Transcranial alternating current stimulation for the treatment of major depressive disorder: from basic mechanisms toward clinical applications

Non-pharmacological treatment is essential for patients with major depressive disorder (MDD) that is medication resistant or who are unable to take medications. Transcranial alternating current stimulation (tACS) is a non-invasive brain stimulation method that manipulates neural oscillations. In recent years, tACS has attracted substantial attention for its potential as an MDD treatment. This review summarizes the latest advances in tACS treatment for MDD and outlines future directions for promoting its clinical application. We first introduce the neurophysiological mechanism of tACS and its novel developments. In particular, two well-validated tACS techniques have high application potential: high-definition tACS targeting local brain oscillations and bifocal tACS modulating interarea functional connectivity. Accordingly, we summarize the underlying mechanisms of tACS modulation for MDD. We sort out the local oscillation abnormalities within the reward network and the interarea oscillatory synchronizations among multiple MDD-related networks in MDD patients, which provide potential modulation targets of tACS interventions. Furthermore, we review the latest clinical studies on tACS treatment for MDD, which were based on different modulation mechanisms and reported alleviations in MDD symptoms. Finally, we discuss the main challenges of current tACS treatments for MDD and outline future directions to improve intervention target selection, tACS implementation, and clinical validations.