Investigating the effects of a 6-month aerobic exercise intervention on brain function and memory in older adults

Episodic memory is particularly susceptible to age-related decline. Research in animal models and cross-sectional studies in humans provide evidence that engaging in aerobic exercise may mitigate the effects of aging on memory. Yet, despite abundant evidence from animal literature, many aerobic exercise interventions in humans have failed to demonstrate improvements in learning and memory (Erickson et al., 2011a; Tamura et al., 2014; Ngandu et al., 2015). Further, we know little about how aerobic exercise affects brain function and whether functional changes are behaviorally relevant. In the present study, we investigated the effect of a 6-month aerobic exercise intervention on episodic memory retrieval using fMRI in healthy older adults. Specifically, 137 older adults (60 - 80 years of age) were randomized across four treatment groups: walking, walking plus nutrition, dance, and stretching and toning (active control). Although we found that the walking groups increased cardiorespiratory fitness (CRF) relative to the dance and control groups, there were no group differences in episodic memory. Consistent with previous studies, we found no association between change in CRF and change in memory performance. However, we did find that change in CRF, across intervention groups, was positively associated with change in hippocampal activation during recognition 'hits'. Furthermore, increased hippocampal activation was associated with improvements in memory performance. Thus, these results demonstrate a mechanism by which increases in CRF may indirectly relate to memory performance improvements in the absence of a significant behavioral effect

Aging brain mechanics: Progress and promise of magnetic resonance elastography

Neuroimaging techniques that can sensitivity characterize healthy brain aging and detect subtle neuropathologies have enormous potential to assist in the early detection of neurodegenerative conditions such as Alzheimer's disease. Magnetic resonance elastography (MRE) has recently emerged as a reliable, high-resolution, and especially sensitive technique that can noninvasively characterize tissue biomechanical properties (i.e., viscoelasticity) in vivo in the living human brain. Brain tissue viscoelasticity provides a unique biophysical signature of neuroanatomy that are representative of the composition and organization of the complex tissue microstructure. In this article, we detail how progress in brain MRE technology has provided unique insights into healthy brain aging, neurodegeneration, and structure-function relationships. We further discuss additional promising technical innovations that will enhance the specificity and sensitivity for brain MRE to reveal considerably more about brain aging as well as its potentially valuable role as an imaging biomarker of neurodegeneration. MRE sensitivity may be particularly useful for assessing the efficacy of rehabilitation strategies, assisting in differentiating between dementia subtypes, and in understanding the causal mechanisms of disease which may lead to eventual pharmacotherapeutic development

Mechanisms of amyloid-beta cytotoxicity in hippocampal network function : rescue strategies in Alzheimer's disease

The origin and nature of cognitive processes are strongly associated with synchronous rhythmic activity in the brain. Gamma oscillations that span the frequency range of 30–80 Hz are particularly important for sensory perception, attention, learning, and memory. These oscillations occur intrinsically in brain regions, such as the hippocampus, that are directly linked to memory and disease. It has been reported that gamma and other rhythms are impaired in brain disorders such as Alzheimer’s disease, Parkinson’s disease, and schizophrenia; however, little is known about how these oscillations are affected. In the studies contained in this thesis, we investigated a possible involvement of toxic Amyloid-beta (Aβ) peptide associated with Alzheimer’s disease in degradation of gamma oscillations and the underlying cellular mechanismsin rodent hippocampi. We also aimed to prevent possible Aβ- induced effects by using specially designed molecular tools known to reduce toxicity associated with Aβ by interfering with its folding and aggregation steps. Using electrophysiological techniques to study thelocal field potentials and cellular properties in the CA3 region of the hippocampus, we found that Aβ in physiological concentrations acutely degrades pharmacologically- induced hippocampal gamma oscillations in vitro in a concentration- and time- dependent manner. The severity of degradation also increased with the amount of fibrillar Aβ present. We report that the underlying cause of degradation of gamma oscillations is Aβ-induced desynchronization of action potentials in pyramidal neurons and a shift in the equilibrium of excitatory-inhibitory synaptic transmission. Using specially designed molecular tools such as Aβ-binding ligands and molecular chaperones, we provide evidence that Aβ-induced effects on gamma oscillations, cellular firing, and synaptic dynamics can be prevented. We also show unpublished data on Aβ effects on parvalbumin-positive baskets cells or fast-spiking interneurons, in which Aβ causes an increase in firing rate during gamma oscillations. This is similar to what is observed in neighboring pyramidal neurons, suggesting a general mechanism behind the effect of Aβ. The studies in this thesis provide a correlative link between Aβ-induced effects on excitatory and inhibitory neurons in the hippocampus and extracellular gamma oscillations, and identify the Aβ aggregation state responsible for its toxicity. We demonstrate that strategies aimed at preventing peptide aggregation are able to prevent the toxic effects of Aβ on neurons and gamma oscillations. The studies have the potential to contribute to the design of future therapeutic interventions that are aimed at preserving neuronal oscillations in the brain to achieve cognitive benefits for patients

Short-term memory conjunctive binding in Alzheimer's disease : a systematic review and meta-analysis

Objective: Short-term memory (STM) binding tests assess the ability to temporarily hold conjunctions between surface features, such as objects and their colors (i.e., feature binding condition), relative to the ability to hold the individual features (i.e., single feature condition). Impairments in performance of these tests have been considered cognitive markers of Alzheimer's disease (AD). The objective of the present study was to conduct a meta-analysis of results from STM binding tests used in the assessment of samples mapped along the AD clinical continuum. Methods: We searched PubMed, Scopus and Web of Science for articles that assessed patients with AD (from preclinical to dementia) using the STM binding tests and compared their results with those of controls. From each relevant article, we extracted the number of participants, the mean and standard deviations from single feature and of feature binding conditions. Results across studies were combined using standardized mean differences (effect sizes) to produce overall estimates of effect. Results: The feature binding condition of the STM binding showed large effects in all stages of AD. However, small sample sizes across studies, the presence of moderate to high heterogeneity and cross-sectional, case-controls designs decreased our confidence in the current evidence. Conclusions: To be considered as a cognitive marker for AD, properly powered longitudinal designs and studies that clearly relate conjunctive memory tests with biomarkers (amyloid and tau) are still needed

The role of cortical morphometry of functional networks in predicting age-related cognition in older adults

Over the next three decades, the 65-and-over population is projected to nearly double, increasing from 8.5% to 16.7% of the world’s total population (He, Goodkind, and Kowal, 2016). Alarmingly, despite longer life expectancies, health is not necessarily improving (He, Goodkind, and Kowal, 2016). While all organs are affected by aging, decline in the brain’s ability to function (cognitive aging) is one of the most impactful consequences of aging on day-to-day activities and one of the most common complaints of older adults (Blazer et al., 2015). In fact, in a recent survey, almost half of individuals aged 65 or older report changes in mental ability (AARP Brain Health Survey, Fall 2015). While almost all older adults acknowledge the importance of brain health, only half actually engage in activities found to be beneficial for brain health (AARP Brain Health Survey, Fall 2015). Thus, understanding individual variability in the older adult brain, both in terms of structure and function, and its relationship with cognition and age is essential (Hedden and Gabrieli 2004). Despite the well-established widespread relationships of age and cognition with cortical structure, the nature and organization of this relationship remains underspecified. In this thesis, I investigate the nature of the relationships between cortical morphometry, cognition, and age in older adults through a contemporary neuroscience lens of the brain as a system of functional networks. In chapter one, I employ a widely-used functional network architecture as the organizing principle of the cortex to investigate how the cortical morphometry of individual networks predicts cognition and mediates the age-cognition relationship in older adults (using both cortical thickness and surface area—phenotypes both implicated in relationships with cognition but not tested in the same sample of older adults). I use a machine learning and cross-validation prediction framework to compare the predictive ability of cortical morphometry of individual functional networks to age-related cognitive abilities (declarative memory and executive function). In a second set of analyses, I apply a novel inferential test to exploratory, whole brain analyses. Specifically, I examine the number of significant point-by-point regional associations within functional networks, providing a test of the spatial extent of each functional network’s relationship with age-related cognitive abilities (compared to chance). Ultimately, making impactful theoretical and practical contributions to the field requires assessing the reproducibility and generalizability of conclusions derived from data-driven techniques. Thus, in chapter 2, I test if regions robustly associated with cognitive ability (executive function) discovered in chapter 1 and regions associated with cognitive task performance discovered in a previous study (Sun et al., 2016) predict well-established cognitive reference abilities in an independent sample of older adults. General patterns of functional connectivity (i.e., group-average functional networks) across a population(s), such as the one used in Chapter 1, provide a picture of the common functional architecture and distinct functional networks across the cortex of healthy adults (i.e., Yeo et al., 2011). These group-based networks of the functional connectome were used to assess the importance of cortical structure of functional networks in Chapter 1. However, this ignores individual differences in the integrity of these functional networks and how these individual differences relate to individual differences in cortical structure. If functional connectivity causes (or is caused by) differences in mechanisms marked by cortical structure or vice versa (e.g., individual variability in older adults’ cortical thickness may be indexing the number of synapses or intracortical myelin important for connectivity between regions as is theorized in previous studies; see Fjell et al., 2015), one would expect the two to be related and share overlapping variance in their relationship with age and cognition. Thus, in chapter 3, I examine whether individual differences in functional connectivity mediates the relationship of cortical structure with age and cognitive ability (as the relationship of structure with cognition emerges as a result of the functional system measured by functional connectivity)

Shedding light on memory retrieval: reactivation of related information and its association with the hippocampus

Memory retrieval is a multifaceted process that involves the coordination of multiple areas of the brain including the cortical memory stores and the hippocampus, an area of the brain shown to be necessary for creating and using flexible bindings between items in memory. One phenomenon that has been shown to be associated with the retrieval of information from those cortical memory stores is reactivation. Reactivation is the finding that when participants retrieve information the areas that were originally active while processing that information come back online and are reactivated. In a previous study I and others had shown that associative or relational bindings between items can be used to reactivate the cortical processors of one another (Walker, Low, Cohen, Fabiani, & Gratton, 2014). The current experiments examined this reactivation of sensory cortices by looking at its association with the hippocampus, both in terms of relating the reactivation activity to structural measures of the hippocampus but also to possible methods by which the hippocampus and sensory cortex communicate. Additionally, this reactivation phenomenon was studied across the lifespan by demonstrating the earliest known time at which infants show this pattern of reactivation as well as showing aging effects in the possible communication between the hippocampus and sensory cortices and subsequent reactivation. The first experiment establishes an association between the hippocampus and reactivation of relationally bound stimuli in older adults aged 55-88 years old. In this study participants learned pairs of faces and scenes and were then shown one of the items (in this case the scene) in order to elicit reactivation of face processing regions. It was found that the magnitude of reactivation in these older adults is related to hippocampal volume. Entrainment of oscillatory activity, particularly in the theta band, has been suggested as a possible route through which the hippocampus communicates with sensory cortices. The second experiment combined data from two previous studies using the same face-scene pair study paradigm and examined whether oscillatory activity in the theta band was associated with memory ability and reactivation. Across all participants, the power of theta and oscillations (8-10 Hz) just above canonical theta (high theta) within the face processing regions was correlated with subsequent memory activity. When looking at the correlation between oscillatory power and reactivation, it was found that oscillatory power in that high theta band in the face processing region of interest was positively correlated with reactivation of that same region but only in young adults. Older adults showed no correlation between oscillatory power in the theta or high theta band and reactivation. These data indicate a possible route through which the hippocampus communicates with the cortex. The third study shows the earliest time in the lifespan to show reactivation effects in the cortex to stimuli that were presented only once. 9-month-old infants studied pairs of movie clips and sounds as well as sounds only and movie clips only. Much like the older and younger adults, presentation of a sound that was previously paired with a movie elicited reactivation of processors for the missing item (in this case reactivation of extrastriate cortex that was originally active for the movie clips) in these infants. The combination of these experiments show that this relational reactivation phenomenon takes place across the lifespan from 9 months old to 88 years old and is associated with the hippocampus. Oscillatory activity, which may represent the communication between the hippocampus and the sensory cortex, is associated with reactivation but this association is not present in old age

Brain Mechanisms of Adaptive Memory: Neuromodulation and Behavior in Humans

A fundamental question in the study of memory is: Why do we remember some events but forget others? It has been proposed that people preferentially remember motivationally relevant information, as these memories may be useful in guiding choices in the future, a framework called adaptive memory. This dissertation examined the brain mechanisms that support adaptive memory, specifically focusing on how memory is shaped by rewards and dopamine, using a combination of pharmacological manipulations and behavioral assays. First, we found that rewards retroactively prioritize memory for preceding neutral events, and consistent with models of hippocampal replay, two periods of consolidation are necessary for this effect: a period of rest immediately following encoding and overnight consolidation. Second, motivated by research showing that neurotransmitters, such as dopamine, potentiate motivationally relevant memories to endure over long durations, we administered d-amphetamine (a dopamine agonist) before encoding. We found that when hippocampus dependent memory is tested after a short delay, working memory best accounts for memory performance, but when tested after a long delay, d-amphetamine level directly predicts memory performance. And third, we tested how d-amphetamine modulates different memory systems after a delay, using two different behavioral paradigms in which participants learned about overlapping associations using either stimulus-response learning or deliberate associative encoding. In both experiments, we found that d-amphetamine during encoding enhanced test performance on the trained items a week later; however, we did not detect any evidence that d-amphetamine modulates the integration of the overlapping pairs. Together, the work reported in this dissertation suggests that memory for motivationally relevant information is prioritized, dopamine enhances performance across different memory and learning systems, the effect of both reward and dopamine on memory and learning emerge after consolidation, and dopamine does not bias the hippocampus to encode memories in an integrated manner

Organization of spatiotemporal information and relational memory in the hippocampus

This work examines the role of the hippocampus and relational memory in organizing episodic memory during navigation and reconstruction. Navigation is a critical component in most organisms’ survival. Reconstruction, on the other hand, provides an incredibly rich method of evaluating the precise information remembered by an individual after attempting to learn and remember that information. Through validating the computational framework in this work on amnesic patients with hippocampal damage, an understanding of some of the specific types of relations which rely on the hippocampus can be established. Then, this framework can be applied to a much more complex, spatiotemporal navigation and reconstruction task in healthy individuals to gain a wider perspective on the organization of episodic memory, which is known to critically rely on the hippocampus. The first experiment and associated analysis framework presented in this document (Chapter 2) uses spatial reconstruction to establish that not all types of spatial relations are impaired in hippocampal damaged patients. In particular, the arbitrary, identity-location relations (i.e. those relationships where the element being bound could have just as easily been anything) are critically impaired in hippocampal damaged patients while location information, disregarding identity, is not. The use of reconstruction in this context allows for the establishment of a set of critical computational metrics which relate to hippocampal function in reconstruction which can then be applied to other reconstruction tasks in healthy individuals to learn more about the wider structure and organization of memory. In the second experiment (Chapters 3 and 4), the methodologies which were applied to hippocampal damaged patients in the first experiment are applied to a novel Spatiotemporal Navigation Task in healthy young adults. In this task, participants are not just asked to study and reconstruct items in space, but instead, participants are asked to, in Virtual Reality, navigate space and time (via normal movement and simulated Time Travel) and study, then reconstruct the locations of events in spacetime. The computational framework established in the previous chapter is then applied to show that relational memory errors in time are far more common in this task than in space, suggesting differences in representations between these two domains even when the navigation and exploration of the domains are put on a more equal footing. Additionally, in time, these relational memory errors are far more likely to occur within a shared contextual region than should occur by chance. In fact, this error (temporal relational memory error within a context) gets worse across the first 3 trials, suggesting a systematic bias due to context. Finally, a more traditional bias, the context boundary effect (i.e. a “squishing” of within context temporal locations and “stretching” of across context temporal locations) is observed even though participants are allowed to reexplore the contexts arbitrarily, multiple times. This suggests that the context boundaries are having a profound impact on both the distance judgements and relational memory structure associated with events in spacetime. Finally, in the fourth chapter, the navigation component of the previous Spatiotemporal Navigation Task is examined to determine if changes in study time navigation and exploration relate to changes in the various test metrics discussed in the previous chapter. More rapid improvements in spatial and temporal navigation are shown to relate to more rapid improvements in memory in those domains, separably, suggesting that spatial and temporal representations may in some way be separable in this task in both the relational representations and the navigation strategies supporting those representations. Relational memory improvements are shown to be uniquely tied to changes in navigation complexity and systematicity, pointing to an interplay between in-the-moment, memory-guided decision making and subsequent relational memory efficacy. Context boundaries are suggested to act as more of a discriminatory feature (at least in this task) than one used to strengthen within-context relational memory organization accuracy as there is a significant relationship between changes in context boundary crossing and both the context boundary effect and across-context temporal relational memory errors. Finally, a preference towards exploring an otherwise temporally-flexible environment in the implied, forward order with increasing contiguity is suggested to be a critical element in improving temporal, relational, and contextual memory organization. Taken together, this work shows the richness of spatiotemporal navigation and reconstruction in observing the complex interplay between navigation in space, navigation in time and how these ultimately may relate to navigation in memory. Through embracing principled approaches to analysis of behavioral data, and the inclusion of complex behavioral mechanics (such as simulated time travel), this work extends our understanding of the role of hippocampal relational memory and overall memory organization