Cognitive control therapy and transcranial direct current stimulation for depression: A randomized, double-blinded, controlled trial

Abstract

Background

Based on findings that major depressive disorder (MDD) is associated to decreased dorsolateral prefrontal cortical (DLPFC) activity; interventions that increase DLPFC activity might theoretically present antidepressant effects. Two of them are cognitive control therapy (CCT), a neurocognitive intervention that uses computer-based working memory exercises, and transcranial direct current stimulation (tDCS), which delivers weak, electric direct currents over the scalp.

Methods

We investigated whether tDCS enhanced the effects of CCT in a double-blind trial, in which participants were randomized to sham tDCS and CCT (n=17) vs. active tDCS and CCT (n=20). CCT and tDCS were applied for 10 consecutive workdays. Clinicaltrials.gov identifier: NCT01434836.

Results

Both CCT alone and combined with tDCS ameliorated depressive symptoms after the acute treatment period and at follow-up, with a response rate of approximately 25%. Older patients and those who presented better performance in the task throughout the trial (possibly indicating greater engagement and activation of the DLPFC) had greater depression improvement in the combined treatment group.

Limitations

Our exploratory findings should be further confirmed in prospective controlled trials.

Discussion

CCT and tDCS combined might be beneficial for older depressed patients, particularly for those who have cognitive resources to adequately learn and improve task performance over time. This combined therapy might be specifically relevant in this subgroup that is more prone to present cognitive decline and prefrontal cortical atrophy.

Introduction

Considerable research has been performed on novel treatments for major depression, a chronic, highly prevalent disorder (Kessler et al., 2003) in which antidepressant drugs present modest efficacy (Trivedi et al., 2006) and important adverse effects (Anderson et al., 2008) that limit their use. Some of these novel interventions aim to improve depression symptoms by directly increasing dorsolateral prefrontal cortical (DLPFC) activity, based on the observation of decreased activity of this area and increased activity of subcortical structures observed in MDD, a pattern that is at least partially restored to normal levels after amelioration of depressive symptoms (Mayberg et al., 2000, Pizzagalli, 2011, Siegle et al., 2007). Two of these interventions are particularly appealing considering their low cost, ease of use and applicability in different scenarios: transcranial direct current stimulation (tDCS) and neurocognitive therapies.

TDCS consists of the induction of a weak, direct electric current through electrodes placed over the scalp that could increase (anode) and decrease (cathode) cortical excitability beyond the period of stimulation (Nitsche and Paulus, 2000). Although the exact mechanisms of action of tDCS are still unclear, it probably operates by inducing small changes (<1 mV) in the membrane potential (Datta et al., 2009), thus acting in the frequency of spike timing and modifying net cortical excitability (Purpura and McMurtry, 1965). Compared to repetitive transcranial magnetic stimulation (rTMS), another somatic therapy, tDCS is cheaper, easier to use and a more portable technique with less adverse effects (Priori et al., 2009); characteristics that have motivated further tDCS research in neuropsychiatric disorders, particularly depression. In fact, recent randomized clinical trials demonstrated that daily, repeated sessions of tDCS show clinical efficacy in the treatment of major depression (Brunoni et al., 2013c, Loo et al., 2012). These studies applied anodal tDCS over the left DLPFC, theoretically increasing the activity in this brain area, which is decreased in MDD.

Neurocognitive therapy is an intervention that addresses the biological mechanisms of psychological disorders (Siegle et al., 2007). For depression, current neurocognitive interventions consist of tasks focused on working memory and sustained attention training, as these cognitive tasks are associated with DLPFC activity—in fact, patients with depression have poorer performance in many of these tasks (Barch et al., 2003, Gotlib and Joormann, 2010, Jones et al., 2010). In recent studies, Siegle et al., 2007, Siegle et al., In press investigated whether these interventions that increase DLPFC activity could be employed as a depression treatment. The authors compared the outcome of depressed patients that were randomized to receive treatment as usual only vs. combined with cognitive control therapy (CCT) designed to increase DLPFC activity. They showed that the CCT group displayed significantly greater improvements in depression symptoms than those in the treatment as usual group. In another study, Segrave et al. (2013) explored the efficacy of CCT combined with tDCS in a 3-arm trial, randomizing 27 patients to receive CCT+sham tDCS, tDCS+sham CCT and both active therapies combined, finding that only CCT and tDCS combined presented sustained antidepressant response at follow-up. However, the sample size of this study was small (n=9 per condition) and the number of sessions was limited (5 sessions). These promising results fostered further investigation in this topic.

Both tDCS and CCT might act in depression improvement via enhancement of DLPFC activity. Theoretically, tDCS could enhance – i.e., present synergistic effects – the influence of CCT, based on previous studies that showed that tDCS increases WM performance in healthy and depressed volunteers (Brunoni and Vanderhasselt, 2014, Brunoni and Vanderhasselt, 2014, Fregni et al., 2005, Oliveira et al., 2013). We examined whether tDCS, by increasing cortical activity in the DLPFC, could enhance performance and therefore the effects of CCT, which actively recruits similar brain areas, thus ameliorating depression. Importantly, we used the Paced Auditory Serial Addition Task (PASAT) training alone (and not combined to the computer-based attention training part as used in the Segrave et al. study) for CCT, because by using two tasks it is impossible to disentangle the specific contribution of each task. We used the PASAT because this task is already known to activate the left middle frontal gyrus, including the DLPFC (Lazeron et al., 2003). The importance of this study is both mechanistic – i.e., to increase the understanding of the pathophysiological mechanisms involved in depression – and clinical, as we investigated whether the combination of two non-pharmacological, affordable therapies presented clinical gains in depressed subjects.