Mechanisms of tDCS: Applications in Research and Practice and Identified Research Gaps

Abstract

Transcranial direct current stimulation is a non-invasive brain stimulation technique increasingly used in both research and practice. This theoretical project explores how different mechanisms – stimulation of the brain (transcranial), stimulation of peripheral nerves [1] (transcutaneous) and changes in blood flow [2] (neurovascular) – each contribute to the effects of tDCS. Understanding how these mechanisms work on its own and together can help make tDCS more effective, safer and better designed.

Current literature shows that tDCS can reduce symptoms in psychiatric conditions such as major depressive disorder or schizophrenia. Neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease and other neurological conditions, such as post-stroke rehabilitation, have shown functional gains after tDCS application. The ageing population demonstrates improvements in motor and cognitive functions. Also, after pain management applications there have been reported reductions in both acute and chronic pain symptoms. Additionally, cognitive neuroscience has used tDCS to modulate perception, learning, and social behavior in healthy individuals, which raises both ethical and methodological concerns.

Despite its wide range of applications,  tDCS remains limited by several unresolved theoretical and methodological challenges. A key issue is the high inter-individual variability in tDCS responses, which are influenced by anatomical factors such as skull thickness, hormonal and gender differences and other personal characteristics [3]. For now, predictive markers and personalized strategies are underdeveloped. Methodological heterogeneity, including variations in electrode placement, intensity and session duration, further undermines reproducibility. Additionally, the dose-response is poorly understood and stimulation beyond certain thresholds can paradoxically reverse intended effects. Computational models used to estimate electric field distribution are rarely validated at physiological or behavioral levels, leaving a gap between theory and outcome. Moreover, most studies asses only short-term effects, while long-term efficacy remains unclear and inconsistent. Importantly, there is notable lack of research how transcranial, transcutaneous and neurovascular mechanisms interact or work together to shape overall effects of tDCS. This theoretical project aims to synthesize current findings into an integrative framework that accounts for these limitations.
By identifying and organizing core mechanistic, methodological and translational gaps, the project provides a foundation for future research to develop more individualized, effective, and reliable tDCS interventions across diverse contexts.

References

[1] L. Van Boekholdt, S. Kerstens, A. Khatoun, B. Asamoah, and M. McLaughlin, “tDCS peripheral nerve stimulation: a neglected mode of action?,” Molecular Psychiatry, vol. 26, no. 2, pp. 456–461, 2021. [Online]. doi: 10.1038/s41380-020-00962-6. [Accessed: May 5, 2025].

[2] D. W. Shin, J. Fan, E. Luu, W. Khalid, Y. Xia, et al., “In vivo modulation of the blood–brain barrier permeability by transcranial direct current stimulation (tDCS),” Annals of Biomedical Engineering, vol. 48, no. 4, pp. 1256–1270, 2020. [Online]. doi: 10.1007/s10439-020-02447-7. [Accessed: May 5, 2025].

[3] S. Madhavan, A. Sriraman, and S. Freels, “Reliability and variability of tDCS induced changes in the lower limb motor cortex,” Brain Sciences, vol. 6, no. 3, p. 26, 2016. [Online]. doi: 10.3390/brainsci6030026. [Accessed: May 5, 2025].