimulation (TPS). Although tFUS involves delivering long trains of acoustic pulses, the newly introduced TPS delivers ultrashort (∼3 μs) pulses repeated at 4 Hz. Accordingly, only a single simulation study with limited geometry currently exists for TPS. We considered a high-resolution three-dimensional (3D) whole human head model in addition to water bath simulations. We anticipate that the results of this study will help researchers investigating LIFU have a better understanding of the effects of the two different techniques., Approach: With an objective to first reproduce previous computational results, we considered two spherical tFUS transducers that were previously modeled. We assumed identical parameters (geometry, position, and imaging data set) to demonstrate differences, purely because of the waveform considered. For simulations with a 3D head data set, we also considered a parabolic transducer that has been used for TPS delivery., Results: Our initial results successfully verified previous modeling workflow. The tFUS distribution was characterized by the typical elliptical profile, with its major axis perpendicular to the face of the transducer. The TPS distribution resembled two mirrored meniscus profiles, with its widest diameter oriented parallel to the face of the transducer. The observed intensity value differences were theoretical because the two waveforms differ in both intensity and time. The consideration of a realistic 3D human head model resulted in only a minor distortion of the two waveforms., Significance: This study simulated TPS administration using a 3D realistic image-derived data set. Although our comparison results are strictly limited to the model parameters and assumptions made, we were able to elucidate some clear differences between the two approaches. We hope this initial study will pave the way for systematic comparison between the two approaches in the future., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

The use of transcranial Electrical Stimulation (tES) in the modulation of cognitive brain functions to improve neuropsychiatric conditions has extensively increased over the decades. tES techniques have also raised new challenges associated with study design, stimulation protocol, functional specificity, and dose-response relationship. In this paper, we addressed challenges through the emerging methodology to investigate the dose-response relationship of High Definition-transcranial Direct Current Stimulation (HD tDCS), identifying the role of negative valence in tinnitus perception. In light of the neurofunctional testable framework and tES application, hypotheses were formulated to measure clinical and surrogate endpoints. We posited that conscious pairing adequately pleasant stimuli with tinnitus perception results in correction of the loudness misperception and would be reinforced by concurrent active HD-tDCS on the left Dorsolateral Prefrontal Cortex (dlPFC). The dose-response relationship between HD-tDCS specificity and the loudness perception is also modeled. We conducted a double-blind, randomized crossover pilot study with six recruited tinnitus patients. Accrued data was utilized to design a well-controlled adaptive seamless Bayesian dose-response study. The sample size ( n = 47, for 90% power and 95% confidence) and optimum interims were anticipated for adaptive decision-making about efficacy, safety, and single session dose parameters. Furthermore, preliminary pilot study results were sufficient to show a significant difference (90% power, 99% confidence) within the longitudinally detected self-report tinnitus loudness between before and under positive emotion induction. This study demonstrated a research methodology used to improve emotion regulation in tinnitus patients. In the projected method, positive emotion induction is essential for promoting functional targeting under HD-tDCS anatomical specificity to indicate the efficacy and facilitate the dose-finding process. The continuous updating of prior knowledge about efficacy and dose during the exploratory stage adapts the anticipated dose-response model. Consequently, the effective dose range to make superiority neuromodulation in correcting loudness misperception of tinnitus will be redefined. Highly effective dose adapts the study to a standard randomized trial and transforms it into the confirmatory stage in which active HD-tDCS protocol is compared with a sham trial (placebo-like). Establishing the HD-tDCS intervention protocols relying on this novel method provides reliable evidence for regulatory agencies to approve or reject the efficacy and safety. Furthermore, this paper supports a technical report for designing multimodality data-driven complementary investigations in emotion regulation, including EEG-driven neuro markers, Stroop-driven attention biases, and neuroimaging-driven brain network dynamics., Competing Interests: ADa and CT were employed by the company Soterix Medical Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ghodratitoostani, Gonzatto, Vaziri, Delbem, Makkiabadi, Datta, Thomas, Hyppolito, Santos, Louzada and Leite.)

Background and Purpose: Acute Respiratory Distress Syndrome (ADRS) due to coronavirus disease 2019 (COVID-19) has been associated with muscle fatigue, corticospinal pathways dysfunction, and mortality. High-Definition transcranial Direct Current Stimulation (HD-tDCS) may be used to attenuate clinical impairment in these patients. The HD-RECOVERY randomized clinical trial was conducted to evaluate the efficacy and safety of HD-tDCS with respiratory rehabilitation in patients with moderate to severe ARDS due to COVID-19., Methods: Fifty-six critically ill patients were randomized 1:1 to active (n = 28) or sham (n = 28) HD-tDCS (twice a day, 30-min, 3-mA) plus respiratory rehabilitation for up to 10 days or until intensive care unit discharge. The primary outcome was ventilator-free days during the first 28 days, defined as the number of days free from mechanical ventilation. Furthermore, secondary outcomes such as delirium, organ failure, hospital length of stay and adverse effects were investigated., Results: Active HD-tDCS induced more ventilator-free days compared to sham HD-tDCS. Patients in the active group vs in the sham group experienced lower organ dysfunction, delirium, and length of stay rates over time. In addition, positive clinical response was higher in the active vs sham group. There was no significant difference in the prespecified secondary outcomes at 5 days. Adverse events were similar between groups., Conclusions: Among patients with COVID-19 and moderate to severe ARDS, use of active HD-tDCS compared with sham HD-tDCS plus respiratory rehabilitation resulted in a statistically significant increase in the number of ventilator-free days over 28 days. HD-tDCS combined with concurrent rehabilitation therapy is a safe, feasible, potentially add-on intervention, and further trials should examine HD-tDCS efficacy in a larger sample of patients with COVID-19 and severe hypoxemia., Competing Interests: Declaration of competing interest The City University of New York holds patents on brain stimulation with MB as inventor. MB has equity in Soterix Medical Inc. MB consults, received grants, assigned inventions, and/or serves on the SAB of SafeToddles, Boston Scientific, GlaxoSmithKline, Biophysics, Mecta, Lumenis, Halo Neuroscience, Google-X, i-Lumen, Humm, Allergan (Abbvie), Apple. AD is an employee and has equity in Soterix Medical Inc., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: The ability to deploy transcranial direct current stimulation (tDCS) at home is a key usability advantage to support scaling for pivotal clinical trials. We have established a home-based tDCS protocol for use in clinical trials termed remotely supervised (RS)-tDCS., Objective: To report the tolerability and feasibility of tDCS sessions completed to date using RS-tDCS in clinical trials., Methods: We analyzed tolerability (i.e., adverse events, AEs) reported in six Class I/II/III trials using RS-tDCS to study symptom outcomes over 10 to 60 daily applications. Across the six clinical trials, 308 participants (18-78 years old) completed an average of 23 sessions for a total of 6779 RS-tDCS administrations. The majority of participants were diagnosed with multiple sclerosis, and open-label trials included those diagnosed with a range of other conditions (e.g., Parkinson's disease, post-stroke aphasia, traumatic brain injury, cerebellar ataxia), with minimum-to-severe neurologic disability. Clinical trial feasibility (i.e., treatment fidelity and blinding integrity) was examined using two Class I randomized controlled trials (RCTs)., Results: No serious AEs occurred. Across administrations, three sessions (0.04%) were aborted due to discomfort, but no participant discontinued due to tolerability. The AEs most commonly reported by participants were tingling (68%), itching (41%) and warmth sensation (42%) at the electrode site, and these were equally reported in active and sham tDCS conditions. The two Class I RCTs resulted in rapid enrollment, high fidelity to treatment completion, and blinding integrity., Conclusions: At-home RS-tDCS is tolerable, including when used over extended periods of time. Home-based RS-tDCS is feasible and can enable Class I tDCS clinical trial designs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Soterix Medical Inc. provided the tDCS equipment used for research use. The City University of New York holds patents on brain stimulation with MB as inventor. The City University of New York holds patents on brain stimulation with AD as inventor. AD is an employee of Soterix Medical Inc. AD has equity in Soterix Medical Inc. MB has equity in Soterix Medical Inc. MB consults, received grants, assigned inventions, and/or serves on the SAB of SafeToddles, Boston Scientific, GlaxoSmithKline, Biovisics, Mecta, Lumenis, Halo Neuroscience, Google-X, i-Lumen, Humm, Allergan (Abbvie), Apple., (Copyright © 2022. Published by Elsevier Inc.)

Low-intensity transcranial electrical stimulation (tES), including alternating or direct current stimulation, applies weak electrical stimulation to modulate the activity of brain circuits. Integration of tES with concurrent functional MRI (fMRI) allows for the mapping of neural activity during neuromodulation, supporting causal studies of both brain function and tES effects. Methodological aspects of tES-fMRI studies underpin the results, and reporting them in appropriate detail is required for reproducibility and interpretability. Despite the growing number of published reports, there are no consensus-based checklists for disclosing methodological details of concurrent tES-fMRI studies. The objective of this work was to develop a consensus-based checklist of reporting standards for concurrent tES-fMRI studies to support methodological rigor, transparency and reproducibility (ContES checklist). A two-phase Delphi consensus process was conducted by a steering committee (SC) of 13 members and 49 expert panelists through the International Network of the tES-fMRI Consortium. The process began with a circulation of a preliminary checklist of essential items and additional recommendations, developed by the SC on the basis of a systematic review of 57 concurrent tES-fMRI studies. Contributors were then invited to suggest revisions or additions to the initial checklist. After the revision phase, contributors rated the importance of the 17 essential items and 42 additional recommendations in the final checklist. The state of methodological transparency within the 57 reviewed concurrent tES-fMRI studies was then assessed by using the checklist. Experts refined the checklist through the revision and rating phases, leading to a checklist with three categories of essential items and additional recommendations: (i) technological factors, (ii) safety and noise tests and (iii) methodological factors. The level of reporting of checklist items varied among the 57 concurrent tES-fMRI papers, ranging from 24% to 76%. On average, 53% of checklist items were reported in a given article. In conclusion, use of the ContES checklist is expected to enhance the methodological reporting quality of future concurrent tES-fMRI studies and increase methodological transparency and reproducibility., (© 2022. © The Author(s).)

Whereas, many debilitating chronic pain disorders are dominantly bilateral (e.g., fibromyalgia, chronic migraine), non-invasive and invasive cortical neuromodulation therapies predominantly apply unilateral stimulation. The development of excitatory stimulation targeting bilateral primary motor (M1) cortices could potentially expand its therapeutic effect to more global pain relief. However, this is hampered by increased procedural and technical complexity. For example, repetitive transcranial magnetic stimulation (rTMS) and 4 × 1/2 × 2 high-definition transcranial direct current stimulation (4 × 1/2 × 2 HD-tDCS) are largely center-based, with unilateral-target focus-bilateral excitation would require two rTMS/4 × 1 HD-tDCS systems. We developed a system that allows for focal, non-invasive, self-applied, and simultaneous bilateral excitatory M1 stimulation, supporting long-term home-based treatment with a well-tolerated wearable battery-powered device. Here, we overviewed the most employed M1 neuromodulation methods, from invasive techniques to non-invasive TMS and tDCS. The evaluation extended from non-invasive diffuse asymmetric bilateral (M1-supraorbital [SO] tDCS), non-invasive and invasive unilateral focal (4 × 1/2 × 2 HD-tDCS, rTMS, MCS), to non-invasive and invasive bilateral bipolar (M1-M1 tDCS, MCS), before outlining our proposal for a neuromodulatory system with unique features. Computational models were applied to compare brain current flow for current laboratory-based unilateral M1 1 and bilateral M1 2 HD-tDCS models with a functional home-based M1 1-2 HD-tDCS prototype. We concluded the study by discussing the promising concept of bilateral excitatory M1 stimulation for more global pain relief, which is also non-invasive, focal, and home-based., Competing Interests: Authors AD and MB have equity in Soterix Medical Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 DaSilva, Datta, Swami, Kim, Patil and Bikson.)

Introduction: Transcutaneous electrical nerve stimulation (TENS) for migraine involves the application of pulsatile stimulation through electrodes placed on the forehead to target the underlying trigeminal nerves. It is a simple, safe modality and has secured clinical approval in several markets including the European Union and the United States. Despite nearing almost 7 years of use (postclinical approval), the exact mechanism of action is not fully known. Guided by the need to stimulate the trigeminal nerves bilaterally, electrode dimensions are simply required to extend enough to cover the underlying nerves. The goal of this study is to examine induced current flow [magnitude and spatial distribution of electric field (EF)] and another driver of stimulation [activating function (AF)] due to TENS therapy for migraine for the first time. We further consider the effect of changing the electrode dimension and shape and propose a design modification to deliver optimal flow. Methods: We developed the first ultra-high-resolution finite element (FE) model of TENS for migraine incorporating the target supratrochlear (ST) and the supraorbital (SO) nerves. We first simulated the clinically approved V-shaped geometry. We then considered three additional designs: extended V-shaped, idealized pill-shaped, and finally an extended V-shaped but with greater contact spacing (extended V-shaped +CS). Results: Our findings revealed that the clinically approved electrode design delivered substantially higher mean current flow to the ST nerve in comparison with the SO nerves (Medial: 53% and Lateral: 194%). Consideration of an extended design (~10 mm longer and ~ 4 mm shorter) and a pill-like design had negligible impact on the induced current flow pattern. The extended V-shaped +CS montage delivered relatively comparable current flow to each of the three target nerves. The EF induced in the ST nerve was 49 and 141% higher in the Medial and Lateral SO nerve, respectively. When considering maximum induced values, the delivery of comparable stimulation was further apparent. Given the existing electrode design's established efficacy, our results imply that preferential targeting of the ST nerve is related to the mechanism of action. Additionally, if comparable targeting of all three nerves continues to hold promise, the extended V-shaped +CS montage presents an optimized configuration to explore in clinical studies., Competing Interests: CT, DT, and AD are employees of Soterix Medical. KL is an employee of Ybrain. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Thomas, Truong, Lee, Deblieck, Androulakis and Datta.)

Neuropathic pain (NP), often treatment-refractory, is one of the most debilitating conditions contributing to suffering and disability worldwide. Recently, non-invasive neuromodulation techniques, particularly repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have emerged as potential therapeutic alternatives due to their ability to alter cortical excitability of neural circuits. However, the magnetic field induced in rTMS may be unsafe for patients with an implanted electrode in the head or neck area while tDCS poses no theoretical risk of injury to these patients. High definition (HD)-tDCS is a novel, more focal technique of tDCS and may be safer to the patient compared to the more diffuse stimulation of conventional tDCS. To our knowledge, no study has ever demonstrated the safety and/or feasibility of HD-tDCS in patients with spinal cord stimulation (SCS) devices using computational modeling of induced electrical fields. Furthermore, this study highlights the potential use of (HD-)tDCS as predictive tool for a positive response in chronic epidural motor cortex stimulation (MCS), especially in patients with an implanted device not suitable for rTMS. In a 54-year-old woman with an implanted spinal cord stimulation (SCS) system for another pain syndrome, HD-tDCS was initiated for refractory post-surgical inferior alveolar nerve neuropathy. She was submitted to 7 days of anodal HD-tDCS over the left motor cortex at 1.5 mA for 30 min. A notable decrease in pain perception was observed, lasting for approximately 5-6 h (Numeric Rating Score decreased from 8 to 4.34). No adverse events were reported. The stimulation parameters and clinical efficacy of the SCS system remained unchanged. Additionally, computational analysis indicated no meaningful alteration of current flow when considering a model with a SCS implant with respect to a model without implant. Regarding the positive therapeutic effect of HD-tDCS, the patient was selected for an epidural MCS trial and subsequent implantation, which showed short-term pain relief of 50-75%. Although one case does not demonstrate efficacy, tolerability, or safety to the novel intervention, it paves the way for better diagnosis and treatment for patients who are otherwise excluded from other non-invasive neuromodulation techniques, such as rTMS. A positive tDCS effect could be a potential biomarker for positive epidural MCS response in patients with an implanted stimulation device non-compatible with rTMS., Competing Interests: AD and CT were employed by Soterix Medical Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Deblieck, Smeijers, Morlion, Datta, Thomas and Theys.)

Electrode position affects the brain current flow intensity and distribution induced by transcranial direct current stimulation (tDCS). The dorsolateral pre-frontal cortex (DLPFC) is a common target in neuropsychology and neuropsychiatry applications. A positioning scheme and subsequently a headgear has previously been developed to target the DLPFC automatically - devoid of any scalp ruler or neuronavigation method. This approach minimizes the time cost for pre-treatment measurements without compromising targeting accuracy and induced electric field focality. The goal of this study was to further develop this headgear to facilitate broader adoption while maintaining its core design elements intact. Briefly, we developed the headset to accommodate all adult head sizes (52-62 cm) rather than having multiple sizes, to have increased robustness, enhanced visual aesthetics, and have improved usability.We recruited 8 subjects and tested the accuracy of electrode placement on various head sizes. We also tested usability with the System Usability Scale (SUS) and asked the subjects to rate visual appeal. Our study demonstrated that the newly developed headset had greater usability and was more visually appealing than its predecessor without compromising targeting accuracy.Clinical Relevance- This study introduces a headset for routine tDCS administration targeting bilateral DLPFC. The headset is highly usable, robust, and is expected to facilitate home and high-volume use.

The vestibular system is responsible for spatial orientation and stability. It can be stimulated with a weak electric current, a mechanism known as Galvanic Vestibular Stimulation (GVS). Typical GVS administration involves holding down electrodes on the mastoids either with a strap (or bandage) wrapped around the head or by positioning a self-adhesive electrode at the mastoid location. While the latter approach is simple to administer, it is limited to exposed skin application as hair impedes adhesion. The reduced access area limits total current delivery allowable due to increased skin sensation. Accordingly the former approach is more typically employed but leads to inconsistent and inaccurate electrode placement. As current flow pattern is directly influenced by electrode position, this results in inconsistent stimulation and replicability issues. The primary goal of this study was to test usability and comfort while developing a GVS-specific headset named "Mastoid Adjustable Robust Stimulation (MARS)" compared to a conventional elastic strap. We recruited 10 subjects, 5 operators and 5 wearers, and tested usability using the System Usability Scale (SUS) as well as comfort levels over a typical 20 minute stimulation session. Additional questions were answered by the operators and wearers on visual appeal, interference, slippage, and electrode placement. The results of this testing guided the development of a final version meeting our requirements of robustness, simple to administer, and subject comfort.Clinical Relevance-This study introduces a headset for routine Bilateral-Bipolar GVS administration that is highly usable and ensures both flexible and consistent electrode application over typical approaches.

Conventional transcranial direct current stimulation (tDCS) protocols typically deliver 2 mA for 20-30 minutes. The most common administration uses a wet electrode approach which dries out in ~60 minutes at room temperature. This restricts its application to limited duration electrode-scalp contact use cases unless additional conductive media (saline, gel, or paste) is re-applied. This problem is further compounded by the subject's hair which not only presents administration challenges (interferes with electrode attachment and adhesion) but also acts as a conduit of current flow into the scalp resulting in current hotspots. This non-uniform current injection results in increased skin sensation. The aim of this study was to determine suitability of a commercially available hydrogel for DC delivery through hair. Experiments involved both non-clinical testing on an agar block and clinical testing on subjects' forearms. Electrodes were positioned on the posterior side of the forearm that has hair for the clinical testing. Typical dose as used in tDCS was delivered and pain scores were collected. Results indicate suitable current delivery performance and all subjects tolerated delivery with pain scores ranging between 0-6. Our study paves the way for future testing on the scalp for tDCS application.Clinical Relevance-This study demonstrates the possibility of delivering tDCS through hair via dry electrodes. Specific use cases that cannot use a traditional wet electrode approach stand to benefit from the results of our work.