Augmenting cognitive training with bifrontal tDCS decreases subclinical depressive symptoms in older adults: Preliminary findings

Abstract

Transcranial direct current stimulation (tDCS) applied to the frontal lobe, either in isolation or as augmentation to another treatment, has antidepressant properties in depressed adults [[1]Wang J. Luo H. Schülke R. et al.Is transcranial direct current stimulation, alone or in combination with antidepressant medications or psychotherapies, effective in treating major depressive disorder? A systematic review and meta-analysis.BMC Med. 2021; 19: 319https://doi.org/10.1186/s12916-021-02181-4Crossref PubMed Scopus (3) Google Scholar]. Pairing tDCS with cognitive training (CT) results in additional benefit [[2]Brunoni A.R. Boggio P.S. Raedt R. De et al.Cognitive control therapy and transcranial direct current stimulationfor 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 (151) Google Scholar,[3]Segrave R.A. Arnold S. Hoy K. et al.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 (154) Google Scholar]. This combination is thought to enhance cortical activity of the underlying frontal neural networks to produce antidepressant effects [[4]Jog M.V. Wang D.J.J. Narr K.L. A review of transcranial direct current stimulation (tDCS) for the individualized treatment of depressive symptoms.Personalized Medicine in Psychiatry. 2019; 17–18: 17-22https://doi.org/10.1016/j.pmjp.2019.03.001Crossref PubMed Google Scholar]. However, these studies have primarily targeted depressed adults under age 65 years and less is known about this combination of interventions in older adults, particularly as the combination may affect milder subthreshold depressive symptoms that are both prevalent and associated with negative outcomes [[5]Meeks T.W. Vahia I.V. Lavretsky H. et al.A tune in “a minor” can “b major”: a review of epidemiology, illness course, and public health implications of subthreshold depression in older adults.J Affect Disord. 2011; 129: 126-142https://doi.org/10.1016/j.jad.2010.09.015Crossref PubMed Scopus (350) Google Scholar]. To our knowledge, only one study has investigated tDCS with CT in older adults with subthreshold mood symptoms, finding no benefit [[6]Freidle M. Nilsson J. Lebedev A.V. et al.No evidence for any effect of multiple sessions of frontal transcranial direct stimulation on mood in healthy older adults.Neuropsychologia. 2020; 137107325https://doi.org/10.1016/j.neuropsychologia.2019.107325Crossref PubMed Scopus (2) Google Scholar]. However, several study parameters may have affected findings, including electrode placement (anode: ∼F3, cathode: contralateral supraorbital area), duration of tDCS (25-min), nature of CT (working memory training), and choice of mood scales (Total Mood Disturbance on POMS-2, daily mood question). Thus, we were interested in whether combining bifrontal tDCS with CT would improve depressive symptoms in older adults without a clinical diagnosis of major depressive disorder. As apathy also increases with age, we explored whether this treatment combination had effects on apathy, as no other studies have investigated these symptoms outside of dementia [[7]Nguyen J. Boutoleau-Bretonniere C. Lefaucheur J. et al.Efficacy of transcranial direct current stimulation combined with cognitive training in the treatment of apathy in patients with Alzheimer's disease: study protocol for a randomized trial.Rev Recent Clin Trials. 2018; 13: 319-327https://doi.org/10.2174/1574887113666180416153316Crossref PubMed Scopus (5) Google Scholar]. We are reporting secondary analyses from Ref. [[8]Nissim N.R. O'Shea A. Indahlastari A. et al.Effects of transcranial direct current stimulation paired with cognitive training on functional connectivity of the working memory network in older adults.Front Aging Neurosci. 2019; 11: 1-11https://doi.org/10.3389/fnagi.2019.00340Crossref PubMed Scopus (32) Google Scholar]. Briefly, 30 adults aged 65–89 years in the parent study were randomized to receive active or sham tDCS in combination with CT for 2 weeks (or 10 intervention days). This trial was preregistered in clinicaltrials.gov (NCT02137122), reviewed and approved by the University of Florida, and participants provided their written informed consent prior to the initiation of study procedures. Active tDCS was delivered bifrontally over F3 (cathode) and F4 (anode) for 20-min at 2 mA intensity through two 5 × 7 cm2 saline saturated sponge electrodes (10 ml/sponge) using the Soterix Medical 1 x 1 tDCS clinical trials device (which allowed for triple-blinding: participant, interventionist, and investigators). Sham tDCS received identical set-up procedures with 2 mA stimulation for 30-sec with 30-sec ramp up and down. An 8-component multidomain commercially available computerized CT intervention focusing on attention/processing speed and working memory from Posit Science's Brain HQ suite (www.brainhq.com) was administered for 40-min daily, with the first 20-min being paired with active or sham tDCS. Following completion of the 2-week intervention, a blinding questionnaire was given to participants asking: Q1: Which brain stimulation treatment condition do you believe you received? (Active, Sham/Placebo, Don't know/Unsure), Q2: If you answered “Don't know/Unsure” above, can you please provide your best (or random) guess of the treatment you received anyway? and Q3: On a scale of 0–10, how confident are you that you received (your selection)? Depressive symptoms were assessed with the Beck Depression Inventory-II (BDI-II) at baseline and after completion of the 2-week intervention. To allow room for symptom improvement, for these preliminary analyses we only included participants with a BDI-II cut-off score of 5 or greater, which is considered in the “minimal” range of depression severity. Fifteen non-demented healthy older adults (70.93 ± 5.41 years old, 10 females, 16.40 ± 2.32 years education, MoCA = 27.27 ± 2.34) met this cutoff (8 sham, 7 active). The tDCS conditions did not significantly differ in age, sex, years of education, MoCA scores, or number of completed intervention days (sham: 9.63 ± 0.74, active: 9.71 ± 0.49, t(13) = −0.27, p = 0.40). They also did not significantly differ in baseline BDI-II scores (sham: 11.38 ± 6.44, active: 7.71 ± 2.93, t(13) = 1.38, p = 0.10). There were no differences in sensation ratings/side effects noted before, during, or after stimulation between the active vs. sham groups (p's > 0.05) from the parent sample (as reported in Ref. [[8]Nissim N.R. O'Shea A. Indahlastari A. et al.Effects of transcranial direct current stimulation paired with cognitive training on functional connectivity of the working memory network in older adults.Front Aging Neurosci. 2019; 11: 1-11https://doi.org/10.3389/fnagi.2019.00340Crossref PubMed Scopus (32) Google Scholar]. Likewise, there were no group differences in the parent sample for frequency of endorsement for Active, Sham or Unsure categories, nor were there differences in confidence ratings for whether participants received Active vs. Sham conditions (all p's > 0.05), suggesting that participant blinding was successful. Results indicated the combination of active (and not sham) tDCS with CT was associated with reduced depressive symptoms. Fig. 1 shows the active tDCS group had BDI-II reduction of 2.7 points following the intervention, while the sham tDCS group decreased 1.4 points (ηp2 = 0.18; large effect size). Including covariates (age, sex, education, MoCA scores, and number of completed intervention days) in the model further strengthened this discrepancy (active: decrease of 3.7 points; sham: decrease of 0.51 points; ηp2 = 0.37; larger effect size). We conducted similar analyses in the initial sample using the Apathy Scale (AS; cut-off ≥ 9; 8 sham, 10 active), which was also administered at baseline and post-intervention. The tDCS conditions did not differ in baseline AS scores (sham: 11.75 ± 2.38, active: 11.80 ± 1.99, t(16) = −0.05, p = 0.48). We did not find differences in apathy symptoms over time for either condition, without or with covariate adjustment (see Fig. 1). While preliminary, these results suggest that the combination of bifrontal active tDCS with CT may be a potential method for improving subthreshold depressive (but not apathy) symptoms in older adults via targeting prefrontal neural circuitry and promoting neuroplasticity of the underlying neural network. While baseline BDI-II scores did not significantly differ, the active tDCS group had a lower score than sham, but saw greater improvement in BDI-II scores post-intervention despite having less room for change. It is more difficult to find effects in those with milder compared to more severe depressive symptoms in depression clinical trials; thus, these results are promising. Adequate treatment of subthreshold depressive symptoms may prevent or reduce negative outcomes associated with depressive symptoms in at-risk older adults, including cognitive dysfunction and reduced brain volumes [[9]Szymkowicz S.M. Woods A.J. Dotson V.M. et al.Associations between subclinical depressive symptoms and reduced brain volume in middle-aged to older adults.Aging Ment Health. 2019; 23: 819-830https://doi.org/10.1080/13607863.2018.1432030Crossref PubMed Scopus (15) Google Scholar], as well as specific health conditions [[10]Agustini B. Lotfaliany M. Mohebbi M. et al.Trajectories of depressive symptoms in older adults and associated health outcomes.Nature Aging. 2022; 2: 295-302https://doi.org/10.1038/s43587-022-00203-1Crossref Scopus (1) Google Scholar]. Larger randomized clinical trials are needed to better understand tDCS plus CT antidepressant effects in older adults. Since apathy increases with age, subclinical apathy symptoms may be “normal” and less prone to changes with intervention (and it is when these symptoms crossover threshold to clinically elevated that we see negative relationships with clinical outcomes). In the current study, the range in apathy scores both pre- and post-intervention was restricted (pre: 9 to 15, post: 7 to 17), making it difficult to find an effect. Moreover, in absence of dementia, symptoms of apathy may reflect amotivation rather than a mood disorder and involve dopaminergic pathways and deeper, more subcortical neural circuitry that is not being appropriately targeted with current intervention combination [[11]Husain M. Roiser J.P. Neuroscience of apathy and anhedonia: a transdiagnostic approach.Nat Rev Neurosci. 2018; 19: 470-484https://doi.org/10.1038/s41583-018-0029-9Crossref PubMed Scopus (192) Google Scholar]. Pairing tDCS (likely with different electrode placement) with an intervention targeting reward circuitry and/or with dopaminergic modulation may be more beneficial for apathy and is an interesting focus for future research. None. This work received funding support from the National Institutes of Health / National Institute on Aging ( K01AG050707 and R01AG054077 to AJW), the McKnight Brain Research Foundation , and the University of Florida, Center for Cognitive Aging and Memory Clinical Translational Research and McKnight Brain Institute . SMS is supported by the McKnight Clinical Translational Research Scholarship in Cognitive Aging and Age-Related Memory Loss funded by the McKnight Brain Research Foundation through the American Brain Foundation and the American Academy of Neurology .