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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.

Abstract: Attempts to dissociate electroconvulsive therapy (ECT) therapeutic efficacy from cognitive side effects of ECT include modifying electrode placement, but traditional electrode placements employing 2 large electrodes are inherently nonfocal, limiting the ability to selectively engage targets associated with clinical benefit while avoiding nontargets associated with adverse side effects. Limited focality represents a technical limitation of conventional ECT, and there is growing evidence that the spatial distribution of the ECT electric fields induced in the brain drives efficacy and side effects. Computational models can be used to predict brain current flow patterns for existing and novel ECT montages. Using finite element method simulations (under quasi-static, nonadaptive assumptions, 800-mA total current), the electric fields generated in the superficial cortex and subcortical structures were predicted for the following traditional ECT montages (bilateral temporal, bifrontal, right unilateral) and experimental montages (focal electrically administered seizure therapy, lateralized high-definition [HD]-ECT, unilateral 4 × 1-ring HD-ECT, bilateral 4 × 1-ring HD-ECT, and a multipolar HD-ECT). Peak brain current density in regions of interest was quantified. Conventional montages (bilateral bifrontal, right unilateral) each produce distinct but diffuse and deep current flow. Focal electrically administered seizure therapy and lateralized HD-ECT produce unique, lateralized current flow, also impacting specific deep regions. A 4 × 1-ring HD-ECT restricts current flow to 1 (unilateral) or 2 (bilateral) cortical regions. Multipolar HD-ECT shows optimization to a specific target set. Future clinical trials are needed to determine whether enhanced control over current distribution is achieved with these experimental montages, and the resultant seizures, improve the risk/benefit ratio of ECT., Competing Interests: Conflicts of Interest: The City University of New York (CUNY) has IP on neuro-stimulation systems and methods with authors NK and MB as inventors. NK is an employee of Synchron Inc and consults for Ceragem Medical. MB has equity in Soterix Medical. MB consults, 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 Medical, Remz. Z-DD is inventor on patents and patent applications on electrical and magnetic brain stimulation therapy systems held by the National Institutes of Health (NIH), Columbia University, and University of New Mexico. SHL is inventor on patents and patent applications on electrical and magnetic brain stimulation therapy systems held by the NIH and Columbia University, with no remuneration. The opinions expressed in this article are the author's own and do not reflect the views of the National Institutes of Health, the Department of Health and Human Services, or the United States government. JAC is an inventor on patents and patent applications on neuromodulation targeting methods held by Massachusetts General Hospital, he is a member of the scientific advisory board of Hyka and Flow Neuroscience, and has been a paid consultant for Neuronetics, Mifu Technologies, Neuroelectrics, and LivaNova., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: The aim of this study was to present key technologic and regulatory milestones in spinal cord stimulation (SCS) for managing chronic pain on a narrative timeline with visual representation, relying on original sources to the extent possible., Materials and Methods: We identified technical advances in SCS that facilitated and enhanced treatment on the basis of scientific publications and approvals from the United States (US) Food and Drug Administration (FDA). We presented milestones limited to first use in key indications and in the context of new technology validation. We focused primarily on pain management, but other indications (eg, motor disorder in multiple sclerosis) were included when they affected technology development., Results: We developed a comprehensive visual and narrative timeline of SCS technology and US FDA milestones. Since its conception in the 1960s, the science and technology of SCS neuromodulation have continuously evolved. Advances span lead design (from paddle-type to percutaneous, and increased electrode contacts) and stimulator technology (from wireless power to internally powered and rechargeable, with miniaturized components, and programmable multichannel devices), with expanding stimulation program flexibility (such as burst and kilohertz stimulation frequencies), as well as usage features (such as remote programming and magnetic resonance imaging conditional compatibility)., Conclusions: This timeline represents the evolution of SCS technology alongside expanding FDA-approved indications for use., Competing Interests: Conflict of Interest Scott Lempka serves as a scientific advisory board member for Abbott Neuromodulation, CereGate, and Presidio Medical, Inc; and holds stock or stock options with CereGate, Hologram Consultants, LLC, Neuronoff, Inc, and Presidio Medical, Inc. Marom Bikson has received payment for expert testimony from Axonics and Wave Neuroscience. Richard North holds royalties or licenses with Abbott and several patents. The remaining authors reported no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

We define and explain the quasistatic approximation (QSA) as applied to field modeling for electrical and magnetic stimulation. Neuromodulation analysis pipelines include discrete stages, and QSA is applied specifically when calculating the electric and magnetic fields generated in tissues by a given stimulation dose. QSA simplifies the modeling equations to support tractable analysis, enhanced understanding, and computational efficiency. The application of QSA in neuromodulation is based on four underlying assumptions: (A1) no wave propagation or self-induction in tissue, (A2) linear tissue properties, (A3) purely resistive tissue, and (A4) non-dispersive tissue. As a consequence of these assumptions, each tissue is assigned a fixed conductivity, and the simplified equations (e.g. Laplace's equation) are solved for the spatial distribution of the field, which is separated from the field's temporal waveform. Recognizing that electrical tissue properties may be more complex, we explain how QSA can be embedded in parallel or iterative pipelines to model frequency dependence or nonlinearity of conductivity. We survey the history and validity of QSA across specific applications, such as microstimulation, deep brain stimulation, spinal cord stimulation, transcranial electrical stimulation, and transcranial magnetic stimulation. The precise definition and explanation of QSA in neuromodulation are essential for rigor when using QSA models or testing their limits., (Creative Commons Attribution license.)

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.)

Across all domains of brain stimulation (neuromodulation), conventional analysis of neuron activation involves two discrete steps: i) prediction of macroscopic electric field, ignoring presence of cells and; ii) prediction of cell activation from tissue electric fields. The first step assumes that current flow is not distorted by the dense tortuous network of cell structures. The deficiencies of this assumption have long been recognized, but - except for trivial geometries - ignored, because it presented intractable computation hurdles. This study introduces a novel approach for analyzing electric fields within a microscopically realistic brain volume. Our pipeline overcomes the technical intractability that prevented such analysis while also showing significant implications for brain stimulation. Contrary to the standard finite element method (FEM), we suggest using a nested iterative boundary element method (BEM) coupled with the fast multipole method (FMM). This approach allows for solving problems with multiple length scales more efficiently. A target application is a subvolume of the L2/3 P36 mouse primary visual cortex containing approximately 400 detailed densely packed neuronal cells at a resolution of 100 nm, which is obtained from scanning electron microscopy data. Our immediate result is a reduction of the stimulation field strength necessary for neuron activation by a factor of 0.85-0.55 (by 15%-45%) as compared to macroscopic predictions. This is in line with modern experimental data stating that existing macroscopic theories substantially overestimate electric field levels necessary for brain stimulation.

Objectives: When administered in repeated daily doses, transcranial direct current stimulation (tDCS) directed to the prefrontal cortex has cumulative efficacy for the treatment of depression. Depression can be marked by altered processing of emotionally salient information. An acute marker of response to tDCS may be measured as an immediate change in emotional information processing. Using an easily administered web-based task, we tested immediate changes in emotional information processing in acute response to tDCS in participants with and without depression., Materials and Methods: We enrolled n = 21 women with mild-to-moderate depression and n = 20 controls without depression to complete a web-based visual search task before and after 30 minutes of tDCS directed to the prefrontal cortex. The timed task required participants to identify a target face among arrays showing sad, neutral, or mixed (distractor) expressions., Results: At baseline, as predicted, the participants with depression differed from those without in emotional processing speed (mean z score difference -0.66 ± 0.27, p = 0.022) and accuracy in identifying sad stimuli (error rate: 4.4% vs 1.8%, p = 0.039). In response to tDCS, the participants with depression became significantly faster on the distractor condition (pre- vs post-tDCS z scores: -0.45 ± 0.65 vs -0.85 ± 0.65, p = 0.009), suggesting a specific reduction in bias toward negative emotional information. In response to tDCS, the depressed group also had significant improvements in self-reported mood (increased happy, decreased sad and anxious mood)., Conclusions: Participants with depression vs those without were differentiated by their performance of the visual search task at baseline and in response to tDCS. Given that measurable effects on depression scales may require weeks of tDCS treatments, acute change in emotional information processing can serve as an easily obtainable marker of depression and its response to tDCS., Clinical Trial Registration: The Clinicaltrials.gov registration number for the study is NCT05188248., Competing Interests: Conflict of Interest The City University of New York holds patents on brain stimulation with Marom Bikson as an inventor. Marom Bikson has equity in Soterix Medical Inc. Marom Bikson consults, 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. Leigh Charvet has consulted for Ybrain, Neuroelectrics, Johnson & Johnson, and Biogen. The remaining authors reported no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Chikungunya virus (CHIKV) is a globally prevalent pathogen, with outbreaks occurring in tropical regions. Chronic pain is the main symptom reported and is associated with decreased mobility and disability. Transcranial direct current stimulation (tDCS) is emerging as a new therapeutic tool for chronic arthralgia., Objective: To evaluate the effectiveness of 10 consecutive sessions of anodal tDCS on pain (primary outcome) in participants with chronic CHIKV arthralgia. Secondary outcomes included functional status, quality of life, and mood., Methods: In this randomized, double-blind, placebo-controlled trial, 30 participants with chronic CHIKV arthralgia were randomly assigned to receive either active (n = 15) or sham (n = 15) tDCS. The active group received 10 consecutive sessions of tDCS over M1 using the C3/Fp2 montage (2 mA for 20 min). Visual analog scale of pain (VAS), health assessment questionnaire (HAQ), short-form 36 health survey (SF-36), pain catastrophizing scale, Hamilton anxiety scale (HAS), timed up and go (TUG) test, lumbar dynamometry, 30-s arm curl and 2-min step test were assessed at baseline, day 10 and at 2 follow-up visits., Results: There was a significant interaction between group and time on pain (p = 0.03; effect size 95 % CI 0.9 (-1.67 to -0.16), with a significant time interaction (p = 0.0001). There was no interaction between time and group for the 2-minute step test (p = 0.18), but the groups differed significantly at day 10 (p = 0.01), first follow-up (p = 0.01) and second follow-up (p = 0.03). HAQ and SF-36 improved but not significantly. There was no significant improvement in mental health, and physical tests., Conclusion: tDCS appears to be a promising intervention for reducing pain in participants with chronic CHIKV arthralgia, although further research is needed to confirm these findings and explore potential long-term benefits., Trial Registration: Brazilian Registry of Clinical Trials (ReBEC): RBR-245rh7., Competing Interests: Declaration of competing interest The City University of New York has a patent on brain stimulation with MB as the inventor. MB has equity in Soterix Medical Inc. No conflict of interest was declared by the other authors., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Notwithstanding advances with low-intensity transcranial electrical stimulation (tES), there remain questions about the efficacy of clinically realistic electric fields on neuronal function., Objective: To measure electric fields magnitude and their effects on neuronal firing rate of hippocampal neurons in freely moving rats, and to establish calibrated computational models of current flow., Methods: Current flow models were calibrated on electric field measures in the motor cortex (n = 2 anesthetized rats) and hippocampus. A Neuropixels 2.0 probe with 384 channels was used in an in-vivo rat model of tES (n = 4 freely moving and 2 urethane anesthetized rats) to detect effects of weak fields on neuronal firing rate. High-density field mapping and computational models verified field intensity (1 V/m in hippocampus per 50 μA of applied skull currents)., Results: Electric fields of as low as 0.35 V/m (0.25-0.47) acutely modulated average firing rate in the hippocampus. At these intensities, firing rate effects increased monotonically with electric field intensity at a rate of 11.5 % per V/m (7.2-18.3). For the majority of excitatory neurons, firing increased for soma-depolarizing stimulation and diminished for soma-hyperpolarizing stimulation. While more diverse, the response of inhibitory neurons followed a similar pattern on average, likely as a result of excitatory drive., Conclusion: In awake animals, electric fields modulate spiking rate above levels previously observed in vitro. Firing rate effects are likely mediated by somatic polarization of pyramidal neurons. We recommend that all future rodent experiments directly measure electric fields to insure rigor and reproducibility., Competing Interests: Declaration of competing interest LP is listed as inventor in patents owned by CCNY, and has shares in Soterix Medical Inc. The City University of New York (CUNY) has IP on neuro-stimulation systems and methods with authors NK and MB as inventors. NK is an employee of Synchron Inc and consults for Ceragem Medical. MB has equity in Soterix Medical. MB consults, received grants, assigned inventions, and/or served on the S A B of SafeToddles, Boston Scientific, GlaxoSmithKline, Biovisics, Mecta, Lumenis, Halo Neuroscience, Google-X, i-Lumen, Humm, Allergan (Abbvie), Apple, Ybrain, Ceragem Medical, Remz., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hypertension is a global issue that is projected to worsen with increasingly obese populations. The central nervous system including the parts of the cortex plays a key role in hemodynamic stability and homeostatic control of blood pressure (BP), making them critical components in understanding and investigating the neural control of BP. This study investigated the effects of anodal transcranial direct current stimulation (tDCS) associated with aerobic physical exercise on BP and heart rate variability in hypertensive patients., Methods: Twenty hypertensive patients were randomized into two groups: active tDCS associated with aerobic exercise or sham tDCS associated with aerobic exercise. BP and heart rate variability were analyzed before (baseline) and after twelve non-consecutive sessions. After each tDCS session (2 mA for 20 min), moderate-intensity aerobic exercise was carried out on a treadmill for 40 min., Results: A total of 20 patients were enrolled (53.9 ± 10.6 years, 30.1 ± 3.7 Kg/m 2 ). There were no significant interactions between time and groups on diastolic BP during wake, sleep, over 24 and 3 h after the last intervention. Heart rate variability variables showed no significant difference for time, groups and interaction analysis, except for HF (ms 2 ) between groups ( p < 0.05)., Conclusion: Anodal tDCS over the temporal cortex associated with aerobic exercise did not induce improvements in BP and heart rate variability., Clinical Trial Registration: https://ensaiosclinicos.gov.br/rg/RBR-56jg3n/1, identifier: RBR-56jg3n., 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, Biovisics, Mecta, Lumenis, Halo Neuroscience, Google-X, i-Lumen, Humm, Allergan (Abbvie), Apple, Ybrain, Ceragem, Remz. 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 Silva-Filho, Bikson, Gebodh, Khadka, da Cruz Santos, Pegado and do Socorro Brasileiro-Santos.)

Noninvasive brain stimulation technologies such as transcranial electrical and magnetic stimulation (tES and TMS) are emerging neuromodulation therapies that are being used to target the neural substrates of substance use disorders. By the end of 2022, 205 trials of tES or TMS in the treatment of substance use disorders had been published, with heterogeneous results, and there is still no consensus on the optimal target brain region. Recent work may help clarify where and how to apply stimulation, owing to expanding databases of neuroimaging studies, new systematic reviews, and improved methods for causal brain mapping. Whereas most previous clinical trials targeted the dorsolateral prefrontal cortex, accumulating data highlight the frontopolar cortex as a promising therapeutic target for transcranial brain stimulation in substance use disorders. This approach is supported by converging multimodal evidence, including lesion-based maps, functional MRI-based maps, tES studies, TMS studies, and dose-response relationships. This review highlights the importance of targeting the frontopolar area and tailoring the treatment according to interindividual variations in brain state and trait and electric field distribution patterns. This converging evidence supports the potential for treatment optimization through context, target, dose, and timing dimensions to improve clinical outcomes of transcranial brain stimulation in people with substance use disorders in future clinical trials., Competing Interests: Dr. Joutsa has received grants from the Finnish Foundation for Alcohol Studies, the Finnish Medical Foundation, the Instrumentarium Research Foundation, the Sigrid Juselius Foundation, Turku University Hospital (VTR funds), and University of Turku, congress travel support from Abbott and AbbVie, and lecturer honoraria from Lundbeck and Novartis, and he has served as consultant for Adamant Health and Summaryx. Dr. Siddiqi has served as a scientific consultant for Magnus Medical and as a clinical consultant for Acacia Mental Health, Boston Precision Neurotherapeutics, and Kaizen Brain Center; he has received investigator-initiated research funding from BrainsWay and Neuronetics; he has served as a speaker for BrainsWay and for PsychU.org (sponsored by Otsuka); he owns intellectual property involving the use of functional connectivity to target TMS; and he owns stock in BrainsWay and Magnus Medical. Dr. Bikson has served as a consultant for, received grants from, served on scientific advisory boards, or has invention assignment agreements with Allergan (AbbVie), Apple, Biovisics, Boston Scientific, Ceragem, GlaxoSmithKline, Google X, Halo Neuroscience, Humm, i-Lumen, Lumenis, Mecta, SafeToddles, and Ybrain; he is an inventor on a patent on brain stimulation held by City University of New York; and he has equity in Soterix Medical. Dr. Paulus has served as an adviser for Hoffmann–La Roche and Spring Care, and he has received royalties from UpToDate. Dr. Fox holds intellectual property on the use of brain connectivity imaging to analyze lesions and guide brain stimulation; he has served as a consultant for Abbott, Boston Scientific, Magnus Medical, and Soterix; and he has received investigator-initiated research funding from Neuronetics. Dr. Hanlon is employed by and has financial interests in BrainsWay. Dr. Ekhtiari has received honoraria from Indivior for speaking at educational events. The other authors report no financial relationships with commercial interests.

High-voltage pulsed electric fields (HV-PEF) delivered with invasive needle electrodes for electroporation applications is known to induce off-target blood-brain barrier (BBB) disruption. In this study, we sought to determine the feasibility of minimally invasive PEF application to produce BBB disruption in rat brain and identify the putative mechanisms mediating the effect. We observed dose-dependent presence of Evans Blue (EB) dye in rat brain when PEF were delivered with a skull mounted electrode used for neurostimulation application. Maximum region of dye uptake was observed while using 1500 V, 100 pulses, 100 µs and 10 Hz. Results of computational models suggested that the region of BBB disruption was occurring at thresholds of 63 V/cm or higher; well below intensity levels for electroporation. In vitro experiments recapitulating this effect with human umbilical vein endothelial cells (HUVEC) demonstrated cellular alterations that underlie BBB manifests at low-voltage high-pulse conditions without affecting cell viability or proliferation. Morphological changes in HUVECs due to PEF were accompanied by disruption of actin cytoskeleton, loss of tight junction protein-ZO-1 and VE-Cadherin at cell junctions and partial translocation into the cytoplasm. Uptake of propidium iodide (PI) in PEF treated conditions is less than 1% and 2.5% of total number of cells in high voltage (HV) and low-voltage (LV) groups, respectively, implying that BBB disruption to be independent of electroporation under these conditions. 3-D microfabricated blood vessel permeability was found to increase significantly following PEF treatment and confirmed with correlative cytoskeletal changes and loss of tight junction proteins. Finally, we show that the rat brain model can be scaled to human brains with a similar effect on BBB disruption characterized by electric field strength (EFS) threshold and using a combination of two bilateral HD electrode configurations., (© 2023. The Author(s) under exclusive licence to Biomedical Engineering Society.)

Introduction: High-density (HD) spinal cord stimulation (SCS) delivers higher charge per time by increasing frequency and/or pulse duration, thus increasing stimulation energy. Previously, through phantom studies and computational modeling, we demonstrated that stimulation energy drives spinal tissue heating during kHz SCS. In this study, we predicted temperature increases in the spinal cord by HD SCS, the first step in considering the potential impact of heating on clinical outcomes., Materials and Methods: We adapted a high-resolution computer-aided design-derived spinal cord model, both with and without a lead encapsulation layer, and applied bioheat transfer finite element method multiphysics to predict temperature increases during SCS. We simulated HD SCS using a commercial SCS lead (eight contacts) with clinically relevant intensities (voltage-controlled: 0.5-7 V rms ) and electrode configuration (proximal bipolar, distal bipolar, guarded tripolar [+-+], and guarded quadripolar [+--+]). Results were compared with the conventional and 10-kHz SCS (current-controlled)., Results: HD SCS waveform energy (reflecting charge per second) governs joule heating in the spinal tissues, increasing temperature supralinearly with stimulation root mean square. Electrode configuration and tissue properties (an encapsulation layer) influence peak tissue temperature increase-but in a manner distinct for voltage-controlled (HD SCS) compared with current-controlled (conventional/10-kHz SCS) stimulation. Therefore, depending on conditions, HD SCS could produce heating greater than that of 10-kHz SCS. For example, with an encapsulation layer, using guarded tripolar configuration (500-Hz, 250-μs pulse width, 5-V peak HD SCS), the peak temperature increases were 0.36 °C at the spinal cord and 1.78 °C in the epidural space., Conclusions: As a direct consequence of the higher charge, HD SCS increases tissue heating; voltage-controlled stimulation introduces special dependencies on electrode configuration and lead encapsulation (reflected in impedance). If validated with an in vivo measurement as a possible mechanism of action of SCS, bioheat models of HD SCS serve as tools for programming optimization., (Published by Elsevier Inc.)

Interest in neurostimulation interventions has significantly grown in recent decades, yet a scientometric analysis objectively mapping scientific knowledge and recent trends remains unpublished. Using relevant keywords, we conducted a search in the Web of Science Core Collection on September 23, 2022, retrieving a total of 47,681 documents with 987,979 references. We identified two prominent research trends: 'noninvasive brain stimulation' and 'invasive brain stimulation.' These methods have interconnected over time, forming a cluster focused on evidence synthesis. Noteworthy emerging research trends encompassed 'transcutaneous auricular vagus nerve stimulation,' 'DBS/epilepsy in the pediatric population,' 'spinal cord stimulation,' and 'brain-machine interface.' While progress has been made for various neurostimulation interventions, their approval as adjuvant treatments remains limited, and optimal stimulation parameters lack consensus. Enhancing communication between experts of both neurostimulation types and encouraging novel translational research could foster further development. These findings offer valuable insights for funding agencies and research groups, guiding future directions in the field., Competing Interests: Declaration of Competing Interest Marco Solmi has received honoraria/has been a consultant for Abbvie, Angelini, Lundbeck and Otsuka. Michael A. Nitsche is a member of the scientific advisory board of Neuroelectrics. Andre R Brunoni holds a small equity of FlowNeuroscience and has been scientific advisor of the company between 2016 and 2018. He also receives research grants from the São Paulo Research State Foundation (19/06009–6) and the Academy of Medical Sciences (NAFR 12/1010) and in-kind support from MagVenture and SoterixMedical. Othman Sentissi has received advisory board honoraria from Otsuka, Lilly, Lundbeck, Sandoz, and Janssen in an institutional account for research and teaching. André Aleman, Luc Mallet, Jonathan Downar, Marom Bikson, Valerie Brandt, Chaomei Chen, Adi Sulstarova, Emmanuel Poulet, Joshua Hyde, Samuele Cortese and Michel Sabe report no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Few studies have investigated tolerability, blinding, and double-blinding of High-Definition transcranial Direct Current Stimulation (HD-tDCS) at amplitudes above 2 milliamps (mA)., Objective: We examined a) tolerability of HD-tDCS during stimulation sessions and b) blinding and double blinding of participants and study team members., Methods: Data from a mixed neurologic sample of 292 older adults were pooled from 3046 HD-tDCS sessions (2329 active; 717 sham). Per electrode amplitudes ranged from 1 mA to 4 mA with total currents up to 10 mA. Participants completed a standardized sensation (tolerability) questionnaire after each session. Participants and study team members stated whether the participant received active or sham stimulation at the end of various sessions. Data were collapsed into the presence/absence of a symptom due to low rates of positive responding and were analyzed for both differences and bioequivalency., Results: There were no safety-related adverse events. HD-tDCS was well tolerated with mostly no ("none") or "mild" sensations reported across sessions, regardless of active or sham condition and in both stimulation naïve and experienced participants. There were no significant differences in side effects between active and sham, with some achieving bioequivalence. Tingling and itching were significantly more common after lower (<2 mA) than higher (≥3 mA) amplitude active sessions, while skin redness was significantly more common after higher amplitudes. Blinding was effective at the participant and study team levels., Conclusions: HD-tDCS was well tolerated with center electrode amplitudes up to 4 mA. The bimodal ramp-up/down format of the sham was effective for blinding. These results support higher scalp-based amplitudes that enable greater brain-based current intensities in older adults., Competing Interests: Declaration of competing interest The City University of New York holds patents on brain stimulation, with MB as an inventor. MB has equity in Soterix Medical Inc. MB consults, 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, Remz. There are no conflicts of interest for any other author., (Published by Elsevier Inc.)

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.)

One of the most critical challenges in using noninvasive brain stimulation (NIBS) techniques for the treatment of psychiatric and neurologic disorders is inter- and intra-individual variability in response to NIBS. Response variations in previous findings suggest that the one-size-fits-all approach does not seem the most appropriate option for enhancing stimulation outcomes. While there is a growing body of evidence for the feasibility and effectiveness of individualized NIBS approaches, the optimal way to achieve this is yet to be determined. Transcranial electrical stimulation (tES) is one of the NIBS techniques showing promising results in modulating treatment outcomes in several psychiatric and neurologic disorders, but it faces the same challenge for individual optimization. With new computational and methodological advances, tES can be integrated with real-time functional magnetic resonance imaging (rtfMRI) to establish closed-loop tES-fMRI for individually optimized neuromodulation. Closed-loop tES-fMRI systems aim to optimize stimulation parameters based on minimizing differences between the model of the current brain state and the desired value to maximize the expected clinical outcome. The methodological space to optimize closed-loop tES fMRI for clinical applications includes (1) stimulation vs. data acquisition timing, (2) fMRI context (task-based or resting-state), (3) inherent brain oscillations, (4) dose-response function, (5) brain target trait and state and (6) optimization algorithm. Closed-loop tES-fMRI technology has several advantages over non-individualized or open-loop systems to reshape the future of neuromodulation with objective optimization in a clinically relevant context such as drug cue reactivity for substance use disorder considering both inter and intra-individual variations. Using multi-level brain and behavior measures as input and desired outcomes to individualize stimulation parameters provides a framework for designing personalized tES protocols in precision psychiatry., (© 2023. Springer Nature Limited.)

Objective . Transcranial direct current stimulation (tDCS) generates sustained electric fields in the brain, that may be amplified when crossing capillary walls (across blood-brain barrier, BBB). Electric fields across the BBB may generate fluid flow by electroosmosis. We consider that tDCS may thus enhance interstitial fluid flow. Approach . We developed a modeling pipeline novel in both (1) spanning the mm (head), μ m (capillary network), and then nm (down to BBB tight junction (TJ)) scales; and (2) coupling electric current flow to fluid current flow across these scales. Electroosmotic coupling was parametrized based on prior measures of fluid flow across isolated BBB layers. Electric field amplification across the BBB in a realistic capillary network was converted to volumetric fluid exchange. Main results . The ultrastructure of the BBB results in peak electric fields (per mA of applied current) of 32-63Vm-1across capillary wall and >1150Vm-1in TJs (contrasted with 0.3Vm-1in parenchyma). Based on an electroosmotic coupling of 1.0 × 10 -9 - 5.6 × 10 -10 m3s-1m2perVm-1, peak water fluxes across the BBB are 2.44 × 10 -10 - 6.94 × 10 -10 m3s-1m2, with a peak 1.5 × 10 -4 - 5.6 × 10 -4 m3min-1m3interstitial water exchange (per mA). Significance . Using this pipeline, the fluid exchange rate per each brain voxel can be predicted for any tDCS dose (electrode montage, current) or anatomy. Under experimentally constrained tissue properties, we predicted tDCS produces a fluid exchange rate comparable to endogenous flow, so doubling fluid exchange with further local flow rate hot spots ('jets'). The validation and implication of such tDCS brain 'flushing' is important to establish., (© 2023 IOP Publishing Ltd.)

Importance: Cathodal transcranial direct current stimulation (C-tDCS) provides neuroprotection in preclinical models of acute ischemic stroke (AIS) by inhibiting peri-infarct excitotoxic effects and enhancing collateral perfusion due to its vasodilatory properties., Objective: To report the first-in-human pilot study using individualized high-definition (HD) C-tDCS as a treatment of AIS., Design, Setting, and Participants: This randomized clinical trial was sham controlled with 3 + 3 dose escalation design, and was conducted at a single center from October 2018 to July 2021. Eligible participants were treated for AIS within 24 hours from onset, had imaging evidence of cortical ischemia with salvageable penumbra, and were ineligible for reperfusion therapies. HD C-tDCS electrode montage was selected for each patient to deliver the electric current to the ischemic region only. Patients were followed for 90 days., Main Outcomes and Measures: Primary outcomes were feasibility, assessed as time from randomization to study stimulation initiation; tolerability, assessed by rate of patients completing the full study stimulation period; and safety, assessed by rates of symptomatic intracranial hemorrhage at 24 hours. The efficacy imaging biomarkers of neuroprotection and collateral enhancement were explored., Results: A total of 10 patients with AIS were enrolled, 7 were randomized to active treatment and 3 to sham. Patient age was mean (SD) 75 (10) years old, 6 (60%) were female, and National Institutes of Health Stroke Scale score was mean (SD) 8 (7). Two doses of HD C-tDCS (1 milliamp [mA] for 20 minutes and 2 mA for 20 minutes) were studied. The speed of HD C-tDCS implementation was a median (IQR) 12.5 minutes (9-15 minutes) in the last 4 patients. Patients tolerated the HD C-tDCS with no permanent stimulation cessation. The hypoperfused region was reduced by a median (IQR) 100% (46% to 100%) in the active group vs increased by 325% (112% to 412%) in sham. Change in quantitative relative cerebral blood volume early poststimulation was a median (IQR) 64% (40% to 110%) in active vs -4% (-7% to 1%) sham patients and followed a dose-response pattern. Penumbral salvage in the active C-tDCS group was median (IQR) 66% (29% to 80.5%) vs 0% (IQR 0% to 0%) in sham., Conclusion and Relevance: In this randomized, first-in-human clinical trial, HD C-tDCS was started efficiently and well tolerated in emergency settings, with signals of beneficial effect upon penumbral salvage. These results support advancing HD C-tDCS to larger trials., Trial Registration: ClinicalTrials.gov Identifier: NCT03574038.

Spinal cord stimulation (SCS) evokes fast epidural evoked compound action potential (ECAP) that represent activity of dorsal column axons, but not necessarily a spinal circuit response. Using a multimodal approach, we identified and characterized a delayed and slower potential evoked by SCS that reflects synaptic activity within the spinal cord. Anesthetized female Sprague Dawley rats were implanted with an epidural SCS lead, epidural motor cortex stimulation electrodes, an epidural spinal cord recording lead, an intraspinal penetrating recording electrode array, and intramuscular electromyography (EMG) electrodes in the hindlimb and trunk. We stimulated the motor cortex or the epidural spinal cord and recorded epidural, intraspinal, and EMG responses. SCS pulses produced characteristic propagating ECAPs (composed of P1, N1, and P2 waves with latencies <2 ms) and an additional wave ("S1") starting after the N2. We verified the S1-wave was not a stimulation artifact and was not a reflection of hindlimb/trunk EMG. The S1-wave has a distinct stimulation-intensity dose response and spatial profile compared with ECAPs. 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX; a selective competitive antagonist of AMPA receptors (AMPARs)] significantly diminished the S1-wave, but not ECAPs. Furthermore, cortical stimulation, which did not evoke ECAPs, produced epidurally detectable and CNQX-sensitive responses at the same spinal sites, confirming epidural recording of an evoked synaptic response. Finally, applying 50-Hz SCS resulted in dampening of S1-wave but not ECAPs. Therefore, we hypothesize that the S1-wave is synaptic in origin, and we term the S1-wave type responses: evoked synaptic activity potentials (ESAPs). The identification and characterization of epidurally recorded ESAPs from the dorsal horn may elucidate SCS mechanisms., Competing Interests: T.Z. and R.E. are employees of Boston Scientific Neuromodulation. T.Z. Owns Boston Scientific Stock. The City University of New York holds patents on brain stimulation with M.B. as inventor. M.B. has equity in Soterix Medical Inc. M.B. consults, received grants, assigned inventions, and/or serves on the SAB of SafeToddles, Boston Scientific (and M.S.), GlaxoSmithKline, Biovisics, Mecta, Lumenis, Halo Neuroscience, Google-X, i-Lumen, Humm (and N.G.), Allergan (Abbvie), Apple, Ybrain, Ceragem, and Remz. All other authors declare no competing financial interests., (Copyright © 2023 Sharma et al.)

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.)

The negative effect of prolonged cognitive demands on psychomotor skills in athletes has been demonstrated. Transcranial direct current stimulation (tDCS) could be used to mitigate this effect. This study examined the effects of tDCS over the left dorsolateral prefrontal cortex (DLPFC) during a 30-min inhibitory Stroop task on cognitive and shooting performances of professional female basketball players. Following a randomised, double-blinded, sham-controlled, cross-over design, players were assigned to receive anodal tDCS (a-tDCS, 2 mA for 20 min) or sham-tDCS in two different sessions. Data from 8 players were retained for analysis. Response Time decreased significantly over time ( p  < 0.001; partial η 2 = 0.44; no effect of condition, or condition vs. time interaction). No difference in mean accuracy and shooting performance was observed between tDCS conditions. The results suggest that a-tDCS exert no additional benefits in reducing the negative effects of prolonged cognitive demands on technical performance compared to sham (placebo). Practitioner summary: Prolonged cognitive demands can negatively affect the athletes' performance. We tested whether transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (DLPFC) could attenuate these effects on cognitive and shooting performance in professional female basketball players. However, tDCS did not exert any additional benefits compared to sham. Abbreviations: tDCS: transcranial direct current stimulation; a-tDCS: anodal transcranial direct current stimulation; PFC: prefrontal cortex; DLPFC: dorsolateral prefrontal cortex; PCT: prolonged cognitive task; TT: time trial; RT: response time; NASA-TLX: National Aeronautics and Space Administration Task Load Index; RPE: ratings of perceived exertion; CR-10 scale: category rating scale; EEG: electroencephalogram; AU: arbitrary units.

Background: Computational models of current flow during Electroconvulsive Therapy (ECT) rely on the quasi-static assumption, yet tissue impedance during ECT may be frequency specific and change adaptively to local electric field intensity., Objectives: We systematically consider the application of the quasi-static pipeline to ECT under conditions where 1) static impedance is measured before ECT and 2) during ECT when dynamic impedance is measured. We propose an update to ECT modeling accounting for frequency-dependent impedance., Methods: The frequency content on an ECT device output is analyzed. The ECT electrode-body impedance under low-current conditions is measured with an impedance analyzer. A framework for ECT modeling under quasi-static conditions based on a single device-specific frequency (e.g., 1 kHz) is proposed., Results: Impedance using ECT electrodes under low-current is frequency dependent and subject specific, and can be approximated at >100 Hz with a subject-specific lumped parameter circuit model but at <100 Hz increased non-linearly. The ECT device uses a 2 μA 800 Hz test signal and reports a static impedance that approximate 1 kHz impedance. Combined with prior evidence suggesting that conductivity does not vary significantly across ECT output frequencies at high-currents (800-900 mA), we update the adaptive pipeline for ECT modeling centered at 1 kHz frequency. Based on individual MRI and adaptive skin properties, models match static impedance (at 2 μA) and dynamic impedance (at 900 mA) of four ECT subjects., Conclusions: By considering ECT modeling at a single representative frequency, ECT adaptive and non-adaptive modeling can be rationalized under a quasi-static pipeline., 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 SafeToddles, 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-NIDAUG3DA048502, NIH-NIGMST34 GM137858, NIH-NINDSR01 NS112996, NIH-NINDSR01 NS101362, and NIH-G-RISET32GM136499., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective. Numerical modeling of electric fields induced by transcranial alternating current stimulation (tACS) is currently a part of the standard procedure to predict and understand neural response. Quasi-static approximation (QSA) for electric field calculations is generally applied to reduce the computational cost. Here, we aimed to analyze and quantify the validity of the approximation over a broad frequency range. Approach. We performed electromagnetic modeling studies using an anatomical head model and considered approximations assuming either a purely ohmic medium (i.e. static formulation) or a lossy dielectric medium (QS formulation). The results were compared with the solution of Maxwell's equations in the cases of harmonic and pulsed signals. Finally, we analyzed the effect of electrode positioning on these errors. Main results. Our findings demonstrate that the QSA is valid and produces a relative error below 1% up to 1.43 MHz. The largest error is introduced in the static case, where the error is over 1% across the entire considered spectrum and as high as 20% in the brain at 10 Hz. We also highlight the special importance of considering the capacitive effect of tissues for pulsed waveforms, which prevents signal distortion induced by the purely ohmic approximation. At the neuron level, the results point a difference of sense electric field as high as 22% at focusing point, impacting pyramidal cells firing times. Significance. QSA remains valid in the frequency range currently used for tACS. However, neglecting permittivity (static formulation) introduces significant error for both harmonic and non-harmonic signals. It points out that reliable low frequency dielectric data are needed for accurate transcranial current stimulation numerical modeling., (Creative Commons Attribution license.)

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: Opioid Use Disorder (OUD) is an escalating public health problem with over 100,000 drug overdose-related deaths last year most of them related to opioid overdose, yet treatment options remain limited. Non-invasive Vagal Nerve Stimulation (nVNS) can be delivered via the ear or the neck and is a non-medication alternative to treatment of opioid withdrawal and OUD with potentially widespread applications., Methods: This paper reviews the neurobiology of opioid withdrawal and OUD and the emerging literature of nVNS for the application of OUD. Literature databases for Pubmed, Psychinfo, and Medline were queried for these topics for 1982-present., Results: Opioid withdrawal in the context of OUD is associated with activation of peripheral sympathetic and inflammatory systems as well as alterations in central brain regions including anterior cingulate, basal ganglia, and amygdala. NVNS has the potential to reduce sympathetic and inflammatory activation and counter the effects of opioid withdrawal in initial pilot studies. Preliminary studies show that it is potentially effective at acting through sympathetic pathways to reduce the effects of opioid withdrawal, in addition to reducing pain and distress., Conclusions: NVNS shows promise as a non-medication approach to OUD, both in terms of its known effect on neurobiology as well as pilot data showing a reduction in withdrawal symptoms as well as physiological manifestations of opioid withdrawal.

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.)

Objectives: We consider two consequences of brain capillary ultrastructure in neuromodulation. First, blood-brain barrier (BBB) polarization as a consequence of current crossing between interstitial space and the blood. Second, interstitial current flow distortion around capillaries impacting neuronal stimulation., Materials and Methods: We developed computational models of BBB ultrastructure morphologies to first assess electric field amplification at the BBB (principle 1) and neuron polarization amplification by the presence of capillaries (principle 2). We adapt neuron cable theory to develop an analytical solution for maximum BBB polarization sensitivity., Results: Electrical current crosses between the brain parenchyma (interstitial space) and capillaries, producing BBB electric fields (E BBB ) that are >400x of the average parenchyma electric field (Ē BRAIN ), which in turn modulates transport across the BBB. Specifically, for a BBB space constant (λ BBB ) and wall thickness (d th-BBB ), the analytical solution for maximal BBB electric field (E A BBB ) is given as: (Ē BRAIN  × λ BBB )/d th-BBB . Electrical current in the brain parenchyma is distorted around brain capillaries, amplifying neuronal polarization. Specifically, capillary ultrastructure produces ∼50% modulation of the Ē BRAIN (Activating function) is thus ∼100 kV/m BRAIN (Activating function) is thus ∼100 kV/m 2 per unit Ē BRAIN ., Conclusions: BBB stimulation by principle 1 suggests novel therapeutic strategies such as boosting metabolic capacity or interstitial fluid clearance. Whereas the spatial profile of E BRAIN is traditionally assumed to depend only on macroscopic anatomy, principle 2 suggests a central role for local capillary ultrastructure-which impact forms of neuromodulation including deep brain stimulation (DBS), spinal cord stimulation (SCS), transcranial magnetic stimulation (TMS), electroconvulsive therapy (ECT), and transcranial electrical stimulation (tES)/transcranial direct current stimulation (tDCS)., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Over 100,000 individuals in the United States lost their lives secondary to drug overdose in 2021, with opioid use disorder (OUD) being a leading cause. Pain is an important component of opioid withdrawal, which can complicate recovery from OUD. This study's objectives were to assess the effects of transcutaneous cervical vagus nerve stimulation (tcVNS), a technique shown to reduce sympathetic arousal in other populations, on pain during acute opioid withdrawal and to study pain's relationships with objective cardiorespiratory markers. Twenty patients with OUD underwent opioid withdrawal while participating in a two-hour protocol. The protocol involved opioid cues to induce opioid craving and neutral conditions for control purposes. Adhering to a double-blind design, patients were randomly assigned to receive active tcVNS ( n  = 9) or sham stimulation ( n  = 11) throughout the protocol. At the beginning and end of the protocol, patients' pain levels were assessed using the numerical rating scale (0-10 scale) for pain (NRS Pain). During the protocol, electrocardiogram and respiratory effort signals were measured, from which heart rate variability (HRV) and respiration pattern variability (RPV) were extracted. Pre- to post- changes (denoted with a Δ) were computed for all measures. Δ NRS Pain scores were lower ( P  = 0.045) for the active group (mean ± standard deviation: -0.8 ± 2.4) compared to the sham group (0.9 ± 1.0). A positive correlation existed between Δ NRS pain scores and Δ RPV (Spearman's ρ  = 0.46; P  = 0.04). Following adjustment for device group, a negative correlation existed between Δ HRV and Δ NRS Pain (Spearman's ρ  = -0.43; P  = 0.04). This randomized, double-blind, sham-controlled pilot study provides the first evidence of tcVNS-induced reductions in pain in patients with OUD experiencing opioid withdrawal. This study also provides the first quantitative evidence of an association between breathing irregularity and pain. The correlations between changes in pain and changes in objective physiological markers add validity to the data. Given the clinical importance of reducing pain non-pharmacologically, the findings support the need for further investigation of tcVNS and wearable cardiorespiratory sensing for pain monitoring and management in patients with OUD., Competing Interests: The active and sham vagus nerve stimulation devices used in this research were provided in-kind by electroCore, Inc. JDB has received grant funding support in the past from electroCore and currently serves on the Scientific Advisory Board and shares grant support from the Department of Defense with Evren Technologies, Inc. All other authors report no commercial or financial relationships that could be construed as potential conflicts of interest., (© 2022 Gazi, Harrison, Lambert, Nawar, Obideen, Driggers, Vaccarino, Shah, Rozell, Bikson, Welsh, Inan and Bremner.)

Background: ADHD is a common neurodevelopmental disorder with a pediatric prevalence of 5.2%.While medication treatment for ADHD is effective, it does not address all symptoms and a small but notable subgroup does not respond to medications. Adverse effects limit its use and some parents and participants resist use of medication. Thus, limitations of medication treatment for ADHD motivate searching for other therapeutic options. Transcranial Direct Current Stimulation (tDCS) has been suggested as a treatment for children with ADHD, with mixed results to date. Protocol variables employed, including combined use of cognitive training (CT) and scheduling of sessions, may explain diverse findings to date. The aim of this study was to examine safety, feasibility and efficacy of tDCS combined with CT provided three-times-per week for one-month to treat children with ADHD., Methods: In a double blind, randomized, sham-controlled pilot study, 25 children with ADHD were randomized to receive 12 sessions of either anodal tDCS or sham-tDCS for 20 min combined with CT three-times-per-week for four weeks. The tDCS anode was over left dorsolateral prefrontal cortex (DLPFC) and cathode over vertex. Assessments were obtained prior to, after 6 sessions, 12 sessions and one-month after intervention., Results: No significant post-intervention differences were found between those receiving tDCS or sham-tDCS. Both groups demonstrated significant improvement on questionnaire measures of ADHD and executive function with mixed results seen on computerized performance measures. Overall, adverse effects were mild with no significant difference between groups. However, three children, all from the tDCS group, experienced headaches with two requiring temporary cessation and one requiring removal from the study., Conclusions: Anodal tDCS to the DLPFC using the above protocol in children with ADHD did not demonstrate additional treatment benefits beyond that of CT., (Copyright © 2022 Elsevier Ltd. 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.)

While the applications of transcranial direct current stimulation (tDCS) across brain disease and cognition are diverse, they rely on changes in brain function outlasting stimulation. The cellular mechanisms of DCS leading to brain plasticity have been studied, but the role of astrocytes remains unaddressed. We previously predicted that during tDCS current is concentrated across the blood brain-barrier. This will amplify exposure of endothelial cells (ECs) that form blood vessels and of astrocytes that wrap around them. The objective of this study was to investigate the effect of tDCS on the gene expression by astrocytes or ECs. DCS (0.1 or 1 mA, 10 min) was applied to monolayers of mouse brain ECs or human astrocytes. Gene expression of a set of neuroactive genes were measured using RT-qPCR. Expression was assessed immediately or 1 h after DCS. Because we previously showed that DCS can produce electroosmotic flow and fluid shear stress known to influence EC and astrocyte function, we compared three interventions: pressure-driven flow across the monolayer alone, pressure-driven flow plus DCS, and DCS alone with flow blocked. We show that DCS can directly modulate gene expression in astrocytes (notably FOS and BDNF), independent of but synergistic with pressure-driven flow gene expression. In ECs, pressure-driven flow activates genes expression with no evidence of further contribution from DCS. In ECs, DCS alone produced mixed effects including an upregulation of FGF9 and downregulation of NTF3. We propose a new adjunct mechanism for tDCS based on glial meditated plasticity., (© 2022. The Author(s).)

This supplementary dataset is supportive of the randomized sham-controlled, double-blind, crossover clinical trial investigating polarity- and intensity-dependent effects of high-definition transcranial electrical stimulation (HD-tDCS) applied over the right temporo-parietal junction on mean middle cerebral artery blood flow velocity (MCA-BFv) bilaterally. Data of eleven healthy right-handed adults (6 women, 5 men; mean age 31 ± 5.6 years old) were analyzed for MCA-BFv, assessed using transcranial doppler ultrasound on the stimulated and the contralateral hemisphere concomitantly, during and after 3 blocks of 2 min HD-tDCS at 1, 2, and 3 mA. Participants received three electrical stimulation conditions (anode center, cathode center, and sham) randomly ordered across different days. The collected data is publicly available at Mendeley Data. This article and the data will inform future related investigations and safety analysis of transcranial non-invasive brain stimulation., Competing Interests: The City University of New York has inventions on tES with M.B. as inventor. M.B. has equity in Soterix Medical and serves on the scientific advisory boards or has grants from Mecta, Halo Neuroscience, Boston Scientific and GlaxoSmithKline. 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., (© 2022 The Authors.)

Context: Chronic pain in end-stage renal disease (ESRD) is an increasingly neglected clinical problem affecting more than 60% of patients. Long-term chronic pain could be associated with brain imbalance in circuits of pain matrix and is associated with poor quality of life (QoL) and mood disturbance., Objectives: The aim of this study was evaluating the effects of transcranial direct current stimulation (tDCS) on pain, QoL, depression, anxiety and affectivity in ESRD patients undergoing hemodialysis (HD)., Methods: This double-blind, randomized, sham-controlled trial included 30 patients with chronic pain undergoing HD. Participants were allocated to Active tDCS and Sham tDCS and received ten non-consecutive sessions of anodal motor cortex stimulation (M1/Sp2 montage) at 2 mA intensity for 20 min. The primary outcome was pain assessed using numeric rating scale (NRS) and collected at baseline, immediately after the 10th day of intervention, one week, two weeks, and four weeks after the last stimulation. Secondary outcomes included QoL, depression, anxiety and affectivity collected before and after intervention., Results: A mixed ANOVA model showed significant interaction between group and time on pain F(4.112) = 3.106, P = 0.01 with main effects of group (P = 0.03). Before and after intervention, a significant improvement was observed in QoL (P = 0.009), general health (P = 0.03), fatigue (P = 0.05), symptoms (P = 0.05) depression (P = 0.01) and anxiety (P = 0.01). No difference was found for affectivity., Conclusion: Anodal tDCS over the motor cortex emerges as a potential therapeutic approach for improving pain, QoL, and mood in patients with ESRD., (Copyright © 2022 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)