Stimulating Memory: Reviewing Interventions Using Repetitive Transcranial Magnetic Stimulation To Enhance Or Restore Memory Abilities Part 2

2.3.2. rTMS of AG: MCI and AD

Although results from healthy young and old adults demonstrate the potential for rTMS to improve memory abilities, similar findings have not been reported for AD and (a)MCI. 

rTMS is a non-invasive brain magnetic stimulation technology that can affect neuronal activity by delivering magnetic fields of specific frequencies to brain areas, thereby changing brain function. Recent studies have shown that rTMS has also achieved some encouraging results in improving memory.

One study showed that rTMS has great potential in promoting working memory and long-term memory. Researchers used rTMS to stimulate the right frontal cortex of subjects and found that this stimulation improved working memory and long-term memory, especially in vocabulary learning tasks. Another study also found that rTMS can improve subjects' working memory and long-term memory while treating depression.

In addition, rTMS may also be beneficial to the memory of the elderly. One study found that rTMS stimulation of the left temporal cortex of subjects can improve the long-term memory ability of the elderly. This shows that rTMS may be a helpful tool to help the elderly overcome memory disorders.

Overall, the relationship between rTMS and memory is positive. Although the research is still in its early stages, it has been shown that rTMS has great potential in promoting working memory and long-term memory, especially for the memory of the elderly. This provides us with a great opportunity to use rTMS, a new technology, to improve people's cognitive abilities and improve their quality of life. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because Cistanche has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidative and inflammatory responses in the brain, thereby protecting the health of the nervous system. In addition, Cistanche can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of neural networks. These effects can help improve memory, learning ability, and thinking speed, and can also prevent the occurrence of cognitive dysfunction and neurodegenerative diseases.

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While new clinical trials are proceeding at the time of this writing [93], only one recent study was identified applying rTMS to AG in individuals with mild to severe AD. Velioglu and colleagues administered ten sessions of 20 Hz rTMS at 100% MT to the left AG [57]. 

Visual recognition memory performance and the clock drawing test improved after stimulation. Notably, the cognitive improvements were associated with changes in RSFC and, somewhat surprisingly, significant changes in other blood-derived, neurally relevant biomarkers. 

Following rTMS, individuals were reported to have elevated blood-brain-derived neurotrophic factor measures and lower oxidative status measures. While intriguing, caution is warranted when interpreting these findings because biomarker measures derived from peripheral blood and CSF do not always exhibit a strong correlation [94].

2.3.3. rTMS of Other Parietal Lobe Sites

Several parietal regions beyond AG have been targeted with rTMS. The next most common stimulation site was the precuneus [62–64]. As precuneus lies at the core of the default mode network [95], several studies have identified significant cognitive or brain changes following rTMS targeting precuneus. 

One such study by Chen and colleagues applied ten sessions of 10 Hz rTMS to precuneus in individuals with subjective cognitive decline [63]. Following stimulation, these researchers observed significantly improved episodic memory and RSFC between the precuneus and posterior hippocampus. 

Improvement in these domains is reminiscent of AG stimulation, mainly due to the notable hippocampal RSFC changes. A similar outcome was also reported by Koch and colleagues [64]. 

Here again, ten sessions of rTMS were administered but with 20 Hz stimulation. Following stimulation, the authors noted significant improvement in episodic memory coupled with changes in RSFC and EEG profiles. Several studies also targeted precuneus with low-frequency or cTBS rTMS and found transient impairments in memory or metacognition [62,96–98]. 

Two studies reported applying rTMS to superior parietal regions, and both reported cognitive changes in healthy young adults. Both studies reported outcomes consistent with expectations for high-frequency and low-frequency rTMS stimulation. 

Specifically, Wang and colleagues observed significant improvement in recalling face/word pairs following two sessions of 10 Hz rTMS of their target in the superior parietal cortex [48]. Alternatively, Ribeiro and colleagues observed acute cognitive impairment following one session of 1 Hz of rTMS to the superior parietal cortex [65]. 

Beyond association regions in the parietal cortex, post-central gyrus has also been targeted due to its functional connections with the insula [66]. Following five sessions of 10 Hz rTMS, Addicott and colleagues reported increased RSFC between the target and left insula. 

The directionality of these findings is consistent with the putative associations between high- and low-frequency stimulation and cognitive enhancement/impairment and in some instances required fewer than five stimulation sessions.

3. Multitarget Stimulation

While rTMS studies have most frequently targeted a single cortical region, some investigators have also tested the effect of multitarget rTMS. As the name suggests, multitarget rTMS involves targeting multiple, distal brain regions for stimulation within the same paradigm either serially or, less often, simultaneously. 

The potential benefits of multitarget stimulation include modulation of brain activity in locations in one or more functional brain networks, and this approach could provide additive or interactive cognitive enhancement [99]. 

For example, one study employing multitarget stimulation serially targeted several temporal and parietal stimulation locations [100]. Here, the researchers used 20 Hz stimulation over frontal and parietal targets every weekday for six weeks. Following stimulation, adults with AD exhibited a significant increase in ADAS-cog performance, and there was evidence that this effect endured for up to 12 weeks. 

The reported durability of this improvement is unusual in the literature and could reflect lasting modulation of underlying functional brain networks. The "neuroAD protocol" is another line of research using a multitarget rTMS approach [68,69,101,102]. The protocol involves stimulation of six distinct target regions: left and right dlPFC, left and right somatosensory association cortex, Broca's area, and Wernicke's area. 

Targeting these areas, the authors sought to improve multiple behaviorally relevant functional networks impacted by AD [70]. During each stimulation session, three of the six targets were serially stimulated. Three different brain regions were selected for stimulation every session, with each site being stimulated in 15 sessions [101]. 

Stimulating at 100–110% RMT was associated with significant improvement in ADAS-Cog performance following rTMS [70]. Meanwhile, stimulation at 90% RMT reported observed increases in MMSE scores [103]. Unique among rTMS therapies for memory, the neuroAD protocol was recently submitted to the FDA for consideration as an intervention for patients with MCI or AD. 

At the time of writing, the most recent FDA determination was that the cognitive benefits were not substantial enough to warrant approval due to their modest efficacy (less than a three-point improvement on ADAS-Cog) [104]. 

Regarding concerns about the protocol's efficacy, it is possible that the limited magnitude of cognitive benefit associated with the protocol could be due to the inclusion of individuals with substantial AD-related cognitive impairment. 

For individuals with mild impairment, evidence of greater cognitive improvement was present: nearly a third of these individuals improved by four or more points on the ADAS-Cog [70]. If upheld, this finding would suggest that the neuroAD intervention is more effective in earlier disease stages, such as MCI, rather than AD. 

Where the neuroAD protocol targeted several locations serially during a session, the development of new TMS coils has also allowed the simulation of multiple cortical areas simultaneously. 

The ability to broadly stimulate bilateral frontal, temporal, and parietal areas has been explored with "H"-style TMS coils. Specifically, 10 Hz rTMS has been applied using an H coil for twelve consecutive sessions in individuals with AD [67]. Improvements were noted in ADAS-Cog scores but not in several other measures (MMSE, depression, or caregiver ratings of subjective improvement).

4. Developments Relevant to Treating Memory loss with rTMS

Approaches using rTMS to treat memory loss have evolved substantially over the last two decades, as have insights from neuroscience regarding functional brain organization, neurodegenerative diseases, and brain mechanisms supporting memory processes. These developments are important considerations for investigators designing new rTMS interventions for memory loss. 

Furthermore, the integration of key concepts into new paradigms could improve the efficacy and reproducibility of future rTMS research. Here, we review some key developments including acknowledgment of the brain's large-scale functional networks, computational modeling of rTMS stimulation fields, and frequency-specific effects of rTMS.

4.1. Functional Brain Networks

The last decade has seen a tremendous expansion of the field's understanding of the brain's intrinsic functional organization. Readily identifiable, large-scale functional brain networks have been reliably observed both in group studies and at the level of individual participants [105,106]. 

This development may offer benefits for rTMS approaches similar to those provided by stereotactic alignment of structural MRI data with the physical brain: improved rigor and reproducibility through precision alignment to previously identified stimulation targets. 

Here, a key concept is the identification of stimulation targets using individualized maps of functional networks overlaid onto the physical brain. Similar targeting has already been applied with success in rTMS studies seeking to treat depression [107,108]. 

If implemented, this approach could supplement and refine earlier approaches that identify targets based on physical distance, gross neuroanatomical landmarks, or coordinate-based targets derived from brain atlases. 

Acknowledging functional network architecture in the design of rTMS interventions will help to ensure that the same functional network is being stimulated across different participants. For example, while dlPFC has shown promise as an rTMS target for treating memory loss [35,41,74], dlPFC is a large region of the association cortex that includes several distinct functional networks [105,106]. 

Furthermore, the territory of these networks varies between individuals [109,110]. Stimulation of the same dlPFC location based on neuroanatomy or template-derived coordinates could therefore affect a different selection of functional networks between subjects unless targets are selected for each participant according to their brain's unique functional organization. 

A related consideration is that stimulation of different functional networks would be expected to affect different cognitive processes. A strong implication of rTMS not guided by functional network consideration is that cognitive benefits of rTMS interventions could vary between individuals as a function of the stimulated networks rather than stimulation efficacy per sse 

Alternatively, otherwise similar cognitive benefits might be attributable to changes in different cognitive processes between individuals. Taking memory performance as an example, deficits in executive functions [111,112] or depressed mood [113] have been associated with memory impairments, so by inference, rTMS-associated improvements in executive functions or mood might be expected to enhance apparent memory performance, but without affecting underlying memory processes. 

While positive outcomes for patients are always welcome, the interpretation of this type of finding could be confounded if superficially similar outcomes are attributable to different mechanisms. Integration of functional neuroimaging data into new TMS protocols to support network-specific targeting could help to avoid this specific confound. 

While integration of functional neuroimaging data in rTMS intervention design is expected to enhance rigor, approaches to processing neuroimaging data can vary greatly and affect interpretation. It has been well documented that even when using the same dataset, different groups can generate significantly different findings [114]. 

This is not surprising because the number of possible analysis paths available to investigators is enormous; one recent report estimated that a typical fMRI dataset might afford nearly 7,000 unique analysis pipelines [115]. Thorough documentation of all steps of functional neuroimaging analysis is therefore essential, and widely-used workflows for analysis might be considered. 

For example, the Human Connectome Project [116] provides a standardized "minimal preprocessing pipeline" for structural and functional MRI data that appears to deliver reliable results [117]. This and similar pipelines can provide investigators with a predetermined workflow for MRI data processing, ensuring that all groups perform the same steps in the same order. 

Also, the adoption of a common approach to analyzing neuroimaging data could reduce a significant source of heterogeneity for rTMS interventions that include neuroimaging outcomes.

4.2. Modeling of TMS Field Locale/Stimulation Strength

Selection of TMS stimulation sites can be refined by anatomical and functional considerations as described above, and recent advances in computational modeling of electrical fields induced by non-invasive brain stimulation techniques (including TMS but also transcranial electrical stimulation) may support still further enhancement. 

Tools such as the SimNIBS toolkit [118] allow researchers to model the induced magnetic and electrical fields for an individual brain based on structural imaging data. The models then estimate the spatial extent of brain tissue affected by each TMS pulse. 

These estimates are important when considering the anatomical locality of the stimulation produced by a set of TMS parameters. Model estimates of stimulation extent may also help investigators understand which functional brain networks are most likely to be affected by TMS at a specific location. In combination with processed functional neuroimaging data, simulation models can highlight functional networks that are most likely to be affected by TMS at a specific location. 

New studies could benefit from this approach, and previous studies might benefit retroactively if the necessary data (structural MRI, resting-state fMRI, stimulation coordinates, and stimulation intensity) were collected.

4.3. Stimulation Frequency and Patterning

Historically, rTMS frequencies have sometimes been dichotomized into either "excitatory" or "inhibitory" stimulation [21] as a function of stimulation frequency (1 Hz vs. 1 Hz, respectively). Classification as excitatory or inhibitory has been driven by changes observed in the motor-evoked potential following rTMS to the primary motor cortex. 

Unfortunately, this simple scheme for classification may be overly reductionist, not addressing potentially important complexities while limiting the exploration of new rTMS protocols. We respectfully suggest that the current "excitatory vs. inhibitory" dichotomy might benefit from a different characterization: high-frequency vs. low-frequency stimulation. 

Our suggestion for revised terminology arises from the neurophysiology of TMS. Crucially, it is not the case that "excitatory" stimulation causes an overt response at the rTMS target while "inhibitory" stimulation suppresses this response. Rather, irrespective of stimulation frequency, some neurons at the target location depolarize, making "inhibitory" a mischaracterization of the stimulatory effect from the standpoint of a cellular response. 

Findings from active rTMS, or rTMS performed during task performance, also weigh against the historical labeling of rTMS protocols. Active rTMS has been reported to invert the expected rTMS response [21,40,119,120]. 

That is, during active rTMS, typical "inhibitory" rTMS protocols have been associated with improvements in cognitive performance in some cases, whereas the same protocol at rest would be associated with reduced performance. "Excitatory" protocols similarly have been reported to swap responses in active conditions further supporting that such classification may be improper. 

Finally, evidence from studies applying physiological considerations in rTMS protocol determination also suggests that these classifications may be unfitting. One example of the importance of physiological considerations is "inhibitory" rTMS to the right dlPFC. In this instance, it has been observed that following rTMS, episodic memory performance is reported to significantly increase despite the "inhibitory" classification of stimulation [33,84]. It is important to note that right dlPFC does exhibit increased connectivity associated with reduced cognition [85,86]. 

In this way, although the "inhibitory" protocol improved cognition, it may have also acted to reduce the associated increase in connectivity. From a RSFC standpoint, "inhibitory" rTMS may be properly named in this instance, but the opposing cognitive outcomes add unnecessary confusion to the rTMS field. In this way, the classification of rTMS frequencies into "excitatory" or "inhibitory" addresses a few specific instances and may inaccurately map onto neurophysiological (or other) outcomes. 

As recent studies have enriched our understanding of how brain tissues and brain networks respond to rTMS frequencies and patterns, investigators now have a larger menu of frequencies from which to choose along with a better understanding of likely effects on underlying brain activity. For example, high-frequency rTMS protocols have been associated with increased within-network connectivity of a targeted functional network [42,50]. 

This may be an important consideration for efficacy because,se in other work, stronger within-network connectivity has been associated with better cognitive outcomes in neurological diseases such as stroke [121]. Meanwhile, low-frequency rTMS has sometimes been associated with decreases in within-network connectivity accompanied by increases in between-network connectivity [42,84]. 

While this association may not be as robust as the association of high-frequency rTMS with stronger within-network connectivity, the potential for frequency-dependent effects on connectomic measures presents exciting possibilities for basic and clinical research. Regarding the effects of different frequencies within the "high" or "low" categories, little is known. 

Very few published studies have measured whether different rTMS frequencies with the same expected activation valence (e.g., high-frequency, 10 Hz vs. 20 Hz) produce different effects. Instead, published work has more often contrasted high and low frequencies or the same stimulation frequency at one stimulation location versus another [42,44,50]. 

This gap in the literature may be important because the few publications on the topic suggest that varying stimulation frequency can affect cognitive outcomes. In one important demonstration, rTMS at 20 Hz and iTBS were associated with different cognitive outcomes following one session of rTMS targeting left AG [53]. 

Future research on rTMS methods may help to titrate stimulation frequencies and patterns that combine continued safety with greater efficacy. For the immediate future, new interventions may benefit by simply acknowledging the expected strengthening of within-network connectivity associated with typical high-frequency rTMS.

5. Suggestions for Studies Using rTMS to Treat Memory Loss

While rTMS shows promise as a potential intervention to enhance declarative/ relational memory abilities or to treat memory loss (age-related or pathological), substantial between-study heterogeneity in design has made direct comparisons difficult. 

Here, we will close our review by discussing study design features and rTMS parameters that we expect will enhance the rigor, reproducibility, and efficacy of new investigations. 

These include but are not limited to, selecting a functional network to target, finding suitable stimulation locations within that network, thoughts on TMS coil placement, selection of rTMS frequency to utilize, numbers of rTMS sessions, and the importance of longitudinal follow-ups.

5.1. Stimulation Site Selection

Any rTMS study must select one or more stimulation sites. Predictably, stimulation at different sites has been associated with different cognitive and behavioral outcomes. Acknowledging this, studies focused on memory enhancement or treatment of memory loss should select one (or more than one) site previously associated with memory abilities. 

Based on prior work and insights from the normative functional organization of the brain, we offer two broad insights and several more specific recommendations. Perhaps our strongest recommendation is that investigators should consider selecting targets based on functional network locations in addition to structural features or coordinates. 

The parallel, interdigitated nature of the brain's functional networks [122] makes reliably targeting a specific network through structural features impractical. 

Conversely, functional targeting is a relatively simple enhancement that can be readily implemented [107,108]. Regarding which networks to target, two may be especially important for normal memory function [24,123]: the default mode network, which is often described as including the medial temporal lobes and hippocampus, structures essential for normal memory; and the frontoparietal network [90], which has been frequently implicated in fMRI studies observing "subsequent memory effects" (increases in activation related to remembered versus forgotten items). 

Importantly, functionally determined rTMS targets could potentially be derived from resting-state or task-based neuroimaging data (or both); each offers advantages. Resting-state fMRI is relatively easy to collect from most populations and affords the opportunity to readily identify intrinsic networks [124–126]. Alternatively, task-based fMRI, perhaps collected during memory task performance, might offer even more refined targets because of the direct association with memory performance [127]. 

In either case, individualized stimulation targets derived from the analysis of functional neuroimaging data are strongly predicted to provide more consistent results than other approaches. 

Turning to specific cortical locations, one possibility is the left posterior lateral parietal lobule, or more specifically, left AG. Left AG is a region the of association cortex that has well-characterized structural connections with the medial temporal lobe and RSFC with the hippocampus [22]. This connectivity and the necessity the of hippocampus for normal memory functions [26,128] make left AG an appealing target. 

As reviewed here, significant prior work has demonstrated that rTMS of left AG can improve declarative/relational memory in healthy young and healthy older participants [12,13,51,58]. 

Additionally, stimulation of left AG does not have any known association with relief from depressive symptoms or executive functions, potential confounds related to stimulating other sites (e.g., dlPFC). rTMS of left dlPFC has also been previously associated with improved memory performance. 

However, the above concerns regarding potential confounds related to mood and executive functions may apply to stimulation of this region. Irrespective of which location is selected, we strongly recommend individual targeting of a specific functional network rather than a location guided by simple distance, neuroanatomical features, or transformed atlas coordinates.

5.2. Stimulation Site Targeting

Less complex but no less important than the selection of a stimulation site is the targeting of the stimulation site during an rTMS session. Earlier methods using EEG or scalp landmarks [37,65,100] can be substantially improved upon by TMS instruments that support real-time stereotactic alignment of structural MRI data and the participant's physical brain [53,56,58,129]. 

Extending the same stereotactic coordinates to the TMS coil allows accurate, reproducible targeting of a specific brain region during one or more TMS sessions. 

Recently, stereotactic localization of a target brain region has been further enhanced by robotic systems that can maintain precise head-coil positioning to account for head motion during rTMS sessions [129]. Whether automated or manual, stereotactic alignment systems substantially enhance experimental rigor for rTMS stud...

5.3. Frequency Selection

rTMS frequencies and protocols are dichotomized into "excitatory" (high-frequency and iTBS) or "inhibitory" (low-frequency and cTBS) frequencies [21]. While this dichotomy captures some important differences, factors beyond rTMS frequency also contribute to the excitatory or inhibitory influence of rTMS. One such factor is the underlying physiology of the rTMS target and the functional network to which it belongs. 

rTMS of right dlPFC is a prime example of the role target physiology can play. Multiple reports suggest that 1 Hz rTMS of right dlPFC caused significant improvement in cognitive abilities [33,82–84]. 

That might be consistent with an "excitatory" influence of an "inhibitory" frequency. Whatever the underlying mechanism, this outcome exemplifies the complex relationship between rTMS parameters and cognitive outcomes. Neurophysiological considerations may also provide insight into what rTMS frequencies may generate potent responses. 

For example, Chung and colleagues investigated whether iTBS at a frequency matched to an individual's brain activity would outperform the "excitatory" 50 Hz iTBS rTMS [130]. While both the individual and 50 Hz iTBS were reported to significantly improve cognition, individualized iTBS was also associated with significant changes in EEG measures. 

These reports illustrate the potential impact of neurophysiological considerations on rTMS outcomes. Stimulation frequency is an rTMS parameter that could benefit from more study, including refinement of methods for determining individualized stimulation frequencies based on observed neurodynamics of a given brain.

5.4. Number of Sessions

Perhaps the greatest degree of consensus in the rTMS literature lies in the number of rTMS sessions necessary for reliable memory enhancement. Specifically, multiple consecutive days of rTMS appear to be necessary to reliably observe improvements in memory performance that endure for one or more days after stimulation. 

Regarding the absolute number of sessions required, some research has been conducted with the explicit goal of dose estimation. Following up on prior work that tested the effects of rTMS applied to left AG, one study estimated that a minimum of five sessions was required for benefits to memory performance [51], while a similar study by the same group estimated that as few as three simulation sessions was adequate to observe significant changes in RSFC between the stimulation site in left AG and the hippocampus [60]. 

To the best of our knowledge, these two studies are the only published works examining the effects of different numbers of rTMS sessions for left AG rTMS. More research the on dosing of rTMS to treat memory impairment would be helpful. However, based on these dose-finding studies and other studies reporting significant changes after left AG stimulation, a minimum of five stimulation sessions appears to be a reasonable criterion [51,60]. 

Notably, ongoing clinical trials in patients with MCI or AD may incorporate even more sessions, such as t20-weekday day sessions during a period of 2 to 4 weeks" in a trial by Taylor and colleagues [93].

5.5. Longitudinal Follow-Up

rTMS therapies for memory would be most beneficial if the effects endured for some prolonged period after stimulation. Unfortunately, many rTMS publications do not report longitudinal measures. Without longitudinal follow-up, the durability and dose-response curves of rTMS therapies are impossible to determine, and this creates challenges for future efforts to translate rTMS research to clinical applications. Collection of longitudinal follow-up measures, perhaps one, three, and six months after completion of an rTMS protocol, would be a welcome addition to the design of future studies.

5.6. Methodological Heterogeneity Versus Discovery Science

We have noted the heterogeneous methodologies of rTMS interventions for memory, and we have suggested that this creates challenges for interpretation and generalization. In that context, the suggestions we offer in this section of our review are intended to highlight opportunities for investigators to enhance their study designs based on recent advances and best practices. 

However, we do not wish to promote a rigidly proscriptive methodological homogeneity; the field of rTMS for memory (or other cognitive) enhancement is much too young to suggest that any single approach is optimal. Discovery science and exploratory research remain essential to progress in rTMS interventions for memory. 

So, while departures from typical rTMS protocols should be well-justified, as long as they are conducted with great scientific rigor, such efforts may well prove effective, informative, or both. Standard approaches for rTMS will only be enhanced by novel efforts, and we fully expect that a review of best practices written a decade from now would differ significantly from our current work largely due to new basic science findings.

6. Conclusions

The brain systems that support declarative/relational memory are imperfect recorders that are negatively impacted by age and disease. Potential treatments for memory loss (or interventions to enhance memory performance) would be beneficial, and published work describing rTMS interventions offers preliminary evidence that non-invasive brain stimulation offers symptom-modifying therapies. 

Our review of the current literature highlights many published examples of rTMS interventions that successfully modulated memory, often through multi-day high-frequency stimulation of regions in the frontal or parietal association cortex. Unfortunately, the current rTMS literature suffers from significant heterogeneity which creates challenges for interpretation and comparison. 

To address this, we have offered suggestions for the design of fuTMS rTMS investigation enhancing rigor and reproducibility. Our intent is not proscriptive; rather, we hope to encourage best practices that will speed the transition of rTMS-based memory modulation from laboratories to memory clinics where new therapies are sorely needed. 

By reducing methodological heterogeneity, introducing neuroimaging measures, and incorporating longitudinal follow-up, forthcoming memory-related rTMS studies have the opportunity to prove the method's validity, generalizability, and translational potential to treat clinical memory loss.

Author Contributions: Conceptualization, C.J.P., D.L.M., and D.E.W.; Methodology, C.J.P. and D.E.W.; Validation, C.J.P., D.L.M., and D.E.W.; data curation, C.J.P.; writing-original draft preparation, C.J.P.; writing-review and editing, C.J.P., D.L.M., and D.E.W.; supervision, D.E.W. All authors have read and agreed to the published version of the manuscript.

Funding: Authors CJP, DLM, and DEW received support from NIH/NIA award R01AG064247.

Conflicts of Interest: The authors declare no conflict of interest.

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