Long-lasting, Dissociable Improvements in Working Memory And Long-term Memory in Older Adults With Repetitive Neuromodulation Part 2

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. 

Experiments and memory are closely related, because the experiment itself is a way of learning and memory, and memory is the result of what we learn in the experiment.

Doing experiments requires us to remember the experimental steps, precautions, and experimental results, which requires us to have good memory. At the same time, experiments can also exercise and improve our memory, because in experiments we need to repeatedly observe and analyze the experimental results, and synthesize and memorize this information.

Scientific experiments, in particular, often require repeated experiments to conclude the comparison and analysis of different experimental results. This requires us not only to have good memory during the experiment but also to flexibly use our thinking, understanding, and analysis skills to extract key information and further improve our learning ability and memory.

The relationship between experiments and memory is also reflected in the extent to which experiments enrich our knowledge reserves. By participating in experiments, we can learn many new concepts, skills, and theories. The accumulation of this knowledge will continue to inject new vitality and power into our memory and learning abilities.

Therefore, in daily life, we need to participate in experiments through various channels and improve our memory and learning abilities through practice. Experiments are one of the best ways to exercise your memory. Let us be positive, good at using experiments and memory, and constantly improve and improve ourselves. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Meat can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.

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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.

DLPFC gamma modulation selectively improves LTM.

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, ηp 2=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, ηp 2=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, ηp 2=0.160), day 3 (F2.9,110.3=15.331, P<0.001, ηp 2=0.287), day 4 (F2.8,107.0=10.698, P<0.001, ηp 2=0.220) and 1month after intervention (F2.6,100.5=3.435, P=0.024, ηp 2=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 concerning sham (F3.6,140.4=7.470, P<0.001, ηp 2=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 the intervention.

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, ηp 2=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, ηp 2=0.131), day 4 (F3.1,120.6=18.93, P<0.001, ηp 2=0.333) and 1month after intervention (F2.8,109.3=3.852, P=0.013, ηp 2=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, ηp 2=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 the 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 the 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 the 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, ηp 2=0.018; Fig. 2b). 

This was not influenced by the inclusion of covariates (F24.3,633.2=0.630, P=0.916, ηp 2=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 time points 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 time points of assessment lasting more than 1month, 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 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 was significantly different relative to sham after Bonferroni correction (Fig. 3). Strikingly, the rate of improvement throughout 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 1month (r18=0.817, Pcorr<0.001), and participants with greater recency improvement rates during IPL modulation showed the largest recency benefits at 1month (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 1month later were highly predicted by the speed of memory improvements during the 4-day intervention.

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 time point, 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 were 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 days (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.

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