Transcranial Alternating Current Stimulation (tACS) and Its Role in Schizophrenia: A Scoping Review

Schizophrenia is a severe mental disorder marked by positive symptoms (delusions, hallucinations, disorganization), negative symptoms, cognitive deficits, and functional impairment, affecting about 1% of the population. While antipsychotics remain first-line and are recommended long-term with psychosocial interventions, they have key limitations: nonresponse or partial response in a large subset, limited effects on negative and cognitive symptoms, and significant adverse effects (e.g., EPS, hyperprolactinemia, weight/metabolic issues). These limitations motivate exploration of neuromodulation approaches such as transcranial alternating current stimulation (tACS), a noninvasive technique delivering sinusoidal alternating current via scalp electrodes to modulate neural oscillations. Key stimulation parameters include current amplitude, frequency, phase, duration, and montage. tACS is hypothesized to influence brain function by entraining endogenous neural oscillations and inducing neuroplastic after-effects via mechanisms like spike-timing-dependent plasticity. In schizophrenia, frequency- and region-specific abnormalities in oscillations are reported: reduced alpha in prefrontal/parietal regions (implicating top-down regulation), deficits in frontal theta linked to working memory, and aberrant gamma oscillations and synchrony related to excitatory–inhibitory imbalance and negative/cognitive symptoms. Accordingly, alpha tACS has been targeted to reduce positive symptoms (e.g., hallucinations/delusions via TPJ and mPFC), and theta/gamma tACS to improve cognitive and negative symptoms through the frontoparietal network. Given this oscillatory framework, the review aims to synthesize protocols, clinical and neurobiological effects, and safety of tACS in schizophrenia.

The paper contextualizes schizophrenia as a disorder of abnormal neural oscillations and summarizes prior evidence linking oscillatory bands to symptom domains: reduced alpha activity relates to positive symptoms and impaired top-down control; frontal theta deficits correlate with working memory impairment; gamma abnormalities (reduced task-related gamma and synchrony) are associated with negative and cognitive symptoms, while increased gamma relates to positive symptoms. It notes emerging translational work with tACS to entrain these rhythms and references a prior review on tACS in psychiatry, highlighting that the application to schizophrenia has expanded primarily over the last five years. The authors also discuss mechanistic literature on entrainment, Arnold’s tongue (amplitude–frequency entrainment range), cross-frequency coupling, and neuroplastic after-effects as bases for therapeutic effects of tACS.

Design: Scoping review following PRISMA guidelines. Databases/registries: MEDLINE, Scopus, and WHO International Clinical Trials Registry Platform (ICTRP). Search strategy: ((tACS [Title/Abstract]) OR (transcranial alternating current stimulation [Title/Abstract])) AND (schizophrenia [Title/Abstract]). Last search date: October 15, 2022. Inclusion criteria: Original studies with published results in English investigating the effect of tACS in patients with schizophrenia. Study selection: Of 59 records after duplicates removed, 45 were excluded (reviews, non-schizophrenia populations, unrelated to tACS, or registered trials without results). Fourteen studies were included after full-text assessment, including two conference abstracts (one with accessible master’s thesis). Data extracted: tACS protocols (montage, frequency, intensity, phase, session number/duration, state-dependence), clinical and neurobiological outcomes, and safety/adverse effects. The authors conducted screening by two reviewers with consensus resolution. One trial with unpublished peer-reviewed results was also included.

- Corpus: 14 studies included; 8 clinical trials (including 4 double-blind RCTs), 4 case reports, and 2 case series. Sample sizes ranged from 1 to 36. - Target domains and protocols: - Positive symptoms: Typically alpha (10 Hz), 2 mA, 20 min, twice daily for 5 days, targeting left DLPFC and left TPJ for auditory hallucinations, or mPFC–vertex for delusions; some continuation protocols delivered weekly 40-min sessions up to 20 sessions. - Negative symptoms: Theta (4.5–6 Hz) or gamma (40 Hz), 2 mA, over bilateral DLPFC or frontoparietal networks; durations 10–20 min per session across 10–20 sessions. - Cognitive/working memory: Theta or gamma tACS over left DLPFC with contralateral/right supraorbital or parietal placement; often administered online during working memory tasks (n-back, dual n-back, cDSST); several single-session crossover studies. - Phase: Where reported, in-phase (0°); no DC offsets (no otDCS). - State dependence: Cognitive/negative symptom studies often used online task engagement; positive symptom studies used resting/relaxed state (e.g., video viewing). - Efficacy: - Auditory hallucinations/delusions: An RCT reported improvement in hallucinations with alpha tACS and associated enhancement in alpha oscillations, connectivity, and ASSR, though superiority over sham/tDCS was not established, likely due to small sample size. A case reported improvement with weekly alpha tACS, but a larger subsequent RCT did not replicate clinical benefits. An open-label study targeting mPFC showed significant and durable (≥1 month) reduction in delusions. - Negative symptoms: One RCT, two case series, and one case report showed reductions in negative symptoms and improvements in cognition using theta or gamma tACS. - Cognition/working memory: Mixed results—two studies found no change; three reported improvements in working memory and processing speed (notably with theta tACS). - Safety/tolerability: Approximately 1,180 tACS sessions across studies reported only mild, transient adverse effects (scalp sensations, tingling, phosphenes, dizziness, increased sleep depth; occasional diarrhea or muscle pain) and no serious adverse events or discontinuations. Standardized adverse-effect questionnaires were commonly used. - Overall: Evidence is preliminary but promising, with signal for domain-specific benefits (alpha for positive symptoms; theta/gamma for negative and cognitive symptoms) and good tolerability. However, rigorous, larger sham-controlled RCTs are sparse and findings are inconsistent across trials.

The review addresses whether modulating pathological neural oscillations via tACS can improve schizophrenia symptoms. Findings suggest domain-aligned, frequency-specific tACS may ameliorate symptoms consistent with oscillatory pathophysiology: alpha-targeted protocols may reduce positive symptoms by enhancing inhibitory top-down control; theta/gamma protocols may improve working memory and negative symptoms by engaging frontoparietal networks and restoring synchrony. Mechanistic observations (e.g., increased alpha power/connectivity, ASSR changes) support target engagement. Yet, clinical efficacy remains inconsistent, with some RCTs failing to show superiority over sham or tDCS, underscoring small samples, heterogeneous protocols, and state- and montage-dependent factors. The discussion emphasizes optimizing parameters (intensity around 2 mA peak-to-peak for tolerability, session number/frequency, in-phase vs anti-phase, online vs offline stimulation), exploring high-definition montages for focality, and accounting for individual neuroanatomical variability via modeling. Safety appears favorable short-term, but long-term effects require study. Overall, tACS is a plausible, mechanism-informed adjunct for symptom domains not fully addressed by antipsychotics, warranting rigorous trials and biomarker integration.

tACS is a safe, noninvasive neuromodulation method that modulates neural oscillations and can induce neuroplastic after-effects. Early studies in schizophrenia show improvements in aberrant oscillations with corresponding clinical benefits across positive, negative, and cognitive domains, particularly with frequency-targeted protocols. However, evidence remains preliminary due to small, heterogeneous studies and mixed RCT outcomes. Future work should include larger, double-blind, sham-controlled RCTs, individualized protocol optimization (e.g., oscillation-informed targeting, computational modeling, HD-tACS), exploration of novel waveforms and multi-site approaches, and longer follow-up to establish durability and safety.

- Limited number of rigorous trials: few sham-controlled RCTs, many open-label or case designs with small samples. - Heterogeneity of protocols: variability in frequency, montage, session number/duration, and state (online/offline) limits comparability. - Mixed efficacy findings: some RCTs negative or not superior to sham; publication bias cannot be excluded. - Short-term assessments dominate: limited data on long-term safety, durability, and optimal maintenance schedules. - Unclear stand-alone vs adjunctive role: most studies as add-on; effects of concomitant medications not fully controlled; few drug-naïve/free samples. - Individual variability: anatomical/electric field differences likely affect response; limited personalization in included studies.