The leading global cause of disability is major depression, affecting over 350 million people worldwide.1 Pharmacological and psychological therapies for depression have changed very little in the past thirty years, despite extensive research for new treatment targets. The most common antidepressant drugs are effective for about 58% of depressed patients in primary care, while 45% respond to placebo.2 The difficulty in developing new treatments arises in part because depression is a disorder of unknown aetiology. The neurobiological correlates of depression, on the other hand, are not entirely unknown: neuroscience research has identified several brain circuits that operate abnormally in depression. Recently, this knowledge has contributed to the development of experimental treatments, including those that stimulate the brain directly in a targeted manner. Among these novel treatments is a form of painless, noninvasive brain stimulation termed transcranial direct current stimulation (tDCS), commonly applied to the dorsolateral prefrontal cortex (DLPFC) in trials for depression. The practical advantages of tDCS are many: tDCS is comparatively inexpensive, portable, and safe. In this article we discuss the evidence that tDCS is effective in depression, and the neural and cognitive mechanisms that may drive its putative antidepressant effect. We also outline the importance of mechanistic studies of DLPFC tDCS to clarify its effects on the brain, and optimise its potential for clinical use.
Recent depression trials place the anodal electrode over the left DLPFC, with the cathodal electrode used as a 'ground' electrode, for instance supraorbitally. In this specific example, this creates an electrical circuit with current travelling from the anodal (positive) to the cathodal (negative) electrode. This delivers low levels of electrical stimulation through the skull immediately under the anode, typically between 1 and 2 milliamps, with a small proportion of that affecting the cortex beneath, facilitating (but not directly evoking) neuronal activity in part through its effects on the resting potential (see below). Although the entire physiological effect is likely more complex, this general potentiation of activity has been reported to produce marked behavioural effects in domains as varied as motor tasks, auditory learning, and language.6 It is because of different electrode montages—electrode placement and current amplitude—that this technology can claim to modulate such an improbably diverse set of cognitive processes, including those involved in depression.
Increased task-related DLPFC neural activation is often interpreted as cortical inefficiency. While the primary role of the DLPFC is in so-called 'executive' function and cognitive control, it also plays a central role in emotion regulation, particularly in the reappraisal and suppression of negative emotions.7 Thus, targeting the DLPFC with tDCS aims to remedy inefficiency in emotion regulation that could be central to depressive symptoms.
The first double-blind, sham-controlled clinical trial of tDCS for depression reported very pronounced effects of tDCS on mood symptoms8 following a relatively short stimulation period. Differences between active and sham (placebo) tDCS even persisted over the succeeding month.
Unfortunately for the purposes of understanding the effect of tDCS in depression, the neurophysiological mechanisms of tDCS have been studied predominantly in the motor cortex. The mechanisms driving 'antidepressant' tDCS over the DLPFC are poorly understood, though most studies corroborate the simple anodal-excitatory/cathodal-inhibitory model (though note that mild anodal currents can sometimes inhibit neuronal activity13).
One study investigating the neurophysiology of DLPFC tDCS found a polarity-specific effect on both working memory performance and EEG measures: anodal tDCS increased both behavioural performance and its electrophysiological correlates, while cathodal stimulation decreased both measures.6 In currently-depressed patients, tDCS was reported to induce neurophysiological changes extending over the medial frontal cortex during working memory performance.14 These studies provide insight into the role of the DLPFC in depression, indicating that tDCS might alter DLPFC efficiency as well as its interaction with more widespread prefrontal regions, driving the resulting behavioural and mood changes.
To date, most research on tDCS for depression has adopted one of two strategies: trials to determine whether tDCS improves depressive symptoms; or experimental studies, usually in healthy subjects, to determine its mechanism of effect. This division inhibits a better understanding of the specific mechanisms driving the antidepressant effects of tDCS. Studies combining both strategies have the ability to resolve this, and determine how tDCS could best target symptoms of depression.
The most well-known electrical therapy in psychiatry is electroconvulsive therapy (ECT). Although evidence strongly indicates that ECT is an effective short-term treatment for depression,15 it is perceived negatively by the public and its therapeutic efficacy is often tempered by concerns about cognitive side-effects. In the case of tDCS, which uses stimulation currents that are orders of magnitude lower than ECT, initial reports of cognitive enhancement with tDCS reignited public interest in electrical current stimulation. From these reports emerged an online community of 'home kit' tDCS users who report finding amazing effects, sometimes far beyond what has been shown experimentally. Within the neuroscience community, researchers have begun to question the magnitude of the reported benefits of tDCS.16 An improved understanding of its mechanisms and effects is key to resolving these debates.
The challenge for basic and translational tDCS researchers is to convince clinicians that it is a credible experimental treatment, with the caveat that understanding its mechanisms will no doubt involve many more years of cellular, neurophysiological, and cognitive research. Putting treatment before mechanism is common in psychiatry: the neural mechanisms of proven effective treatments—cognitive therapy, electroconvulsive therapy, and many psychiatric drugs—are still relatively poorly understood. Still, history need not dictate future treatment discovery, and the tools of neuroscience can illuminate the biological and behavioural effects of tDCS alongside tests of its clinical efficacy. tDCS is only one of a number of experimental treatments for depression with origins in neuroscience, but it may hold particular potential as a new therapy, or as an augmentative strategy for existing therapies. The key will be honing the technology to target the complex and heterogenous nature of this debilitating disorder.
Arroll B, et al. Efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo for treatment of depression in primary care: a meta-analysis. Ann. Fam. Med. 2005;3:449-56.
Fritsch G, Hitzig E. Neurosurgical Classics. Thieme Medical Publishers, Inc. 1992.
Arul-Anandam AP, Loo C. Transcranial direct current stimulation: a new tool for the treatment of depression? J. Affect. Disord. 2009;117:137-45.
Bishop G, O'Leary J. The effects of polarizing currents on cell potentials and their significance in the interpretation of central nervous system activity. Electroencephalogr. Clin. Neurophysiol. 1950;2:401-16.
Zaehle T, Sandmann P, Thorne JD, Jäncke L, Herrmann CS. Transcranial direct current stimulation of the prefrontal cortex modulates working memory performance: combined behavioural and electrophysiological evidence. BMC Neurosci. 2011:12:2.
Koenigs M, Grafman J. The functional neuroanatomy of depression: distinct roles for ventromedial and dorsolateral prefrontal cortex. Behav. Brain Res. 2009;201:239-43.
Fregni F et al. Treatment of major depression with transcranial direct current stimulation. Bipolar Disord. 2006;8:203-4.
Loo CK et al. Transcranial direct current stimulation for depression: 3-week, randomised, sham-controlled trial. Br. J. Psychiatry 2012;200:52-9.
Brunoni AR et al. The sertraline vs electrical current therapy for treating depression clinical study: results from a factorial, randomized, controlled trial. JAMA Psychiatry 2013;70:383-91.
Shiozawa P et al. Transcranial direct current stimulation for major depression: an updated systematic review and meta-analysis. Int. J. Neuropsychopharmacol. 2014;1-10.
Wachter D et al. Transcranial direct current stimulation induces polarity-specific changes of cortical blood perfusion in the rat. Exp. Neurol. 2011;227:322-7.
Priori A, Berardelli A, Rona S, Accornero N, Manfredi M. Polarization of the human motor cortex through the scalp. Neuroreport 1998;9:2257-60.
Powell TY, Boonstra TW, Martin DM, Loo CK, Breakspear M. Modulation of Cortical Activity by Transcranial Direct Current Stimulation in Patients with Affective Disorder. PloS One 2014;9:e98503.
The U. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and meta-analysis. The Lancet 2003;361:799-808.
Horvath JC, Forte JD, Carter O. Quantitative Review Finds No Evidence of Cognitive Effects in Healthy Populations from Single-Session Transcranial Direct Current Stimulation (tDCS). Brain Stimulat. 2015.