How effective is transcranial direct current stimulation?
Authors: Stephane Perrey
Journal: The Lancet (2024)

Gerrit Burkhardt and colleagues1Burkhardt G Kumpf U Crispin A et al.Transcranial direct current stimulation as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder in Germany (DepressionDC): a triple-blind, randomised, sham-controlled, multicentre trial.Lancet. 2023; 402: 545-554Summary Full Text Full Text PDF Google Scholar reported that the use of transcranial direct current stimulation (tDCS) as an additional treatment to stable selective serotonin reuptake inhibitor pharmacotherapy did not elicit further antidepressant effects in patients with major depressive disorder (MDD). The authors conducted a 6-week, triple-blind, randomised sham-controlled, multicentre trial in patients with MDD to assess the efficacy of tDCS when combined with sertraline. However, the main outcome of this well designed study contributes to an ongoing debate, in connection with which some methodological concerns can be raised. Although non-invasive brain stimulation techniques such as tDCS have established many clinical applications, this field suffers from a major drawback: the absence of a clear understanding of the underlying mechanisms and effects on brain function, in part due to the large variability of experimental protocols, poor specificity of the intervention, and associated lack of reproducibility in treating depression diseases.2Wang J Luo H Schülke R Geng X Sahakian BJ Wang S 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: 319Crossref PubMed Scopus (0) Google Scholar Two fundamental concerns indicated by Burkhardt and colleagues1Burkhardt G Kumpf U Crispin A et al.Transcranial direct current stimulation as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder in Germany (DepressionDC): a triple-blind, randomised, sham-controlled, multicentre trial.Lancet. 2023; 402: 545-554Summary Full Text Full Text PDF Google Scholar are tDCS dose requirements in adult patients for advancing treatment efficacy and the potential efficacy of personalised tDCS methods in depressive disorders. The conventional one-size-fits-all approach used by the authors, with a fixed intensity and duration of tDCS (ie, 2 mA for 30 min) delivered over 24 sessions across individuals, ignores how much current actually reaches the brain in a given individual. First evidence from current flow models showed that, compared with individualised dose control, fixed-dose tDCS yields substantially variable electric field intensities and heterogeneous electric field distribution in the brain across individuals.3Evans C Bachmann C Lee JSA Gregoriou E Ward N Bestmann S Dose-controlled tDCS reduces electric field intensity variability at a cortical target site.Brain Stimul. 2020; 13: 125-136Summary Full Text Full Text PDF PubMed Scopus (90) Google Scholar To overcome this limitation, advances in portable neuroimaging methods outside or inside the clinical setting offer the individual quantification of brain connectivity and haemodynamic and neural physiological states during a tDCS session. Electroencephalography capable of non-invasively measuring the temporal aspects of ongoing neuronal activity and its fluctuations, thereby capturing various parameters of neural oscillations, can be used to guide the optimisation of when and how to stimulate a targeted brain area.4Thut G Bergmann TO Fröhlich F et al.Guiding transcranial brain stimulation by EEG/MEG to interact with ongoing brain activity and associated functions: a position paper.Clin Neurophysiol. 2017; 128: 843-857Crossref PubMed Scopus (176) Google Scholar Complementary to the temporal domain, functional near-infrared spectroscopy allows the examination of activity changes in localised brain regions and networks across the whole brain.5Vergotte G Torre K Chirumamilla VC et al.Dynamics of the human brain network revealed by time-frequency effective connectivity in fNIRS.Biomed Opt Express. 2017; 8: 5326-5341Crossref Scopus (23) Google Scholar Another promising, emerging means for guiding tDCS intervention is the use of machine learning algorithms to provide individual prognostic classification of tDCS treatment (eg, a conventional dosage of 20 min of 2 mA tDCS stimulation over the prefrontal cortices) response with high accuracy, interaction of direction and intensity being the most essential dosing feature for predicting behavioural response.6Albizu A Fang R Indahlastari A et al.Machine learning and individual variability in electric field characteristics predict tDCS treatment response.Brain Stimul. 2020; 13: 1753-1764Summary Full Text Full Text PDF PubMed Scopus (42) Google Scholar Finally, another uncertain and most crucial issue refers to the modality of transcranial electrical stimulation used in the study by Burkhardt and colleagues1Burkhardt G Kumpf U Crispin A et al.Transcranial direct current stimulation as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder in Germany (DepressionDC): a triple-blind, randomised, sham-controlled, multicentre trial.Lancet. 2023; 402: 545-554Summary Full Text Full Text PDF Google Scholar as a neuromodulation method (ie, delivering current at subthreshold stimulation, unable to induce neuronal firing). The potential therapeutic benefit of using transcranial alternating current stimulation (tACS) appears to be considerably greater than that of tDCS, as tACS allows the adjustment of stimulation frequency to adapt to specific disorders or endogenous brain rhythms, with measurable changes in cognition and behaviour in multiple systems.7Wang H Wang K Xue Q et al.Transcranial alternating current stimulation for treating depression: a randomized controlled trial.Brain. 2022; 145: 83-91Crossref PubMed Scopus (0) Google Scholar The study by Burkhardt and colleagues1Burkhardt G Kumpf U Crispin A et al.Transcranial direct current stimulation as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder in Germany (DepressionDC): a triple-blind, randomised, sham-controlled, multicentre trial.Lancet. 2023; 402: 545-554Summary Full Text Full Text PDF Google Scholar proposed stable selective serotonin reuptake inhibitor treatment with additional tDCS (mediating neurochemical and neuroelectric effects, respectively) in MDD in order to act on different levels of biological organisation ranging from the genome to brain networks, targeted as two interconnected mechanisms of action of an antidepressant treatment.8Leuchter AF Hunter AM Krantz DE Cook IA Rhythms and blues: modulation of oscillatory synchrony and the mechanism of action of antidepressant treatments.Ann N Y Acad Sci. 2015; 1344: 78-91Crossref PubMed Scopus (46) Google Scholar Within this context, ultradian oscillatory synchrony was shown to be related to fluctuation in serotonergic tone, suggesting it could play a prominent role in the efficacy of antidepressant medication.9Salomon RM Cowan RL Oscillatory serotonin function in depression.Synapse. 2013; 67: 801-820Crossref PubMed Scopus (0) Google Scholar Hence, manipulation of oscillations in neuronal networks through tACS is warranted, possibly as a more efficient treatment modality for MDD. tACS that delivers synchronised current to the bilateral prefrontal cortex might induce disinhibition of the left frontal cortex to produce positive experiences in patients with MDD.10Riddle J Alexander ML Schiller CE Rubinow DR Frohlich F Reduction in left frontal alpha oscillations by transcranial alternating current stimulation in major depressive disorder is context dependent in a randomized clinical Trial.Biol Psychiatry Cogn Neurosci Neuroimaging. 2022; 7: 302-311Summary Full Text Full Text PDF PubMed Scopus (24) Google Scholar Together, these points suggest the potential benefits of a precision approach with transcranial electrical stimulation, as highlighted by Burkhardt and colleagues, probably using tACS. Such an approach would enable tailoring of both the individual neuroanatomy through structural imaging and computer modelling and the temporal characteristics of stimulation with regard to endogenous oscillatory activity, potentially maximising the efficacy of therapeutic brain stimulation in MDD with personalised dosing. I declare no competing interests. Transcranial direct current stimulation as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder in Germany (DepressionDC): a triple-blind, randomised, sham-controlled, multicentre trialActive tDCS was not superior to sham stimulation during a 6-week period. Our trial does not support the efficacy of tDCS as an additional treatment to SSRIs in adults with MDD. Full-Text PDF