tDCS for treatment-resistant depression

Introduction

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation (NIBS) technique, whereby a subthreshold, continuous electrical current (typically 1–2 mA) is applied to the brain via two or more electrodes, placed over the scalp ( ). The conventional tDCS device consists of a portable, battery-operated machine, connected through conductive cables to two electrodes (an anode and a cathode), that are cushioned in saline-humidified sponge pads ( Fig. 18.1 ).

The device generates a current that passes through the skin, subcutaneous tissue, skull, meninges, cerebrospinal fluid, and finally, brain gray and white matter, with the direction of the electrical current flowing from the anode toward the cathode ( ). In general terms, the neurons under the anode tend to be partially depolarized, increasing their excitability and facilitating synaptic transmission ( ). On the other hand, in the area under the cathode, the neurons tend to hyperpolarize, decreasing their excitability and inhibiting synaptic transmission ( ).

These processes take place, however, with tDCS not directly eliciting action potentials, but rather facilitating or inhibiting (modulating) the already ongoing neuronal activity taking place in the stimulated regions ( ). This biophysical change in the target region also tends to influence other brain areas that are anatomically or functionally connected to it ( ). It is with this underlying rationale that different electrode montages are considered when treating a disorder in which a specific brain region or network is involved (for a detailed description of the biophysical and network mechanisms of tDCS, please see “ Mechanism(s) of action ” section).

tDCS has been intensively researched in diverse neuropsychiatric disorders, with variable degrees of efficacy, but with consistent safety and tolerability profiles ( ; ). In the treatment of major depressive disorder (MDD) in particular, tDCS has been found to be superior to sham, with moderate effect sizes ( ; ; ). Furthermore, pivotal trials have suggested tDCS’ synergistic effects with sertraline ( ), albeit being inferior, as monotherapy, to escitalopram ( ).

Currently, tDCS is not yet placed on the same level of clinical efficacy as other forms of NIBS for treatment-resistant depression (TRD), such as transcranial magnetic stimulation (TMS), which is an approved alternative after treatment failure with at least one antidepressant , or electroconvulsive therapy (ECT), for severe cases of depression, especially with psychotic symptoms ( ).

However, some advantages associated with tDCS, in comparison with other NIBS techniques (i.e., TMS and ECT), are its relatively low cost, portability, easiness of use, and the possibility of home-based treatment ( ). Moreover, tDCS is not associated with many of the most common adverse events observed with antidepressant medications (i.e., appetite, libido, and sleep alterations), nor with the adverse cognitive effects of ECT ( ).

In the treatment of MDD in general, and more specifically in the case of TRD, tDCS displays an augmentative and synergistic potential, both to an existing regimen of antidepressants, and/or to cognitive behavioral therapy (CBT) ( ).

In this chapter, we provide a detailed overview of tDCS as a potentializing intervention in TRD, encompassing recent advancements and interesting lines for future research.

History and development

Animal studies involving basic aspects of direct electrical current stimulation in the brain began in the 1950s, with observations that brief periods of intracerebral or epidural stimulation could produce long-lasting effects on neuronal membrane resting potential, depending on the polarity of the electrodes: the anode was found to increase the rate of neuronal firing, while the cathode led to hyperpolarization of neurons and to the decrease of the neuronal firing rate ( ; ). However, since the 1960s, it has been known that opposite polarization effects might also be observed in individual cortical layers, suggesting that effects of direct current stimulation might depend on other factors besides polarity, such as current direction and neuronal geometry ( ).

Perhaps the first placebo-controlled clinical trial to use noninvasive electrical brain polarization in the treatment of depressed patients was published in 1964, with the observation of clinical improvement in depressive patients receiving active treatment, especially regarding anxiety, agitation, and somatic symptom domains ( ). In this cross-over trial involving 24 inpatients, the electrical current was passed through 2 electrodes (anodes) placed over each eyebrow, while the cathode was placed on one leg, using a protocol of 0.25 mA during 8 h per day, for 12 consecutive days ( ). The protocol used in this trial was based on previous observations of optimal antidepressant response with current amplitudes at a maximum of 0.3 mA; however, antidepressant effects were observed to change in other amplitudes, depending on current density parameters ( ). At the time of the first brain polarization trials for depression, limitations in methodology and incipient neurobiological knowledge related to the disorder became obstacles in the development of the technique, which went gradually into oblivion over the next 40 years ( ).

Beginning around the year 2000, renewed observations involving the application of tDCS in humans began to shed deeper light on the technique’s longer-lasting behavioral and therapeutic effects. In a seminal study by , noninvasive electrical stimulation of the human motor cortex was shown to alter motor-evoked potentials as elicited by single-TMS pulses  ( ). In this study, anodal stimulation led to an increases in cortical excitability, while cathodal stimulation led to subsequent decreases in this parameter; the authors also noted that strength and duration of after-effects could be controlled by modifications of current intensity and duration of stimulation ( ).

Later, it was observed that patients with depression commonly display an asymmetrical pattern of functional interhemispheric activity, with a reduction in prefrontal activity of the left hemisphere, and an increase in the right in comparison to heathy individuals ( ; ). This neurobiological model offered a rationale for the most commonly used tDCS montages in the treatment of MDD, whereby the "excitatory" anode is usually placed over the left hemisphere, while the cathode is placed over the right hemisphere ( ).

The first modern RCT involving the use of tDCS in MDD was published in 2006 ( ). In this trial, 10 patients with MDD received 5 days of anodal stimulation (1 mA for 20 min/day) over the left dorsolateral prefrontal cortex (DLPFC) or sham. Results showed four treatment responders in the active group,no responders in the sham group, and no reports of major adverse effects ( ).

These positive initial results gradually led to dozens of trials involving the use of tDCS for MDD, with varying individual degrees of efficacy, but with overall moderate effect sizes versus placebo. Additionally, consistent patient tolerability and general safety allowed for the continued research of this NIBS modality, as shall be described below.

Mechanisms of action

The exact mechanism of action of tDCS is still to be fully elucidated. At the cellular level, tDCS is believed to induce a change in neuronal membrane potentials, affecting the probability and timing of spikes (neural firing rates) ( ; ). In vitro experiments using rat motor cortex brain slices indicated that anodal stimulation produces partial depolarization of the neuronal soma, with the cathode producing somatic hyperpolarization, respectively increasing or decreasing the probability of triggering action potentials ( ).

Initial neurophysiological studies with tDCS applied to the motor area also pointed in the same direction. When accessing motor-evoked potentials (MEPs) elicited by simple TMS pulses, researchers showed an increase in amplitude after anodal and a decrease after cathodal stimulation ( ). The latest research, however, suggests that this relationship is more complex and that parameters such as current intensity and duration of stimulation may have a nonlinear relationship with the effects of tDCS on cortical excitability. For instance, a study has shown that the application of both anodal and cathodal tDCS to the motor cortex, with an intensity of 2 mA for 20 min, led to an increase in the amplitude of MEPs, changing the direction of cathodal  effects to excitability enhancement ( ).

More recent evidence also expands on classic findings and suggests that tDCS impacts neural functioning also at a network level, with its local effects spreading to other regions anatomically and functionally connected to the target area ( ). The current intensity commonly used in clinical studies in humans (typically 2 mA) is not sufficient to elicit action potentials. Therefore, tDCS would act influencing the ongoing oscillatory dynamics of nodes of the network and in that sense, selectively affecting the "active" neurons, which are receiving synaptic inputs (in contrast to the neurons “at rest” of the inactive networks at the time of stimulation) ( ).

Therefore, for depression, most of the studies that place the anode over the left DLPFC use this region as a “window” to enter large-scale brain networks like the default mode network (DMN), for which the DLPFC is a key hub. The DMN is believed to be involved in self-referential processing, affective cognition, and emotion regulation ( ). Facilitating its endogenous activity and normalizing functional connectivity with key regions within the network (like the subgenual anterior cingulate cortex, sACC) could potentially lead to an improvement in depressive symptoms, as shown after a course of TMS treatment ( ; ).

Moreover, due to the diffuse nature of tDCS, it can stimulate other regions and potentially, deeper structures that are in the path of the current between the electrodes ( ). Although evidence suggests that tDCS may functionally target neuronal dynamics ( ), the arrangement of the electrodes (montage) also plays an important role in the final effect of the stimulation ( ).

The long-term effects of tDCS are believed to be due to synaptic plasticity modulated by LTP- (long-term potentiation) and LTD- (long-term depression)-like mechanisms ( ). Pharmacological studies in humans ( ) and animal electrophysiology experiments ( ; ) corroborate this hypothesis, although the exact biophysical mechanism involved is still unknown ( ).