Sinha N, Berg CN, Yassa MA, Gluck MA. Increased dynamic flexibility in the medial temporal lobe network following an exercise intervention mediates generalization of prior learning. Neurobiol Learn Mem. 2021;177:107340.
To examine the effect of exercise on cognitive function—specifically, if exercise increases network flexibility in the medial temporal lobe (MTL) and if this predicts improved performance on cognitive tasks associated with MTL flexibility.
Two-group, nonrandomized, matched control trial of a 20-week, dance-based aerobic exercise program vs “treatment as usual.”
Participants included 34 healthy adult participants (31 female, 3 male), aged 55 years or more. Researchers gathered participant data from a parent study investigating best ways to implement culturally appropriate exercise interventions in African American populations.
Study Parameters Assessed
The study measured a number of assessments at baseline and at the end of the intervention period:
- Standardized neuropsychological testing (Mini-Mental State Exam [MMSE], Rey Auditory Verbal Learning Test [RAVLT], North American Adult Reading Test 35 [NAART35], Wechsler Adult Intelligence Scale 4th Edition [WAIS-IV])
- Physical health assessment (including body mass index [BMI])
- Aerobic fitness assessment (6-minute walk)
- Acquired equivalence task (which tests generalization of prior learning association)
- Functional magnetic resonance imaging (MRI)
Primary Outcome Measure
The primary outcome measure of the study was the effect of exercise on network flexibility in the MTL, as measured by functional MRI. Secondary to this was whether the effect of exercise on the MTL flexibility correlated to improved performance on assessment of generalization tasks, as measured through comparative errors on the acquired equivalence task test.
There were statistically significant greater declines in errors in the generalization tasks of the acquired equivalence test in the intervention group compared to the control group from baseline (P=0.018). There were no significant differences between groups at baseline or at the end of the intervention on the training and retention aspects of the acquired equivalence test.
There was a statistically significant increase in MTL network flexibility in the intervention group from baseline (P=.038). This increase was negatively correlated with increases in generalization errors (P=.003), inferring that the better performance on generalization tasks was associated with an increase in MTL flexibility.
There were no significant changes in the standardized neuropsychological testing, the aerobic fitness, or the BMI of the participants after the 20-week exercise intervention.
The cognitive benefits of exercise are well-documented, and as research explores these connections further, more focus is being drawn to how exactly these benefits manifest. The medial temporal lobe and hippocampus are primary sites for the neurodegenerative changes observed in Alzheimer's disease,1 and localized deficits were historically thought to be how the disease develops. However, a shift in the understanding of the disease process now suggests that dysfunction in the interactions between networks might better explain the pathogenesis.2 Resting-state functional connectivity may be a strong predictor of risk of developing Alzheimer's disease or other cognitive impairments; the repeated and/or hyperactive use of the same regional network pathways (synchronisation) has been linked with cognitive decline,3,4 while network flexibility (a region’s ability to communicate with multiple network pathways) is associated with neuroprotection and enhanced cognitive performance.5 Unique to this study was evaluating this network flexibility within the MTL region itself in response to exercise.
The functional MRI results from this study clearly demonstrate a significant impact on MTL flexibility in the intervention group compared to the control. There was an approximately 50% increase in the measure of MTL network flexibility in the intervention group, with no change in the control group. While exercise seems like the obvious reason for this effect, attention should be given to the aspects of social interaction and community involvement that may have contributed to the benefits of this intervention. The treatment group in this study participated in a 20-week, group-dance-aerobics class, meeting twice weekly for 60-minute sessions. Over the course of the program, it is reasonable to assume that participants interacted with each other socially at the classes and potentially outside of them, as well. Social isolation has been associated with cognitive decline,6 so the mental stimulation provided through social interactions, especially new ones, might have also contributed to the positive cognitive effects of the intervention. Especially as the “treatment as usual” group was not engaging in this extra social activity every week and did not show any improvements, it is quite possible this played a beneficial role for those in the intervention group.
There was almost a 50% reduction in the average number of errors on the generalization tasks in the intervention group, while the average scores of the control group actually worsened from baseline.
It is also interesting to consider if the form of exercise intervention could have impacted results. Dance aerobics are generally fun and create a positive atmosphere, and the actual practice may be more mentally stimulating (eg, learning routines, frequently incorporating new movements) than other monotonous forms of physical activity. It is possible that the type of exercise intervention may be quite variable in terms of its impacts on cognitive health if these other aspects have varying degrees of influence as well.
The most clinically relevant assessment in this study that showed significant changes with exercise was the acquired equivalence generalization task. This assessment involves the training of an individual to identify associations between sets of images and is learned through repeated example tests with feedback in the first phase of the assessment. Once the test taker has learned the association “rule,” the test giver administers the tests without feedback in the second phase. Some of the tests are the same as previous examples provided during training (retention), while others have new associations that follow the same rule that individuals should be able to recognize (generalization). Retention is being able to repeat the same outcome as was taught exactly the same way before. Generalization is predicting the same outcome for something that is not the same as before, but equivalent. This assessment is relevant because prodromal Alzheimer's disease has been associated with regular scores on the training and retention aspects of the test, but poor scores on generalization.7 (It’s interesting to note that Parkinson disease patients demonstrate the opposite trend—poorer learning, but normal generalization.8) The fact that exercise showed a significant impact and association between cognitive and neural function in this way makes MTL flexibility not only a compelling target for Alzheimer's therapies, but it may become more widely used in the screening and early detection of the development of the disease.
Worth noting is the relatively short amount of time it took to have such a significant impact on this aspect of neurocognitive function. There was almost a 50% reduction in the average number of errors on the generalization tasks in the intervention group, while the average scores of the control group actually worsened from baseline. This would imply that the benefits of exercise intervention on cognition do not require implementation for many years in advance in order to have an impact. “It’s too late for me” may not be a reasonable excuse.
The results of the study also bring to awareness the idea that we need to appreciate exercise for more than just its potential benefits to physical health and the measures we use to assess physical health (such as weight loss), because while exercise may not always offer these visually objective changes as quickly as we hope, its impacts on our cognitive health may be much sooner realized.
Some methodological considerations to note when appraising this study include the fact that the majority of participants were women. We know the physical effects of exercise can differ significantly based on biological sex, so the extrapolation of these results to men is questionable when they were so underrepresented. While the sample size was small, the statistical significance of the results, especially when collapsed amongst all groups, still makes this study valuable. Lastly, all participants in this study were African American, which may influence the applicability of results to other races. The authors of this study acknowledge some significant differences in research outcomes for exercise interventions between age, biological sex, and race.9-11 Balanced against this is the fact that African Americans comprise the racial demographic with the highest rates of Alzheimer's disease,12 though the social awareness, medical attention, and patient research regarding this fact are extremely lacking.13 As such, research specific to this group is warranted and needed.
While the parent study to this trial, the Rutgers University–Newark African-American Brain Health Initiative, is not the subject of this report, clinicians and researchers would benefit from reviewing it, as it discusses ways to overcome obstacles to participation in research from marginalized groups.14 Due to a history of healthcare injustice and abuse that is still current, engaging oppressed communities, like the older urban African American population in this study, through conventional research recruitment approaches may not be as effective as working with cultural institutions and community leaders to facilitate the participation process. If implemented responsibly, this approach can help to repair distrust of the medical system over time and bring to groups more positive research and/or medical opportunities that were not as accessible to them before. There is still opportunity to do harm in this paradigm; communities and their leaders must be approached as people to work with, not manipulate. Long-term relationship building should be the goal.
If you work specifically with individuals with Alzheimer's disease or with older populations, or have a clinical interest in neurocognitive decline, assessing and enhancing MTL flexibility may be an important part of supporting your patients. The Rutgers Acquired Equivalence Test (Fish-Face Test) is the computer-based acquired equivalence test used in this study and in many others for evaluating this aspect of MTL functionality, “mnemonic flexibility,” and generalization. However, its use in the clinical setting has not been validated, and sourcing the program is not readily available. Though similar versions can probably be recreated, scoring and interpreting the results may not be straightforward, so the clinician’s capacity to evaluate this may be difficult in the general practitioner’s office. Similarly, access to functional MRI for determining MTL flexibility may not be a tool we can use readily.
While the direct benefit from exercise has been demonstrated in this study and warrants recommendation, other natural therapies that may enhance the functional flexibility of the MTL should also be considered in these patients. Functional MRI studies to evaluate this activity in humans receiving natural agents are limited, but currently the Australian Research Council Longevity Intervention (ARCLI) is evaluating these neuroimaging targets (including MTL functionality) in healthy, older adults receiving pycnogenol and bacopa, as well as comparing this neurocognitive activity against gut microbiome profiles.15
As clinical neuroscience continues to evolve, more attention will center on these particular aspects of network flexibility for better informing treatments and in diagnosis and monitoring. Now that these associations have been well-established, efforts should focus on developing validated and standardized clinical tools to bring these methods of early detection into the primary care setting. Other treatments, previous and novel, may also benefit from specific investigation into their effects on MTL flexibility and assessed generalization ability to validate their therapeutic potential.
- Wenk GL. Neuropathologic changes in Alzheimer’s disease. J Clin Psychiatry. 2003;64 Suppl 9:7-10.
- Delbeuck X, Van der Linden M, Collette F. Alzheimer’s disease as a disconnection syndrome? Neuropsychol Rev. 2003;13(2):79-92.
- Salami A, Pudas S, Nyberg L. Elevated hippocampal resting-state connectivity underlies deficient neurocognitive function in aging. Proc Natl Acad Sci U S A. 2014;111(49):17654-17659. 1
- Berron D, van Westen D, Ossenkoppele R, Strandberg O, Hansson O. Medial temporal lobe connectivity and its associations with cognition in early Alzheimer’s disease. Brain. 2020;143(4):1233-1248. 8
- Jia H, Hu X, Deshpande G. Behavioral relevance of the dynamics of the functional brain connectome. Brain Connect. 2014;4(9):741-759.
- Shankar A, Hamer M, McMunn A, Steptoe A. Social isolation and loneliness: relationships with cognitive function during 4 years of follow-up in the English Longitudinal Study of Ageing. Psychosom Med. 2013;75(2):161-170.
- Bódi N, Csibri E, Myers CE, Gluck MA, Kéri S. Associative learning, acquired equivalence, and flexible generalization of knowledge in mild Alzheimer disease. Cogn Behav Neurol. 2009;22(2):89-94.
- Myers CE, Shohamy D, Gluck MA, et al. Dissociating hippocampal versus basal ganglia contributions to learning and transfer. J Cogn Neurosci. 2003;15(2):185-193.
- White J, Jago R. Prospective associations between physical activity and obesity among adolescent girls: racial differences and implications for prevention. Arch Pediatr Adolesc Med. 2012;166(6):522-527.
- Allard JS, Ntekim O, Johnson SP, et al. APOEε4 impacts up-regulation of brain-derived neurotrophic factor after a six-month stretch and aerobic exercise intervention in mild cognitively impaired elderly African Americans: a pilot study. Exp Gerontol. 2017;87(Pt A):129-136.
- Hickner RC, Privette J, McIver K, Barakat H. Fatty acid oxidation in African-American and Caucasian women during physical activity. J Appl Physiol (1985). 2001;90(6):2319-2324.
- Matthews KA, Xu W, Gaglioti AH, et al. Racial and ethnic estimates of Alzheimer’s disease and related dementias in the United States (2015-2060) in adults aged ≥65 years. Alzheimers Dement. 2019;15(1):17-24.
- Denny A, Streitz M, Stock K, et al. Perspective on the “African American participation in Alzheimer disease research: Effective strategies” workshop, 2018. Alzheimers Dement. 2020;16(12):1734-1744.
- Gluck MA, Shaw A, Hill D. Recruiting Older African Americans to Brain Health and Aging Research Through Community Engagement: Lessons from the African-American Brain Health Initiative at Rutgers University-Newark. Generations. 2018;42(2):78-82.
- Simpson T, Deleuil S, Echeverria N, et al. The Australian Research Council Longevity Intervention (ARCLI) study protocol (ANZCTR12611000487910) addendum: neuroimaging and gut microbiota protocol. Nutr J. 2019;18(1):1. Published 2019 Jan 5. doi:10.1186/s12937-018-0428-9