Comparison of Transcranial Focused Ultrasound and Transcranial Pulse Stimulation for Neuromodulation: A Computational Study.

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

Tissue Temperature Increases by a 10 kHz Spinal Cord Stimulation System: Phantom and Bioheat Model.

OBJECTIVE: A recently introduced Spinal Cord Stimulation (SCS) system operates at 10 kHz, faster than conventional SCS systems, resulting in significantly more power delivered to tissues. Using a SCS heat phantom and bioheat multi-physics model, we characterized tissue temperature increases by this 10 kHz system. We also evaluated its Implanted Pulse Generator (IPG) output compliance and the role of impedance in temperature increases. MATERIALS AND METHODS: The 10 kHz SCS system output was characterized under resistive loads (1-10 KΩ). Separately, fiber optic temperature probes quantified temperature increases (ΔTs) around the SCS lead in specially developed heat phantoms. The role of stimulation Level (1-7; ideal pulse peak-to-peak of 1-7mA) was considered, specifically in the context of stimulation current Root Mean Square (RMS). Data from the heat phantom were verified with the SCS heat-transfer models. A custom high-bandwidth stimulator provided 10 kHz pulses and sinusoidal stimulation for control experiments. RESULTS: The 10 kHz SCS system delivers 10 kHz biphasic pulses (30-20-30 µs). Voltage compliance was 15.6V. Even below voltage compliance, IPG bandwidth attenuated pulse waveform, limiting applied RMS. Temperature increased supralinearly with stimulation Level in a manner predicted by applied RMS. ΔT increases with Level and impedance until stimulator compliance was reached. Therefore, IPG bandwidth and compliance dampen peak heating. Nonetheless, temperature increases predicted by bioheat multi-physic models (ΔT = 0.64°C and 1.42°C respectively at Level 4 and 7 at the cervical segment; ΔT = 0.68°C and 1.72°C respectively at Level 4 and 7 at the thoracic spinal cord)-within ranges previously reported to effect neurophysiology. CONCLUSIONS: Heating of spinal tissues by this 10 kHz SCS system theoretically increases quickly with stimulation level and load impedance, while dampened by IPG pulse bandwidth and voltage compliance limitations. If validated in vivo as a mechanism of kHz SCS, bioheat models informed by IPG limitations allow prediction and optimization of temperature changes.

Neuromodulation of Axon Terminals.

Understanding which cellular compartments are influenced during neuromodulation underpins any rational effort to explain and optimize outcomes. Axon terminals have long been speculated to be sensitive to polarization, but experimentally informed models for CNS stimulation are lacking. We conducted simultaneous intracellular recording from the neuron soma and axon terminal (blebs) during extracellular stimulation with weak sustained (DC) uniform electric fields in mouse cortical slices. Use of weak direct current stimulation (DCS) allowed isolation and quantification of changes in axon terminal biophysics, relevant to both suprathreshold (e.g., deep brain stimulation, spinal cord stimulation, and transcranial magnetic stimulation) and subthreshold (e.g., transcranial DCS and transcranial alternating current stimulation) neuromodulation approaches. Axon terminals polarized with sensitivity (mV of membrane polarization per V/m electric field) 4 times than somas. Even weak polarization (<2 mV) of axon terminals significantly changes action potential dynamics (including amplitude, duration, conduction velocity) in response to an intracellular pulse. Regarding a cellular theory of neuromodulation, we explain how suprathreshold CNS stimulation activates the action potential at terminals while subthreshold approaches modulate synaptic efficacy through axon terminal polarization. We demonstrate that by virtue of axon polarization and resulting changes in action potential dynamics, neuromodulation can influence analog-digital information processing.

Automatic M1-SO Montage Headgear for Transcranial Direct Current Stimulation (TDCS) Suitable for Home and High-Throughput In-Clinic Applications.

OBJECTIVES: Non-invasive transcranial direct current stimulation (tDCS) over the motor cortex is broadly investigated to modulate functional outcomes such as motor function, sleep characteristics, or pain. The most common montages that use two large electrodes (25-35 cm2 ) placed over the area of motor cortex and contralateral supraorbital region (M1-SO montages) require precise measurements, usually using the 10-20 EEG system, which is cumbersome in clinics and not suitable for applications by patients at home. The objective was to develop and test novel headgear allowing for reproduction of the M1-SO montage without the 10-20 EEG measurements, neuronavigation, or TMS. MATERIALS AND METHODS: Points C3/C4 of the 10-20 EEG system is the conventional reference for the M1 electrode. The headgear was designed using an orthogonal, fixed-angle approach for connection of frontal and coronal headgear components. The headgear prototype was evaluated for accuracy and replicability of the M1 electrode position in 600 repeated measurements compared to manually determined C3 in 30 volunteers. Computational modeling was used to estimate brain current flow at the mean and maximum recorded electrode placement deviations from C3. RESULTS: The headgear includes navigational points for accurate placement and assemblies to hold electrodes in the M1-SO position without measurement by the user. Repeated measurements indicated accuracy and replicability of the electrode position: the mean [SD] deviation of the M1 electrode (size 5 × 5 cm) from C3 was 1.57 [1.51] mm, median 1 mm. Computational modeling suggests that the potential deviation from C3 does not produce a significant change in brain current flow. CONCLUSIONS: The novel approach to M1-SO montage using a fixed-angle headgear not requiring measurements by patients or caregivers facilitates tDCS studies in home settings and can replace cumbersome C3 measurements for clinical tDCS applications.

Physics of Transcranial Direct Current Stimulation Devices and Their History.

Transcranial direct current stimulation (tDCS) devices apply direct current through electrodes on the scalp with the intention to modulate brain function for experimental or clinical purposes. All tDCS devices include a current controlled stimulator, electrodes that include a disposable electrolyte, and headgear to position the electrodes on the scalp. Transcranial direct current stimulation dose can be defined by the size and position of electrodes and the duration and intensity of current applied across electrodes. Electrode design and preparation are important for reproducibility and tolerability. High-definition tDCS uses smaller electrodes that can be arranged in arrays to optimize brain current flow. When intended to be used at home, tDCS devices require specific device design considerations. Computational models of current flow have been validated and support optimization and hypothesis testing. Consensus on the safety and tolerability of tDCS is protocol specific, but medical-grade tDCS devices minimize risk.

High-Resolution Multi-Scale Computational Model for Non-Invasive Cervical Vagus Nerve Stimulation.

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-, Aß- 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.

Minimal Heating at the Skin Surface During Transcranial Direct Current Stimulation.

OBJECTIVE: To assess if transcranial direct current stimulation (tDCS) produces a temperature change at the skin surface, if any change is stimulation polarity (anode or cathode) specific, and the contribution of passive heating (joule heat) or blood flow on such change. MATERIAL AND METHODS: Temperature differences (ΔTs) in an agar phantom study and an in vivo study (forearm stimulation) including 20 volunteers with both experimental measures and finite element method (FEM) multiphysics prediction (current flow and bioheat) models of skin comprising three tissue layers (epidermis, dermis, and subcutaneous layer with blood perfusion) or of the phantom for active stimulation and control cases were compared. Temperature was measured during pre, post, and stimulation phases for both phantom and subject's forearms using thermocouples. RESULTS: In the phantom, ΔT under both anode and cathode, compared to control, was not significantly different and less than 0.1°C. Stimulation of subjects resulted in a gradual increase in temperature under both anode and cathode electrodes, compared to control (at t = 20 min: ΔTanode = 0.9°C, ΔTcathode = 1.1°C, ΔTcontrol = 0.05°C). The FEM phantom model predicted comparable maximum ΔT of 0.27°C and 0.28°C (at t = 20 min) for the control and anode/cathode cases, respectively. The FEM skin model predicted a maximum ΔT at t = 20 min of 0.98°C for control and 1.36°C under anode/cathode electrodes. CONCLUSIONS: Taken together, our results indicate a moderate and nonhazardous increase in temperature at the skin surface during 2 mA tDCS that is independent of polarity, and results from stimulation induced blood flow rather than joule heat.

Direct current stimulation over the anterior temporal areas boosts semantic processing in primary progressive aphasia.

OBJECTIVE: Noninvasive brain stimulation in primary progressive aphasia (PPA) is a promising approach. Yet, applied to single cases or insufficiently controlled small-cohort studies, it has not clarified its therapeutic value. We here address the effectiveness of transcranial direct current stimulation (tDCS) on the semantic PPA variant (sv-PPA), applying a rigorous study design to a large, homogeneous sv-PPA cohort. METHODS: Using a double-blind, sham-controlled counterbalanced cross-over design, we applied three tDCS conditions targeting the temporal poles of 12 sv-PPA patients. Efficiency was assessed by a semantic matching task orthogonally manipulating "living"/"nonliving" categories and verbal/visual modalities. Conforming to predominantly left-lateralized damage in sv-PPA and accounts of interhemispheric inhibition, we applied left hemisphere anodal-excitatory and right hemisphere cathodal-inhibitory tDCS, compared to sham stimulation. RESULTS: Prestimulation data, compared to 15 healthy controls, showed that patients had semantic disorders predominating with living categories in the verbal modality. Stimulation selectively impacted these most impaired domains: Left-excitatory and right-inhibitory tDCS improved semantic accuracy in verbal modality, and right-inhibitory tDCS improved processing speed with living categories and accuracy and processing speed in the combined verbal × living condition. INTERPRETATION: Our findings demonstrate the efficiency of tDCS in sv-PPA by generating highly specific intrasemantic effects. They provide "proof of concept" for future applications of tDCS in therapeutic multiday regimes, potentially driving sustained improvement of semantic processing. Our data also support the hotly debated existence of a left temporal-pole network for verbal semantics selectively modulated through both left-excitatory and right-inhibitory brain stimulation. Ann Neurol 2016;80:693-707.

Transspinal direct current stimulation immediately modifies motor cortex sensorimotor maps.

Motor cortex (MCX) motor representation reorganization occurs after injury, learning, and different long-term stimulation paradigms. The neuromodulatory approach of transspinal direct current stimulation (tsDCS) has been used to promote evoked cortical motor responses. In the present study, we used cathodal tsDCS (c-tsDCS) of the rat cervical cord to determine if spinal cord activation can modify the MCX forelimb motor map. We used a finite-element method model based on coregistered high-resolution rat MRI and microcomputed tomography imaging data to predict spinal current density to target stimulation to the caudal cervical enlargement. We examined the effects of cathodal and anodal tsDCS on the H-reflex and c-tsDCS on responses evoked by intracortical microstimulation (ICMS). To determine if cervical c-tsDCS also modified MCX somatic sensory processing, we examined sensory evoked potentials (SEPs) produced by wrist electrical stimulation and induced changes in ongoing activity. Cervical c-tsDCS enhanced the H-reflex, and anodal depressed the H-reflex. Using cathodal stimulation to examine cortical effects, we found that cervical c-tsDCS immediately modified the forelimb MCX motor map, with decreased thresholds and an expanded area. c-tsDCS also increased SEP amplitude in the MCX. The magnitude of changes produced by c-tsDCS were greater on the motor than sensory response. Cervical c-tsDCS more strongly enhanced forelimb than hindlimb motor representation and had no effect on vibrissal representation. The finite-element model indicated current density localized to caudal cervical segments, informing forelimb motor selectivity. Our results suggest that c-tsDCS augments spinal excitability in a spatially selective manner and may improve voluntary motor function through MCX representational plasticity.

A Feasibility Study of Bilateral Anodal Stimulation of the Prefrontal Cortex Using High-Definition Electrodes in Healthy Participants.

Transcranial direct current stimulation (tDCS) studies often use one anode to increase cortical excitability in one hemisphere. However, mental processes may involve cortical regions in both hemispheres. This study's aim was to assess the safety and possible effects on affect and working memory of tDCS using two anodes for bifrontal stimulation. A group of healthy subjects participated in two bifrontal tDCS sessions on two different days, one for real and the other for sham stimulation. They performed a working memory task and reported their affect immediately before and after each tDCS session. Relative to sham, real bifrontal stimulation did not induce significant adverse effects, reduced decrement in vigor-activity during the study session, and did not improve working memory. These preliminary findings suggest that bifrontal anodal stimulation is feasible and safe and may reduce task-related fatigue in healthy participants. Its effects on neuropsychiatric patients deserve further study.

Unpacking Galvanic Vestibular Stimulation using simulations and relating current flow to reported motions: Comparison across common and specialized electrode placements.

BACKGROUND: Galvanic Vestibular Stimulation (GVS) is a non-invasive electrical stimulation technique that is typically used to probe the vestibular system. When using direct current or very low frequency sine, GVS causes postural sway or perception of illusory (virtual) motions. GVS is commonly delivered using two electrodes placed at the mastoids, however, placements involving additional electrodes / locations have been employed. Our objective was to systematically evaluate all known GVS electrode placements, compare induced current flow, and how it relates to the archetypal sway and virtual motions. The ultimate goal is to help users in having a better understanding of the effects of different placements. METHODS: We simulated seven GVS electrode placements with same total injected current using an ultra-high resolution model. Induced electric field (EF) patterns at the cortical and the level of vestibular organs (left and right) were determined. A range of current flow metrics including potential factors such as inter-electrode separation, percentage of current entering the cranial cavity, and symmetricity were calculated. Finally, we relate current flow to reported GVS motions. RESULTS: As expected, current flow patterns are electrode placement specific. Placements with two electrodes generally result in higher EF magnitude. Placements with four electrodes result in lower percentage of current entering the cranial cavity. Symmetric placements do not result in similar EF values in the left and the right organs respectively- highlighting inherent anatomical asymmetry of the human head. Asymmetric placements were found to induce as much as ~3-fold higher EF in one organ over the other. The percentage of current entering the cranial cavity varies between ~15% and ~40% depending on the placement. CONCLUSIONS: We expect our study to advance understanding of GVS and provide insight on probable mechanism of action of a certain electrode placement choice. The dataset generated across several metrics will support hypothesis testing relating empirical outcomes to current flow patterns. Further, the differences in current flow will guide stimulation strategy (what placement and how much scalp current to use) and facilitate a quantitatively informed rational / optimal decision.

Optimized high-definition tDCS in patients with skull defects and skull plates.

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

Impact of galvanic vestibular stimulation electrode current density on brain current flow patterns: Does electrode size matter?

BACKGROUND: Galvanic vestibular stimulation (GVS) uses at least one electrode placed on the mastoid process with one or multiple placed over other head areas to stimulate the vestibular system. The exact electrode size used is not given much importance in the literature and has not been reported in several studies. In a previous study, we compared the clinical effects of using different electrode sizes (3 cm2 and 35 cm2) with placebo but with the same injected current, on postural control. We observed significant improvement using the smaller size electrode but not with the bigger size electrode. The goal of this study was to simulate the current flow patterns with the intent to shed light and potentially explain the experimental outcome. METHODS: We used an ultra-high-resolution structural dataset and developed a model to simulate the application of different electrode sizes. We considered current flow in the brain and in the vestibular labyrinth. RESULTS: Our simulation results verified the focality increase using smaller electrodes that we postulated as the main reason for our clinical effect. The use of smaller size electrodes in combination with the montage employed also result in higher induced electric field (E-field) in the brain. CONCLUSIONS: Electrode size and related current density is a critical parameter to characterize any GVS administration as the choice impacts the induced E-field. It is evident that the higher induced E-field likely contributed to the clinical outcome reported in our prior study.

Impact of modeled field of view in electroconvulsive therapy current flow simulations.

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

Selective augmentation of corticospinal motor drive with trans-spinal direct current stimulation in the cat.

BACKGROUND: A key outcome for spinal cord stimulation for neurorehabilitation after injury is to strengthen corticospinal system control of the arm and hand. Non-invasive, compared with invasive, spinal stimulation minimizes risk but depends on muscle-specific actions for restorative functions. OBJECTIVE: We developed a large-animal (cat) model, combining computational and experimental techniques, to characterize neuromodulation with transcutaneous spinal direct current stimulation (tsDCS) for facilitation of corticospinal motor drive to specific forelimb muscles. METHODS: Acute modulation of corticospinal function by tsDCS was measured using motor cortex-evoked muscle potentials (MEPs). The effects of current intensity, polarity (cathodal, anodal), and electrode position on specific forelimb muscle (biceps vs extensor carpi radialis, ECR) MEP modulation were examined. Locations of a key target, the motoneuron pools, were determined using neuronal tracing. A high-resolution anatomical (MRI and CT) model was developed for computational simulation of spinal current flow during tsDCS. RESULTS: Effects of tsDCS on corticospinal excitability were robust and immediate, therefore supporting MEPs as a sensitive marker of tsDCS targeting. Varying cathodal/anodal current intensity modulated MEP enhancement/suppression, with higher cathodal sensitivity. Muscle-specificity depended on cathode position; the rostral position preferentially augmented biceps responses and the caudal position, ECR responses. Precise anatomical current-flow modeling, supplemented with target motor pool distributions, can explain tsDCS focality on muscle groups. CONCLUSION: Anatomical current-flow modeling with physiological validation based on MEPs provides a framework to optimize muscle-specific tsDCS interventions. tsDCS targeting of representative motor pools enables muscle- and response-specific neuromodulation of corticospinal motor drive.

Evaluation of the effect of transcranial direct current stimulation on language impairments in the behavioural variant of frontotemporal dementia.

The behavioural variant of frontotemporal dementia is a neurodegenerative disease characterized by bilateral atrophy of the prefrontal cortex, gradual deterioration of behavioural and executive capacities, a breakdown of language initiation and impaired search mechanisms in the lexicon. To date, only a few studies have analysed the modulation of language deficits in the behavioural variant of frontotemporal dementia patients with transcranial direct current stimulation, yet with inconsistent results. Our goal was to assess the impact on language performance of a single session of transcranial direct current stimulation on patients with the behavioural variant of frontotemporal dementia. Using a sham-controlled double-blind crossover design in a cohort of behavioural frontotemporal dementia patients (n = 12), we explored the impact on language performance of a single transcranial direct current stimulation session delivering anodal or cathodal transcranial direct current stimulation, over the left and right dorsolateral prefrontal cortex, compared with sham stimulation. A Letter fluency and a Picture naming task were performed prior and following transcranial direct current stimulation, to assess modulatory effects on language. Behavioural frontotemporal dementia patients were impaired in all evaluation tasks at baseline compared with healthy controls. Computational finite element method (FEM) models of cortical field distribution corroborated expected impacts of left-anodal and right-cathodal transcranial direct current stimulation over the dorsolateral prefrontal cortex and showed lower radial field strength in case of atrophy. However, none of the two tasks showed statistically significant evidence of language improvement caused by active transcranial direct current stimulation compared with sham. Our findings do not argue in favour of pre-therapeutic effects and suggest that stimulation strategies evaluating the modulatory role of transcranial direct current stimulation in the behavioural variant of frontotemporal dementia must carefully weigh the influence of symptom severity and cortical atrophy affecting prefrontal regions to ensure clinical success.

Determination of Current Flow Induced by Transcutaneous Electrical Nerve Stimulation for the Treatment of Migraine: Potential for Optimization.

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

Enhanced tES and tDCS computational models by meninges emulation.

OBJECTIVE: Understanding how current reaches the brain during transcranial electrical stimulation (tES) underpins efforts to rationalize outcomes and optimize interventions. To this end, computational models of current flow relate applied dose to brain electric field. Conventional tES modeling considers distinct tissues like scalp, skull, cerebrospinal fluid (CSF), gray matter and white matter. The properties of highly conductive CSF are especially important. However, modeling the space between skull and brain as entirely CSF is not an accurate representation of anatomy. The space conventionally modeled as CSF is approximately half meninges (dura, arachnoid, and pia) with lower conductivity. However, the resolution required to describe individual meningeal layers is computationally restrictive in an MRI-derived head model. Emulating the effect of meninges through CSF conductivity modification could improve accuracy with minimal cost. APPROACH: Models with meningeal layers were developed in a concentric sphere head model. Then, in a model with only CSF between skull and brain, CSF conductivity was optimized to emulate the effect of meningeal layers on cortical electric field for multiple electrode positions. This emulated conductivity was applied to MRI-derived models. MAIN RESULTS: Compared to a model with conventional CSF conductivity (1.65 S m-1), emulated CSF conductivity (0.85 S m-1) produced voltage fields better correlated with intracranial recordings from epilepsy patients. SIGNIFICANCE: Conventional tES models have been validated using intracranial recording. Residual errors may nonetheless impact model utility. Because CSF is so conductive to current flow, misrepresentation of the skull-brain interface as entirely CSF is not realistic for tES modeling. Updating the conventional model with a CSF conductivity emulating the effect of the meninges enhances modeling accuracy without increasing model complexity. This allows existing modeling pipelines to be leveraged with a simple conductivity change. Using 0.85 S m-1 emulated CSF conductivity is recommended as the new standard in non-invasive brain stimulation modeling.

Cerebellar transcranial alternating current stimulation modulates human gait rhythm.

Although specific brain regions are important for regularly patterned limb movements, the rhythm generation system that governs bipedal locomotion in humans is not thoroughly understood. We investigated whether rhythmic transcranial brain stimulation over the cerebellum could alter walking rhythm. Fourteen healthy subjects performed over-ground walking for 10 min during which they were given, in a random order, transcranial alternating current stimulation (tACS) over the left cerebellum at the approximated frequency of their gait cycle, tACS over the skin of the scalp, and during sham stimulation. Cerebellar tACS showed a significant entrainment of gait rhythm compared with the control conditions. When the direction of the tACS currents was symmetrically inverted, some subjects showed entrainment at an approximately 180° inverted phase, suggesting that gait modulation is dependent on current orientation. These findings indicate that tACS over cerebellum can modulate gait generation system in cerebellum and become an innovative approach for the recovery of locomotion in patients with gait disturbances caused by CNS disorders.

The Quasi-uniform assumption for Spinal Cord Stimulation translational research.

BACKGROUND: Quasi-uniform assumption is a general theory that postulates local electric field predicts neuronal activation. Computational current flow model of spinal cord stimulation (SCS) of humans and animal models inform how the quasi-uniform assumption can support scaling neuromodulation dose between humans and translational animal. NEW METHOD: Here we developed finite element models of cat and rat SCS, and brain slice, alongside SCS models. Boundary conditions related to species specific electrode dimensions applied, and electric fields per unit current (mA) predicted. RESULTS: Clinically and across animal, electric fields change abruptly over small distance compared to the neuronal morphology, such that each neuron is exposed to multiple electric fields. Per unit current, electric fields generally decrease with body mass, but not necessarily and proportionally across tissues. Peak electric field in dorsal column rat and cat were ∼17x and ∼1x of clinical values, for scaled electrodes and equal current. Within the spinal cord, the electric field for rat, cat, and human decreased to 50% of peak value caudo-rostrally (C5-C6) at 0.48 mm, 3.2 mm, and 8 mm, and mediolaterally at 0.14 mm, 2.3 mm, and 3.1 mm. Because these space constants are different, electric field across species cannot be matched without selecting a region of interest (ROI). COMPARISON WITH EXISTING METHOD: This is the first computational model to support scaling neuromodulation dose between humans and translational animal. CONCLUSIONS: Inter-species reproduction of the electric field profile across the entire surface of neuron populations is intractable. Approximating quasi-uniform electric field in a ROI is a rational step to translational scaling.