Fatemeh Gholamali Nezhad ¹ Josh Martin ¹ Vanessa K. Tassone ^1,2 Alyssa Swiderski ¹ Ilya Demchenko ^1,2,3 Somieya Khan ¹ Hamzah E. Chaudhry ¹ Annalisa Palmisano ^4,5 Emiliano Santarnecchi ⁴ Venkat Bhat ^1,2,3,6,7*

• ¹ Other, Toronto, Canada
• ² Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
• ³ Institute for Biomedical Engineering, Science, and Technology (iBEST), Keenan Research Center for Biomedical Science, St. Michael’s Hospital – Unity Health Toronto, Toronto, Ontario, Canada
• ⁴ Other, Boston, United States
• ⁵ Chair of Lifespan Developmental Neuroscience, Technical University Dresden, Dresden, Germany
• ⁶ Neuroscience Research Program, St. Michael’s Hospital – Unity Health Toronto, Toronto, Ontario, Canada
• ⁷ Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

Background: Transcranial alternating current stimulation (tACS) alters cortical excitability with low-intensity alternating current and thereby modulates aberrant brain oscillations. Despite the recent increase in studies investigating the feasibility and efficacy of tACS in treating neuropsychiatric disorders, its mechanisms, as well as optimal stimulation parameters, are not fully understood. Objectives: This systematic review aimed to compile human research on tACS for neuropsychiatric disorders to delineate typical treatment parameters for these conditions and evaluate its outcomes. Methods: A search for published studies and unpublished registered clinical trials was conducted through OVID (MEDLINE, PsycINFO, and Embase), ClinicalTrials.gov, and the International Clinical Trials Registry Platform. Studies utilizing tACS to treat neuropsychiatric disorders in a clinical trial setting were included. Results: In total, 783 published studies and 373 clinical trials were screened; 53 published studies and 70 clinical trials were included. Published studies demonstrated a low risk of bias, as assessed by the Joanna Briggs Institute Critical Appraisal Tools. Neurocognitive, psychotic, and depressive disorders were the most common disorders treated with tACS. Both published studies (58.5%) and registered clinical trials (52%) most commonly utilized gamma frequency bands and tACS was typically administered at an intensity of 2 mA peak-to-peak, once daily for 20 or fewer sessions. Although the targeted brain locations and tACS montages varied across studies based on the outcome measures and specific pathophysiology of the disorders, the dorsolateral prefrontal cortex (DLPFC) was the most common target in both published studies (30.2%) and registered clinical trials (25.6%). Across studies that published results on tACS outcome measures, tACS resulted in enhanced symptoms and/or improvements in overall psychopathology for neurocognitive (all 11 studies), psychotic (11 out of 14 studies), and depressive (7 out of 8 studies) disorders. Additionally, 17 studies reported alterations in the power spectrum of the electroencephalogram around the entrained frequency band at the targeted locations following tACS. Conclusion: Behavioral and cognitive symptoms have been positively impacted by tACS. The most consistent changes were reported in cognitive symptoms following gamma-tACS over the DLPFC. However, the paucity of neuroimaging studies for each neuropsychiatric condition highlights the necessity for replication studies employing biomarker- and mechanism-centric approaches.