Transcranial Electrical Stimulation (tES): Mechanisms, Technology and Therapeutic Applications

The NIMH Division of Translational Research sponsored a workshop to critically assess the use and potential of contemporary forms of low current transcranial electrical stimulation (tES), particularly transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS). Experts in basic and human neuroscience, electrical technologies, and clinical trialists met to discuss physiological mechanisms, protocol and technology optimization, therapeutic applications and trial designs, and future directions.

Physiological mechanisms
Physiological studies support synaptic plasticity as an underlying mechanism of tDCS. Effects of tDCS in humans appear task specific, i.e., dependent on which circuits are active. This argues for pairing stimulation with a relevant learning paradigm. tACS targets activity in cortex using a weak, alternating electrical current, which interacts with networks of neurons. Effective tACS requires synchronization with ongoing brain rhythms. In this case, electroencephalogram (EEG) provides a built-in measure of target engagement at the network level. tACS may take advantage of cross-frequency coupling (e.g., using theta rhythms to drive gamma rhythms). Brain imaging can be used to investigate mechanisms at several levels (e.g., molecular, network), as well as to model electrical current flow in the head and brain, provide measures of target engagement, and help optimize and customize stimulation protocols. tES-induced modulations can be reflected in changes in EEG and in blood-oxygen-level dependent functional magnetic resonance imaging (BOLD-fMRI) signal. tES-induced modulations can also be reflected in neurochemistry as measured by positron emission tomography (PET) or magnetic resonance spectroscopy (MRS). The combination of brain stimulation with neuroimaging allows investigation of causal relationships that hold potential for advancing treatments.

Protocol and technology optimization
Several methodological issues impacting tES research were identified. Issues relating to hardware and variations in tDCS/tACS approaches were reviewed, and common errors in technique were identified. For research purposes, improved “blinding” of participants, investigators, and technicians is needed to minimize placebo effects. Inclusion of an active control condition (e.g., stimulating a different brain region) might improve the interpretability of results. Reproducibility of experimental conditions is hindered by lack of detail in reporting of intervention methods. Gold-standard protocols, pre-registration of trials with pre-specified analyses, publication of null results, and data sharing are needed to address reproducibility issues.

Workshop participants described computational modeling approaches for defining the complex patterns of brain current flow and electric fields induced by tES methods. Such models are pivotal for appropriate dose selection, stimulation protocol design, and tailoring treatment based on individual head and brain anatomy and electrophysiology. These approaches show promise for increasing the precision of stimulation and maximizing neuromodulation effects. Reliable outcome measures or biomarkers for confirming the accuracy of dosing and stimulation are needed.

Therapeutic applications and trial designs
A number of tDCS trials in depression were reviewed, most of which targeted dorsolateral prefrontal cortex, and many of which achieved effects extending beyond the end of tDCS treatment. As with electro-convulsive therapy, a tendency toward relapse after remission of depression raises questions about the need for additional maintenance sessions. Concurrent interventions (e.g., medications, psychotherapy) complicate trials, but a combined-treatment approach may provide more effective therapy.

Increasingly, tDCS research involves augmentation of behavioral- or learning-based interventions. Such studies raise questions about when stimulation should be applied - before, during or following the behavioral or learning-based intervention - and when to measure learning/behavioral results. Pilot work with tACS is targeting cortical oscillations (i.e., neural rhythms reflected in EEG recordings) and shows potential for reducing auditory hallucinations in schizophrenia and boosting memory consolidation during sleep. Ideally, outcome measures would include a physiological measure that correlates highly with a behavioral measure which, in turn, would predict clinical/functioning effects. A professionally-supervised protocol for home-based, remotely-supervised tDCS, supported by specially designed equipment and a telemedicine platform, has shown feasibility in research settings. This approach shows promise for reducing patient burden and enabling longer duration of treatment.

Future Directions
Clinical applications of noninvasive stimulation are at an early stage of development, particularly in neuropsychiatry. Advances in understanding mechanisms, biomarkers of responsiveness, and technology are helping to inform protocols and therapeutic applications, but many needs remain.

Therapeutic use must be grounded in an improved understanding of physiological mechanisms at multiple levels, methods are needed for individual dosing, and improved “blinding” of subjects and staff are needed. Tools for selecting electrode arrangements and stimulation patterns and direct measures of electrical currents in the brain induced by these methods are needed. As stimulation is increasingly combined with cognitive or behavioral interventions, guidelines for determining the optimal timing of stimulation in combined interventions are needed. Well-rationalized outcome measures should span the levels of physiology, behavior and clinical effects. Optimal measures of target engagement should be defined for various applications.

As well, reporting guidelines for publications are needed to ensure sufficient information to achieve reproducibility. Transparency can be achieved by prospective registration of trials, including data analytic plans, and making access to raw individual-level data accessible through data repositories. Progress in these areas promises to advance therapeutic applications of these methods.

A report from the meeting is available online .