Long-lasting, dissociable improvements in working memory and long-term memory in older adults with repetitive neuromodulation

Abstract

The development of technologies to protect or enhance memory in older people is an enduring goal of translational medicine. Here we describe repetitive (4-day) transcranial alternating current stimulation (tACS) protocols for the selective, sustainable enhancement of auditory-verbal working memory and long-term memory in 65-88-year-old people. Modulation of synchronous low-frequency, but not high-frequency, activity in parietal cortex preferentially improved working memory on day 3 and day 4 and 1 month after intervention, whereas modulation of synchronous high-frequency, but not low-frequency, activity in prefrontal cortex preferentially improved long-term memory on days 2-4 and 1 month after intervention. The rate of memory improvements over 4 days predicted the size of memory benefits 1 month later. Individuals with lower baseline cognitive function experienced larger, more enduring memory improvements. Our findings demonstrate that the plasticity of the aging brain can be selectively and sustainably exploited using repetitive and highly focalized neuromodulation grounded in spatiospectral parameters of memory-specific cortical circuitry.

Extended Data Fig. 1 |. Differences in memory performance according to biological sex in the DLPFC gamma group in experiment 1.

Exploratory analyses examining the impact of biological sex showed a significant interaction effect of serial position × group × biological sex (F_6.1,164.7 = 6.139, p = 7 × 10⁻⁶, η_p² = 0.185) in Experiment 1 (N = 20 in the DLPFC gamma group, N = 20 in the IPL theta group, and N = 20 in the sham group). Follow-up analyses showed that the serial position × biological sex interaction was significant in the DLPFC gamma group (F_2.4,43.2 = 19.160, p = 2.86 × 10⁻⁷, ηp² = 0.516) but not in the IPL theta and sham groups (Fs < 1.754, ps > 0.173). Independent samples t-tests were performed to compare the memory performance for a given serial position on a given day between males and females in the DLPFC gamma group. Better primacy performance was observed among males in the DLPFC gamma group than females on day 2 (t₁₈ = 2.619, p = 0.017, d = 1.177), day 3 (t₁₈ = 2.288, p = 0.034, d = 1.028), day 4 (t₁₈ = 3.151, p = 0.006, d = 1.416), and 1 month (t_13.4 = 2.477, p = 0.027, d = 1.029) timepoints. Other trends observed were improved performance in males on day 2 of neuromodulation, evident in the middle 1 (t₁₈ = 2.490, p = 0.023, d = 1.119) and the middle 3 (t₁₈ = 2.136, p = 0.047, d = 0.960) clusters, and better performance among females at the offline timepoint 1 month after intervention in the middle 2 (t₁₈ = −2.226, p = 0.039, d = −1.001) and recency (t₁₈ = −2.448, p = 0.025, d = −1.1) clusters. However, none of these effects survived correction for multiple comparisons (Bonferroni correction; p_cutoff = 0.0017). Data are represented as mean values +/− S.E.M. across participants.

Fig. 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).

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.

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 (t_29.97 = 4.090, P_corr = 2.98 × 10⁻⁴, d = 1.29) but not the recency cluster (t₃₈ = 2.110, P_corr = 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, P_corr = 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, P_corr = 9.5 × 10⁻⁵, d = 1.38). These analyses were exploratory and were subjected to Bonferroni correction for multiple comparisons (P_corr < 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 (P_corr < 0.0125). CI, confidence interval.

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.

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⁻, 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.