Long-lasting, Dissociable Improvements in Working Memory And Long-term Memory in Older Adults With Repetitive Neuromodulation Part 1

The development of technologies to protect or enhance memory in older people is an enduring goal of translational medicine. 

As age increases, the memory of the elderly gradually declines, which is also one of the manifestations of Alzheimer's disease. However, modern scientific research shows that the memory of the elderly can be trained and improved through some methods, thus achieving quite good results.

First, seniors should maintain a positive attitude and stay healthy. This is because mental and physical conditions have a great impact on memory. If the elderly always complain about their poor memory, this negative mentality will cause their memory to plummet. Therefore, we should adjust our mentality in time, make ourselves relaxed and happy, and keep our bodies healthy and active.

In addition, good living habits are also very helpful in improving memory. Getting enough sleep, eating right, being moderately active, and getting enough rest are all beneficial. These habits can allow our bodies to get adequate rest and maintain reasonable physical strength, thus ensuring the effective use of memory.

In addition, the elderly can improve their memory through some memory training methods. These methods include solidifying memories, creating associations, and strengthening memory links, all of which improve memory through the continuous use of memories. For example, practicing memory and memory-exploring abilities, such as memory cards and memory palaces, and doing some memory exercises every day can help improve memory.

In short, older people can stay active and improve their memory through good living habits and memory training. As long as the elderly have confidence and continue to work hard, they will certainly be able to continue to maintain good memory and fully enjoy a high-quality life. 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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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 the 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 the 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.

The world is facing many challenges due to a rapidly aging global population. The shift in age demographics is associated with considerable personal, social, healthcare, and economic costs1. 

A critical factor contributing to aging-induced costs is the impairment in basic memory systems essential for activities of daily living, such as making financial decisions or comprehending language2. Emerging reports suggest an increased likelihood of such impairments due to the ongoing Coronavirus Disease 2019 (COVID-19) pandemic3. 

Moreover, there exists considerable variability in memory decline across individuals during aging4, with accelerated decline potentially predicting subsequent Alzheimer's disease and other dementias5. 

Substantial progress in neuroscience has identified the brain circuits and networks that underpin memory capacities, and studies have suggested that the rhythmic activity of cognitive circuitry may be important for the coordination of information processing. 

What is needed now are technologies to non-invasively isolate and augment the rhythmic activity of neural circuits, inspired by models of healthy aging, to determine whether it is possible to protect or even enhance memory function for older adults in a rapid and sustainable fashion6,7 .

A challenge in improving memory function in older adults is that memory function may not be instantiated by a single cognitive mechanism. Previous research has characterized a capacity-limited working memory (WM) store for brief maintenance of information and an unlimited long-term memory (LTM) store for sustained maintenance of information. 

Within this dual-store framework, previous research has identified both concurrent deficits9 and selective deficits10 in WM and LTM function with aging, using the classic immediate free recall paradigm, associating these stores with the canonical recency and primacy effects, respectively11. 

Neuropsychological research has long alluded to distinct anatomical and functional substrates of primacy and recency effects and the corresponding WM and LTM stores11–13. 

Differential contributions of the dorsolateral prefrontal cortex (DLPFC) and the inferior parietal lobule (IPL) have been suggested14. However, it is not known whether distinct rhythmic mechanisms in these regions subserve distinct memory processes during free recall. 

If unique rhythmic mechanisms in spatially distinct brain regions can be identified, then these brain rhythms can be independently and non-invasively manipulated using techniques such as high-definition transcranial alternating current stimulation (HD-tACS) for selectively improving memory function in older adults.

Rhythmic activity in the theta and gamma frequency ranges are thought to contribute to both WM15 and LTM16 functions, particularly during free recall17. However, previous attempts at modulating these rhythms to improve memory have yielded inconsistent findings. 

Although there are some suggestions of improvements in WM with modulation of parietal theta rhythms18, changing theta rhythms in the frontal regions7,19 and gamma rhythms in the parietal20 and frontal21 regions have yielded contradictory results. 

Similarly, although frontal gamma tACS has previously suggested improvements in LTM22,23, other spatiospectral combinations, such as frontal theta24,25 and parietal theta26 modulation, have shown variable effects. 

In addition, although modulation of gamma rhythms in the medial parietal cortex has shown some benefits to LTM27, causal evidence for the involvement of these rhythms in lateral parietal cortices is scarce. 

Moreover, much of this evidence comes from studies in young adults, using paradigms targeting visuospatial memory and using conventional tACS, which has poorer spatial resolution and target engagement than techniques such as HD-tACS guided by current flow models28. 

Thus, which specific combinations of location and frequency of neuromodulation are effective for selectively improving WM and LTM function, particularly in older adults, are unknown.

Based on the balance of evidence, we tested the hypotheses that modulation of theta rhythms in the IPL would improve auditory–verbal WM function (recency effect), whereas modulation of gamma rhythms in the DLPFC would improve auditory–verbal LTM function (primacy effect) in older adults (Experiment 1). 

To modulate these rhythms, we applied tACS with optimal source-sink configurations of nine 12-mm ring electrodes (8×1 tACS) guided by current flow models to improve the facility of current flow28. 

Moreover, we sought to induce long-lasting effects by performing repetitive neuromodulation over multiple days and tested memory performance up to 1month after the intervention. Furthermore, we examined the effect of interindividual differences4 and tested whether older individuals with lower general cognitive performance would benefit more from neuromodulation. 

To confirm the location specificity and frequency specificity of our hypotheses and address the conflicting findings in the field, we performed a second experiment (Experiment 2) in which we switched the entrainment frequencies in the two regions to examine the effect of gamma entrainment in the IPL and theta entrainment in the DLPFC on memory function. 

To explicitly test the replicability of the principal findings, we performed a third experiment (Experiment 3), similar to Experiment 1, examining the effect of gamma modulation in the DLPFC and theta modulation in the IPL in an independent sample of participants. 

Across these three experiments, we sought evidence for a double dissociation in the two memory stores according to the distinct spatiospectral characteristics of their underlying anatomical and functional substrates and, consequently, for selective and long-lasting improvements in memory function in older adults.

Results

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 60Hz, whereas theta frequency 8×1 tACS was administered at 4Hz, 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 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.

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