Depression treatment by tDCS-enhanced cognitive control training: A test of two stimulation intensities

Hypoactivity of the dorsolateral prefrontal cortex (dlPFC) has been described as a pathophysiological characteristic of major depression disorder (MDD) [[1]Fales C.L. Barch D.M. Rundle M.M. Mintun M.A. Snyder A.Z. Cohen J.D. et al.Altered emotional interference processing in affective and cognitive-control brain circuitry in major depression.Biol Psychiatr. 2008; 63: 377-384https://doi.org/10.1016/j.biopsych.2007.06.012Abstract Full Text Full Text PDF PubMed Scopus (349) Google Scholar] which is associated with impaired cognitive control over negative emotional information, underlying the development and maintenance of MDD symptomatology [[2]Gotlib I.H. Joormann J. Cognition and depression: current status and future directions.Annu Rev Clin Psychol. 2010; 6: 285-312https://doi.org/10.1146/annurev.clinpsy.121208.131305Crossref PubMed Scopus (1261) Google Scholar]. DlPFC activity can be modulated by transcranial direct current stimulation (tDCS) and studies on the efficacy of tDCS for MDD are promising [[3]Razza L.B. Palumbo P. Moffa A.H. Carvalho A.F. Solmi M. Loo C.K. et al.A systematic review and meta-analysis on the effects of transcranial direct current stimulation in depressive episodes.Depress Anxiety. 2020; 37: 594-608https://doi.org/10.1002/da.23004Crossref PubMed Scopus (32) Google Scholar]. However, the reported effect sizes are moderate and knowledge on optimal stimulation parameters, like intensity is still lacking. Since tDCS itself does not induce neuronal activity, its effect depends on concurrent brain activity. Thus, a targeted combination with cognitive control training (CCT) has been put forward as a promising approach to support antidepressive effects of tDCS [[4]Segrave R.A. Arnold S. Hoy K. Fitzgerald P.B. Concurrent cognitive control training augments the antidepressant efficacy of tDCS: a pilot study.Brain Stimul. 2014; 7: 325-331https://doi.org/10.1016/j.brs.2013.12.008Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar,[5]Brunoni A.R. Boggio P.S. De Raedt R. Benseñor I.M. Lotufo P.A. Namur V. et al.Cognitive control therapy and transcranial direct current stimulation for depression: a randomized, double-blinded, controlled trial.J Affect Disord. 2014; 162: 43-49https://doi.org/10.1016/j.jad.2014.03.026Crossref PubMed Scopus (139) Google Scholar]. Particularly trainings of the paced auditory serial addition task [PASAT, [6]Gronwall D. Paced auditory serial-addition task: a measure of recovery from concussion.Percept Mot Skills. 1977; 44: 367-373https://doi.org/10.2466/pms.1977.44.2.367Crossref PubMed Scopus (1830) Google Scholar indicated efficacy on depressive symptoms [[7]Siegle G.J. Ghinassi F. Thase M.E. Neurobehavioral therapies in the 21st century: summary of an emerging field and an extended example of cognitive control training for depression.Cognit Ther Res. 2007; 31: 235-262https://doi.org/10.1007/s10608-006-9118-6Crossref Scopus (311) Google Scholar]. The PASAT challenges cognitive control and negative information processing by means of continuous working memory updating in a stressful and frustrating environment [[7]Siegle G.J. Ghinassi F. Thase M.E. Neurobehavioral therapies in the 21st century: summary of an emerging field and an extended example of cognitive control training for depression.Cognit Ther Res. 2007; 31: 235-262https://doi.org/10.1007/s10608-006-9118-6Crossref Scopus (311) Google Scholar]. Consistently, PASAT performance activates the dlPFC [[8]Lazeron R.H. Rombouts S.A.R. de Sonneville L. Barkhof F. Scheltens P. A paced visual serial addition test for fMRI.J Neurol Sci. 2003; 213: 29-34https://doi.org/10.1016/S0022-510X(03)00144-8Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar]. Given this complementary impact of tDCS and CCT on the cognitive control network and biased information processing, synergistic effects can be expected. Therefore, we tested a tDCS supported CCT on MDD using two stimulation intensities (1 and 2mA) to investigate the most effective intensity in MDD based on previous results in healthy subjects showing a non-linear influence of stimulation intensity with a beneficial effect of 1 but not 2 mA [[9]Weller S. Nitsche M.A. Plewnia C. Enhancing cognitive control training with transcranial direct current stimulation: a systematic parameter study.Brain Stimul. 2020; 13: 1358-1369https://doi.org/10.1016/j.brs.2020.07.006Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. 51 depressed patients (30 female, M = 37.71 years, SD = 14.02) were randomly allocated into one of three training conditions CCT + sham tDCS, CCT + 1mA tDCS and CCT + 2mA tDCS (N = 3 × 17, Sup. Table 1). Exclusion criteria were left-handedness, instable intake of antidepressive medication, intake of anticonvulsants, opiates, excessive benzodiazepine use (>1mg Lorazepam/equivalent dose of other Benzodiazepines per day), bipolar disorder, schizophrenia spectrum disorder, substance use disorder, eating disorder, Cluster A, antisocial or borderline personality disorder and acute suicidality. The study was approved by the local ethics committee and was conducted in compliance with the Declaration of Helsinki. All participants gave their written informed consent. The study was registered at ClinicalTrials.gov (Identifier: NCT03518749). All patients completed a four-week training, comprising three intermittent CCT sessions per week (Monday, Wednesday, Friday). As CCT task, we used an adaptive version of the PASAT. One-digit numbers were presented via headphones and participants added the digit they just heard with the one before. Simultaneously with the new digit, feedback was given by presenting green (red) light after correct (incorrect) responses. An adaptive inter-stimulus interval (ISI) ensured that patients processed at their individual performance limits but are not overstrained. Starting at 3 s it was increased (decreased) by 0.1 s after four consecutive incorrect (correct) trials. The stimulation was administered parallel to the PASAT performance for 23 minutes (5 seconds ramp up/down) using a multichannel DC Stimulator (NeuroConn GmbH, Germany) and 35cm2 rubber electrodes placed over the left dlPFC (F3 active, anodal electrode) and the right deltoid muscle (reference, cathodal electrode). In the sham group, stimulation was terminated after 30 seconds. Depressive symptoms were assessed using the Montgomery Asberg Depression Rating Scale (MADRS) conducted by blinded, trained psychologists at seven time points: baseline (BL), training weeks1–4, post session and three-month follow-up (FU). The study followed a randomized, sham controlled, between-subjects design. The experimenter was not blinded. Of note however, MADRS raters as well as participants were blinded. To analyze the effect on MADRS scores, a linear mixed-effects model was conducted, comprising the factors group [sham (= reference), 1mA, 2mA], week (BL, training weeks 1–4, post), group × week and for random effects intercepts and by session random slopes for subjects: ∼1 + week | subject. The model showed a significant effect of week, demonstrating a considerable reduction of MADRS scores over the course of the training from BL to post (Fig. 1). The lack of significant interaction effects for 1mA [t (51) = 0.09, p = .946, B = 0.04, SE = 0.55] and 2mA [t (51) = 0.22, p = .830, B = 0.12, SE = 0.55] indicates that the reduction of MADRS scores in the active tDCS groups was not different to the sham group. Two ANCOVAs, each comprising the two-level factor group (sham vs. 1mA, sham vs. 2mA) and the covariate MADRS BL score, showed no significant effect of the factor group for sham vs. 2mA F (2, 28) = 0.155, p = .679, ηp2 = .006 but a marginal significant effect of group for sham vs. 1 mA F (2, 29) = 3.281, p = .080, ηp2 = .102 on change of MADRS scores from BL to FU: 1mA M = -18.29, SD = 8.84, sham M = -12.93, SD = 11.51. These results do not support the concept of a synergistic effect of tDCS and CCT in the treatment of MDD. Considering previous studies demonstrating antidepressant efficacy of tDCS for the treatment of MDD (for a review see Ref. [[3]Razza L.B. Palumbo P. Moffa A.H. Carvalho A.F. Solmi M. Loo C.K. et al.A systematic review and meta-analysis on the effects of transcranial direct current stimulation in depressive episodes.Depress Anxiety. 2020; 37: 594-608https://doi.org/10.1002/da.23004Crossref PubMed Scopus (32) Google Scholar]), most likely specific design characteristics are responsible for the lack of difference between active and sham tDCS. First, in contrast to previous studies, days of stimulation alternated with stimulation-free days. Although this intermitted schedule has been found to promote neuroplasticity [[9]Weller S. Nitsche M.A. Plewnia C. Enhancing cognitive control training with transcranial direct current stimulation: a systematic parameter study.Brain Stimul. 2020; 13: 1358-1369https://doi.org/10.1016/j.brs.2020.07.006Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar,[10]Ruf S.P. Fallgatter A.J. Plewnia C. Augmentation of working memory training by transcranial direct current stimulation (tDCS).Sci Rep. 2017; 7: 876https://doi.org/10.1038/s41598-017-01055-1Crossref PubMed Scopus (82) Google Scholar], this approach may have not been intensive enough for MDD patients. Second, to allow for a better understanding of the relevant mechanisms and based on previous positive results [[9]Weller S. Nitsche M.A. Plewnia C. Enhancing cognitive control training with transcranial direct current stimulation: a systematic parameter study.Brain Stimul. 2020; 13: 1358-1369https://doi.org/10.1016/j.brs.2020.07.006Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar,[10]Ruf S.P. Fallgatter A.J. Plewnia C. Augmentation of working memory training by transcranial direct current stimulation (tDCS).Sci Rep. 2017; 7: 876https://doi.org/10.1038/s41598-017-01055-1Crossref PubMed Scopus (82) Google Scholar], we refrained from integrating the right dlPFC in our stimulation protocol. This leaves room for the possibility that cathodal stimulation of the right dlPFC is critical for an antidepressive tDCS effect. Of note, the medium effect sized tendency towards a lower score in the 1mA than the sham group at FU (Fig. 1, Sup. Table 2), resembles similar patterns in previous studies [[4]Segrave R.A. Arnold S. Hoy K. Fitzgerald P.B. Concurrent cognitive control training augments the antidepressant efficacy of tDCS: a pilot study.Brain Stimul. 2014; 7: 325-331https://doi.org/10.1016/j.brs.2013.12.008Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar,[5]Brunoni A.R. Boggio P.S. De Raedt R. Benseñor I.M. Lotufo P.A. Namur V. et al.Cognitive control therapy and transcranial direct current stimulation for depression: a randomized, double-blinded, controlled trial.J Affect Disord. 2014; 162: 43-49https://doi.org/10.1016/j.jad.2014.03.026Crossref PubMed Scopus (139) Google Scholar] that found significant differences between active and sham tDCS not directly after training, but only at FU. Moreover, in accordance with previous studies [[7]Siegle G.J. Ghinassi F. Thase M.E. Neurobehavioral therapies in the 21st century: summary of an emerging field and an extended example of cognitive control training for depression.Cognit Ther Res. 2007; 31: 235-262https://doi.org/10.1007/s10608-006-9118-6Crossref Scopus (311) Google Scholar], showing beneficial effects of PASAT training alone on depressive symptoms, we can observe a substantial improvement in depressive symptoms across all groups in our study, which, at least in parts, is likely to be based on PASAT training effects. This aspect is most important since a small to medium effect of tDCS might have been obscured by a more prominent PASAT effect. Taken together, our study does not add evidence for a synergistic antidepressive effect of tDCS in combination with CCT. However, modifications in treatment schedule or stimulation parameter might improve efficacy. In consideration of promising results of other studies our findings may help to inform future research on optimizing protocols for effective brain stimulation treatment of MDD. This work was supported by the GCBS research consortium (FKZ 01EE1403D awarded to CP) funded by the German Federal Ministry of Education and Research .