Transcranial alternating current stimulation (tACS) has emerged as a promising noninvasive brain stimulation technique for treating neuropsychiatric disorders. Unlike transcranial direct current stimulation, tACS employs sinusoidal, biphasic alternating current at specific frequencies to modulate brain oscillatory activity with enhanced frequency selectivity and minimal sensory side effects. This innovative approach offers significant advantages, including safety, cost-effectiveness, and resistance to interference, positioning it as a potential breakthrough in neuromodulatory interventions for brain-related diseases. This review, led by Professor Hongxing Wang, was published in Volume 139, Issue 7, of the Chinese Medical Journal on April 05, 2026.
The therapeutic mechanisms of tACS involve four pathways that restore brain function. It regulates neural oscillations across theta (4–8 Hz), alpha (8–13 Hz), beta (13–30 Hz), and gamma (30–100 Hz) bands, correcting abnormal rhythms. Theta modulates memory and emotion, alpha regulates anxiety and attention, beta aids motor control and working memory, while gamma improves cognition. Second, tACS induces synaptic plasticity via long-term potentiation and depression, driven by spike-timing-dependent plasticity and NMDA receptors, creating enduring changes. Third, it modulates neurotransmitter release, including serotonin, norepinephrine, dopamine, and β-endorphin, which are key to emotion, sleep, and pain. Fourth, tACS enhances brain network connectivity between the prefrontal cortex and limbic system and strengthens structural links through white matter modulation.
Clinical applications have demonstrated encouraging results across multiple neuropsychiatric conditions. For major depressive disorder, 77.5 Hz tACS applied to the prefrontal cortex and bilateral mastoids at 15 mA has shown significant antidepressant effects in randomized controlled trials, particularly demonstrating acute therapeutic benefits in treatment-resistant cases when administered twice daily. Combination therapy with low-dose escitalopram further enhances efficacy through the reduction of left frontal alpha power. In schizophrenia, gamma-tACS targeting the dorsolateral prefrontal cortex alleviates negative symptoms and cognitive impairment, while alpha-tACS reduces auditory hallucinations by stimulating the temporoparietal junction, and theta-tACS improves working memory and attention performance.
Patients with obsessive-compulsive disorder benefit from personalized high-definition tACS at beta-gamma frequencies over the orbitofrontal cortex, with substantial symptom reduction persisting for at least three months through increased local activity and decreased dopamine levels. In Alzheimer's disease, 40 Hz gamma-tACS enhances episodic memory and functional connectivity between the default mode network and hippocampus, while potentially serving as a diagnostic biomarker to distinguish mild cognitive impairment from dementia and predict progression risk. Notably, non-responders to gamma-tACS may indicate imminent conversion to Alzheimer's disease.
In Parkinson's disease, personalized tACS protocols based on individual electroencephalography (EEG) profiles improve both motor symptoms, including tremor and bradykinesia, and cognitive performance. Stroke rehabilitation utilizes gait-synchronized tACS combined with neuromuscular electrical stimulation to enhance walking speed and motor recovery, while theta-tACS paired with speech therapy improves language performance in post-stroke aphasia. Additionally, 77.5 Hz stimulation shows efficacy for chronic insomnia by improving sleep quality and duration, particularly in elderly patients, and for migraine without aura by increasing β-endorphin and serotonin levels to reduce attack frequency and severity.
Treatment efficacy depends on three critical factors requiring careful optimization. Stimulation parameters, including frequency, intensity, phase, duration, and session number, must be tailored to specific conditions, with higher intensities (up to 15 mA) potentially reaching deeper brain structures like the hippocampus and amygdala. Target selection guided by functional neuroimaging or high-density EEG ensures accurate localization of abnormal neural oscillations. Individual patient characteristics such as age, disease severity, illness duration, brain anatomy, and baseline neural activity necessitate personalized approaches, with closed-loop systems enabling real-time parameter adjustment based on EEG monitoring.
Despite promising findings, significant challenges remain in translating tACS to widespread clinical practice. Current evidence relies heavily on small-scale feasibility studies, case reports, and single-center trials with limited sample sizes. The field requires large-scale, multicenter, randomized controlled double-blind trials to establish standardized protocols, optimal stimulation parameters, and long-term safety profiles. Technical limitations, including insufficient spatial resolution and penetration depth, may be overcome by emerging temporal interference stimulation techniques.
Future directions emphasize precision medicine through intelligent closed-loop neuromodulation systems integrating neuroimaging and machine learning algorithms for real-time adaptive stimulation. Multidisciplinary collaboration combining advances in neuroscience, bioengineering, clinical medicine, and computational science will drive technological innovation. As research progresses, tACS is anticipated to become an essential personalized treatment modality for neuropsychiatric disorders, though rigorous scientific validation remains essential for clinical translation and standardization.
Reference
DOI: https://doi.org/10.1097/cm9.0000000000004012
About Hongxing Wang from Capital Medical University
Professor Hongxing Wang is a Chief Physician and Doctoral Supervisor in the Department of Neurology at Xuanwu Hospital, Capital Medical University. He has long been dedicated to clinical and basic research on the early identification and intervention of neuropsychiatric disorders, with a specific focus on neuropsychology and neuromodulation. He has (co-)authored numerous papers as first or corresponding author in high-impact journals such as Brain, Psychotherapy and Psychosomatics, Psychological Medicine, Molecular Psychiatry, and General Psychiatry. Among these, eight papers have an impact factor greater than 10, with total citations exceeding 3,000.
Funding information
This work was supported by the National Natural Science Foundation of China (grant number: 82371490).
Chinese Medical Journal
Literature review
Not applicable
Mechanisms and clinical applications of transcranial alternating current stimulation in the treatment of neuropsychiatric disorders: Current evidence and future directions
5-Apr-2026
The authors declare no conflict of interest.