Exploring the Mechanism of Action of Transcranial Direct Current Stimulation (tDCS) in the Treatment of Depression
Dr. Leigh Charvet Director of Neuromodulation - NYU Langone
Dr. Charvet leads NYU Langone’s tDCS program, treating conditions such as depression, anxiety, and substance use disorder.
There is an urgent need for new treatment alternatives for depression worldwide. Many people find that antidepressant medications do not fully address their symptoms, and they often come with side effects that can be hard to tolerate. Accessing effective therapies like cognitive behavioral therapy (CBT) is not always feasible due to high costs and limited availability.
Noninvasive brain stimulation (NIBS) therapies are becoming increasingly promising alternatives for treating depression due to both their safety and effectiveness. One approved technique, transcranial magnetic stimulation (TMS), can be effective but is costly. The large machines require patients to repeatedly travel to a site where they can receive daily treatments. While still considered investigational in the U.S., transcranial direct current stimulation (tDCS) offers a more practical alternative as these devices have lower costs and can be mobile for telehealth delivery.
How tDCS Works
tDCS involves passing a low-grade electrical current, usually about two milliamperes (2 mA), through two electrodes placed on the scalp. These electrodes are strategically placed to target specific brain regions. The fundamental mechanism of tDCS is its ability to modulate neuronal activity. When the current passes through the brain, it changes the neuronal membrane potentials, making neurons more or less likely to fire. The electrodes in tDCS are classified as anodal (positive) and cathodal (negative). The anodal electrode typically increases neuronal excitability in the underlying cortex, while the cathodal electrode decreases it. This modulation can alter brain activity in the targeted regions, influencing thoughts, moods, and behaviors. Additionally, tDCS is known to induce mechanisms of neuroplasticity, the brain's ability to reorganize itself by forming new neural connections. tDCS is often used with concurrent brain activities, providing a "boost" to cognitive functions. This synergistic use is common in learning and rehabilitation, where tDCS enhances the effects of specific tasks or exercises performed during stimulation. With different placements of the electrodes and the selection of simultaneous activities during the stimulation, tDCS has been studied as a treatment for a wide range of neurological and psychiatric conditions.
tDCS and Depression
When treating depression, tDCS targets the brain's frontal region in an area called the dorsolateral prefrontal cortex (DLPFC). The DLPFC is a brain region that governs mood regulation and aspects of attention. People with depression often have relatively reduced activation of the left frontal region, and the right frontal region may even be increased in activity, and this corresponds to both the mood and thought patterns that define depression. By modulating neuronal activity, tDCS can facilitate changes in synaptic strength, potentially leading to long-term improvements in mood and cognitive function.
Therefore, the typical tDCS treatment for depression places the anodal electrode on the left side and the cathodal electrode on the right side to restore more balanced neural activity. Enhancing activity in the left DLPFC can improve its connectivity with other regions involved in emotion regulation, such as the amygdala and hippocampus. This improved connectivity can help normalize the brain's response to emotional stimuli, reducing symptoms of depression.
Like all NIBS techniques, the effect of tDCS is cumulative over time, and it must be dosed in enough daily repeated sessions for clinical benefit. For example, most studies showing its effectiveness for depression administer a month of daily sessions or more. This is where its advantage of delivery to people at home becomes especially important for its promise as a solution for depression treatment.
tDCS has the Benefit of Safety and Tolerability
One of the critical advantages of tDCS is its safety profile. The technique is generally well-tolerated, with minor side effects like skin irritation at the electrode sites or a mild tingling sensation during stimulation. These minimal adverse effects make tDCS an attractive option, especially for people who may not tolerate the standard treatment of antidepressant medication. The safety and tolerability of tDCS also make it an appealing alternative for special populations, for instance, children and teens, older adults, and pregnant or breastfeeding women, where there is an especially urgent need for medication alternatives.
What Does the Research Say?
tDCS has been extensively studied for its clinical use, especially over the past decade. Collectively, the treatment of depression is the only use of tDCS that we can conclude from the evidence to be “definitely effective” (Fregni et al. 2021). In fact, the use of tDCS is at least moderately effective in the treatment of depression (Razza) and can have persisting benefits (Razza). However, while collectively supporting its effectiveness, like all treatments of depression, there have been overall mixed results from the clinical trials on tDCS for depression. Some studies show significant benefits, while others report minimal to no effect compared to sham (placebo) treatments. We also don’t yet know if it is most effective in more severe depression or as a standalone or adjunctive treatment. As we know, you need many repeated tDCS sessions for treatment. A significant limitation is that many of the studies have been “under-dosed” because of administering too few treatment sessions to evaluate its effect fully. Another problem in depression research is explicitly challenges to trial design because there is often a strong placebo effect in depression, and also, episodes naturally go into remission with time.
Unknowns and Dosing Challenges
While we know that tDCS can be effective, there are still many unknowns about its optimal use. One clear finding is that "more is better," but we don't yet understand how much more. The optimal "dose" of tDCS in terms of the intensity and duration of stimulation sessions is still unclear. Additionally, the ideal number of "doses" needed over days or weeks to achieve a lasting benefit remains a subject of ongoing research. Also, as we know that pairing tDCS with a therapeutic activity can “boost” its effect through functional targeting, this may become an essential feature of tDCS treatment in depression, for instance, pairing tDCS with behavioral practices that are also known to benefit depression.
A Call for tDCS as an Option for Depression Treatment
tDCS represents a promising therapeutic intervention for depression that deserves placement alongside the standard options of medication and/or therapy. Continued research is essential to optimize treatment protocols and identify patient characteristics that predict the best outcomes, ultimately enhancing the clinical utility of tDCS in managing depression. While the efficacy of tDCS can vary, its potential as an adjunctive treatment and its favorable safety profile make it a valuable tool that should be available now to the many people in urgent need of depression treatment.
Papers Referenced:
uidelines and Secondary Meta-Analysis for the Use of Transcranial Direct Current Stimulation in Neurological and Psychiatric Disorders
Fregni F, El-Hagrassy MM, Pacheco-Barrios K, Carvalho S, Leite J, Simis M, Brunelin J, Nakamura-Palacios EM, Marangolo P, Venkatasubramanian G, San-Juan D, Caumo W, Bikson M, Brunoni AR; Neuromodulation Center Working Group. Evidence-Based Guidelines and Secondary Meta-Analysis for the Use of Transcranial Direct Current Stimulation in Neurological and Psychiatric Disorders. Int J Neuropsychopharmacol. 2021 Apr 21;24(4):256-313. doi: 10.1093/ijnp/pyaa051. PMID: 32710772; PMCID: PMC8059493.
Cognitive effects of repeated sessions of transcranial direct current stimulation in patients with depression
Fregni F, Boggio PS, Nitsche MA, Rigonatti SP, Pascual-Leone A. Cognitive effects of repeated sessions of transcranial direct current stimulation in patients with depression. Depress Anxiety. 2006;23(8):482-4. doi: 10.1002/da.20201. PMID: 16845648.
Follow-up effects of transcranial direct current stimulation (tDCS) for the major depressive episode: A systematic review and meta-analysis
Razza LB, De Smet S, Moffa A, Sudbrack-Oliveira P, Vanderhasselt MA, Brunoni AR. Follow-up effects of transcranial direct current stimulation (tDCS) for the major depressive episode: A systematic review and meta-analysis. Psychiatry Res. 2021 Aug;302:114024. doi: 10.1016/j.psychres.2021.114024. Epub 2021 May 21. PMID: 34058716.
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Great read!