Schizophrenia, a severe mental disorder affecting approximately 1% of the population, is characterized by delusions, hallucinations, disorganized thinking, negative symptoms, and cognitive impairments. While antipsychotic medications remain the primary treatment, they have limitations including treatment resistance, suboptimal effects on negative and cognitive symptoms, and significant side effects. Neuromodulation techniques, such as transcranial alternating current stimulation (tACS), offer a potential alternative or adjunct treatment. tACS is a non-invasive brain stimulation technique that uses alternating electric currents to modulate neuronal oscillations. The technique involves various parameters: current amplitude (generally 0.5-2 mA), frequency (0.5-80 Hz), phase difference (0-360°), and duration of stimulation, along with electrode placement. The mechanism of action is believed to involve entrainment of endogenous neural oscillations and inducing neuroplasticity. Abnormalities in neural oscillations are implicated in schizophrenia, with deficits in alpha, theta, and gamma rhythms reported across various brain regions. The application of tACS aims to correct these abnormalities, potentially alleviating associated symptoms. This review aimed to systematically examine the existing literature on tACS in schizophrenia to evaluate its clinical utility and safety.

The introduction extensively reviews the existing literature on schizophrenia treatment limitations and the rationale for exploring neuromodulation techniques, specifically tACS, as a potential therapeutic intervention. It discusses the pathophysiology of schizophrenia focusing on the role of neural oscillations and highlights how tACS, by modulating these oscillations, could offer a novel approach to treat schizophrenia's various symptoms. The existing literature establishes that abnormal neural oscillations are a hallmark of schizophrenia and suggests targeting these oscillations to improve symptoms.

This scoping review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. A systematic literature search was conducted in MEDLINE, Scopus, and the WHO International Clinical Trials Registry Platform (ICTRP) using keywords related to tACS and schizophrenia. The search was last performed on October 15, 2022. Initially, 59 publications were identified, with 45 excluded due to being review articles, not involving schizophrenia patients, being unrelated to tACS, or lacking published results. The remaining 14 studies, including 8 clinical trials (4 double-blind, randomized controlled trials), 4 case reports, and 2 case series, were reviewed in full text. The review assessed the tACS protocols, clinical and neurobiological outcomes, and safety profiles of these studies.

Fourteen studies were included in the review, with varying sample sizes (1-36 participants) and clinical profiles. Studies targeted specific symptom domains, such as treatment-resistant negative symptoms, delusions, or auditory hallucinations, or focused on cognitive deficits. Stimulation parameters varied across studies, with alpha tACS (10 Hz) primarily used to target positive symptoms (hallucinations and delusions) and theta/gamma tACS targeting negative and cognitive symptoms. Electrode placement also varied, but frequently involved the dorsolateral prefrontal cortex (DLPFC), temporoparietal junction (TPJ), and medial prefrontal cortex. Session duration and frequency were inconsistent. Most studies reported good tolerability with transient, mild side effects such as scalp pain, itching, tingling, or phosphenes. The studies yielded mixed results. While some showed promising reductions in hallucinations and delusions with alpha tACS and improvements in negative and cognitive symptoms with theta and gamma tACS, others, including a randomized controlled trial targeting hallucinations, did not replicate these positive findings. The differences in effect size may be due to small sample sizes.

The review's findings partially support the hypothesis that tACS can modulate abnormal neural oscillations associated with schizophrenia symptoms. The efficacy of tACS seems to depend on the targeted frequency and brain region, with alpha tACS potentially beneficial for positive symptoms, and theta and gamma tACS for negative and cognitive symptoms. However, the inconsistencies across studies highlight the need for larger, more rigorous trials. The lack of a consistent, optimal tACS protocol underscores the need for further research to optimize stimulation parameters and identify potential biomarkers to predict individual responses to tACS. Several factors including inter-individual variability in neuroanatomy, the influence of medication, the optimal number of sessions and session duration requires further investigation.

tACS is a safe, non-invasive neuromodulation technique with potential for treating schizophrenia. Preliminary findings suggest improvements in various symptom domains, but more robust, large-scale, sham-controlled randomized controlled trials are necessary to validate these results. Future research should focus on optimizing stimulation parameters, exploring the use of high-definition tACS, investigating individualised protocols based on neuroimaging data, and examining long-term efficacy and safety. Further exploration of novel tACS approaches such as temporal interferential stimulation, amplitude-modulated tACS, and transcranial electrical theta burst stimulation, are also warranted.

The review's limitations include the small number of rigorous studies available, heterogeneity in study designs and protocols, and relatively small sample sizes, hindering the ability to draw definitive conclusions about the efficacy of tACS in treating schizophrenia. The small sample size and inconsistent stimulation protocols across studies limited the ability to robustly establish the efficacy and optimal parameters of tACS for different symptom domains. The majority of the included studies were either case reports, case series, or open-label trials, which may have introduced bias into the results.