Low-intensity Transcranial Electrical Stimulation Research Articles

The consequences of the new European reclassification of non-invasive brain stimulation devices and the medical device regulations pose an existential threat to research and treatment: An invited opinion paper

A significant amount of European basic and clinical neuroscience research includes the use of transcranial magnetic stimulation (TMS) and low intensity transcranial electrical stimulation (tES), mainly transcranial direct current stimulation (tDCS). Two recent changes in the EU regulations, the introduction of the Medical Device Regulation (MDR) (2017/745) and the Annex XVI have caused significant problems and confusions in the brain stimulation field. The negative consequences of the MDR for non-invasive brain stimulation (NIBS) have been largely overlooked and until today, have not been consequently addressed by National Competent Authorities, local ethical committees, politicians and by the scientific communities. In addition, a rushed bureaucratic decision led to seemingly wrong classification of NIBS products without an intended medical purpose into the same risk group III as invasive stimulators.Overregulation is detrimental for any research and for future developments, therefore researchers, clinicians, industry, patient representatives and an ethicist were invited to contribute to this document with the aim of starting a constructive dialogue and enacting positive changes in the regulatory environment.

Transcranial electric stimulation modulates firing rate at clinically relevant intensities

BackgroundNotwithstanding advances with low-intensity transcranial electrical stimulation (tES), there remain questions about the efficacy of clinically realistic electric fields on neuronal function. ObjectiveTo measure electric fields magnitude and their effects on neuronal firing rate of hippocampal neurons in freely moving rats, and to establish calibrated computational models of current flow. MethodsCurrent flow models were calibrated on electric field measures in the motor cortex (n=2 anesthetized rats) and hippocampus. A Neuropixels 2.0 probe with 384 channels was used in an in-vivo rat model of tES (n = 4 freely moving and 2 urethane anesthetized rats) to detect effects of weak fields on neuronal firing rate. High-density field mapping and computational models verified field intensity (1 V/m in hippocampus per 50 μA of applied skull currents). ResultsElectric fields of as low as 0.35 V/m (0.25 - 0.47) acutely modulated average firing rate in the hippocampus. At these intensities, firing rate effects increased monotonically with electric field intensity at a rate of 11.5 % per V/m (7.2 - 18.3). For the majority of excitatory neurons, firing increased for soma-depolarizing stimulation and diminished for soma-hyperpolarizing stimulation. While more diverse, the response of inhibitory neurons followed a similar pattern on average, likely as a result of excitatory drive. ConclusionIn awake animals, electric fields modulate spiking rate above levels previously observed in vitro. Firing rate effects are likely mediated by somatic polarization of pyramidal neurons. We recommend that all future rodent experiments directly measure electric fields to insure rigor and reproducibility.

Behavioral Validation of Individualized Low-Intensity Transcranial Electrical Stimulation (tES) Protocols.

Large interindividual variability in the effects of low-intensity transcranial electrical stimulation (tES) considerably limits its potential for clinical applications. It has been recently proposed that individualizing stimulation dose by accounting for interindividual anatomic differences would reduce the variability in electric fields (E-fields) over the targeted cortical site and therefore produce more consistent behavioral outcomes. However, improvement in behavioral outcomes following individualized dose tES has never been compared with that of conventional fixed dose tES. In this study, we aimed to empirically evaluate the effect of individualized dose tES on behavior and further compare it with the effects of sham and fixed dose stimulations. We conducted a single-blinded, sham-controlled, repeated-measures study to examine the impact of transcranial direct current stimulation on motor learning and that of transcranial alternating current stimulation on the working memory of 42 healthy adult individuals. Each participant underwent three sessions of tES, receiving fixed dose, individualized dose, or sham stimulation over the targeted brain region for the entire behavioral task. Our results showed that the individualized dose reduced the variability in E-fields at the targeted cortical surfaces. However, there was no significant effect of tES on behavioral outcomes. We argue that although the stimulation dose and E-field intensity at the targeted cortical site are linearly correlated, the effect of E-fields on behavior seems to be more complex. Effective optimization of tES protocols warrants further research considering both neuroanatomical and functional aspects of behavior.

Stimulated brains and meditative minds: A systematic review on combining low intensity transcranial electrical stimulation and meditation in humans.

Low intensity transcranial electrical stimulation (tES) and meditation are two promising, yet variable, non-pharmacological interventions. Growing research is investigating combined effects of both techniques on one's cognitive, emotional, and physical health. This article reviews the current research that combines tES and meditation interventions in healthy and diseased participants. The review considers the intervention parameters and their effects in a well-organized manner. A systematic search for clinical and experimental published studies was conducted in the PubMed, Cochrane, and transcranial direct current stimulation (tDCS) databases using common keywords for tES and for meditation techniques well defined by previous studies. Unpublished ongoing studies were identified with the ClinicalTrials.gov and DRKS.de clinical trial websites. 20 published studies and 13 ongoing studies were included for qualitative analysis. 13 published articles studied patients with chronic pain, psychological disorders, cognitive impairment, and movement disorders. Anodal tDCS was the only tES technique while mindfulness meditation was the most common meditation type. Eight studies had a main group effect, with outcome improvement in the active combined intervention. However, most published studies showed improvements after at least one combined intervention with variable effects. Pairing anodal tDCS with meditation shows promising improvements of the physical, mental, and emotional aspects of daily life. Further studies are required to confirm the relevance of this combination in the clinic.

A checklist for assessing the methodological quality of concurrent tES-fMRI studies (ContES checklist): a consensus study and statement.

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

Sensitivity and resolution improvement for in vivo magnetic resonance current‐density imaging of the human brain

Magnetic resonance current-density imaging (MRCDI) combines MRI with low-intensity transcranial electrical stimulation (TES; 1-2 mA) to map current flow in the brain. However, usage of MRCDI is still hampered by low measurement sensitivity and image quality. Recently, a multigradient-echo-based MRCDI approach has been introduced that presently has the best-documented efficiency. This MRCDI approach has now been advanced in three directions and has been validated by phantom and in vivo experiments. First, the importance of optimum spoiling for brain imaging was verified. Second, the sensitivity and spatial resolution were improved by using acquisition weighting. Third, navigators were added as a quality control measure for tracking physiological noise. Combining these advancements, the optimized MRCDI method was tested by using 1 mA TES for two different injection profiles. For a session duration of 4:20 min, the new MRCDI method was able to detect TES-induced magnetic fields at a sensitivity level of 84 picotesla, representing a twofold efficiency increase against our original method. A comparison between measurements and simulations based on personalized head models showed a consistent increase in the coefficient of determination of ΔR2 = 0.12 for the current-induced magnetic fields and ΔR2 = 0.22 for the current flow reconstructions. Interestingly, some of the simulations still clearly deviated from the measurements despite the strongly improved measurement quality. This highlights the utility of MRCDI to improve head models for TES simulations. The achieved sensitivity improvement is an important step from proof-of-concept studies toward a broader application of MRCDI in clinical and basic neuroscience research.

Neurobiological After-Effects of Low Intensity Transcranial Electric Stimulation of the Human Nervous System: From Basic Mechanisms to Metaplasticity.

Non-invasive low-intensity transcranial electrical stimulation (tES) of the brain is an evolving field that has brought remarkable attention in the past few decades for its ability to directly modulate specific brain functions. Neurobiological after-effects of tES seems to be related to changes in neuronal and synaptic excitability and plasticity, however mechanisms are still far from being elucidated. We aim to review recent results from in vitro and in vivo studies that highlight molecular and cellular mechanisms of transcranial direct (tDCS) and alternating (tACS) current stimulation. Changes in membrane potential and neural synchronization explain the ongoing and short-lasting effects of tES, while changes induced in existing proteins and new protein synthesis is required for long-lasting plastic changes (LTP/LTD). Glial cells, for decades supporting elements, are now considered constitutive part of the synapse and might contribute to the mechanisms of synaptic plasticity. This review brings into focus the neurobiological mechanisms and after-effects of tDCS and tACS from in vitro and in vivo studies, in both animals and humans, highlighting possible pathways for the development of targeted therapeutic applications.

Guidelines for TMS/tES clinical services and research through the COVID-19 pandemic

BackgroundThe COVID-19 pandemic has broadly disrupted biomedical treatment and research including non-invasive brain stimulation (NIBS). Moreover, the rapid onset of societal disruption and evolving regulatory restrictions may not have allowed for systematic planning of how clinical and research work may continue throughout the pandemic or be restarted as restrictions are abated. The urgency to provide and develop NIBS as an intervention for diverse neurological and mental health indications, and as a catalyst of fundamental brain research, is not dampened by the parallel efforts to address the most life-threatening aspects of COVID-19; rather in many cases the need for NIBS is heightened including the potential to mitigate mental health consequences related to COVID-19. ObjectiveTo facilitate the re-establishment of access to NIBS clinical services and research operations during the current COVID-19 pandemic and possible future outbreaks, we develop and discuss a framework for balancing the importance of NIBS operations with safety considerations, while addressing the needs of all stakeholders. We focus on Transcranial Magnetic Stimulation (TMS) and low intensity transcranial Electrical Stimulation (tES) - including transcranial Direct Current Stimulation (tDCS) and transcranial Alternating Current Stimulation (tACS). MethodsThe present consensus paper provides guidelines and good practices for managing and reopening NIBS clinics and laboratories through the immediate and ongoing stages of COVID-19. The document reflects the analysis of experts with domain-relevant expertise spanning NIBS technology, clinical services, and basic and clinical research – with an international perspective. We outline regulatory aspects, human resources, NIBS optimization, as well as accommodations for specific demographics. ResultsA model based on three phases (early COVID-19 impact, current practices, and future preparation) with an 11-step checklist (spanning removing or streamlining in-person protocols, incorporating telemedicine, and addressing COVID-19-associated adverse events) is proposed. Recommendations on implementing social distancing and sterilization of NIBS related equipment, specific considerations of COVID-19 positive populations including mental health comorbidities, as well as considerations regarding regulatory and human resource in the era of COVID-19 are outlined. We discuss COVID-19 considerations specifically for clinical (sub-)populations including pediatric, stroke, addiction, and the elderly. Numerous case-examples across the world are described. ConclusionThere is an evident, and in cases urgent, need to maintain NIBS operations through the COVID-19 pandemic, including anticipating future pandemic waves and addressing effects of COVID-19 on brain and mind. The proposed robust and structured strategy aims to address the current and anticipated future challenges while maintaining scientific rigor and managing risk.

Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines.

Low intensity transcranial electrical stimulation (TES) in humans, encompassing transcranial direct current (tDCS), transcutaneous spinal Direct Current Stimulation (tsDCS), transcranial alternating current (tACS), and transcranial random noise (tRNS) stimulation or their combinations, appears to be safe. No serious adverse events (SAEs) have been reported so far in over 18,000 sessions administered to healthy subjects, neurological and psychiatric patients, as summarized here. Moderate adverse events (AEs), as defined by the necessity to intervene, are rare, and include skin burns with tDCS due to suboptimal electrode-skin contact. Very rarely mania or hypomania was induced in patients with depression (11 documented cases), yet a causal relationship is difficult to prove because of the low incidence rate and limited numbers of subjects in controlled trials. Mild AEs (MAEs) include headache and fatigue following stimulation as well as prickling and burning sensations occurring during tDCS at peak-to-baseline intensities of 1-2mA and during tACS at higher peak-to-peak intensities above 2mA. The prevalence of published AEs is different in studies specifically assessing AEs vs. those not assessing them, being higher in the former. AEs are frequently reported by individuals receiving placebo stimulation. The profile of AEs in terms of frequency, magnitude and type is comparable in healthy and clinical populations, and this is also the case for more vulnerable populations, such as children, elderly persons, or pregnant women. Combined interventions (e.g., co-application of drugs, electrophysiological measurements, neuroimaging) were not associated with further safety issues. Safety is established for low-intensity 'conventional' TES defined as <4mA, up to 60min duration per day. Animal studies and modeling evidence indicate that brain injury could occur at predicted current densities in the brain of 6.3-13A/m2 that are over an order of magnitude above those produced by tDCS in humans. Using AC stimulation fewer AEs were reported compared to DC. In specific paradigms with amplitudes of up to 10mA, frequencies in the kHz range appear to be safe. In this paper we provide structured interviews and recommend their use in future controlled studies, in particular when trying to extend the parameters applied. We also discuss recent regulatory issues, reporting practices and ethical issues. These recommendations achieved consensus in a meeting, which took place in Göttingen, Germany, on September 6-7, 2016 and were refined thereafter by email correspondence.

Application of Transcranial Electric Stimulation (tDCS, tACS, tRNS)

Abstract. Low-intensity transcranial electrical stimulation (tES) techniques are a group of noninvasive brain stimulation approaches, where currents are applied with intensities ranging between 0.4 and 2 mA through the human scalp. The most frequently used tES methods are transcranial direct current (tDCS), alternating current (tACS), and random noise stimulation (tRNS). These methods have been shown to induce changes in cortical excitability and activity during and after the stimulation in a reversible manner. It was observed that while anodal and cathodal tDCS acts on the membrane potentials by depolarizing or hyperpolarizing them, tACS probably modifies cortical oscillations. tRNS, that is a special form of tACS, might act through affecting the signal-to-noise ratio in the brain. Currently, an exponentially increasing number of studies have been published regarding the effects of tES on physiological processes and cognition. The aim of this review is to summarize the basic aspects of tES methods.

The impact of electrical stimulation techniques on behavior.

Low-intensity transcranial electrical stimulation (tES) methods are a group of noninvasive brain stimulation techniques, whereby currents are applied with intensities typically ranging between 1 and 2 mA, through the human scalp. These techniques have been shown to induce changes in cortical excitability and activity during and after the stimulation in a reversible manner. They include transcranial direct current simulation (tDCS), transcranial alternating current simulation (tACS), and transcranial random noise stimulation (tRNS). Currently, an increasing number of studies have been published regarding the effects of tES on cognitive performance and behavior. Processes of learning and increases in cognitive performance are accompanied by changes in cortical plasticity. tES can impact upon these processes and is able to affect task execution. Many studies have been based on the accepted idea that by increasing cortical excitability (e.g., by applying anodal tDCS) or coherence of oscillatory activity (e.g., by applying tACS) an increase in performance should be detected; however, a number of studies now suggest that the basic knowledge of the mechanisms of action is insufficient to predict the outcome of applied stimulation on the execution of a cognitive or behavioral task, and so far no standard paradigms for increasing cortical plasticity changes during learning or cognitive tasks have been established. The aim of this review is to summarize recent findings with regard to the effects of tES on behavior concentrating on the motor and visual areas. WIREs Cogn Sci 2014, 5:649-659. doi: 10.1002/wcs.1319 For further resources related to this article, please visit the WIREs website. The authors have declared no conflicts of interest for this article.

Validation of finite element model of transcranial electrical stimulation using scalp potentials: implications for clinical dose

Objective. During transcranial electrical stimulation, current passage across the scalp generates voltage across the scalp surface. The goal was to characterize these scalp voltages for the purpose of validating subject-specific finite element method (FEM) models of current flow. Approach. Using a recording electrode array, we mapped skin voltages resulting from low-intensity transcranial electrical stimulation. These voltage recordings were used to compare the predictions obtained from the high-resolution model based on the subject undergoing transcranial stimulation. Main results. Each of the four stimulation electrode configurations tested resulted in a distinct distribution of scalp voltages; these spatial maps were linear with applied current amplitude (0.1 to 1 mA) over low frequencies (1 to 10 Hz). The FEM model accurately predicted the distinct voltage distributions and correlated the induced scalp voltages with current flow through cortex. Significance. Our results provide the first direct model validation for these subject-specific modeling approaches. In addition, the monitoring of scalp voltages may be used to verify electrode placement to increase transcranial electrical stimulation safety and reproducibility.