We conducted a randomized, double-blind study consisting of two sham-controlled experiments to target memory function in older adults and an additional experiment to test the replicability of the principal findings. In Experiment 1, 60 participants (Table 1) were randomized into three groups (sham, DLPFC gamma and IPL theta; Fig. 1). We used a repetitive neuromodulation protocol in which each participant received 8 × 1 tACS according to their assigned group for 20 minutes each day on four consecutive days. Gamma frequency 8 × 1 tACS was administered at 60 Hz, whereas theta frequency 8 × 1 tACS was administered at 4 Hz, following previous studies suggesting stronger benefits at these frequencies18,22. On each day, participants performed five runs of the free recall task. In each run, they encoded a list of 20 words and were asked to immediately recall the words at the end of the presentation of the list. Neuromodulation was performed through the entire duration of encoding and recall of all five lists to increase functional specificity29, and this procedure took approximately 20 minutes (Methods). We examined memory performance across the five runs as a function of the serial position of the presented words. This allowed us to isolate changes in LTM and WM, separately, indexed by the primacy and recency serial position curve effects according to dual-store models11. In addition to these online assessments, we evaluated memory performance offline, at baseline and at 1 month after intervention. We also determined general cognitive function, quantified using the Montreal Cognitive Assessment (MoCA)30, and depression symptoms, assessed using the Geriatric Depression Scale (GDS)31, at baseline. Experiment 2 served as a control to test the frequency specificity of the effects in Experiment 1. Here, we switched the neuromodulation frequency between the two regions of interest. Sixty older participants (Table 1) were randomized into three groups (sham, DLPFC theta and IPL gamma; Fig. 1) and proceeded similarly to Experiment 1. Experiment 3 served as a test for replication of the primary findings from Experiment 1. Here, a new sample of 30 participants was randomized into the two critical conditions of interest from Experiment 1 (DLPFC gamma and IPL theta) and received neuromodulation for only three consecutive days; as in Experiment 1, we examined memory performance at baseline and during each neuromodulation session.

Table 1 Demographic characteristics by neuromodulation groupFig. 1: Model-guided, high-definition neuromodulation.

The theta-rate IPL and gamma-rate DLPFC HD-tACS protocols and corresponding electric field models shown on three-dimensional reconstructions of the cortical surface. The left DLPFC and left IPL were targeted, each protocol using nine electrodes configured in a center-surround, source-sink pattern to achieve maximum focality. The location and current intensity value of each modulating electrode are shown. The DLPFC protocol included (in mA): FP1 (−0.6662), Fz (0.0739), F1 (−0.4438), AF3 (1.5892), FC3 (−0.0048), F5 (−0.2312), AF7 (−0.194), AFz (−0.3744) and EX17 (0.2513). The IPL protocol included (in mA): C3 (−0.2997), T7 (−0.3386), CP1 (−0.2975), FC5 (−0.1284), CP5 (1.5818), FT7 (−0.0852), TP7 (−0.1413), PO7 (−0.2366) and EX13 (−0.0545).

DLPFC gamma modulation selectively improves LTM

In Experiment 1, free recall performance across the five word lists administered during neuromodulation was averaged and entered into a mixed ANOVA with day (baseline, day 1, day 2, day 3, day 4 and 1 month after intervention) and serial position (primacy, middle 1, middle 2, middle 3 and recency) as within-subjects factors and group (sham, DLPFC gamma and IPL theta) as a between-subjects factor. We observed a significant day × serial position × group interaction (F21.4,611.5 = 3.875, P < 0.001, ηp2 = 0.120). A follow-up mixed ANOVA examining performance between the sham and DLPFC gamma groups showed a similar day × serial position × group interaction effect (F10.1,384.0 = 3.064, P < 0.001, ηp2 = 0.087). Additional follow-up analyses testing the effect of day on the serial position × group interaction showed that the differences in the sham and DLPFC gamma groups were present on day 2 (F3.3,126.8 = 7.228, P < 0.001, ηp2 = 0.160), day 3 (F2.9,110.3 = 15.331, P < 0.001, ηp2 = 0.287), day 4 (F2.8,107.0 = 10.698, P < 0.001, ηp2 = 0.220) and 1 month after intervention (F2.6,100.5 = 3.435, P = 0.024, ηp2 = 0.083). Examining the effect of serial position on the day × group interaction, we observed significant improvements in memory performance for the primacy cluster in the DLPFC gamma group with respect to sham (F3.6,140.4 = 7.470, P < 0.001, ηp2 = 0.164) and no differences in any other serial position cluster (Fs < 2.262, ps > 0.085). Parsing the improvements in the primacy cluster, independent-sample t-tests revealed significantly higher primacy performance in the DLPFC gamma group relative to the sham group on day 2, day 3, day 4 and 1 month after intervention (Fig. 2a, top, middle). The pattern of results remained unchanged when accounting for additional factors such as age, sex, years of education, MoCA and GDS scores as covariates (Supplementary Tables 1–3). Exploratory analyses suggested potentially greater improvements in males than females, but these effects did not survive correction for multiple comparisons (Extended Data Fig. 1). The results suggest that rhythmic neuromodulation in the gamma band targeting left DLPFC preferentially improved LTM in older adults. The improvements were rapidly induced by the second day of neuromodulation, persisted on all following neuromodulation days and lasted for at least 1 month after intervention.

Fig. 2: Selective, sustainable memory improvements via spatiospectral-dissociable neuromodulation.

A mixed ANOVA was performed to examine differences in recall probabilities in each experiment with the following factors: day (baseline, days 1–4 and 1 month), serial position (primacy, middles 1–3 and recency) and groups (E1: sham, DLPFC gamma and IPL theta; E2: sham, DLPFC theta and IPL gamma). Interaction effects were parsed with follow-up ANOVAs and two-sided independent-sample t-tests. a, Mean recall probabilities plotted across serial position clusters (primacy, three middles and recency) at pre-intervention baseline, day 1, day 2, day 3, day 4 and 1 month after intervention for Experiment 1 groups: sham (top, grays, n = 20), DLPFC gamma (middle, blues, n = 20) and IPL theta (bottom, oranges, n = 20) neuromodulation groups. Gray dots show individual participant data. Mean of center shows the average recall probability, and the error bars show 95% CI across participants. Asterisks identify days on which significant differences were observed among the modulation groups and serial positions during the follow-up two-sided independent-sample t-tests. These indicate significantly higher recall probability within the primacy cluster in the DLPFC group, relative to the sham group, in Experiment 1, on day 2 (t38 = 2.075, P = 0.045, d = 0.66), day 3 (t38 = 3.660, P = 0.001, d = 1.16), day 4 (t38 = 3.381, P = 0.002, d = 1.07) and 1 month (t38 = 2.381, P = 0.022, d = 0.75) timepoints and significantly higher recall probability within the recency cluster in the IPL theta group, relative to the sham group, in Experiment 1, on day 3 (t38 = 2.631, P = 0.012, d = 0.83), day 4 (t38 = 4.650, P = 3.9 × 10−5, d = 1.47) and 1 month (t38 = 2.253, P = 0.030, d = 0.98) timepoints. b, Mean recall probabilities as in a for Experiment 2 groups: sham (top, grays, n = 20), DLPFC theta (middle, blues, n = 20) and IPL gamma (bottom, oranges, n = 20). No significant differences in mean recall probabilities were observed in Experiment 2. Comparisons within the primacy and recency cluster were hypothesis driven and were not subjected to any corrections for multiple comparisons. Comparisons within the middle position clusters were exploratory and subjected to Bonferroni correction. *P < 0.05, **P < 0.01 and ***P < 0.001. CI, confidence interval; NS, not significant.

IPL theta modulation selectively improves WM

We also examined a day × serial position × group interaction effect between sham and IPL theta groups in Experiment 1, using a mixed ANOVA. This interaction effect was significant (F9.0,342.9 = 3.111, P = 0.001, ηp2 = 0.076). Follow-up mixed ANOVAs demonstrated the specific days at which the serial position × group interaction was significant. Improvements in memory performance were observed on day 3 (F3.6,137.3 = 5.713, P < 0.001, ηp2 = 0.131), day 4 (F3.1,120.6 = 18.93, P < 0.001, ηp2 = 0.333) and 1 month after intervention (F2.8,109.3 = 3.852, P = 0.013, ηp2 = 0.092). Additional ANOVAs revealed that the day × group interaction was significant only for the recency serial position cluster (F2.6,100.7 = 5.116, P = 0.004, ηp2 = 0.119) but not other position clusters (Fs < 1.005, ps > 0.407). Independent-sample t-tests revealed significant improvements in the recency effect in the IPL theta group relative to sham group on day 3 and day 4 of neuromodulation, and these improvements were sustained at the 1-month post-intervention timepoint (Fig. 2a, top and bottom). The pattern of effects was not affected by inclusion of additional covariates (Supplementary Tables 1–3). The results suggest that theta-rate neuromodulation aimed at left IPL selectively enhanced WM in older individuals without behavioral costs to other memory systems. These selective memory improvements were evident by day 3 of the intervention and lasted for at least 1 month, relative to memory performance of participants in the sham group.

Specific location and frequency combinations are necessary

Experiment 1 demonstrated improved WM function with repetitive modulation of IPL theta rhythms. However, both theta and gamma frequency rhythms contribute to WM function32. As a result, it is important to confirm whether WM improvements occur specifically due to theta modulation in the IPL or whether they are also possible with gamma modulation in the IPL. Likewise, it is important to confirm whether LTM improvements with DLPFC modulation are specifically due to gamma entrainment or whether theta entrainment can produce similar effects. To test these possibilities, we performed Experiment 2 following the same design as Experiment 1, except that the three experimental groups received sham, IPL gamma or DLPFC theta modulation. A mixed ANOVA with day (baseline, day 1, day 2, day 3, day 4 and 1 month) and serial position (primacy, middle 1, middle 2, middle 3 and recency) as within-subjects factors and group (sham, DLPFC theta and IPL gamma) as between-subjects factor failed to find any significant differences in the recall performance (day × serial position × group: F25.3,721.9 = 0.535, P = 0.971, ηp2 = 0.018; Fig. 2b). This was not influenced by inclusion of covariates (F24.3,633.2 = 0.630, P = 0.916, ηp2 = 0.024). This indicates that the improvements we observed in Experiment 1 are both location specific and frequency specific: modulation of theta rhythms in the IPL, and not gamma rhythms, improved WM without affecting LTM; and modulation of gamma rhythms in the DLPFC, and not theta rhythms, improved LTM without affecting WM. Moreover, the two different frequency conditions for a given brain region across the two experiments serve as active controls for each other. Consequently, these findings confirm that the effects observed in Experiment 1 are not due to any non-specific effect of tACS such as transretinal or transcutaneous modulation33 but due to frequency-specific entrainment of relevant brain circuits.

Validation of sham and pre-intervention baseline controls

To test the validity of the control procedures and, thus, the strength of the principal findings, we examined the recall performance at the pre-intervention baseline timepoint across groups (Experiment 1: sham, DLPFC gamma and IPL theta; Experiment 2: sham, DLPFC theta and IPL gamma; Fig. 2a,b, ‘Baseline’ timepoint) and serial positions. A mixed ANOVA comparing these groups did not find a significant interaction effect of serial position (primacy, middle 1, middle 2, middle 3 and recency) or group (Experiment 1: sham, DLPFC gamma and IPL theta; Experiment 2: sham, DLPFC theta and IPL gamma) on performance at the pre-intervention baseline timepoint with or without covariates in either experiment (Fs < 0.925, ps > 0.488). These results suggest that the three groups in each experiment did not differ in their baseline memory performance for any serial position cluster. Thus, the selective effects of neuromodulation on serial positions were not driven by any inherent differences within the three groups in either experiment. Furthermore, we tested how stable and reliable the recall performance was for serial position clusters within the sham group across timepoints in each experiment (baseline, day 1, day 2, day 3, day 4 and 1 month; Fig. 2a,b, top). A repeated-measures ANOVA examining the day × serial position interaction effect within the sham group did not show any significant differences with or without covariates in either experiment (Fs < 1.603, ps > 0.135). Together, these results demonstrate the stability and reliability of memory performance during the pre-intervention baseline across different groups of participants and within the same group of participants over different timepoints of assessment lasting more than 1 month, which together strengthen confidence in the validity of the control procedures and the resulting tACS improvements.

Four-day improvement rate predicts benefits 1 month later

Having established the location specificity and frequency specificity of the memory improvements, we next explored factors that predict sustainable effects. We evaluated the rates of improvement in LTM (primacy) and WM (recency) over the 4-day intervention in Experiment 1. Of the 20 participants in the DLPFC gamma group, 17 (85%) showed a positive rate of primacy improvements over the 4 days. Similarly, of the 20 participants receiving IPL theta modulation, 18 (90%) showed a positive rate of recency improvements over the 4 days. By modeling these data using linear regression, we observed a significantly higher mean rate of improvement for primacy over 4 days of DLPFC modulation relative to sham and for recency during IPL modulation relative to sham (Fig. 3), but the reverse was not true. Neither recency in the DLPFC gamma group nor primacy in the IPL theta group were significantly different relative to sham after Bonferroni correction (Fig. 3). Strikingly, the rate of improvement over the course of the intervention was highly predictive of post-intervention memory benefits: participants with greater primacy improvement rates during DLPFC modulation showed the largest primacy benefits at 1 month (r18 = 0.817, Pcorr < 0.001), and participants with greater recency improvement rates during IPL modulation showed the largest recency benefits at 1 month (r18 = 0.655, Pcorr = 0.002) (Fig. 4a,b). Again, the opposite was not true (DLPFC recency: r18 = 0.243, Pcorr = 0.303; IPL primacy: r18 = 0.385, Pcorr = 0.094; Pearson test, two-sided, Bonferroni correction, Pcorr < 0.0125). The results indicate that not only did the overwhelming majority of older individuals experience memory improvements—selectively for WM or LTM depending on the nature of neuromodulation—the size and, thus, the sustainability of the memory improvements 1 month later were highly predicted by the speed of memory improvements during the 4-day intervention.

Fig. 3: Neuromodulation selectively determines speed of memory improvement over days in Experiment 1.

Mean rates of change in primacy (a) and recency (b) over the 4-day intervention shown for the DLPFC gamma group (blue, n = 20) compared to sham (gray, n = 20). Gray dots show individual participant data. Center of the error bars shows the mean rate of change in primacy or recency recall probabilities across the 4 days of the intervention, and the error bars show 95% CI across participants. Insets show the strength (or slope) of each participant’s linear relationship between primacy or recency recall probabilities and time over the 4-day intervention, in gray, and the average slope for the specific group and the serial position cluster is highlighted in color. Two-sided independent-sample t-tests showed differences in mean rates of change between DLPFC gamma and sham groups in the primacy cluster (t29.97 = 4.090, Pcorr = 2.98 × 10−4, d = 1.29) but not the recency cluster (t38 = 2.110, Pcorr = 0.042, d = 0.67). c, Similar plot as in a showing the rate of change in the primacy cluster in the IPL theta group (orange, n = 20) compared to sham. No significant differences were observed (t38 = 0.225, Pcorr = 0.824, d = 0.07). d, Similar plot as in b showing the rate of change in the recency cluster in the IPL theta group (orange, n = 20) compared to sham. Two-sided independent-sample t-tests showed significantly higher rates of change in the IPL theta group relative to sham for the recency cluster (t38 = 4.361, Pcorr = 9.5 × 10−5, d = 1.38). These analyses were exploratory and were subjected to Bonferroni correction for multiple comparisons (Pcorr < 0.0125). *P < 0.05, **P < 0.01 and ***P < 0.001. CI, confidence interval; NS, not significant.

Fig. 4: Speed of memory improvement during neuromodulation predicts size of memory benefits at 1 month in Experiment 1.

Regression analyses were performed to test for the presence of a linear relationship across participants between the rate of change in recall performance during neuromodulation and the recall performance 1 month after the intervention. a, Scatter plot shows the speed (rate of change) of each participant’s improvement in primacy over 4 days of DLPFC gamma neuromodulation against the same individual’s primacy score 1 month after intervention in Experiment 1. Gray dots show individual participant data (n = 20). The solid line indicates a regression fit, and the error bands show 95% CI. This exploratory analysis identified significant, positive linear relationships between the rate of primacy improvements and 1-month primacy performance in the DLPFC gamma group (r18 = 0.817, P = 1.1 × 10−5). b, Scatter plot as in a for recency in the IPL theta group (n = 20) in Experiment 1. Significant, positive, linear relationship was observed between the rate of recency improvements and 1-month recency performance in the IPL theta group (r18 = 0.655, P = 0.002). These analyses were subjected to Bonferroni correction for multiple comparisons (Pcorr < 0.0125). CI, confidence interval.

General cognitive function moderates memory improvements

Previous studies demonstrated that the effects of tACS can be modulated by baseline behavioral34 and neural35 states. We, therefore, examined whether memory improvements due to neuromodulation in Experiment 1 were moderated by levels of baseline cognitive function. We performed participant-wise regression of MoCA scores, memory performance at the 1-month post-intervention timepoint and the rate of change in memory performance during days 1–4 for the primacy and recency serial position clusters (Fig. 5). Participants with lower baseline cognitive performance in the DLPFC gamma group showed higher rates of primacy improvement over the 4-day intervention (r18 = −0.822, P < 0.001; Fig. 5a) and showed larger primacy gains at 1 month after intervention (r18 = −0.795, P < 0.001; Fig. 5b). No such relationships held for recency in the DLPFC gamma group (rs18 > −0.25, ps > 0.288; Fig. 5c,d). Moreover, participants with lower baseline cognitive performance in the IPL theta group showed higher recency improvement rates over the 4-day period (r18 = −0.824, P < 0.001; Fig. 5g) and greater recency improvements after 1 month (r18 = −0.499, P = 0.025; Fig. 5h). Consistent with previous analyses, the level of cognitive performance did not predict changes in primacy during or after IPL modulation (rs18 > −0.274, ps > 0.242; Fig. 5e,f). Thus, older participants with relatively low baseline cognition more strongly revealed the preferential nature of the gamma-rate DLPFC and theta-rate IPL modulation effects on primacy and recency, respectively. This conclusion, which suggests distinctive functions of prefrontal gamma rhythms for LTM and parietal theta rhythms for WM, was reinforced by the absence of participant-wise correlations in the sham group between baseline cognitive behavior and primacy or recency measured during or after sham (rs18 > 0.064, ps > 0.79). These results suggest that the large-scale population dynamics that support memory function in older people can be differentially modulated depending on the individual level of general cognitive performance.

Fig. 5: Individual differences in general cognitive function moderate selectivity and sustainability of neuromodulation effects on memory performance in Experiment 1.

Participant-wise correlations between general cognitive function, quantified by MoCA scores and memory performance measures in the DLPFC gamma (n = 20) and IPL theta (n = 20) groups. Memory performance measures include ‘online’ measures quantified by the rate of change in memory performance across days 1–4 of neuromodulation and ‘offline’ measures quantified by the memory performance at the 1-month post-intervention timepoint, separately computed for the primacy and recency clusters. a, Correlation between MoCA scores and online measure for the primacy cluster in the DLPFC gamma group (r18 = −0.822, P = 9 × 10−6). b, Correlation between MoCA scores and offline measure for the primacy cluster in the DLPFC gamma group (r18 = −0.795, P = 2.8 × 10−5). c, Correlation between MoCA scores and online measure for the recency cluster in the DLPFC gamma group (r18 = −0.250, P = 0.288). d, Correlation between MoCA scores and offline measure for the recency cluster in the DLPFC gamma group (r18 = −0.018, P = 0.941). e, Correlation between MoCA scores and online measure for the primacy cluster in the IPL theta group (r18 = −0.180, P = 0.448). f, Correlation between MoCA scores and offline measure for the primacy cluster in the IPL theta group (r18 = −0.274, P = 0.242). g, Correlation between MoCA scores and online measure for the recency cluster in the IPL theta group (r18 = −0.824, P = 8 × 10−6). h, Correlation between MoCA scores and offline measure for the recency cluster in the IPL theta group (r18 = −0.499, P = 0.025). Solid lines indicate the regression fit across participants between the MoCA scores and the neuromodulation effects (rate of change during modulation/recall probability after 1 month) in the primacy or recency clusters. Error bands show 95% CI. These hypothesis-driven analyses were not subjected to multiple comparisons correction. CI, confidence interval.

Replication of primary findings in an independent sample

We performed an additional experiment to test whether the primary observations from Experiment 1 replicate in an independent sample. Experiment 3 consisted of 30 older participants randomized to receive either DLPFC gamma or IPL theta neuromodulation during performance of the free recall task. The neuromodulation protocol followed was largely similar to Experiment 1, except that the neuromodulation was performed for three rather than four consecutive days and did not include a long-term follow-up. Memory performance was examined at baseline and during each neuromodulation session. A mixed ANOVA with day (baseline, day 1, day 2 and day 3) and serial position (primacy, middle 1, middle 2, middle 3 and recency) as within-subjects factors and group (DLPFC gamma and IPL theta) as between-subjects factor revealed significant differences in memory performance (day × serial position × group: F7.9,220.8 = 6.315, P < 0.001, ηp2 = 0.184; Fig. 6a), and this effect remained significant even after accounting for covariates (F7.7,176.1 = 5.887, P < 0.001, ηp2 = 0.204). Follow-up ANOVAs revealed a significant interaction between serial position and group on days 2 and 3 of neuromodulation and a significant interaction between day and group for the primacy and recency clusters (Supplementary Table 4). Two-sided independent-sample t-tests showed that memory performance in the primacy cluster was significantly improved in the DLPFC gamma group relative to the IPL theta group on day 2 and day 3 of neuromodulation (Fig. 6a, top). Performance in the recency cluster was significantly higher in the IPL theta group relative to the DLPFC gamma group on day 3 of the intervention (Fig. 6a, bottom). These results parallel observations from Experiment 1 (Fig. 2a, left). Baseline performance did not differ between the two groups (Supplementary Table 4), thus ruling out non-specific between-group differences. Examining the relationship between baseline cognitive function and memory performance, we found that individuals with lower MoCA scores in the DLPFC gamma group showed better memory performance at day 3 only in the primacy cluster (r13 = −0.672, P = 0.006; Fig. 6b,c), whereas those with lower MoCA scores in the IPL theta group showed better memory performance on day 3 only in the recency cluster (r13 = −0.618, P = 0.014; Fig. 6d,e), similar to the findings in Experiment 1 (Fig. 5). Together, these observations in an independent sample of participants replicate the primary findings of Experiment 1, further strengthening confidence in the inferences drawn from them.

Fig. 6: Replication of selective improvements in memory, associated with individual differences in general cognitive function, in Experiment 3.

a, Mean recall probabilities plotted across serial position clusters on all measurement days for Experiment 3 groups: DLPFC gamma (top, blues, n = 15) and IPL theta (bottom, oranges, n = 15). Gray dots show individual participant data. Mean of center shows the average recall probability, and the error bars show 95% CI across participants. Following mixed ANOVAs (see text), two-sided independent-sample t-tests identified significant differences in recall probability across days, groups and serial positions (see asterisks). Participants in the DLPFC gamma group showed higher recall probability within the primacy cluster on day 2 (t28 = 2.2, P = 0.037, d = 0.80) and day 3 (t28 = 4.467, P = 1.25 × 10−4, d = 1.63). Participants in the IPL theta group showed higher recall probability within the recency cluster on day 3 (t28 = −2.868, P = 0.008, d = 1.05). Comparisons within the primacy and recency cluster were hypothesis driven and were not subjected to any corrections for multiple comparisons. Comparisons within the middle position clusters were exploratory and subjected to Bonferroni correction. *P < 0.05, **P < 0.01 and ***P < 0.001. NS, not significant. b, Participant-wise correlations between MoCA scores and memory performance in the primacy cluster on day 3 of neuromodulation in the DLPFC gamma group (r13 = −0.672, P = 0.006). Similar correlations are shown for the recency cluster performance on day 3 in the DLPFC gamma group (r13 = −0.363, P = 0.183) in c, for the primacy cluster performance in the IPL theta group (r13 = −0.302, P = 0.274) in d and for the recency cluster performance in the IPL theta group (r13 = −0.618, P = 0.014) in e. Gray dots indicate individual participant data. Solid line indicates a regression fit, and the error bands show 95% CI across participants. These hypothesis-driven regression analyses were not subjected to multiple comparisons correction. CI, confidence interval.