Craig E. L. Stark - US grants

behavioral /social science research tag; temporal lobe /cortex disorder

The ability to learn and retrieve information is essential to the success of our efforts to effectively cope with daily life, and our individual collections of long-term declarative memories serve to guide us through time by forming the core of our personal identities. Further, as we age, long-term memory concerns are the most common cognitive complaint and are key concerns in neurological disorders. Understanding the neural mechanism that underlie declarative memory is thus a core problem in neuroscience. With support from the NSF Craig Stark and colleagues at Johns Hopkins University are making inroads into clarifying the way in which memories are stored and accessed in the human brain.

Structures in the medial temporal lobe (MTL) (including the hippocampus and the adjacent entorhinal, perirhinal, and parahippocampal cortices) are known to play a critical role in the ability to learn and remember facts and events. However it is not yet clear what the role is that each structure plays and how the structures interoperate to give us this remarkable ability to rapidly learn new information. In this project a total of ten experiments will be conducted that will further our understanding of this problem. The proposed experiments utilize a wide array of techniques in order to provide converging and complementary evidence: functional magnetic resonance imaging (fMRI) of brain activity in healthy volunteers, neuropsychological study of patients with damage to the hippocampus, and cognitive behavioral measures on healthy volunteers. In so doing, it will develop novel techniques for integrating these sources of information and it will explore new paradigms and new theoretical grounds.

The project is divided into three Aims. In the Aims 1 and 2, the neuroanatomical basis for pattern completion and pattern separation are examined. Pattern separation refers to the isolation of two or more similar patterns of activity (things to be remembered) into distinct, non-overlapping representations. Pattern separation is required whenever one needs to separate similar pieces of information that might otherwise interfere with each other (e.g., remembering that today, you parked your car in Lot B, although you usually park your car in Lot A). Pattern completion is pattern separation's complement. It refers to transforming an incomplete, distorted, or otherwise degraded pattern of activity into a complete pattern of activity based on your knowledge (e.g., while not having stored a perfect memory of where you parked today specifically, filling in the partial memory with details of Lot A...usually, but not always, correctly). Both are critical to successful memory, as we must both isolate similar memories when the differences are important and we must utilize the redundancy present in similar memories to overcome noise and capacity limitations when the differences do not matter. Computational models and evidence from animal studies have stressed these competing computational properties and have used neuroanatomical constraints to isolate a specific role for the hippocampus (or even a subregion of the hippocampus) in pattern separation. In the third Aim, the dynamics of single-item and associative memory encoding are explored using a backward-masking technique. This technique has revealed a novel dissociation in performance between single-item and associative memory. This project will determine whether the dissociation is dependent on the MTL by testing how the effect maps onto existing theories of memory such as the declarative / nondeclarative and remember / know dichotomies and how it is influenced by damage to the hippocampus and the rest of the MTL.

[unreadable] DESCRIPTION (provided by applicant): There is substantial evidence that changes in memory function occur during healthy aging. Recent findings with aged rats suggest that aging is associated with impairment in pattern separation or the process of creating different representations from similar inputs. Additional evidence also suggests that this impairment may be linked to hyperactivity in CA3 hippocampal neurons. Functional MRI has been used extensively to study memory changes with aging, but due to the method's coarse resolution, studying activation at the level of hippocampal subfields in a manner similar to the animal studies has posed quite a challenge. However, recent technological advances have allowed us to overcome this limitation giving us the potential to assess subtle changes in function and corresponding changes in neural computations. The aim of the current proposal is to study these changes using high-resolution (1.5 mm) fMRI coupled with sophisticated alignment techniques that respect individuals' anatomy at the level of hippocampal subfields, and tasks designed to test computations specific to hippocampal subfields. We propose to test young healthy and aged healthy individuals using two tasks: a continuous paired-associate learning task and a incidental encoding task, both of which manipulate demand on pattern separation in different ways. We hypothesize that as pattern separation demands increase, behavioral and neural differences between groups will be more pronounced, and that the earliest neural changes will be detected in the CA3 region. If successful, this study will provide a clear picture of the exact locus and nature of the changes in memory computations with healthy aging. This will help us make the critical link between animal and human studies, enhance our understanding of aging as the primary risk factor for dementia, and pave the way to identifying pre-clinical markers and developing therapies to decelerate progression to dementia. PUBLIC HEALTH RELEVANCE: The proposed research examines detailed aspects about the neural bases of age-related memory decline (the most common cognitive complaint associated with aging). If successful, this study will provide a clear picture of the exact locus and nature of the changes in memory computations with healthy aging. This will help us make the critical link between animal and human studies, enhance our understanding of aging as the primary risk factor for dementia, and pave the way to identifying pre-clinical markers for disorders such as Mild Cognitive Impairment and Alzheimer's disease. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Cognitive decline with aging, especially in the memory domain, has been documented as an important risk factor for Alzheimer's disease (AD). Examining neurocognitive aging will help us better characterize pathological and non-pathological changes in the brain throughout the lifespan and identify preclinical markers for cognitive decline. It will also help us pinpoint cognitive processes and mechanisms that can be altered to delay onset or reverse pathology altogether. With the population over 60 rising rapidly, discoveries in this domain will likely have dramatic impact on public health and substantially reduce the burden on families as well as government and social programs. There is a clear need for targeted investigations of memory and the brain that cover the entire spectrum of aging throughout the adult lifespan. The goal of this proposal is to collect a comprehensive set of behavioral and high-resolution neuroimaging data to test several key predictions of a neurocognitive model of age-related memory impairment. This work is based on converging insights from computational models as well as behavioral, electrophysiological, and neuroanatomical findings in rodent models of aging. The approach is based on the premise that the hippocampal dentate gyrus is critically involved in episodic memory by virtue of its exceptional capacity for performing pattern separation, or the ability to isolate similar memories from each other. Pattern separation is a key computational component of many forms of memory often attributed to the hippocampus (e.g., episodic memory, recollection, etc). The model posits that degraded input to the dentate gyrus and CA3 region from layer II entorhinal cortex neurons with aging leaves the system with an impaired ability to perform pattern separation. We propose to test predictions of this model using behavioral experiments and a combination of cutting-edge neuroimaging techniques (functional and structural MRI, DTI, and PIB PET). We predict that aging will result in behavioral impairments consistent with a reduction in pattern separation abilities, and that there will be neural changes in CA3/DG activity consistent with this reduction. We also predict that aging will result in changes in the connectivity within the hippocampus and between the hippocampus and surrounding cortices (e.g. entorhinal cortex). Finally, we predict that individual differences in memory performance, imaging data, and ApoE4 genetic susceptibility will differentiate healthy from pathological aging and that these differences will be key to predicting subsequent decline. Critically, this rich dataset will have uses beyond our questions and hypotheses. We will provide and share all components of this extensive dataset for other researchers to study using the robust Biomedical Informatics Research Network (BIRN) infrastructure. PUBLIC HEALTH RELEVANCE: The population over 65 is projected to increase to 86.7 million by 2050 (U.S. Census Bureau, Population Estimates and Projections, 2004) and the impact of aging and aging-related disorders e.g. Alzheimer's disease (AD) on the health care system will rise dramatically as the rate of AD doubles for every five year period beyond the age of 65. Even outside of AD, one of the primary complaints and deficits observed with aging is a decline in learning and memory function, leading to decreased quality of life and a greater burden on families and social services. Understanding the neural mechanisms that underlie these age-related deficits is crucial to understanding the effect of aging on dementia, and paving the way to improving treatments for both normal and pathological changes in memory and for early prevention.

PROJECT 1: NEUROIMAGING OF HIPPOCAMPAL SUBFIELDS IN OLDER ADULTS &MCI A major goal for health research in the U.S. is to discover new disease-modifying therapies and target individuals susceptible to AD as early as possible. Episodic memory deficits and changes in the medial temporal lobes have been highlighted both in healthy aging and for their potential as early markers of AD. We propose to collect a comprehensive set of behavioral and high-resolution neuroimaging data from (1) healthy elderly individuals, (2) elderly individuals with diagnosed amnestic mild cognitive impairment (aMCI), and (3) elderly individuals with milder impairments who do not reach criteria for an MCI diagnosis, but are nevertheless impaired on memory tests (amnetic, early impairment - aEI). We will use these data to test several key predictions of a neurocognitive model of age-related memory impairment. This work is based on converging insights from computational models as well as behavioral, electrophysiological, and neuroanatomical findings in rodent models of aging that place emphasis on the role of the dentate gyrus in pattern separation (the ability to isolate similar memories from each other). The model posits that memory impairments in the course of aging and early dementia are due to the degradation in input to the dentate gyrus and CAS region from layer II entorhinal cortex neurons, which leaves the system with an impaired ability to perform pattern separation. We propose to test predictions of this model using targeted behavioral assays sensitive to hippocampal and perforant path integrity as well as cutting-edge neuroimaging techniques (high-resolution functional and structural MRI, resting state functional connectivity, ultrahigh-resolution microstructural diffusion tensor imaging). We predict that compared to healthy elderly, those with memory impairments will have behavioral deficits consistent with reductions in pattern separation and that these are tied to structural and functional changes in the dentate gyrus, the CA3, and their perforant path input. We will also investigate the modulatory effect of individual differences in our healthy elderly group, as well as the potential effect of ApoE4 genetic susceptibility. This rich dataset will also be useful beyond our hypotheses and questions. Thus, we will work with the ADRC's Data Core to generate new hypotheses, accurately quantify our outcome measures in a reliable way, and conduct statistically rigorous analyses that combine multiple imaging modalities with behavioral and neuropsychological data in order to isolate useful biomarkers that accurately discrminate among groups and potentially predict conversion from healthy aging to dementia.

DESCRIPTION (provided by applicant): While strong evidence suggests that the medial temporal lobe (MTL) is essential for learning and retaining new information for facts and events and the striatum is important for acquiring new skills and habits, the nature of the specific interactions between these two brain regions remains poorly understood. The goal of this dual-PI proposal is to take advantage of the precise spatial and temporal resolution of behavioral neurophysiology studies in animal model systems (Suzuki) together with the broad activation monitoring and flexible behavioral manipulation available in BOLD fMRI studies in humans (Stark) to characterize the specific contributions and interactions between the MTL and the striatum during a conditional motor associative learning task known to be dependent on both areas. In Aim 1, we will use the same task in both experimental animals and humans to assess the patterns and temporal dynamics of neural activity in the MTL and striatum during new conditional motor associative learning. Neurophysiology studies will include single unit tetrode recording, network correlation analyses and LFP analyses across both the MTL and the striatum. The BOLD fMRI studies will include characterization of functional connectivity between these areas. We will test the hypothesis that both the MTL and striatum signal learning during new conditional motor associative learning, but utilize distinct computational principles during the learning process such that the MTL associates random element together in memory while the role of the striatum includes motor- based or direction-based stimulus-response learning as well as a prominent role in signaling reward prediction error. We will also test the hypothesis that the role of the striatum in signaling reward prediction error interacts directly with the MTL defining a declarative portion of the striatum described in previous studies. In Aim 2, Stark will use various task manipulations hypothesized to make the associative learning task more dependent on either the MTL or the striatum to better characterize the unique contributions of these two different brain areas to associative learning. In Aim 3 Stark and Suzuki will conduct a detailed comparison of the pattern of single unit activity, LFP signals and spike-field coherence measured in animals to the pattern of BOLD fMRI signals and functional connectivity measured in humans to define the relationship between these different levels of analysis. Understanding the details of this relationship will be essential for ultimately translating experimental single cell findings in animals to our understanding of human brain function. Understanding the functional interactions between the MTL and striatum also has important implications for the development of treatments of a wide variety of disease states that affect these brain areas including Alzheimer's disease, attention deficit disorders, cognitive impairments present in aging, Parkinson's disease and Huntington's disease.

DESCRIPTION (provided by applicant): Cognitive decline with aging, especially in the memory domain, has been documented as an important risk factor for Alzheimer's disease (AD). Examining neurocognitive aging will help us better characterize pathological and non-pathological changes in the brain throughout the lifespan and identify preclinical markers for cognitive decline. It will also help us pinpoint cognitive processes and mechanisms that can be altered to delay onset or reverse pathology altogether. With the population over 60 rising rapidly, discoveries in this domain will likely have dramatic impact on public health and substantially reduce the burden on families as well as government and social programs. There is a clear need for targeted investigations of memory and the brain that cover the entire spectrum of aging throughout the adult lifespan. The goal of this proposal is to collect a comprehensive set of behavioral and high-resolution neuroimaging data to test several key predictions of a neurocognitive model of age-related memory impairment. This work is based on converging insights from computational models as well as behavioral, electrophysiological, and neuroanatomical findings in rodent models of aging. The approach is based on the premise that the hippocampal dentate gyrus is critically involved in episodic memory by virtue of its exceptional capacity for performing pattern separation, or the ability to isolate similar memories from each other. Pattern separation is a key computational component of many forms of memory often attributed to the hippocampus (e.g., episodic memory, recollection, etc). The model posits that degraded input to the dentate gyrus and CA3 region from layer II entorhinal cortex neurons with aging leaves the system with an impaired ability to perform pattern separation. We propose to test predictions of this model using behavioral experiments and a combination of cutting-edge neuroimaging techniques (functional and structural MRI, DTI, and PIB PET). We predict that aging will result in behavioral impairments consistent with a reduction in pattern separation abilities, and that there will be neural changes in CA3/DG activity consistent with this reduction. We also predict that aging will result in changes in the connectivity within the hippocampus and between the hippocampus and surrounding cortices (e.g. entorhinal cortex). Finally, we predict that individual differences in memory performance, imaging data, and ApoE4 genetic susceptibility will differentiate healthy from pathological aging and that these differences will be key to predicting subsequent decline. Critically, this rich dataset will have uses beyond our questions and hypotheses. We will provide and share all components of this extensive dataset for other researchers to study using the robust Biomedical Informatics Research Network (BIRN) infrastructure. PUBLIC HEALTH RELEVANCE: The population over 65 is projected to increase to 86.7 million by 2050 (U.S. Census Bureau, Population Estimates and Projections, 2004) and the impact of aging and aging-related disorders e.g. Alzheimer's disease (AD) on the health care system will rise dramatically as the rate of AD doubles for every five year period beyond the age of 65. Even outside of AD, one of the primary complaints and deficits observed with aging is a decline in learning and memory function, leading to decreased quality of life and a greater burden on families and social services. Understanding the neural mechanisms that underlie these age-related deficits is crucial to understanding the effect of aging on dementia, and paving the way to improving treatments for both normal and pathological changes in memory and for early prevention.

PROJECT 1: NEUROIMAGING OF HIPPOCAMPAL SUBFIELDS IN OLDER ADULTS & MCI A major goal for health research in the U.S. is to discover new disease-modifying therapies and target individuals susceptible to AD as early as possible. Episodic memory deficits and changes in the medial temporal lobes have been highlighted both in healthy aging and for their potential as early markers of AD. We propose to collect a comprehensive set of behavioral and high-resolution neuroimaging data from (1) healthy elderly individuals, (2) elderly individuals with diagnosed amnestic mild cognitive impairment (aMCI), and (3) elderly individuals with milder impairments who do not reach criteria for an MCI diagnosis, but are nevertheless impaired on memory tests (amnetic, early impairment - aEI). We will use these data to test several key predictions of a neurocognitive model of age-related memory impairment. This work is based on converging insights from computational models as well as behavioral, electrophysiological, and neuroanatomical findings in rodent models of aging that place emphasis on the role of the dentate gyrus in pattern separation (the ability to isolate similar memories from each other). The model posits that memory impairments in the course of aging and early dementia are due to the degradation in input to the dentate gyrus and CAS region from layer II entorhinal cortex neurons, which leaves the system with an impaired ability to perform pattern separation. We propose to test predictions of this model using targeted behavioral assays sensitive to hippocampal and perforant path integrity as well as cutting-edge neuroimaging techniques (high-resolution functional and structural MRI, resting state functional connectivity, ultrahigh-resolution microstructural diffusion tensor imaging). We predict that compared to healthy elderly, those with memory impairments will have behavioral deficits consistent with reductions in pattern separation and that these are tied to structural and functional changes in the dentate gyrus, the CA3, and their perforant path input. We will also investigate the modulatory effect of individual differences in our healthy elderly group, as well as the potential effect of ApoE4 genetic susceptibility. This rich dataset will also be useful beyond our hypotheses and questions. Thus, we will work with the ADRC's Data Core to generate new hypotheses, accurately quantify our outcome measures in a reliable way, and conduct statistically rigorous analyses that combine multiple imaging modalities with behavioral and neuropsychological data in order to isolate useful biomarkers that accurately discrminate among groups and potentially predict conversion from healthy aging to dementia.

DESCRIPTION (provided by applicant): Our memory changes as we age. Age-related memory decline in and of itself represents a significant public health impact, but cognitive decline - and in particular memory decline - has been shown to be an important risk factor for Alzheimer's Disease (AD). Examining neurocognitive aging will help us better characterize pathological and non-pathological changes in the brain throughout the lifespan and identify preclinical markers for cognitive decline. This project extends our prior work into the exact nature of age-related memory decline and into its neural bases. Like our prior project, this proposal draws heavily on animal models of aging and computational models of memory to test specific hypotheses about age-related memory decline. In our prior funding period, we focused almost exclusively on the hippocampus, demonstrating age- related disruptions in the hippocampal circuit that parallel those found in the rodent and demonstrating how these changes affect specific kinds of memory. In particular, we showed how the human hippocampal dentate gyrus is critically involved in episodic memory by virtue of its exceptional capacity for performing pattern separation, or the ability to isolate similar memories from each other. We also showed how this circuit is disrupted gradually over the course of aging and how this is linked to age-related loss of the detail or episodic components of a memory. One goal of the project is to build extensively on the behavioral tasks that we have pioneered and that are being widely adopted in the field so that we can develop and neurobiologically validate an entire suite of behavioral tasks that are maximally sensitive to hippocampal function and to age- related cognitive decline. As this loss is not confined to the hippocampus, but includes changes in the adjacent medial temporal lobe cortices and in the prefrontal cortex, we propose to examine in detail changes in these regions and in their interactions with the hippocampus. Here again we draw heavily on neurobiological findings from the rodent to test specific hypotheses about age-related changes in regions like the perirhinal cortex and to assess changes in the functional contributions of and interrelationship between hippocampal and prefrontal age-related changes in memory. Like our prior work, we propose to collect a comprehensive suite of behavioral and neuroimaging data from a large sample of adults. By collecting an extensive set of measures on each participant, we can examine interrelationships that would otherwise be impossible. In addition to our own specific questions and hypotheses, the extensive set of measures (which includes longitudinal assessment of participants from our prior work) will be valuable to other researchers. As before, we will make all components of the data widely available to others.

The capacity to remember where and when certain events occur in one's life is of critical importance for survival and for participation in society function. This capacity, called episodic memory, is associated with the functions of the hippocampus and prefrontal cortex. Several neurological and psychiatric disorders involve dysfunctions in these brain regions. With support from the National Science Foundation, Dr. Norbert Fortin and colleague Dr. Craig Stark of the University of California at Irvine respectively will conduct an innovative series of parallel experiments in humans and rats, which are expected to contribute to a better understanding of the neural mechanisms underlying both normal and abnormal memory functions. This cross-species investigation will utilize a memory task that can be performed by humans and the rats, which is critical to make findings from animal studies relevant to our understanding of human memory and treatment of its deficit. This project will also provide an opportunity to develop effective educational practices and materials to promote early science training and awareness. These educational activities have a special emphasis on groups underrepresented in science (women and minority students), including a "Memory and the Brain" workshop that will be offered at schools with diverse student populations that also consistently perform below standard on the science portion of the California Standards Tests.

Although episodic memory has been extensively investigated, its neurobiological basis remains elusive. A major reason for this limited progress has been the inability to directly link evidence obtained from invasive techniques used in animal models (e.g. rodents) with that from non-invasive techniques used in humans because of differences in the demands of memory tasks used across these two species. Drs. Fortin and Stark will address this critical issue by using an integrated approach combining single-cell electrophysiological recordings in rats and BOLD fMRI in humans, to study episodic memory using their newly developed sequence memory task that can be performed by both rats and humans. This cross-species study will provide the first systematic examination of the functional correspondence between rodent and human sub-regions of the hippocampus and prefrontal cortex, known to play a critical role in memory and other higher-level cognitive functions. The knowledge gained from this study will significantly advance our understanding of the contribution of these brain structures to the memory for sequences of events, as well as of their fundamental role in learning and memory, executive functions, and decision-making.

? DESCRIPTION (provided by applicant): Our memory changes as we age. Age-related memory decline in and of itself represents a significant public health impact, but cognitive decline - and in particular memory decline - has been shown to be an important risk factor for Alzheimer's Disease (AD). Examining neurocognitive aging will help us better characterize pathological and non-­pathological changes in the brain throughout the lifespan and identify preclinical markers for cognitive decline. The goal of this proposal is to test key predictions of neurocognitive model of aging and amnestic Mild Cognitive Impairment (aMCI) that suggests changes in connectivity and activity within structures in the MTL underlie behavioral deficits in memory. In particular, in both rodent and human studies, the hippocampus exhibits hyperactivity - a potentially dysfunctional state that has been tied to behavioral shifts away from successful mnemonic discrimination (derived from pattern separation and leading to accurate memory for details) and towards over-­generalization (derived from pattern completion). To this end, reduction of this hyperactivity in aMCI using a low-­dose antiepileptic s associated with improved performance in a mnemonic discrimination task that we have used many times to index hippocampal function and age-­ and aMCI-­related changes. Without the direct recording of hyperactivity possible in rodents, human studies have often relied on the indirect and relative measures provided by BOLD fMRI. Here, we propose a directed, novel, metabolic investigation into the neuronal pathways responsible for this hyperactivity to determine the applicability of the rodent model. Using magnetic resonance imaging spectroscopy (MRS) and metabolite imaging methods, we aim to measure the metabolic signatures for excitatory and inhibitory activity (e.g. GABA, glutamate, choline, etc.), testing th hypothesis that hippocampal hyperactivity arises from the release of inhibition on the CA3 recurrent collaterals within the hippocampus, leading to an increase in excitatory activity and a decrease in inhibitory activity when the hippocampus is actively processing new information. We propose utilizing two MRS scans, 1H-­MRS and 31P-­MRS to determine which scan is more sensitive to this hyperactivity. Finally, we will evaluate if these MRS measures of hyperactivity have an inverse relationship with performance on several hippocampal-­dependent memory tasks, known to be sensitive to aging and MCI.

Project Summary Our memory changes as we age. Age-related memory decline in and of itself represents a significant public health impact, but cognitive decline ? and in particular memory decline ? has been shown to be an important risk factor for Alzheimer's Disease (AD). Examining neurocognitive aging will help us better characterize pathological and non-pathological changes in the brain throughout the lifespan and identify preclinical markers for cognitive decline. The goal of this proposal is to develop and compare a novel method of brain imaging, functional magnetic resonance imaging spectroscopy (fMRS) with the more traditional BOLD functional magnetic resonance imaging (MRI) techniques in healthy aging and mild cognitive impairment (MCI). BOLD fMRI has been used extensively to study differences in neural activity associated with aging and MCI, but it has limitations that may be critical to our interpretation of these data. In particular, the neuro-vasculature coupling ratio (M) is altered in aging, such that age-related changes in BOLD measures may not be due to age-related changes in underlying neural activity, but in vasculature instead. Here, we propose an altogether different approach in fMRS that has the added advantage of providing a measure that may be might be more directly linked to neural activity than the link we have with blood flow. We will develop a novel fMRS technique that will collect metabolite data while participants engage in various cognitive tasks. The fMRS signal will more directly measure cellular activity, energetics, and markers of cellular structure and loss in the aging brain. In particular, excitation and inhibition will be dynamically measured during a memory task by quantifying glutamate, glutamine and GABA while simultaneously measuring BOLD fMRI at the same location. Together, these measurements will allow us to examine the relationship between BOLD fMRI and metabolics and how these are altered with aging and early dementia. It will also give us the opportunity to test whether any of several tasks can serve as an age-invariant baseline in BOLD fMRI tasks as well as to help us more directly link human data and memory decline to the neurobiological models from the rodent. They will also give us the opportunity to explore biomarker / behavioral relationships and to further our understanding of changes in cellular structure related to aging.

Project Summary The positive effects of environmental enrichment and their neural bases have been extensively studied in the rodent. For example, simply modifying an animal?s living environment to promote sensory stimulation can lead to enhancements in hippocampal cognition and neuroplasticity as well as to improve memory deficits associated with neurodegenerative diseases such as Alzheimer?s Disease and aging. While many studies of human aging have focused on individuals aged 65 and older, there are many aspects of cognition (including memory), which show a decline across the lifespan. In addition, current strategies for combating Alzheimer?s Disease are focused heavily on early prevention. Thus, the age group of 40-49 years old represents an understudied age group, which may benefit from a cognitive intervention aimed at improving memory performance. In this proposal, we hypothesize that the exploration of the vast and visually stimulating virtual environments within video games, is a human correlate of environmental enrichment. Although humans, in many ways, already live in an enriched environment, we are constantly adapting to new experiences and situations within our own environment on a daily basis. Video game training may provide a conduit for optimizing the cognitive and neural benefits of environmental enrichment for use as a behavioral intervention for improving memory performance, and possibly, hippocampal function. Recent published data from our lab has already provided evidence that memory performance on unrelated hippocampal-dependent tasks is improved following a 2-week training period on a 3D video game in young adults. In contrast, training on a 2D video game did not result in a boost in memory performance. Here, we seek to explore the neural contributions to this training by evaluating hippocampal structure and function in a pre/post design in adults, aged 40-49 years old. Further, we seek to determine the key features of such an intervention paradigm to explore the key features of video games (the spatial aspect, the complexity of the game, or some combination) to evaluate the potential benefit of environmental enrichment training. These data provide a bridge to much of the rodent literature exploring the benefits of environmental enrichment, extending these principles into humans. Most of the cognitive intervention paradigms currently studied or in use provide a benefit for the precise skill being trained (e.g. improved reaction time over the course of many trials), but they do not generalize to other tasks or cognitive domains. Our preliminary data suggests that following 3D video game training, performance on unrelated, hippocampal-dependent tasks is improved, which is extremely rare and offers great potential as a rehabilitation technique. By focusing on an age group that is fluent with technology, but beginning to exhibit subtle signs of age-related cognitive decline, we can explore the neural and cognitive benefits of such training. The benefits of such training have the potential to be applied to rehabilitation following brain injury and neurological disease, education, and possibly even the benefit of the general population.

Core G: Biomarker Core Project Summary/Abstract Alzheimer's is a devastating, progressive disease that affects almost 6 million Americans and this number is expected to rise to almost 14 million in the next three decades. The cost to us is immense, both on a personal and on a financial level. Our National Plan to Address Alzheimer's Disease (https://aspe.hhs.gov/report/national-plan-address-alzheimers-disease-2018-update) sets us on a path with several concrete goals and strategies to cure and prevent AD. In particular, one goal we must achieve is the early diagnosis of AD and its related disorders (AD/ADRD). If we can detect the disease early, even before symptoms have started, efforts to slow or even halt the disease may be more effective and can lead to many more years with a high quality of life. A key to this early detection is to develop biomarkers for the disease ? ways in which, through testing of blood or cerebrospinal fluid (CSF ? collectively known as biofluids), brain scans, or even cognitive testing ? we can detect and efficiently monitor the disease and assess treatment. The goal of the UCI Biomarker Core is to help researchers here and across the globe in both collecting and analyzing data from existing measures and by developing novel measures for the purposes of identifying, quantifying, and validating factors that influence the risk of AD across the lifespan. The UCI ADRC Biomarker Core is set to provide state-of-the-art biomarker data and analyses and we will apply these to both existing data in our ADRC and to new data we are collecting. We will collect not only traditional biomarkers (blood, CSF for amyloid beta and tau, structural MRI scans, PET scans, etc.), but develop novel biomarkers as well. Our researchers have several innovative potential MRI and cognitive / behavioral biomarkers that the Core will be assisting with that have the potential to advance our overall goal of effectively determining disease etiology, measuring progression, and assessing effectiveness of treatment. In addition, we know that curing and preventing AD is a monumental challenge and that our final goal will only happen through collaborative teams and over the course of academic generations. Part of our mission in the UCI ADRC Biomarker core is therefore to share data and techniques with the research community. As big a part, however, is to share our knowledge and expertise with the next generation of clinicians and researchers, providing them with training and mentorship needed to rise to this challenge.

Project Summary The Alzheimer?s Association?s 2019 Facts and Figures Report reports that while a cognitive assessment is required for all Medicare Annual Wellness Visit, only 16% of surveyed older adults reported having any form of memory assessment. While standardized neuropsychological tasks are sensitive to gross memory deficits, they are not as sensitive to milder deficits associated with healthy aging or early disease stages and they are often poorly suited for routine testing outside of trained neuropsychologist practitioners. Thus, there is a critical need for an easy-to administer, reliable, and sensitive measure of hippocampal memory function for clinical use. We have designed the Mnemonic Similarity Task (MST), a modified object recognition memory task, to provide not only a traditional measure of object recognition memory, but also a measure of ?mnemonic discrimination? that is highly sensitive hippocampal function by placing strong demands on pattern separation. Thus, the goal of this proposal is to complete the development and validation of version of the clinical MST (cMST) as a fully encapsulated tool that would be ready for use in clinical research and for evaluation as a routine clinical tool. First, we will develop an optimized version of the MST designed for clinical use as a sensitive assay of hippocampal function that rapidly, but robustly, estimates hippocampal memory performance. The design goals are that it is: 1) easy to administer in a short amount of time, 2) has clear scoring and interpretation of results, 3) is sensitive to modest hippocampal dysfunction, 4) demonstrates reliability, and 5) exhibits general utility across a range of racial/ethnic/age groups. At the core of the MST is the use of highly similar lure items that have a range of pre-determined ?mnemonic similarity? to the original studied item. We have now developed a version of the MST that uses a continuous recognition memory format and optimizes the distribution of targets, foils, and lures, along with the mnemonic similarity of those lures, for use in the cMST. Here, we will determine whether that is an ideal format or whether a Bayesian adaptive version is superior. Then we will establish normative data on the cMST across the lifespan and in early dementia. In Aim 2.1, we will evaluate the sensitivity and validity of the cMST to memory decline in healthy aging, comparing it to the standard research-grade MST and to traditional neuropsychological tests in a large lifespan sample. Repeat testing of individuals will be used to establish reliability and assess practice effects. We will use these data to create normative data. In Aim 2.2, we will extend these investigations to clinical populations - specifically to those with Mild Cognitive Impairment or early AD through the UCI Alzheimer?s Disease Research Center (ADRC) to determine both viability and normative performance of our measures in these impaired populations and diagnostic ability of the cMST. By working with our ADRC for testing both healthy and impaired individuals, we will gain access to a host of other existing biomarkers of hippocampal decline available in this cohort, such as word recall, CSF tau levels, and hippocampal volume measures via structural MRI. Finally, we will create a model for large-scale distribution of the cMST via online administration. The ultimate goal of this proposal is to create an encapsulated version of the cMST that can be adopted for clinical use that is independent of a research lab. In Aim 3, we will distribute this task via a downloadable link that can be used on either desktop/laptop devices or on touchscreen tablets to a large and diverse sample. UCI?s large Consent 2 Contact (C2C) database (N=3250) provides an outstanding test case for large-scale data collection outside of a clinical or lab-based setting and for testing its potential use as a diagnostic screening tool.