Long-lasting, Dissociable Improvements in Working Memory And Long-term Memory in Older Adults With Repetitive Neuromodulation Part 3

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 the performance of the free recall task. 

There is a close relationship between neuromodulation and memory. Neuromodulation enhances memory by promoting connections and information transfer between brain cells. Memory is an important cornerstone of human survival and development. Through neural regulation, it can help us better master and apply knowledge.

Neuromodulation can affect many aspects of memory. First, neuromodulation can influence activity in the cerebral cortex, thereby modulating perception, attention, and cognitive abilities. These are the basis for memory formation, and through neuromodulation, they can help us better understand, remember, and apply information.

Second, neuromodulation can also modulate the connections and signaling between neurons. The number and structure of connections between neurons can directly affect memory ability. The connections and signaling between neurons can be enhanced through neuromodulation, thereby improving memory ability.

In addition, neuromodulation can influence the hippocampus and other neuronal populations in the brain to promote long-term memory retention and review. Through neuromodulation, we can better regulate the connections between populations of neurons and improve the encoding and storage of memories.

In conclusion, the relationship between neuromodulation and memory is very close. By enhancing neuromodulation, we can improve our memory and better grasp and apply knowledge. This has a positive impact on our study, work, and life, so we should pay attention to the impact of neuromodulation on memory, and promote the development of neuromodulation and memory through physical exercise, dietary regulation, etc. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory because Cistanche deserticola is a traditional Chinese medicinal material that has many unique effects, one of which is to improve memory. The efficacy of minced meat comes from the various active ingredients it contains, including acid, polysaccharides, flavonoids, etc. These ingredients can promote brain health in various ways.

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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, ηp 2=0.184; Fig. 6a), and this effect remained significant even after accounting for covariates (F7.7,176.1=5.887, P<0.001, ηp 2=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.

Discussion

We present evidence for selective improvements in WM and LTM in older adults through dissociable spatiospectral entrainment of brain rhythms, and the improvements are sustained for at least 1month after intervention. Experiment 1 showed that selective changes to WM and LTM function are possible through entrainment of theta rhythms in the IPL and gamma rhythms in the DLPFC, respectively. 

Experiment 2 showed that switching the modulation frequencies between the two regions did not produce any benefits. Consequently, it is the combination of anatomical location and rhythmic frequency that determines the appropriate substrate for memory improvement. 

Moreover, it confirmed that the improvements observed during Experiment 1 were due to entrainment of functionally specific brain circuits and not due to non-specific effects such as transretinal or transcutaneous stimulation 33. 

In addition, we observed greater improvements in individuals with poorer cognitive function. These findings were further replicated in an independent sample in Experiment 3. 

We further found that the speed with which the memory function improves during the intervention predicts memory strength 1month after the intervention, thus yielding an important metric to measure treatment responsiveness in future studies. 

Together, these findings suggest that memory function can be selectively and sustainably improved in older adults through modulation of functionally specific brain rhythms.

The specificity with which distinct rhythmic neuromodulation protocols affected different memory functions may seem surprising given the literature documenting the general involvement of both frontal and parietal regions and both theta and gamma rhythms to WM and LTM function36,37. 

This is particularly the case because neuromodulation was performed during both encoding and recall of all words presented during a list. Our findings strongly suggest that our interventions manipulated two distinct cognitive operations. Following the dual-store framework, we hypothesize that IPL theta modulation improved WM operations. 

However, unlike previous neuromodulation studies with visuospatial memoranda18, we do not think that IPL theta modulation improved WM capacity per se. If that were the case, then improvements in memory performance would have also been observed in some middle position clusters in addition to the recency cluster. 

We also do not expect increases in general attention function with IPL theta modulation. Although parietal theta rhythms are hypothesized to facilitate attentional sampling38, there is little evidence to suggest changes in attention with parietal theta entrainment39. 

Instead, we propose that IPL theta modulation may have facilitated the temporal segregation between successive memory representations, minimizing interference among them15. 

Moreover, theta rhythms are also known to facilitate temporal context-mediated recall40, potentially reflecting a common neurophysiological mechanism underlying preserved maintenance and context-based retrieval of WM representations. Intrinsic limitations on the WM capacity, unaffected by neuromodulation, may constrain these improvements to only the later words in the list, thereby only improving the recency cluster.

If so, then these findings may reflect an additional approach for non-invasively improving WM function within the influential theta–gamma cross-frequency coupling theory15, besides changing memory capacity18. 

The possibility that, although IPL theta modulation may have facilitated maintenance and recall of later list items, it may not have improved the transfer of previously presented information to LTM, may have further contributed to the selectivity of effects. This could be due to the presence of distinct encoding mechanisms for the two memory stores, a possibility supported by a recent transcranial magnetic stimulation (TMS) study14. 

Alternatively, the transfer of representations between the two memory systems may involve separate executive control processes41 unaffected by the current neuromodulation design. Consequently, IPL theta modulation may not have affected memory representations in the primacy cluster. Instead, improvements in the primacy effect emerged selectively with DLPFC gamma modulation. 

This protocol may have selectively improved the ability to retrieve the representations separately encoded or transferred to LTM, by potentially affecting the hippocampus and other temporal lobe structures42, which also simultaneously exhibit gamma activity during delayed recall36. A previous neuromodulation study, although examining memory function in young adults with single-session conventional tACS, aligns with this proposal22. 

Thus, although both theta and gamma rhythms, and both DLPFC and IPL regions, are known to generally contribute to WM and LTM performance, they may index distinct cognitive processes that selectively underlie the dissociable improvements observed in the current study.

The findings of the present study also contribute to the debate surrounding theoretical models of free recall. Segregated neural bases of primacy and recency effects have been a hotly debated topic in neuropsychology with conflicting evidence14,43. The selective modulation of primacy and recency effects observed in the current study support distinct underlying mechanisms, in agreement with the dual-store models11 and neuropsychological observations12,13. 

However, our findings, at present, are not incompatible with alternative models of free recall. For instance, one theory attributes primacy effects to 'long-term working memory' in which long-term storage and retrieval operations support WM function contingent upon expertise-dependent retrieval structures44,45. This view is not inconsistent with the aforementioned hypothesis that DLPFC gamma neuromodulation may have affected retrieval from LTM, albeit- in this view-in service of WM. 

A way to disambiguate between these two perspectives is to use the method of personalization to modulate expertise45, in which case this theory would predict a stronger effect of DLPFC gamma neuromodulation in the presence of stronger expertise-dependent retrieval structures. Furthermore, although the contextual retrieval theories are not designed to explain primacy effects, deficits in primacy effects in older adults have been attributed to attentional processes46, which, in turn, are associated with DLPFC gamma activity47. DLPFC gamma neuromodulation may have further enhanced the intrinsic gradient in the efficiency of encoding mechanisms with benefits to early events in a series46. Notably, increased gamma activity in the temporal lobe is associated with this effect17. 

As discussed above, DLPFC gamma neuromodulation may have led to downstream effects on gamma activity in the temporal lobe structures42, enhancing the primacy effect. Whether DLPFC gamma neuromodulation specifically affects LTM retrieval processes or attentional mechanisms can be potentially addressed through a granular analysis of memory performance within the primacy cluster. 

For instance, the LTM retrieval account predicts an additive shift to memory performance with increasing serial position in the primacy cluster due to similar benefits to retrieval processes at all serial positions, whereas the attentional account predicts a reduction in the slope of memory performance as a function of the serial position, thereby reflecting a stabilization in sustained attention46. 

The success of the neuromodulation protocol in selectively manipulating the primacy effect will be a powerful tool to test these competing predictions. Future studies that are sufficiently powered to systematically test these hypotheses can disambiguate between these competing predictions to refine and reconcile the various theories of free recall.

This work contributes to the growing literature that suggests potential clinical benefits for memory function in older adults with non-invasive techniques7. The protocols used in the current study demonstrate that memory function can be selectively improved for at least 1month after a 4-day intervention. These long-lasting effects may arise due to neuroplastic changes48 after phase-locking of intrinsic brain rhythms with tACS49. 

In addition, these findings suggest that functional differentiation, which typically reduces with aging50, can be promoted through functionally specific neuromodulation. Findings from the present study may motivate several lines of investigation to examine their clinical potential further. For instance, future studies should examine the generalizability of these findings to different cognitive paradigms spanning memory function across various sensory domains and replicate them in larger study samples. 

Moreover, how to promote sustainable effects that go beyond the 1-month duration observed in the current study needs to be determined. Personalization of the neuromodulation protocol according to individual anatomical and functional characteristics is one possible approach6. 

In addition, the specific frequency within the theta and gamma ranges, the number and duration of modulation sessions, the optimal gap between successive sessions, and the interaction of baseline cognitive and neural function with these metrics can be systematically varied to determine the most optimal modulation designs. 

Furthermore, in addition to MoCA, future studies should use more comprehensive neuropsychological assessments to quantify baseline cognitive function and its association with tACS-induced improvements. 

Finally, beyond potential benefits to healthy older adults, the translational implications for people with neuropsychiatric and neurodegenerative disorders, particularly those with selective memory deficits10 and at risk for dementia5, should be examined. Findings from the present study serve as a stepping stone toward investigating these questions of clinical interest.

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Any methods, additional references, Nature Research reporting summaries, source data, extended data, supplementary information, acknowledgments, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at https://doi.org/10.1038/ s41593-022-01132-3.

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