High-resolution computational modeling of the current flow in the outer ear during transcutaneous auricular Vagus Nerve Stimulation (taVNS).

BACKGROUND: Transcutaneous 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). OBJECTIVE: We compare different electrodes designs for taVNS considering both the predicted peak electric fields (sensitivity) and their spatial distribution (selectivity). METHODS: Based 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. RESULTS: Current 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. DISCUSSION: Computational 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.

Electrical stimulation of cranial nerves in cognition and disease.

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.

Laboratory Administration of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS): Technique, Targeting, and Considerations.

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.

Limited output transcranial electrical stimulation (LOTES-2017): Engineering principles, regulatory statutes, and industry standards for wellness, over-the-counter, or prescription devices with low risk.

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.

Modeling sequence and quasi-uniform assumption in computational neurostimulation.

Computational neurostimulation aims to develop mathematical constructs that link the application of neuromodulation with changes in behavior and cognition. This process is critical but daunting for technical challenges and scientific unknowns. The overarching goal of this review is to address how this complex task can be made tractable. We describe a framework of sequential modeling steps to achieve this: (1) current flow models, (2) cell polarization models, (3) network and information processing models, and (4) models of the neuroscientific correlates of behavior. Each step is explained with a specific emphasis on the assumptions underpinning underlying sequential implementation. We explain the further implementation of the quasi-uniform assumption to overcome technical limitations and unknowns. We specifically focus on examples in electrical stimulation, such as transcranial direct current stimulation. Our approach and conclusions are broadly applied to immediate and ongoing efforts to deploy computational neurostimulation.