Further insights into the efficacy and moderators of transcranial alternating current stimulation for working memory

Abstract

This letter offers a critical appraisal of the systematic review and meta-analysis by Hou et al, which examined the effect of theta-band transcranial alternating current stimulation (theta-tACS) on working memory in healthy adults. The authors initially reported a moderate, statistically significant enhancement of working memory performance (Hedges’ g = 0.405), although this effect became non-significant following adjustment for publication bias. This commentary highlights key strengths of the meta-analysis, including its targeted focus on a frequency band theoretically relevant to working memory, comprehensive moderator analyses, and task-specific subgroup comparisons (N-back vs delayed match-to-sample). At the same time, it emphasizes the substantial impact of publication bias, the considerable heterogeneity among included studies, and the unexpected finding that fixed-frequency stimulation protocols outperformed individualized approaches. While uncertainty remains regarding the overall efficacy of theta-tACS, the observed task-specific improvements in N-back performance and the identification of critical stimulation parameters (such as frequency, duration, and stimulation timing relative to task performance) offer valuable direction for protocol refinement. Taken together, this meta-analysis provides an important and cautionary synthesis that reinforces the need for pre-registered, methodologically rigorous studies to establish the cognitive and potential clinical benefits of theta-tACS with greater confidence.

Key Words: Theta-band transcranial alternating current stimulation; Working memory; Meta-analysis; Publication bias; N-back task

Core Tip: The meta-analysis by Hou et al on theta-band transcranial alternating current stimulation (theta-tACS) for working memory in healthy adults reveals a complex picture. An initial moderate effect was nullified after correcting for significant publication bias, urging caution in interpreting efficacy. However, the study's key contribution lies in its detailed moderator analysis. It found that theta-tACS significantly enhances performance on N-back tasks, but not delayed match-to-sample tasks. Furthermore, the effectiveness in N-back tasks was moderated by stimulation parameters like frequency (fixed > personalized) and duration. These nuanced findings are crucial for designing future, more targeted transcranial alternating current stimulation protocols for both cognitive enhancement and potential clinical applications in psychiatric disorders with working memory deficits.

TO THE EDITOR

Working memory, the cognitive system responsible for the temporary storage and manipulation of information, is fundamental to higher-order cognition and supports key functions such as reasoning, problem-solving, and language comprehension[1,2]. Deficits in working memory are recognized as a transdiagnostic hallmark across numerous psychiatric and neurological disorders, including schizophrenia, major depressive disorder, and attention-deficit/hyperactivity disorder. These widespread impairments underscore the value of working memory as a critical therapeutic target[3]. Neurophysiologically, working memory processes are closely linked to synchronized neural oscillations, with theta-band activity (4-8 Hz), particularly within frontoparietal networks, playing a central role in organizing and coordinating neural information processing[4].

This framework has generated substantial interest in non-invasive brain stimulation technologies that directly modulate oscillatory dynamics. Transcranial alternating current stimulation (tACS) has emerged as a promising modality because of its frequency-specific entrainment capabilities, which allow modulation of endogenous oscillations in patterns associated with targeted cognitive functions[5]. When low-intensity sinusoidal electrical current is applied at a task-relevant frequency such as theta, tACS is hypothesized to enhance the power and coherence of the stimulated rhythm, thereby potentially improving working memory performance.

Despite this theoretical rationale, empirical findings on the efficacy of theta-tACS for working memory enhancement have been inconsistent and disputed. The literature exhibits substantial heterogeneity, with some studies demonstrating significant behavioral improvements and others reporting no measurable effect[6]. This variability is likely attributable to differences in stimulation parameters, including frequency, intensity, duration, and electrode montage, as well as variability in task paradigms[6]. Against this backdrop, the systematic review and meta-analysis by Hou et al[7] provides a timely and comprehensive synthesis of the current evidence. This letter critically appraises their work, evaluates its methodological rigor, and considers the implications of its findings for advancing the field of cognitive neuromodulation.

Comparison with existing literature

The meta-analysis by Hou et al[7] is positioned within a rapidly expanding yet contentious body of tACS research. Prior meta-analyses investigating the effects of tACS on working memory have produced mixed and often inconclusive findings. Recent comprehensive analyses that pooled results across diverse stimulation frequencies (alpha, beta, gamma, theta) reported very small or negligible overall effects[8], or effects that were rendered non-significant once publication bias was considered[9]. These inconsistent outcomes highlight a key limitation of earlier work. By collapsing across multiple oscillatory frequencies, previous reviews may have obscured frequency-specific effects. Given the functional segregation of neural oscillations, it is neurobiologically plausible that only stimulation within a rhythm directly implicated in working memory processes, specifically the theta band, would elicit measurable behavioral enhancement.

Hou et al[7] make a notable contribution by being among the first to restrict their analysis exclusively to theta-band stimulation. This focused approach represents a significant conceptual advance, as it aligns with evidence that neuromodulatory effects are highly specific both to the cognitive domain under investigation and to the neural oscillatory mechanisms engaged during task performance.

Additionally, the authors addressed another critical gap in the field by conducting separate meta-analyses for different working memory paradigms, specifically the N-back and delayed match-to-sample (DMTS) tasks. Prior research indicates that the effects of tACS may vary substantially based on task demands[10]. The N-back task engages executive functions such as active updating and manipulation, whereas the DMTS task primarily assesses maintenance and recognition processes. By disentangling these paradigms, Hou et al[7] were able to evaluate whether theta-tACS differentially modulates these distinct cognitive components. Their finding of significant benefits in N-back performance but no detectable effects in DMTS tasks provides important nuance that was absent from earlier meta-analyses. It further suggests that theta-tACS may preferentially enhance the more executively demanding aspects of working memory.

Critical appraisal of the study

The methodology employed by Hou et al[7] is rigorous and consistent with PRISMA guidelines for systematic reviews and meta-analyses. The literature search was comprehensive, and the study selection procedures were clearly delineated. A notable methodological strength is the use of robust variance estimation to account for statistical dependency among multiple effect sizes derived from individual studies, an issue that is often overlooked in neuromodulation meta-analyses. Additionally, the inclusion of pre-specified moderator analyses and a thorough evaluation of publication bias further reflects strong statistical planning and transparency.

The results, however, convey a nuanced and cautionary message. The initially observed moderate effect size for theta-tACS on working memory performance was eliminated after applying the trim-and-fill procedure to correct for publication bias (adjusted Hedges’ g = 0.082, 95%CI: -0.052 to 0.217). This is a critically important observation as it implies a likely skew in the published literature toward positive findings and indicates the presence of unpublished studies reporting null effects. These findings are aligned with broader concerns regarding publication bias within the brain stimulation field and demonstrate the necessity of cautious interpretation when evaluating uncorrected meta-analytic results. The authors’ transparency in reporting this outcome strengthens the credibility of the work.

Despite the absence of a significant overall effect following bias correction, the moderator analyses represent the most informative contribution of the study. The identification of significant improvement in N-back performance (Hedges’ g = 0.463) but not DMTS performance provides compelling evidence for task-specific effects of theta-tACS. The detailed subgroup analyses within the N-back literature yielded several important insights (Table 1). Fixed-frequency protocols (for example, 6 Hz) were found to be more effective than protocols employing individually determined theta frequencies, a counterintuitive finding that suggests either limitations in current personalization methods or that fixed-frequency stimulation may better target relevant oscillatory dynamics in working memory. Additionally, online stimulation during task performance produced stronger behavioral benefits than offline stimulation, supporting the hypothesis that tACS modulates cognition primarily through real-time entrainment of ongoing neural activity rather than through lasting neuroplastic changes from single sessions. A positive dose-response relationship was also observed, with longer stimulation durations associated with larger effect sizes.

Table 1 Identifying key moderators of theta-band transcranial alternating current stimulation efficacy on N-back performance.

Moderator variable	Category/relationship	Effect on working memory performance
Stimulation protocol	Fixed frequency (e.g., 6 Hz)	> Personalized frequency
Timing of stimulation	Online (during task)	> Offline (before task)
Stimulation duration	Longer duration	Larger effect size (positive relationship)
Task paradigm	N-back	> Delayed match-to-sample

The authors’ interpretation of these moderator patterns is thoughtful and neurobiologically grounded. They appropriately emphasize that different working memory tasks engage distinct cognitive and neural processes that may vary in their susceptibility to theta modulation. Their mechanistic discussion, including the potential roles of immediate network synchronization vs spike-timing-dependent plasticity, provides a valuable conceptual framework for guiding future experimental designs.

Strengths and limitations of the study

The meta-analysis by Hou et al[7] demonstrates considerable methodological rigor and conceptual precision. First, its exclusive focus on the theta band represents a clear advancement over prior meta-analyses that aggregated stimulation effects across heterogeneous frequency ranges. Second, the separate analyses of N-back and DMTS tasks provide critical insight into the task-specific nature of tACS effects on working memory. Third, the comprehensive moderator analyses offer valuable, evidence-based guidance for optimizing stimulation parameters in future research. The transparent use of trim-and-fill procedures to assess and adjust for publication bias further strengthens the validity of the conclusions and sets a commendable standard for reporting in this field. In addition, the incorporation of robust variance estimation to account for dependent effect sizes enhances the accuracy of the pooled effect estimates.

Despite these strengths, several important limitations must be acknowledged. Foremost, the substantial publication bias identified raises concerns regarding whether a true overall effect of theta-tACS on working memory has been reliably demonstrated. Significant statistical heterogeneity was also observed across included studies, indicating considerable variability in outcomes even when stimulation frequency and task type were controlled. Although the moderator analyses accounted for some of this heterogeneity, a notable proportion remains unexplained. Furthermore, many of the underlying studies exhibited moderate to high risk of bias, particularly with respect to blinding of participants and personnel, which could artificially inflate reported effects. Finally, some subgroup analyses were based on a limited number of studies, reducing statistical power and necessitating cautious interpretation of those findings.

Clinical implications and future directions

The clinical implications of this meta-analysis are multifaceted. Following correction for publication bias, the absence of a significant overall effect underscores the need for caution in translating theta-tACS to clinical practice for broad working memory enhancement. At present, the evidence supporting a robust and transferable effect remains insufficient. However, the positive and task-specific findings for the N-back paradigm provide a promising direction for future inquiry. These results suggest that theta-tACS may demonstrate efficacy under carefully optimized and context-specific conditions rather than functioning as a universal cognitive enhancer.

For researchers, this study provides an evidence-based framework for designing subsequent tACS investigations. First, future research should prioritize task specificity by selecting working memory paradigms that align with the cognitive processes most likely to benefit from theta-band modulation. The N-back task appears particularly suitable given its reliance on executive updating processes.

Second, protocol optimization is essential. Based on the moderator analyses, stimulation approaches aimed at improving N-back performance should consider online delivery during task engagement, the use of fixed frequencies near 6 Hz, and longer stimulation durations, while also examining potential non-linear dose-response relationships.

Third, addressing publication bias is a critical priority. Pre-registration of tACS studies and publication of null results are needed to support a more accurate and complete evidence base for future syntheses.

Fourth, mechanistic research is warranted to move beyond behavioral outcomes. Integrating theta-tACS with neuroimaging modalities such as electroencephalography or functional magnetic resonance imaging will allow direct assessment of target engagement and elucidation of how modulation of frontoparietal network dynamics translates to cognitive enhancement.

Fifth, cautiously advancing optimized protocols toward clinical application will require trials in patient populations to determine whether the observed benefits extend beyond healthy adults and produce clinically meaningful improvements. Additionally, systematic comparisons with other neuromodulation approaches, including transcranial direct current stimulation and repetitive transcranial magnetic stimulation, will be necessary to evaluate relative efficacy and practicality for cognitive remediation.

Finally, future studies should investigate the role of individual differences, such as age, sex, baseline cognitive performance, and neuroanatomical variability, as these factors may critically influence responsiveness to tACS and help explain persistent heterogeneity in outcomes.

CONCLUSION

The meta-analysis by Hou et al[7] offers a methodologically rigorous and highly informative synthesis of existing evidence regarding theta-tACS for working memory enhancement. By demonstrating that the initially observed moderate effect size is likely inflated by substantial publication bias, their findings appropriately temper early enthusiasm for the widespread application of theta-tACS. Importantly, the nuanced analytical approach advances the field beyond the basic question of whether theta-tACS is effective toward a more refined understanding of the conditions under which it may yield measurable benefits. The study provides compelling evidence of enhancement specifically in executive components of working memory, as reflected in N-back task performance, and identifies critical stimulation parameters that influence treatment response. As such, this work functions not only as a necessary reality check but also as a strategic guide for future development. It encourages the adoption of more rigorous, mechanistically grounded methodologies to facilitate the translation of theta-tACS into reliably effective cognitive neuromodulation interventions.