A meta-analysis suggests that tACS improves cognition in healthy, aging, and psychiatric populations

Abstract

Transcranial alternating current stimulation (tACS) has attracted interest as a technique for causal investigations into how rhythmic fluctuations in brain neural activity influence cognition and for promoting cognitive rehabilitation. We conducted a systematic review and meta-analysis of the effects of tACS on cognitive function across 102 published studies, which included 2893 individuals in healthy, aging, and neuropsychiatric populations. A total of 304 effects were extracted from these 102 studies. We found modest to moderate improvements in cognitive function with tACS treatment that were evident in several cognitive domains, including working memory, long-term memory, attention, executive control, and fluid intelligence. Improvements in cognitive function were generally stronger after completion of tACS ("offline" effects) than during tACS treatment ("online" effects). Improvements in cognitive function were greater in studies that used current flow models to optimize or confirm neuromodulation targets by stimulating electric fields generated in the brain by tACS protocols. In studies targeting multiple brain regions concurrently, cognitive function changed bidirectionally (improved or decreased) according to the relative phase, or alignment, of the alternating current in the two brain regions (in phase versus antiphase). We also noted improvements in cognitive function separately in older adults and in individuals with neuropsychiatric illnesses. Overall, our findings contribute to the debate surrounding the effectiveness of tACS for cognitive rehabilitation, quantitatively demonstrate its potential, and indicate further directions for optimal tACS clinical study design.

Fig. 1.. Summary characteristics of tACS studies included in the meta-analysis.

(A) A proportional representation of the brain regions targeted by tACS across the 304 effects in the 102 published studies of the meta-analysis. The left panel shows single-region brain targets, and the right panel describes studies targeting at least two brain regions, including bilateral tACS study designs and phase-dependent multisite high-definition (HD)–tACS study designs. The sizes of the circles over the respective brain regions correspond to the proportion of effects targeting those regions (right inset, scale). The most common targets were bilateral frontal regions (22.4% of all effects examined; right), followed by left frontal regions (12.2% of all effects examined; left). (B) The different stimulation frequencies used and the corresponding proportion of effects are shown. Note that frequencies were entered as a continuous variable in the analysis but are represented here categorically using conventional frequency ranges (slow: <0.5 Hz; delta: 0.5 to 4 Hz; theta: 4 to 8 Hz; alpha: 8 to 12 Hz; beta: 12 to 30 Hz; gamma: 30 to 40 Hz; high-gamma: >40 Hz). Instances when complex phase-amplitude coupled waveforms were used are marked as “coupled.” (C) The proportion of effects in which tACS frequencies were personalized to every individual versus those in which a standardized frequency was used is shown. (D) The proportion of effects in which a tACS condition of interest was compared against an active sham condition versus a passive sham condition is shown. (E) The graph shows the distribution of neuromodulation duration across the examined effects. A total of 20- to 25-min stimulation duration was the most common in the literature. (F) The proportion of effects using conventional tACS versus HD-tACS is shown. (G) The proportion of effects observed in experiments with and without current flow models is shown. (H) The proportion of effects in which the behavioral measurements were made during tACS administration (“online”) versus after tACS had finished (“offline”) is shown. (I) The graph shows the distribution of peak-to-peak modulation intensity across the examined effects. The most popular intensity ranges in the literature were 0.75 to 1 mA and 1.75 to 2 mA.

Fig. 2.. Summary of meta-analysis results.

(A) Box plots and point estimates of outcome-based effects on cognitive function overall (Performance, RT, and clinical symptoms combined) and on Performance and RT-based outcomes separately are shown. (B) Box plots and point estimates for offline and online effects on outcome-based Performance measures are shown. (C) Box plots and point estimates of interaction effects according to the timing of behavioral assessment and use of current flow models (CM) that simulate the flow of electrical current and strength of the electric field in the human brain are shown. Performance, RT measures, and clinical symptoms were combined. (D) Box plots and point estimates of hypothesis-based effects of phase manipulation are shown.“In-phase” represents the improving effect of in-phase synchronization on functional outcome, and “antiphase” represents the disrupting effect of antiphase synchronization on functional outcome. All plots show data before outlier removal. In all plots, individual points represent individual effect size point estimates for each experiment. Box plot center line, median; box plot limits, upper and lower quartiles; whiskers, maximum and minimum values. Error bars around point estimates reflect 95% confidence intervals. Perf, Performance; RT, reaction time; Offline w/o CM, offline effects in experiments without the current flow model; Offline with CM, offline effects in experiments with the current flow model; Online w/o CM, online effects in experiments without the current flow model; Online with CM, online effects in experiments with the current flow model.

Fig. 3.. Forest plots of the effects on All outcomes organized by cognitive domains.

Outcome-based Hedges’ g effect size estimates are represented along with 95% confidence intervals for individual experiments within each cognitive domain and for each cognitive domain overall (total effect) before outlier removal (the black diamond). Experiments identified as outliers within the respective cognitive domains are marked in brown, and the overall effect size after removal of these outliers is indicated by the brown diamond. Note that outlier detection was performed individually for each analysis, so outlier identification may differ between the omnibus and the domain-specific analyses. Sizes of squares reflect the weight attributed to a given experiment by the robust variance estimation procedure, with larger sizes reflecting greater contributions of that experiment to the overall effect size. Experiment names correspond to the list of studies in data file S1.

Fig. 4.. Summary of effects on All outcomes in cognitive domains after outlier removal.

(A) Box plots of outcome-based effect size estimates in cognitive domains after outlier removal are shown. Individual points represent individual effect size point estimates for each experiment within a specific domain. (B) Overall effect size estimates after outlier removal in cognitive domains with the corresponding 95% confidence intervals are shown. Box plot center line, median; box limits, upper and lower quartiles; whiskers, maximum and minimum values. WM, working memory; LTM, long-term memory; Att, attention; EC, executive control; Int, intelligence; ML, motor learning; MM, motor memory.

Fig. 5.. Effects of tACS on healthy older adults and in clinical populations.

(A) Forest plot of outcome-based effect sizes along with 95% confidence intervals for All outcomes in older adults is shown. The overall effect size before outlier removal is indicated by the black diamond. Outlier experiments are highlighted in brown, and the overall effect size after outlier removal is indicated by the brown diamond. Sizes of squares reflect the weight attributed to a given experiment by the robust variance estimation procedure, with larger sizes reflecting greater contributions of that experiment to the overall effect size. Experiment names correspond to the list of studies in data file S1. (B) Box plot of the effects of tACS on All outcomes in healthy older adults before (left) and after (right) outlier removal (OR) is shown. Individual points represent individual effect size point estimates for each experiment. (C) Point estimate with the corresponding 95% confidence intervals of the overall effect of tACS on healthy older adults (All outcomes) before (left) and after (right) outlier removal is shown. (D) Forest plot of outcome-based effect sizes along with 95% confidence intervals for All cognitive measures (not including clinical symptoms) in clinical neuropsychiatric populations is shown. (E) Box plot of the effects of tACS on All cognitive measures in clinical neuropsychiatric populations before (left) and after (right) outlier removal is shown. (F) Point estimate with the corresponding 95% confidence intervals of the overall effect of tACS in clinical neuropsychiatric populations (All cognitive measures) before (left) and after (right) outlier removal is shown. Box plot center line, median; box limits, upper and lower quartiles; whiskers, maximum and minimum values.