Search

Memory decline is characteristic of cognitive ageing and it has been suggested that one important factor underpinning the magnitude of age deficits is a reduction in the fidelity or quality of perceptual and mnemonic representations. This thesis examined cognitive and neural underpinnings of individual differences in representational quality in healthy ageing and individuals at increased risk for cognitive decline to evaluate the potential of fidelity metrics for the early detection of memory impairment. Chapters 2 and 3 demonstrate that the ability to discriminate targets from highly similar lures in memory generally declines with age and in non-clinical older adults at risk for mild cognitive impairment. Importantly, the contribution of executive functions and the quality of perceptual representations to individual differences in mnemonic discrimination depends on the degree to which tasks provide retrieval support. Even when familiarity-based responding can be relied upon, memory deficits remain in both cognitively normal and at-risk older adults, suggesting that demands on complex stimulus representations are a key determinant of age-dependent memory deficits. Structural markers of medial temporal lobe regions contributed little to individual differences in mnemonic discrimination and complex perception. Chapter 4 shows that age-related declines are already present in midlife provided a task requires complex, precise stimulus representations. In contrast, ageing may spare the accessibility of coarse-grained representations, suggesting that memory decline was not due to forgetting but due to a decline in the availability of stimulus details. These age-related declines in high-quality representations were ubiquitous across tasks of perception, short- term and long-term memory. Chapters 5 and 6 tested whether tasks of mnemonic discrimination of highly similar objects and precision for object-location relational binding are sensitive to risk for Alzheimer's disease and resilience against memory decline. Neither family history nor genetic risk for late-onset Alzheimer's disease were associated with a decline in representational fidelity among cognitively unimpaired middle-aged and older adults. Cognitive reserve as measured based on a socially engaged and cognitively active lifestyle was associated with better long- term memory regardless of demands on representational quality. These findings demonstrate that ageing is associated with cognitive decline in any task that indexes the fidelity of complex stimulus representations. This reduction in representational quality is already present at midlife. The results also underscore the utility of representational fidelity measures for future investigations into individual differences in memory decline in both healthy and at-risk ageing.

The aim of this thesis is to examine the underlying cognitive and neural processes at play during retrieval of temporal and contextual source information. This was assessed across three experimental chapters. In the first experimental chapter, Chapter 2, the neural loci of context associations were assessed. Rats trained on an odour-context association task were given lesions to either the Lateral Entorhinal Cortex (LEC) or sham lesions. After surgery, performance on the odour-context task was assessed. It was hypothesised that memory for previously learned odour-context associations would be impaired following LEC lesions but not sham lesions. The results supported this hypothesis, demonstrating impaired memory for the previously learned odour-context associations in the LEC lesion group compared to the Sham lesion. In Chapter 3, the underlying retrieval processes used to retrieve time and context in human memory was assessed across three experiments. It was hypothesised that time would be remembered accurately using both recollection and familiarity, while correct context memory should rely on recollection alone. Two out of the three experiments supported this hypothesis, demonstrating that temporal information can be retrieved using familiarity in certain instances. The final experimental Chapter 4 used fMRI to extend Chapter 3 and examine whether neural activity would be greater in regions associated with recollection during memory for context, while activity in familiarity-related regions would be higher during memory for time. Results revealed no support for these predictions with no regions linked to recollection showing greater context-related activity, and no regions previously linked to familiarity exhibiting increased activation as temporal information was retrieved. The results are discussed in relation to established recollection and familiarity frameworks and previous work examining the neural substrates supporting memory for time and context.

Recollection, the process by which an item provokes the retrieval of associated information stored in the brain, is a key component of recognition memory. It is explored in this thesis through the use of a paradigm designed to allow the neural correlates of amount recalled to be identified through parametric fMRI analysis. A series of experiments were carried out during the development and optimisation of this paradigm in order to ensure that the various demands of this analysis were met. Subsequently this paradigm was applied during an fMRI experiment which provided data from both the encoding and retrieval stages of recollection.Whilst the development work was chiefly concerned with producing a suitable task design for the parametric fMRI analysis, these experiments provided some interesting results in their own right. The task design, which required participants to associate multiple item types within a story context, showed that there are significant differences in the frequency with which different stimuli are recollected. Participants were found to be particularly poor at recollecting faces whilst words were also shown to be recollected less frequently than either object or animal picture stimuli. A possible explanation for these differences may be related to the picture superiority effect although eye-tracking data collected from these experiments demonstrates large differences in viewing behaviour between different target stimulus types which is not correlated with later recall success. The amount of time participants spend engaging with the highly contextual scene item does predict later recall success.The fMRI analysis (Chapter 5) carried out during the encoding and retrieval stages of recollection found a variety of regions exhibiting a positive linear relationship with recollection at both these stages. This result provides support for the cortical reinstatement hypothesis of recollection despite the fact that the hippocampus only showed parametric modulation of activity during retrieval. It is proposed that parahippocampal activity during encoding and retrieval supports the recollection of contextual information whilst the same pattern of activity in parietal regions related to recollection may reflect the reinstatement of the global image of the story created during the encoding task.

Exercise is emerging as a promising low-cost intervention to mitigate age-related memory decline and promote successful aging. Aerobic exercise training enhances cardiorespiratory fitness (CRF) and improves integrity of the medial temporal lobe (MTL) memory system. The hippocampus, a brain region located within the MTL, is critically involved in episodic and spatial memory formation, including spatial navigation, and demonstrates subfield-specific plasticity in response to aerobic exercise among both animals and young adult humans. Yet it remains unclear whether hippocampal subfield-specific exercise training and CRF effects also extend to older adults. Another modulator of structural and functional integrity of the MTL is chronic stress. Importantly, chronic stress was shown to predominantly impact brain regions such as the hippocampus and associated cognitive functions, including episodic memory, that are highly vulnerable to the effects of chronic stress and decline with age. Allostatic load (AL), or the integrative biological dysregulation of multiple biological systems resulting from chronic stress, is associated with poorer cognition, and reduced structural brain integrity. Black Americans were shown to have high burden of AL compared to non-Hispanic White Americans, and this was associated with reports of greater perceived discrimination, a salient psychosocial stressor, among the former group. Although race is a sociocultural construct, Black-White disparities exist in cognitive task performance, and risk of Alzheimer’s disease (AD) and dementia, with Black Americans displaying significantly worse cognitive task performance scores, and a greater likelihood to be diagnosed with AD and dementia compared to non-Hispanic White Americans. Thus, greater AL and discriminatory experiences in Black compared to non-Hispanic White older adults may underlie the racial disparity in neurocognitive aging. The goal of this dissertation was to examine the opposing impact of chronic stress and exercise on neurocognitive aging. This was accomplished by 1) investigating aerobic exercise intervention effects on hippocampal subfield volume and fMRI activity during spatial navigation, a complex cognitive function that declines with age and that is, in part, supported by the MTL (Project 1), 2) examining the effect of AL as a cumulative, physiological stress measure on neurocognitive aging (Project 2), and 3) examining the effect of chronic psychosocial stress through the lens of social discrimination on the functional connectivity of the MTL subsystem of the default mode network, a resting state network that has been linked to episodic memory (Project 3). The secondary aim of this dissertation was to look at the effect of AL (Project 2) and social discrimination (Project 3) on racial neurocognitive disparities in cognitively intact older Black and non-Hispanic White adults. In the first project, data from two randomized controlled clinical trials of aerobic exercise intervention targeting healthy, initially sedentary adults aged 55-85 years were used to examine the effect of exercise training and exercise-related CRF on the hippocampal integrity on the subfield level. Both randomized controlled trials randomly assigned participants to either: aerobic exercise group or active control group and underwent baseline and end-of-study fitness testing, cognitive testing, and high resolution structural and functional MRI. The first objective of this project aimed to test whether aerobic exercise training increases CRF level, which, in turn, increases anterior hippocampal subfield volume and/or attenuates volumetric decline among older adults undergoing aerobic exercise training compared to those in the active control group. Partially supporting our prediction, results displayed that following the period of the 12-week exercise intervention, the active control group but not the aerobic exercise group showed a right dentate gyrus (DG) head volumetric decline that was trending toward statistical significance. Additionally, a positive significant association between changes in CRF and left subiculum (SUB) head volume following the exercise intervention among women was found. The second objective sought to examine whether aerobic exercise intervention modulates the activation in the hippocampus in a subfield-specific manner during virtual reality navigation task performance, particularly modulating activation in the SUB subfield. Consistent with our structural results an increase in CRF was associated with a decrease fMRI activity in the left SUB. Whole-brain analysis during virtual reality navigation task performance showed that an increase in CRF was associated with a decrease in fMRI activity in the cuneus and right middle frontal gyrus, both brain regions that repeatedly display activation during virtual navigation. In the second project, existing data from the Framingham Heart Study (FHS) was used. Cognitively intact men and women, who identified as either Black or African American from the first multiracial Omni group 1 cohort (OMNI1), or White non-Hispanic from the second-generation cohort (Gen2), and were native English speakers, were included in the study. AL was calculated using the values for 10 biomarkers available in the FHS database for the two cohorts studied that are biomarkers for immune, metabolic, and cardiovascular system function. The objective of this project sought to test the prediction that AL correlates with cognitive function and brain structures, particularly hippocampal volume. We additionally sought to examine the secondary prediction that AL mediates the relationship between race and cognitive task performance and structural brain integrity, in age- sex- and education matched racial groups of cognitively intact older adults after controlling for quality of education, cardiovascular-related comorbidities and depression in the FHS cohorts. Results demonstrated that there was no significant correlation between AL and cognitive and brain volumetric measures, however there were significant Black-White disparities in cognitive task performance in verbal and visual learning and memory, abstract reasoning and attention span. These Black-White cognitive task performance disparities existed even after controlling for quality of education, and cardiovascular-related comorbidities. Although there was no significant racial disparity in the mean score of AL index, our physiological stress measure, AL partially explained the observed Black-White disparity in cognitive task performance in verbal learning and memory. Importantly the observed AL effect was not driven by the cardio-metabolic component biomarkers that are part of the AL index, known to overlap with cardiovascular risk factors, but rather, the AL index drove this effect as a whole. There were no racial disparities in brain volumetric measures after controlling for cardiovascular-related comorbidities. Furthermore, there were no sex differences in the effect of AL in any of our neurocognitive outcome measures. In the third project, cognitively intact older Black and White adults (aged 55-80 years) were recruited from the greater Boston area. To measure perceived social discrimination, participants were asked to complete the Experiences of Discrimination questionnaires. Additionally, participants underwent fMRI scanning to examine the functional connectivity of resting-state brain networks. This project sought to test the prediction that greater perceived everyday discrimination would be associated with alteration of resting state functional connectivity, particularly in the MTL subsystem. Results showed that greater perceived everyday discrimination predicted stronger resting-state connectivity between the MTL subsystem, and a cluster located in the right control network, suggesting that perceived discrimination, a psychosocial stressor, may cause functional alteration in brain networks supporting memory and cognitive control in older adults. In conclusion, findings of these studies suggest a neuroprotective effect of exercise, where exercise may attenuate aging-related decline in the structure and function of hippocampal subfields, especially among women, and possibly by targeting the SUB. Furthermore, findings of these studies suggest stress related mechanisms underlying neurocognitive integrity, particularly in the MTL memory system.

Distinct patterns of connectivity are thought to give rise to specialized functions within the anterior and posterior hippocampus. Consequently, there are several hypotheses regarding hippocampal long-axis specialization, including memory encoding versus retrieval, broad/gist-like representations versus detailed/fine-grained representations, and other cognitive processes versus spatial processing. This dissertation investigates the contributions of the anterior and posterior hippocampus to long-term memory. Chapter 1 investigates domain specificity in the hippocampus to determine how retrieval activity differs for two types of context information. Chapter 2 distinguishes between two prominent hypotheses of long-axis specialization to determine whether spatial memory encoding involves the anterior or posterior hippocampus. Chapter 3 investigates functional connectivity with the anterior and posterior hippocampus during spatial memory encoding and retrieval to test the predictions of the hippocampal encoding/retrieval and network (HERNET) model of memory (Kim, 2015). Together, the results presented in this dissertation provide insights into the roles of the anterior and posterior hippocampus and their interactions with the rest of the brain.

Remembering a salient experience and discriminating between similar events are two cognitive abilities that are critical for human adaptation and survival. They depend on optimal functioning of neurobiological mechanisms underlying episodic memory processing. Enhanced memory for emotional stimuli requires more pronounced memory encoding of emotional, relative to neutral stimuli. Discrimination between two different events depends on a neural computation of pattern separation. However, the exact neural mechanisms underlying memory encoding and pattern separation are still unclear.In the present thesis, I applied an emotional memory encoding and discrimination task in human participants and examined the neural dynamics in the medial temporal lobe, known as a critical brain structure for memory processing. Local field potentials were recorded in the amygdala, hippocampus and peri-hippocampal regions, including entorhinal, parahippocampal and perirhinal cortex, from drug-resistant epilepsy patients undergoing pre-surgical monitoring. First, I examined the role of hippocampal awake sharp-wave ripples (aSWRs) on emotional memory encoding, finding increased aSWRs after encoding of emotional, compared to neutral stimuli. The aSWRs were accompanied by memory reinstatement in the amygdala-hippocampal network. Additionally, the cross-structure joint-reinstatement during aSWR events was predictive of later memory performance. Next, I investigated the neural mechanisms of pattern separation during memory discrimination. Stimulus-specific neural representation in the hippocampus predicted memory discrimination. Moreover, I designed a machine learning algorithm to decode the neural state, and found that the neural trajectory of dentate gyrus/Cornu Ammonis3 (DG/CA3) visited more unexplored state and predicted successful pattern separation. Finally, continuously increasing dimensionality predicts correct discrimination, suggesting code expansion as a mechanism implementing the pattern separation in the DG/CA3 region. Overall, these results suggest a putative mechanism for encoding and discriminating for emotional experience.

The amount of sensory input received by the human brain far surpasses its capacity for conscious processing. Attention serves to gate incoming inputs to enable the receiver to select aspects of the environment for further processing based on its relevance to higher-level goals. When attention is impaired, behavior goes awry, and this often has serious consequences. While it is clear that attentional processes are critical for humans’ ability to interact effectively with the environment, the lack of a clear and conclusive definition of attention itself has, at times, impeded research progress on attention in the neural and behavioral sciences.In this dissertation, I examine the construct of human attention from both empirical and theoretical standpoints. In Chapter 1, I provide an introduction to the concept of attention, including diverging definitions. I also articulate the urgency of obtaining a clearer understanding of the neurocognitive processes that support attention. Chapter 2 presents an empirical study of a specific type of attention, known as visual search. The study uses rare intracranial recordings in humans to present evidence consistent with the view that visual search, a classical attention behavior, may need to be reinterpreted as navigation in visual space. In Chapter 3, I present a theoretical discussion of the distinctions and similarities between attention and expectation, including interpretational pitfalls in experimental designs aiming to directly compare the two. Chapter 4 provides closing thoughts with emphasis on future directions for this field of research.

Working memory (WM) is the ability to hold information for online processing. As the basis of long-term memory formation and a fundamental construct of thinking, it is paramount that we understand how WM works. Distributed network models posit that the prefrontal cortex (PFC) supports WM by coordinating top-down control over other regions involved in sensory representation and long-term memory. We utilized an episodic memory paradigm that probes WM for identity, spatial, and temporal information to examine the PFC dependent model of WM. In two studies, multimodal electrophysiology data reveal that PFC control over WM is fundamentally dynamic in nature, and that WM is dependent on activity distributed across anterior and posterior cortical regions. Results challenge the simple PFC model of WM.Ch. 1 presents evidence from intracranial recordings that frontal and medial temporal lobe (MTL) theta rhythms carry WM-related activity, and uncovers two WM systems. The PFC-MTL system exhibits bidirectional interaction that shifts with msec precision in response to task demands. In contrast, MTL rhythms direct activity in the orbitofrontal cortex via theta rhythms that do not vary with task demands. These findings support a bidirectional PFC-MTL system in humans – in which theta rhythms subserve executive control during episodic memory formation. Ch. 2 presents evidence from patients with unilateral PFC damage, which shows that a posteriorly-sourced alpha-beta network provides adequate resources for well above-chance WM accuracy. However, when the PFC is intact, PFC low theta activity increases commensurate with executive demand, and PFC-sourced slow rhythms and posteriorly-sourced alpha-beta rhythms travel in opposite directions to support optimal WM.Ch. 3 reviews 15 years of intracranial research on human memory, and considers the potential of intracranial electrophysiology as a technique to address unresolved questions in the neuroscience of human memory. Ch. 4 presents key themes from this work for younger readers; specifically, it introduces the concepts of cross-frequency coupling between theta rhythms and fast activities in the MTL, and inter-regional PFC-MTL synchrony for memory formation. In a second public outreach piece, appendix 1 introduces the logic of neuropsychology to younger readers to understand why memories of music are resilient to the deleterious effects of amnesia and dementia. Appendix 2 shows that WM develops in children along with increases in sustained attention, and appendix 3 reviews evidence that executive control develops commensurate with PFC connectivity across distributed neural networks. Finally, appendices 4-5 present applications of research on WM and control, together delineating behavioral and neural underpinnings of optimal relational reasoning in neurologically healthy adults.

Memory serves as a critical bridge between our present and our past, allowing previously formed associations to guide our present decision-making and inform our expectations about what is to come. Our ability to learn and retrieve certain types of associative knowledge, as well as to make projections about the world based on this knowledge, depends on the neural circuitry of the hippocampus, along with surrounding structures that comprise the medial temporal lobe (MTL) (Squire, 2009b). Declarative memory has been posited to rely on processes such as pattern completion and separation (Yassa & Stark, 2011), sequence encoding (MacDonald, Lepage, Eden, & Eichenbaum, 2011), and mismatch detection (Kumaran & Maguire, 2006). These processes enable memory to be flexibly encoded and retrieved so that it can inform all aspects of experience. This dissertation address three specific questions regarding how subfield functions work within a broader system of goals and motivations to facilitate flexible declarative memory. The project described in Chapter 3 focuses on the different degree to which discrimination and generalization responses, previously observed in hippocampal subfields in response to close lure stimuli, is affected by task demands. Using high-resolution functional magnetic resonance imaging (hr-fMRI), we find diverging sensitivity to changes in stimuli and task demands in the responses within the left CA1 and CA3DG subfields. CA3DG discriminates old visual stimuli from new stimuli, irrespective of the task-relevant context. In contrast, CA1 responds to incorrectly paired repeats as it would to novels, while generalizes to different exemplars of the expected image. In Chapter 4, we use hr-fMRI investigate the impact of value on memory and show that items assigned a low reward value exhibit reduced encoding-retrieval neural similarity than either items assigned high reward value, or the similarity between items at encoding and unvalued items at retrieval. These results suggest that low value items may be processed in a less consistent manner within MTL regions than higher value items during encoding, possibly reflecting different encoding processes due to assigned values. Chapter 5 describes a set of behavioral studies aimed at evaluating whether mnemonic mismatches can lead to improved subsequent recollection of the item that violated memory based predictions. We show that when an item triggers a mismatch that item is recalled at greater rates than items that did not constitute a mismatch. Our results also show that this putative mismatch-induced encoding benefit is susceptible to disruption by numerous goal-related or motivational factors.

The transformation of sensory inputs into complex memory representations is fundamental to human experience; yet, little is known about how this crucial process is achieved. When you meet your friend at the new cafe in town, what part of the brain encodes this novel scene into long term memory? What part encoded your friend’s favorite t-shirt, so that the sight of it gives you a feeling of familiarity rather than surprise? It is well-established that the medial temporal lobe (MTL) is crucial to both processes, but the MTL is not a single homogeneous region. In fact, it is composed of several anatomically distinct subregions including hippocampus, perirhinal cortex (PRC) and parahippocampal cortex (PHC). However, the computations performed by each subregion to encode individual events is still unclear. The present research tests the central hypothesis that different forms of event content are transformed into memory by distinct subregions within the MTL. A critical barrier in the study of content representation thus far has been its focus on comparing univariate peak activations in a region to different stimulus materials. To go beyond this limited approach, we employed multivariate statistical analyses that takes into account how event content is represented by distributed activity in MTL subregions. First, we examine the content-specific contributions of MTL subregions to episodic encoding and retrieval. Then, we demonstrate how these distributed representations support memory-based prediction to resolve ambiguities in our environment.

Temporal context memory is memory for the timing of events. People can make temporal judgments based on strategies such as assessing the relative familiarity of events or inferring temporal order from the semantic associations among events. The purpose of present study is to investigate the brain regions that support temporal context retrieval in the absence of such non-temporal strategies (i.e. pure temporal context memory). We used three word familiar phrases (triplets) as stimuli. In study phase, three words were presented quickly one after another in either familiar or scrambled order. Participants were instructed to read aloud each word and try to remember the order of the words. Then they were tested on their memory for the order of the words in each triplet. We propose that memory for the scrambled triplets reflects primarily temporal retrieval for two reasons. First, participants were prevented from using semantic strategies during encoding. Second, the relative familiarity of the words in each triplet was similar and not diagnostic of the order of the words during encoding. Neuroimaging results indicate that temporal context retrieval, memory for the order of words in scrambled triplets, was associated with the hippocampus, parahippocampal cortex, ventromedial prefrontal cortex, retrosplenial cortex, and posterior cingulate, which are consistent with the retrieval of non-temporal context in episodic memory. The results also suggest that temporal context retrieval could rely on familiarity, which was demonstrated by the higher accuracy and greater activation of PRc in familiar phrases and scrambled triplets presented in studied order in the test phase.