Abstract Background Transcutaneous auricular vagus nerve stimulation (taVNS) depends on activating afferent vagal pathways, leading to central and physiological (parasympathetic) modulation. Explaining how taVNS changes cardiorespiratory physiology requires systematic characterization of the effects of electrode location and stimulation waveform using rigorous experimental controls. Objective To determine the acute effects of four taVNS stimulation configurations (left unilateral 25 Hz, 100 Hz, burst, and bilateral 25 Hz) on physiological markers of parasympathetic activation compared with configuration-matched earlobe stimulation in healthy subjects at rest. Methods Customized 8-mm ear-clip electrodes delivered monophasic 500 μs pulses (anode anterior) to the tragus or a configuration-matched earlobe control across four stimulation configurations (left unilateral 25 Hz, 100 Hz, burst, and bilateral 25 Hz). Twenty-five healthy participants completed a randomized, single-blind, within-subject crossover study, undergoing both active and control stimulation for all four configurations (200 sessions total). Each session consisted of five 60-second stimulation blocks (1,000 stimuli total). Heart rate (HR), heart rate variability (HRV; RMSSD), and respiration were recorded continuously. Linear mixed-effects models compared physiological responses between tragus and earlobe stimulation during the first stimulation block (primary analysis), across 5-second HR intervals (secondary analysis), and averaged across all five stimulation blocks (post hoc analysis). Results During the first stimulation block, HRV was significantly higher during unilateral left 25 Hz tragus stimulation than during the matched earlobe control (β = −10.34, t(33) = −2.63, p = .01, 95% CI [−18.05, −2.64]), consistent with increased parasympathetic activity. No significant differences were observed for HRV with the other stimulation configurations, or for HR or respiration under any configuration. Analysis of 5-second HR intervals likewise revealed no significant temporal effects for block one. Analysis of 5-second heart rate intervals across the five blocks identified differences between tragus and earlobe at discrete time points but did not show a consistent temporal pattern across the stimulation period. Across all five stimulation blocks, unilateral left 25 Hz tragus stimulation remained associated with higher HRV (β = −6.56, t(124) = −3.85, p < .01, 95% CI [−9.90, −3.22]) and also produced an increase in HR relative to earlobe stimulation (β = −1.05, t(24) = −2.57, p = .01, 95% CI [−1.85, −0.24]). Respiration was unaffected throughout. Conclusion In this systematic study, unilateral left 25 Hz tragus stimulation produced physiological modulation consistent with vagal target engagement. These findings underscore the importance of rigorous dose-specific taVNS studies to establish reproducible physiological biomarkers.

BackgroundTranscutaneous auricular Vagus Nerve Stimulation (taVNS) applies low-intensity electrical current to the ear with the intention of activating the auricular branch of the Vagus nerve. The sensitivity and selectivity of stimulation applied to the ear depends on current flow pattern produced by a given electrode montage (size and placement).ObjectiveWe compare different electrodes designs for taVNS considering both the predicted peak electric fields (sensitivity) and their spatial distribution (selectivity).MethodsBased on optimized high-resolution (0.47 mm) T1 and T2 weighted MRI, we developed an anatomical model of the left ear and the surrounding head tissues including brain, CSF/meninges, skull, muscle, blood vessels, fat, cartilage, and skin. The ear was further segmented into 6 regions of interest (ROI) based on various nerve densities: cavum concha, cymba concha, crus of helix, tragus, antitragus, and earlobe. A range of taVNS electrode montages were reproduced spanning varied electrodes sizes and placements over the tragus, cymba concha, earlobe, cavum concha, and crus of helix. Electric field across the ear (from superficial skin to cartilage) for each montage at 1 mA or 2 mA taVNS, assuming an activation threshold of 6.15 V/m, 12.3 V/m or 24.6 V/m was predicted using a Finite element method (FEM). Finally, considering every ROI, we calculated the sensitivity and selectivity of each montage.ResultsCurrent flow patterns through the ear were highly specific to the electrode montage. Electric field was maximal at the ear regions directly under the electrodes, and for a given total current, increases with decreasing electrode size. Depending on the applied current and nerves threshold, activation may also occur in the regions between multiple anterior surface electrodes. Each considered montage was selective for one or two regions of interest. For example, electrodes across the tragus restricted significant electric field to the tragus. Stimulation across the earlobe restricted significant electric field to the earlobe and the antitragus. Because of this relative selectivity, use of control ear montages in experimental studies, support testing of targeting. Relative targeting was robust across assumptions of activation threshold and tissue properties.DiscussionComputational models provide additional insight on how details in electrode shape and placement impact sensitivity (how much current is needed) and selectivity (spatial distribution), thereby supporting analysis of existing approaches and optimization of new devices. Our result suggest taVNS current patterns and relative target are robust across individuals, though (variance in) axon morphology was not represented.

tDCS is a non-invasive brain stimulation approach in which low level currents are applied across the scalp to influence underlying brain function [1Weller S. Nitsche M.A. Plewnia C. Enhancing cognitive control training with transcranial direct current stimulation: a systematic parameter study.Brain Stimul. 2020; 13: 1358-1369Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 2Polanía R. Nitsche M.A. Ruff C.C. Studying and modifying brain function with non-invasive brain stimulation.Nat Neurosci. 2018; 21: 174-187Crossref PubMed Scopus (316) Google Scholar, 3Bikson M. Brunoni A.R. Charvet L.E. Clark V.P. Cohen L.G. Deng Z.-D. et al.Rigor and reproducibility in research with transcranial electrical stimulation: an NIMH-sponsored workshop.Brain Stimul. 2018; 11: 465-480Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar]. The Serial Reaction Time Task (SRTT) is commonly used to investigate neural mechanisms underlying motor-learning [[4]Buch E.R. Santarnecchi E. Antal A. Born J. Celnik P.A. Classen J. et al.Effects of tDCS on motor learning and memory formation: a consensus and critical position paper.Clin Neurophysiol : Off. J. Int. Federat. Clin. Neurophysiol. 2017; 128: 589-603Crossref PubMed Scopus (161) Google Scholar]. In the SRTT, subjects make a series of button presses based upon visual location cues. When the sequence is random, mean RT remains relatively stable over time. However, when the sequence is repetitive and fixed, individuals show a progressive motor learning reflected in a reduction in reaction time (RT) across trials even if they are not told of the sequence in advance. The rate of motor learning may be modulated by tDCS applied to the visuomotor learning circuit consisting of dorsal-stream visual cortex and motor/premotor regions of frontal cortex [[5]Hardwick R.M. Rottschy C. Miall R.C. Eickhoff S.B. A quantitative meta-analysis and review of motor learning in the human brain.Neuroimage. 2013; 67: 283-297Crossref PubMed Scopus (371) Google Scholar,[6]Savic B. Meier B. How transcranial direct current stimulation can modulate implicit motor sequence learning and consolidation: a brief review.Front Hum Neurosci. 2016; 10: 26Crossref PubMed Scopus (28) Google Scholar]. We recently [[7]Sehatpour P. Donde C. Hoptman M.J. Kreither J. Adair D. Dias E. et al.Network-level mechanisms underlying effects of transcranial direct current stimulation (tDCS) on visuomotor learning.Neuroimage. 2020; 117311Crossref PubMed Scopus (6) Google Scholar] demonstrated that RT distributions during the fixed version of the SRTT are bimodal, with intermixed fast, “proactive” and slow, “reactive” trials, and that tDCS functions primarily by altering the ratio between trials reflecting enhanced motor learning. Further, we have demonstrated that the different trial types are associated with differential connectivity patterns within the visuomotor network. Finally, we demonstrated that the shift in connectivity pattern explained the shift in RT distribution. Specifically, cathodal stimulation of dorsal-stream visual cortex, with cathode at POz and anode at Cz according to the 10–20 EEG system, brought about a change in connectivity between motor and visual cortices accompanied by improved task performance. Traditional tDCS uses relatively large (3 × 3 cm) pads placed over specific scalp regions, which leads to relatively coarse targeting of the electrical field within underlying brain regions. More recently, high-definition (HD-tDCS) approaches have been developed to better focus the energy to key underlying brain regions [[8]Dmochowski J.P. Datta A. Bikson M. Su Y. Parra L.C. Optimized multi-electrode stimulation increases focality and intensity at target.J Neural Eng. 2011; 8046011Crossref PubMed Scopus (337) Google Scholar]. Here we investigate the relative effectiveness of HD-vs. conventional tDCS [[9]Kuo H.-I. Bikson M. Datta A. Minhas P. Paulus W. Kuo M.-F. et al.Comparing cortical plasticity induced by conventional and high-definition 4 × 1 ring tDCS: a neurophysiological study.Brain Stimul. 2013; 6: 644-648Abstract Full Text Full Text PDF PubMed Scopus (368) Google Scholar] in improving motor learning when applied to the visual node of the visuomotor network, along with the relative effects on underlying brain connectivity patterns. We predicted increased efficacy of HD-vs. conventional tDCS, reflecting its greater focality within target regions. This study involved 10 healthy participants (3 females, 7 males), mean age 41.7 ± 9.6. All subjects provided written informed consent, and the procedures were approved by the Nathan Kline Institute Review Board. All participants reported normal vision. All were right-handed. Cathodal (2 mA) or sham tDCS over visual cortex was administered using the Soterix Medical HD-tDCS 4 × 1 stimulator while subjects performed repeat trial blocks (“runs”) of the SRTT using a previously described paradigm. Simultaneous EEG was recorded using an AC-coupled BrainVision recording system. Participants received four tDCS conditions on separate days in random order: HD-active, HD-sham, conventional-active, and conventional-sham (see Figs. A, B). Separate analyses were performed for random and fixed conditions using 2 × 2 mixed-model regression with factors of run-number, active/sham and HD/conventional stimulation as described previously [[7]Sehatpour P. Donde C. Hoptman M.J. Kreither J. Adair D. Dias E. et al.Network-level mechanisms underlying effects of transcranial direct current stimulation (tDCS) on visuomotor learning.Neuroimage. 2020; 117311Crossref PubMed Scopus (6) Google Scholar]. Mean RT Results: No significant tDCS effects were observed during the “random” sequences as reflected in a non-significant effect of run (F1,140 = 0.76, p = .39). During “fixed” sequences, significant main effects of run-number (F1,781 = 18.3, p < .0001), active/sham stimulation (F1,781 = 18.3, p < .0001), and tDCS type (HD/conventional, F1,781 = 18.8, p < .0001), the 2-way interactions between active/sham X run# (F1,781 = 4.13, p = .043), tDCS type X run# (F1,781 = 12.1, p = .001) and active/sham X type (F1,781 = 5.74, p = .018) as well as the 3-way interaction between factors (F1,781 = 5.85, p = .016) were observed. Across all runs, active stimulation was significantly superior to sham (F1,781 = 27.9, p < .0001) and HD was significantly superior to conventional (F1,781 = 7.29, p = .007) (Fig. 1C, D). Single-trial RT Results: Across all random conditions, data fit best to a 1-Gaussian distribution (R2 = 0.999) with mean RT across conditions of 2.676 ±.001 log-ms (474.2 ms) (Fig. 1E). By contrast, in the fixed condition, a 2-Gaussian solution was statistically superior (F3,23 = 220.9, p < .0001, R2 = 0.989), with mean RT of the fast and slow trials of 2.305 ±.009 and 2.635 ±.006 log-ms (201.8 and 431.5 ms), respectively. When analyses were conducted across conditions, the ratio of fast to slow trials was significantly higher (F1,50 = 40.3, p < .0001) in the HD (62.5 ±.01) than conventional (49.6 ±.02) condition, consistent with mean RT results. Furthermore, when a cut-off value of 2.47 log-ms (295 ms) was used to differentiate fast vs. slow responses, the 3-way run X active/passive X type (HD/conventional) interaction (F1,797 = 13.2, p < .0001) was also significant (Fig. F). Electrophysiological Results: As reported previously [[7]Sehatpour P. Donde C. Hoptman M.J. Kreither J. Adair D. Dias E. et al.Network-level mechanisms underlying effects of transcranial direct current stimulation (tDCS) on visuomotor learning.Neuroimage. 2020; 117311Crossref PubMed Scopus (6) Google Scholar], under sham condition significant coherence is observed across Motor, SMA, Visual cortical regions revealing a functional network engaged in SRTT task performance (Figure, Panel G left). Conventional visual-cathodal tDCS significantly modulated coherence across the visual-motor nodes of this network compared to sham (Figure, Panel G middle). HD-tDCS however not only modulated the coherence across the visual-motor nodes but also across visual-SMA and motor-SMA regions compared to sham. Moreover, when comparing HD-tDCS vs. conventional, HD-tDCS brought about a significantly higher coherence between the motor-SMA and lower coherence between visual-SMA regions (Figure, Panel G right). In summary, tDCS alters mean RT during motor learning primarily by facilitating a shift from slow, “reactive” to fast, “proactive” responses, in which the subject can predict in advance where the stimulus will appear. Here, we show performance improvement with HD-tDCS also follows the same pattern albeit more so compared to conventional configuration. We also show HD-tDCS modulated the coherence across all the cortical nodes engaged in SRTT with greater effectiveness compared to conventional tDCS. This is note-worthy considering the current flow distribution of HD-tDCS shows minimal direct current spread to non-visual nodes of the visuomotor circuit. This suggests the observed significant change in coherence between the motor and SMA regions result from more efficient use of visual information, rather than local modulation of the interaction between these regions. tDCS has been shown to have robust effects on brain plasticity across a range of paradigms. Nevertheless, effects of conventional tDCS may be limited by non-focality of conventional stimulation approaches. HD-tDCS produces greater focality by surrounding a central “active” electrode with multiple “returns”, limiting current spread. Here, we show both superior behavioral and superior neurophysiological effects of HD-vs. conventional tDCS, supporting its more widespread use across learning paradigms. This work was supported by National Institute of Mental Health grants MH49334 and MH109289 to DCJ.

The term perceptual closure refers to the neural processes responsible for “filling-in” missing information in the visual image under highly adverse viewing conditions such as fog or camouflage. Here we used a closure task that required the participants to identify barely recognizable fragmented line-drawings of common objects. Patients with schizophrenia have been shown to perform poorly on this task. Following priming, controls and importantly patients can complete the line-drawings at greater levels of fragmentation behaviorally, suggesting an improvement in their ability to perform the task. Closure phenomena have been shown to involve a distributed network of cortical regions, notably the lateral occipital complex (LOC) of the ventral visual stream, dorsal visual stream (DS), hippocampal formation (HIPP) and the prefrontal cortex (PFC). We have previously demonstrated the failure of closure processes in schizophrenia and shown that the dysregulation in the sensory information transmitted to the prefrontal cortex plays a critical role in this failure. Here, using a multimodal imaging approach in patients, combining event related electrophysiological recordings (ERP) and functional magnetic resonance imaging (fMRI), we characterize the spatiotemporal dynamics of priming in perceptual closure. Using directed functional connectivity measures we demonstrate that priming modifies the network-level interactions between the nodes of closure processing in a manner that is functionally advantageous to patients resulting in the mitigation of their deficit in perceptual closure.

The cranial nerves are the pathways through which environmental information (sensation) is directly communicated to the brain, leading to perception, and giving rise to higher cognition. Because cranial nerves determine and modulate brain function, invasive and non-invasive cranial nerve electrical stimulation methods have applications in the clinical, behavioral, and cognitive domains. Among other neuromodulation approaches such as peripheral, transcranial and deep brain stimulation, cranial nerve stimulation is unique in allowing axon pathway-specific engagement of brain circuits, including thalamo-cortical networks. In this review we amalgamate relevant knowledge of 1) cranial nerve anatomy and biophysics; 2) evidence of the modulatory effects of cranial nerves on cognition; 3) clinical and behavioral outcomes of cranial nerve stimulation; and 4) biomarkers of nerve target engagement including physiology, electroencephalography, neuroimaging, and behavioral metrics. Existing non-invasive stimulation methods cannot feasibly activate the axons of only individual cranial nerves. Even with invasive stimulation methods, selective targeting of one nerve fiber type requires nuance since each nerve is composed of functionally distinct axon-types that differentially branch and can anastomose onto other nerves. None-the-less, precisely controlling stimulation parameters can aid in affecting distinct sets of axons, thus supporting specific actions on cognition and behavior. To this end, a rubric for reproducible dose-response stimulation parameters is defined here. Given that afferent cranial nerve axons project directly to the brain, targeting structures (e.g. thalamus, cortex) that are critical nodes in higher order brain networks, potent effects on cognition are plausible. We propose an intervention design framework based on driving cranial nerve pathways in targeted brain circuits, which are in turn linked to specific higher cognitive processes. State-of-the-art current flow models that are used to explain and design cranial-nerve-activating stimulation technology require multi-scale detail that includes: gross anatomy; skull foramina and superficial tissue layers; and precise nerve morphology. Detailed simulations also predict that some non-invasive electrical or magnetic stimulation approaches that do not intend to modulate cranial nerves per se, such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS), may also modulate activity of specific cranial nerves. Much prior cranial nerve stimulation work was conceptually limited to the production of sensory perception, with individual titration of intensity based on the level of perception and tolerability. However, disregarding sensory emulation allows consideration of temporal stimulation patterns (axon recruitment) that modulate the tone of cortical networks independent of sensory cortices, without necessarily titrating perception. For example, leveraging the role of the thalamus as a gatekeeper for information to the cerebral cortex, preventing or enhancing the passage of specific information depending on the behavioral state. We show that properly parameterized computational models at multiple scales are needed to rationally optimize neuromodulation that target sets of cranial nerves, determining which and how specific brain circuitries are modulated, which can in turn influence cognition in a designed manner.

Introduction: Early onset epileptic encephalopathy syndromes are a devastating and rare form of infantile epilepsy, associated with structural brain abnormalities, mental deterioration, and seizure intractability. These electroclinical conditions generally have a poor prognosis and few cases survive past infancy. Significant reduction in clinical seizures is likely to attenuate the progression of pathology, which can in turn greatly impact infants' survival and recovery.The main goal in the current investigation was to examine the feasibility of High-Definition tDCS (HD-tDCS) in reducing seizure frequency and attenuating epileptiform electroencephalogram (EEG) activity in a 30-month old child suffering from early onset epileptic encephalopathy.

Introduction: Online image-guided neuromodulation is irrational if stimulation distorts measurements beyond the point of discernibility. In theory, combining transcranial Direct Current Stimulation (tDCS) with electroencephalography (EEG) is compelling, as both use non-invasive electrodes and subject-specific dose can be informed by the reciprocity principle. To distinguish online changes in EEG from stimulation artifacts, prior studies applied conventional signal processing (e.g. high-pass filtering, ICA). Here we address the suitability of these approaches. We distinguish "non-physiologic stimulation artifacts" - arising from non-ideal stimulation and recording equipment performance - from "physiologic artifacts" - defined as artifacts resulting from interactions between the stimulation induced voltage and the body, and so occurring regardless of tDCS or EEG hardware performance.

Transcranial electrical stimulation (tES) aims to alter brain function non-invasively by applying current to electrodes on the scalp. Decades of research and technological advancement are associated with a growing diversity of tES methods and the associated nomenclature for describing these methods. Whether intended to produce a specific response so the brain can be studied or lead to a more enduring change in behavior (e.g. for treatment), the motivations for using tES have themselves influenced the evolution of nomenclature, leading to some scientific, clinical, and public confusion. This ambiguity arises from (i) the infinite parameter space available in designing tES methods of application and (ii) varied naming conventions based upon the intended effects and/or methods of application. Here, we compile a cohesive nomenclature for contemporary tES technologies that respects existing and historical norms, while incorporating insight and classifications based on state-of-the-art findings. We consolidate and clarify existing terminology conventions, but do not aim to create new nomenclature. The presented nomenclature aims to balance adopting broad definitions that encourage flexibility and innovation in research approaches, against classification specificity that minimizes ambiguity about protocols but can hinder progress. Constructive research around tES classification, such as transcranial direct current stimulation (tDCS), should allow some variations in protocol but also distinguish from approaches that bear so little resemblance that their safety and efficacy should not be compared directly. The proposed framework includes terms in contemporary use across peer-reviewed publications, including relatively new nomenclature introduced in the past decade, such as transcranial alternating current stimulation (tACS) and transcranial pulsed current stimulation (tPCS), as well as terms with long historical use such as electroconvulsive therapy (ECT). We also define commonly used terms-of-the-trade including electrode, lead, anode, and cathode, whose prior use, in varied contexts, can also be a source of confusion. This comprehensive clarification of nomenclature and associated preliminary proposals for standardized terminology can support the development of consensus on efficacy, safety, and regulatory standards.

The cranial nerves are the pathways through which environmental information is directly communicated to the brain, leading to perception, and giving rise to higher cognition. As cranial nerves determine and modulate brain function, invasive and non-invasive cranial nerve electrical stimulation methods have applications in clinical, behavioral, and cognitive domains. Whereas transcranial and deep brain stimulation techniques are intended to engage (top-down) specific brain regions and processes, we develop a framework for cranial nerves stimulation modulation of cognition based on engaging specific thalamo-cortical networks (bottom-up) modulated by brain stem engagement. We also describe how non-invasive brain stimulation techniques, which produce a significantly higher current density in the skin than in the brain, can incidentally activate cranial nerves. We amalgamate relevant knowledge of 1)cranial nerve anatomy and biophysics; 2)evidence of modulatory effects on cognition by cranial nerves; 3)clinical and behavioral studies on cranial nerve stimulation; and 4)biomarkers of nerve target engagement including physiology, electroencephalography, neuroimaging, and behavioral. State-of-the-art computational models of cranial nerve neuromodulation are developed, and conventional non-invasive electrical stimulation montages simulated. Regarding anatomy and biophysics, our analysis points to a need for subtle and integrated mechanisms. Using non-invasive stimulation, activating axons in exclusively one cranial nerve is not feasible. Even isolated targeting of a single nerve using invasive stimulation requires nuance because each nerve is composed of functionally distinct axon-types that differentially branch and can anastomose to other nerves. Nevertheless, controlling stimulation parameters can aid in activating distinct nerves supporting specific actions on cognition and behavior. To this end, a rubric for reproducible dose parameter is defined here. We propose an intervention design framework based on driving cranial nerve pathways in targeted brain circuits. Current flow models that are used to explain and design cranial-nerve-activating stimulation technology require multi-scale detail that includes: gross anatomy; skull foramen and superficial tissue layers; and precise nerve morphology. Detailed simulations also predict non-invasive electrical stimulation approaches that do not intend to modulate cranial nerves, such as transcranial direct current stimulation, may activate specific nerve branches. There is extensive evidence that there are circuit pathways to modulate higher cognitive processes by electrically stimulating cranial nerves, however much of prior work was conceptually limited to cranial nerve stimulation as sensory replacement or modulation. We show that computational models, properly parameterized at multiple scales, are needed to rationally optimize neuromodulation that targets specific cranial nerves and so influence cognition in a designed manner.

Non-invasive vagus nerve stimulation (VNS) may be administered via a novel, emerging neuromodulatory technique known as transcutaneous auricular vagus nerve stimulation (taVNS). Unlike cervically-implanted VNS, taVNS is an inexpensive and non-surgical method used to modulate the vagus system. taVNS is appealing as it allows for rapid translation of basic VNS research and serves as a safe, inexpensive, and portable neurostimulation system for the future treatment of central and peripheral disease. The background and rationale for taVNS is described, along with electrical and parametric considerations, proper ear targeting and attachment of stimulation electrodes, individual dosing via determination of perception threshold (PT), and safe administration of taVNS.

Varying modes of non-invasive electrical stimulation techniques have been investigated to induce endogenous sleep-like states (historically called Electrosleep). These include transcranial pulsed current stimulation (tPCS) such as Cranial Electrical Stimulation, transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS) such as 10 Hz sinusoidal stimulation. Prior efforts used synthetic (simple) waveforms selected to modulate excitability (e.g. tDCS) or reproduce a single predominant frequency of endogenous neuronal rhythms of sleep induction (e.g. 10 Hz). To examine the effects of electrical stimulation with a complete spectrum sleep-related endogenous neural activity, we designed and applied an endogenous sleep-derived stimulation waveform to subjects while assessing a range subjective performance and objective physiological data. We hypothesized that a stimulation with complex high-bandwidth waveform reflecting endogenous sleep-associated neuronal activity patterns (transcranial Endogenous Sleep-Derived; tESD) would be more effective, than synthetic frequency-specific waveforms such at tACS, in supporting the transition to sleepiness. The basis for the transcranial Endogenous Sleep-Derived (tESD) waveform was acquired during a resting, sleepy-state EEG session. Data were examined for markers of sleepiness and corresponding segments were extracted, compressed, and scaled to produce a current signal. Stimulation was applied through a custom, high-bandwidth current-control stimulator. Subjects were supine in a light and sound attenuated environment. Using HD bipolar montage (AF7, AF8) with a maximal current amplitude of 0.5 mA over 10 minutes. tESD was also simulated in a computational model. Physiology (EEG, ECG, respiration, EOG, EMG) and behavior (questionnaires, reaction time) was assessed before, during (only for physiology), and after stimulation. Each subject underwent tESD, 10 Hz tACS, and a no-stimulation (non-interventional) sessions in a counterbalanced manner with at least 24 hours between each session. tESD polarized the frontal lobe. Changes in the no-stimulation condition confirms the testing environment was conducive to a wakefulness–sleep transition. Preliminary data indicate an enhanced shift in physiological measures in directions consistent with a relaxed and sleepy state with tESD compared to tACS and no-stimulation conditions. Behavioral data indicate a delay in reactions times post stimulation and subjective sleepiness reports indicate higher sleepiness post stimulation. tESD was well tolerated and blinding was effective. tESD aims to “replay” the endogenous neuronal signature of sleep. Neurophysiological (EEG), physiological (heart rate, respiration) and behavioral (simple reaction time, PVT) indicate that tESD, directed to frontal brain regions, that are associated with top-down thalamo-cortical sleep control mechanisms, accelerated wakefulness–sleep transition in subjects in a baseline relaxed state.

Transcranial electrical stimulation (tES) aims to alter brain function non-invasively by applying current to electrodes on the scalp. Decades of research and technological advancement are associated with a growing diversity of tES methods and the associated nomenclature for describing these methods. Whether intended to produce a specific response so the brain can be studied or lead to a more enduring change in behavior (e.g. for treatment), the motivations for using tES have themselves influenced the evolution of nomenclature, leading to some scientific, clinical, and public confusion. This ambiguity arises from (i) the infinite parameter space available in designing tES methods of application and (ii) varied naming conventions based upon the intended effects and/or methods of application. Here, we compile a cohesive nomenclature for contemporary tES technologies that respects existing and historical norms, while incorporating insight and classifications based on state-of-the-art findings. We consolidate and clarify existing terminology conventions, but do not aim to create new nomenclature. The presented nomenclature aims to balance adopting broad definitions that encourage flexibility and innovation in research approaches, against classification specificity that minimizes ambiguity about protocols but can hinder progress. Constructive research around tES classification, such as transcranial direct current stimulation (tDCS), should allow some variations in protocol but also distinguish from approaches that bear so little resemblance that their safety and efficacy should not be compared directly. The proposed framework includes terms in contemporary use across peer-reviewed publications, including relatively new nomenclature introduced in the past decade, such as transcranial alternating current stimulation (tACS) and transcranial pulsed current stimulation (tPCS), as well as terms with long historical use such as electroconvulsive therapy (ECT). We also define commonly used terms-of-the-trade including electrode, lead, anode, and cathode, whose prior use, in varied contexts, can also be a source of confusion. This comprehensive clarification of nomenclature and associated preliminary proposals for standardized terminology can support the development of consensus on efficacy, safety, and regulatory standards.

OBJECTIVES:To develop the first high-resolution, multi-scale model of cervical non-invasive vagus nerve stimulation (nVNS) and to predict vagus fiber type activation, given clinically relevant rheobase thresholds. METHODS:An MRI-derived Finite Element Method (FEM) model was developed to accurately simulate key macroscopic (e.g., skin, soft tissue, muscle) and mesoscopic (cervical enlargement, vertebral arch and foramen, cerebral spinal fluid [CSF], nerve sheath) tissue components to predict extracellular potential, electric field (E-Field), and activating function along the vagus nerve. Microscopic scale biophysical models of axons were developed to compare axons of varying size (Aα-, Aβ- and Aδ-, B-, and C-fibers). Rheobase threshold estimates were based on a step function waveform. RESULTS:Macro-scale accuracy was found to determine E-Field magnitudes around the vagus nerve, while meso-scale precision determined E-field changes (activating function). Mesoscopic anatomical details that capture vagus nerve passage through a changing tissue environment (e.g., bone to soft tissue) profoundly enhanced predicted axon sensitivity while encapsulation in homogenous tissue (e.g., nerve sheath) dulled axon sensitivity to nVNS. CONCLUSIONS:These findings indicate that realistic and precise modeling at both macroscopic and mesoscopic scales are needed for quantitative predictions of vagus nerve activation. Based on this approach, we predict conventional cervical nVNS protocols can activate A- and B- but not C-fibers. Our state-of-the-art implementation across scales is equally valuable for models of spinal cord stimulation, cortex/deep brain stimulation, and other peripheral/cranial nerve models.

ABSTRACT Primary objective: Early onset epileptic encephalopathy is characterized by high daily seizure-frequency, multifocal epileptic discharges, severe psychomotor retardation, and death at infancy. Currently, there are no effective treatments to alleviate seizure frequency and high-voltage epileptic discharges in these catastrophic epilepsy cases. The current study examined the safety and feasibility of High-Definition transcranial direct current stimulation (HD-tDCS) in reducing epileptiform activity in a 30-month-old child suffering from early onset epileptic encephalopathy. Design and Methods: HD-tDCS was administered over 10 intervention days spanning two weeks including pre- and post-intervention video-EEG monitoring. Results: There were no serious adverse events or side effects related to the HD-tDCS intervention. Frequency of clinical seizures was not significantly reduced. However, interictal sharp wave amplitudes were significantly lower during the post-intervention period versus baseline. Vital signs and blood biochemistry remained stable throughout the entire study. Conclusions: These exploratory findings support the safety and feasibility of 4 × 1 HD-tDCS in early onset epileptic encephalopathy and provide the first evidence of HD-tDCS effects on paroxysmal EEG features in electroclinical cases under the age of 36 months. Extending HD-tDCS treatment may enhance electrographic findings and clinical effects.

We present device standards for low-power non-invasive electrical brain stimulation devices classified as limited output transcranial electrical stimulation (tES). Emerging applications of limited output tES to modulate brain function span techniques to stimulate brain or nerve structures, including transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial pulsed current stimulation (tPCS), have engendered discussion on how access to technology should be regulated. In regards to legal regulations and manufacturing standards for comparable technologies, a comprehensive framework already exists, including quality systems (QS), risk management, and (inter)national electrotechnical standards (IEC). In Part 1, relevant statutes are described for medical and wellness application. While agencies overseeing medical devices have broad jurisdiction, enforcement typically focuses on those devices with medical claims or posing significant risk. Consumer protections regarding responsible marketing and manufacture apply regardless. In Part 2 of this paper, we classify the electrical output performance of devices cleared by the United States Food and Drug Administration (FDA) including over-the-counter (OTC) and prescription electrostimulation devices, devices available for therapeutic or cosmetic purposes, and devices indicated for stimulation of the body or head. Examples include iontophoresis devices, powered muscle stimulators (PMS), cranial electrotherapy stimulation (CES), and transcutaneous electrical nerve stimulation (TENS) devices. Spanning over 13 FDA product codes, more than 1200 electrical stimulators have been cleared for marketing since 1977. The output characteristics of conventional tDCS, tACS, and tPCS techniques are well below those of most FDA cleared devices, including devices that are available OTC and those intended for stimulation on the head. This engineering analysis demonstrates that with regard to output performance and standing regulation, the availability of tDCS, tACS, or tPCS to the public would not introduce risk, provided such devices are responsibly manufactured and legally marketed. In Part 3, we develop voluntary manufacturer guidance for limited output tES that is aligned with current regulatory standards. Based on established medical engineering and scientific principles, we outline a robust and transparent technical framework for ensuring limited output tES devices are designed to minimize risks, while also supporting access and innovation. Alongside applicable medical and government activities, this voluntary industry standard (LOTES-2017) further serves an important role in supporting informed decisions by the public.

The field of non invasive brain stimulation (NIBS) has benefited from integration with imaging including magnetic resonance imaging (MRI) and electroencephalography (EEG). Several studies have reported on concurrent tDCS and EEG, and used signal processing of varying complexity (e.g. high-pass filtering to ICA) to remove “non-physiologic stimulation artifacts” – namely artifacts arising from non-ideal stimulation and recording amplifier performance. None has addressed “physiologic artifacts” which are defined here as non-stationary changes in artifacts resulting from interactions between the stimulation induced voltage and body. We identified and systematically characterized a series of tDCS induced physiologic and non-physiologic artifacts during concurrent EEG and High Definition (HD)-tDCS, and adapted subject-specific computational modeling to corroborate physiological EEG findings. Physiologic artifacts include (1) cardiac distortion; (2) ocular motor distortion; (3) movement (myogenic) distortion. In each case, the artifact was montage, intensity, and polarity specific; as such contamination from these physiologic artifacts cannot be accounted for by typical control experiments (e.g. EEG changes that are dose specific). High resolution finite element models explained artifact based on specific impedance changes. Importantly (a) physiologic artifacts are universal, they are nominally independent of device and so exist regardless of devices; (b) the broad-band nature of contamination may confound a broad range of experiments (e.g. oscillations, ERP); (c) removal of artifacts requires recognition of their peculiar dynamic and individualized nature.

Transcranial direct current stimulation (tDCS) is a technique for modulating brain function and performance on cognitive tasks through the application of a constant low current to corresponding regions of the scalp. It is noninvasive and can be repeated over time within the same subject. Therefore it represents a practical new approach in the study of mechanisms underlying cognition as well as mechanisms of neurocognitive disorders.

Transcranial direct current stimulation (tDCS) is a technique for modulating brain function and performance on cognitive tasks through the application of a constant low current to corresponding regions of the scalp. Here we applied a 1 mA direct current and observed its effects in a critical cortical network engaged during a motor sequence task (pressing four color-coded keys according to a prompted sequence that appears on a computer screen) through an innovative process of behavioral and EEG recording with simultaneous tDCS application. As this is a visio-motor task, here we used four types of stimulation namely anodal, cathodal, visual and sham. Time-frequency decomposition of the EEG data revealed significant effects of stimulation on modulating specific frequency bands within specific cortical nodes engaged in the performance of the task. This effect is polarity and task dependant such that there is a dynamic interaction between the current stimulation and the neuronal networks engaged in task performance. Implementation of tDCS combined with behavioral and electrophysiological measures contributes greatly to our understanding of neural mechanisms of cognition. The methodology is noninvasive and can be repeated over time within the same subject. Therefore it represents a practical new approach in the study of mechanisms underlying cognition as well as mechanisms of neurocognitive disorders. Additionally, there are potential future implications for its use as an intervention approach for neurocognitive disorders.