Roberto Cabeza - US grants

DESCRIPTION (provided by applicant) The main goal of the proposed research is to use functional magnetic resonance imaging (fMRI) to elucidate the effects of aging on the neural correlates of cognition. In particular, we will investigate the generalizability and functional significance of the finding that brain activity during cognitive performance tends to be less lateralized between the left and right hemispheres in old adults than in young adults. To investigate the generalizability of age-related asymmetry reductions across cognitive tasks, we will compare the effects of aging on brain activity during episodic memory encoding, episodic memory retrieval, semantic memory retrieval, and working memory. To investigate the generalizability of age-related asymmetry reductions across the adult population, we will investigate individual differences in cognitive performance, education, and frontal-lobe function, and will examine a large group of subjects evenly distributed from young to old age. To investigate the generalizability of age-related asymmetry reductions across the brain, we will analyze brain activity data using a regions-of-interest (ROIs) approach, and will calculate a lateralization index for each ROI. ROI analyses will be complemented with voxel-wise analyses. Finally, to investigate the functional significance of age-related asymmetry reductions, we will test compensation and dedifferentiation hypotheses by correlating brain activity with cognitive performance and by using event-related fMRI analyses. According to the compensation hypothesis, age-related asymmetry reductions reflect an age-related reorganization of brain functions that is beneficial for cognitive performance. According to the dedifferentiation hypothesis, it reflects an age-related difficulty in engaging specialized neural mechanisms. Deciding between these hypotheses has important practical implications. For example, if age-related asymmetry reductions reflect a compensatory mechanism, bihemispheric involvement could be targeted as a goal of cognitive rehabilitation programs. The proposed research program has direct implications for the promotion of health. Understanding the neural basis of cognitive functions in the normal brain is a precondition for any rational attempt to cure or rehabilitate cognitive deficits due to brain dysfunction, Moreover, understanding the neural basis of age-related cognitive deficits will eventually allow the development of drugs and rehabilitation methods to ameliorate these deficits.

DESCRIPTION (provided by applicant): Whereas stroke and traumatic brain injury affect only a fraction of the population, there is a type of brain dysfunction that will affect us all if we live long enough---normal aging. As we age, the anatomical and functional integrity of our brain declines as do our cognitive abilities. Even if relatively mild, this decline impacts a large number of the population. The development of any rational remedial approach depends on a clear understanding of the effects of aging on the neural basis of cognition. In humans these effects can be revealed using functional neuroimaging techniques such as functional MRI (fMRI), which can directly link age-related cognitive deficits to changes in brain activity. One of the cognitive functions most affected by aging is relational memory. Older adults' memory deficits are twice as large on relational memory (RM) than on item memory (IM). Whereas IM refers to remembering what happened in the past, RM refers to remembering the associated information of where, when, and how. It is known that RM is more dependent on the medial temporal lobes (MTL) and the prefrontal cortex (PFC) than IM, but the contributions of various MTL and PFC regions to different forms of RM are unclear. It is also uncertain how these contributions change as a function of aging. Moreover, the neural bases of critical factors modulating the effects of aging on RM, such as the role of pre-existent knowledge and interference, are largely unknown. We propose to conduct five fMRI studies to address these issues. In particular, we have four specific aims: (1) Compare the neural correlates of different forms of RM in younger and older adults. Study 1 will compare featural, spatial, and temporal-order RM, Study 2 will compare featural and semantic RM, and Study 3 will compare associations between similar vs. different kinds of stimuli; (2) Reveal the neural correlates of factors affecting semantic RM in younger and older adults. Study 4 will investigate the role of pre-existent semantic associations and Study 5, the role of proactive interference; (3) Clarify the neural correlates of RM encoding and retrieval in younger and older adults. To accomplish this aim, all five fMRI studies proposed will compare encoding and retrieval activity directly within-subjects; (4) Investigate the interaction between PFC and MTL during RM in younger and older adults. Age-related RM deficits may reflect a disconnection between PFC and MTL regions. To investigate this issue, we will relate age-related changes in RM performance to changes in PFC-MTL connectivity, both in terms of function (correlation in activity) and anatomy (white-matter integrity measured with diffusion tensor imaging). Taken together, the results of these studies will clarify the neural correlates of age-related deficits in RM and will have important implications for the promotion of health.

[unreadable] DESCRIPTION (provided by applicant): Whereas dementia and stroke affect only fraction of the population, there is a type of brain dysfunction that will affect all of us if we live long enough: normal aging. As we age, the anatomical and functional integrity of our brain declines, and so do our cognitive abilities. Even if relatively mild, this decline affects a large number of people, and hence, it has a great impact at the population level. The development of any rational remedial approach depends on a clear understanding of the effects of healthy aging on the neural basis of cognition. Moreover, this knowledge is critical for research on the devastating effects of Alzheimer's Disease. The proposed research will contribute to this knowledge by directly linking age-related deficits in cognitive abilities to age-related deficits in brain anatomy and function. The approach integrates 3 methodological approaches that have been seldom combined in the past. First, we will use functional MRI (fMRI) to brain activity that changes as a function of aging. We expect to find not age-related decreases in activity signaling deficit cognitive processing, but also age-related increases in activity signaling compensatory mechanisms in the aging brain. Second, we will use diffusion tensor imaging (DTI) to measure the effects of aging on white-matter integrity, as there is evidence that aging impairs not only individual brain regions but also the connections between them. Finally, we will use a comprehensive batter of standardized tests to identify individual differences in neuropsychological status within the aging population. One of the cognitive functions most affected by healthy (and pathological) aging is episodic memory, which refers to memory for personally experienced past events. We propose six fMRI studies to investigate the effects of aging on brain activity associated with acquiring episodic information (encoding). Two brain regions are particularly important for encoding: the prefrontal cortex and the medial temporal lobes. We will measure activity in these regions, and their interactions, while young and older participants learn new episodic information in the scanner. In particular, we will investigate two critical factors accounting for age-related deficits in encoding (1) Reduced cognitive resources. To investigate this factor, we will divide attention and vary the speed of stimuli presentation during encoding. (2) Impaired binding processes. To investigate this factor we will compare memory for items vs. memory for semantic or perceptual associations. Finally, we will investigate the interactions between these two factors. PUBLIC HEALTH RELEVANCE: The results of the proposed studies will clarify the neural correlates of age-related deficits in episodic encoding, and will have important implications for the promotion of health. They will help develop cognitive training methods and will provide an essential baseline for research on Alzheimer's Disease. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Emotion regulation is critical for social behavior because social interactions can be the source of considerable stress. In particular, emotion regulation is essential for responding to social threat, which is defined as threats to self-esteem or social status. Such threats may be particularly salient in later life as individuals deal with loss of status and the negative stereotypes associated with old age. We will use behavioral methods in combination with functional MRI (fMRI) and diffusion tensor imaging (DTI) to investigate how older adults'emotion regulation system cope with social threat. Additionally, we will investigate factors that either challenge or facilitate the operation of this system. Taken together, the proposed 5 neuroimaging studies will achieve 3 specific aims. First, they will investigate how older adults'emotion regulation system responds to social threat. The emotion regulation system depends on the interplay between brain regions involved in generating emotions, such as the amygdala, and regions that exert control over emotional expression and experience, such as the prefrontal cortex. We will examine how the emotional regulation system operates in condition of threat to the individual at personal level (personal threat) and threat to the individual as a memory of a group (stereotype threat). Second, the proposed studies will also investigate how executive control resources modulate older adults'ability to regulate emotions elicited by social threat. Although healthy elderly are normally well adjusted at the emotional level, there is evidence that they maintain their emotional well-being by actively down-regulating negative emotions. This continuous emotion regulation strategy is taxing for executive control resources, which depend on frontoparietal networks that are known to decline with age. We will investigate how individual differences in executive resources modulate the operation of the emotional regulation system in older adults. Finally, the proposed studies will investigate how older adults'emotion regulation responses to social threat are enhanced by social support. Theoretical views suggest that close interpersonal relationships become increasingly important with age. Among other methods, we will study the role of social support by having a spouse or partner provide encouragement and physical contact under conditions of stereotype threat. Taken together, the studies proposed will clarify neural mechanisms of emotional regulation in older adults and how they respond to social threat. Given that emotion regulation depends on executive control networks that are known to be impaired by aging, this research has direct implications for understanding the interaction between cognitive and emotional processing in healthy aging, as well as in individuals at risk of Alzheimer's disease. PUBLIC HEALTH RELEVANCE: Taken together, the studies proposed will clarify neural mechanisms of emotion regulation in older adults and how they respond to social threat. Given that emotion regulation depends on executive control networks that are known to be impaired by aging, this research has direct implications for understanding the interaction between cognitive and emotional processing in healthy aging, as well as in individuals at risk of Alzheimer's disease (AD). The results will also contribute to the understanding of how social factors may contribute to geriatric depression.

DESCRIPTION (provided by applicant): Where as dementia and stroke affect only fraction of the population, there is a type of brain dysfunction that will affect all of us-if we live long enough: normal aging. As we age, the anatomical and functional integrity of our brain declines, and so do our cognitive abilities. Even if relatively mild, this decline affects a large number of people, and hence, it has a great impact at the population level. The development of any rational remedial approach depends on a clear understanding of the effects of healthy aging on the neural basis of cognition. Moreover, this knowledge is critical for research on the devastating effects of Alzheimer's disease. The proposed research will contribute to this knowledge by directly linking age-related deficits in memory abilities to age-related deficits in brain anatomy and function. The approach integrates 3 methodological approaches that have been seldom combined in the past. First, we will use functional MRI (fMRI) to measure changes in brain activity as a function of aging. We expect to find not only age-related decreases in activity signaling cognitive deficits, but also age- related increases in activity signaling compensatory mechanisms in the aging brain. Second, we will use diffusion tensor imaging (DTI) to measure the effects of aging on white-matter integrity, as there is evidence that aging impairs not only individual brain regions but also the connections between them. Finally, we will use a comprehensive batter of standardized tests to identify individual differences in neuropsychological status within the aging population. One of the cognitive functions most affected by healthy (and pathological) aging is episodic memory, which refers to memory for personally experienced past events. We propose several fMRI studies to investigate the effects of aging on brain activity associated with recovery of episodic information (episodic retrieval). We will investigate activity in a number of brain regions (prefrontal regions, medial temporal regions, etc) and the interactions among these regions, while young and older participants retrieve new episodic information in the scanner. In particular, we will identify age effects on specific episodic retrieval processes, including generation, familiarity, recollection, and monitoring. In sum, the results of the proposed studies will clarify the neural correlates of age-related deficits in episodic retrieval, and will have important implications for the promotion of health. They will help develop cognitive training methods and will provide an essential baseline for research on Alzheimer's disease.

DESCRIPTION (provided by applicant): Aging is associated with substantial deterioration of the visual system and associated sensory-perceptual processes. This decline in visual processing is a strong predictor of cognitive decline in healthy aging and of Alzheimer's disease. Yet, the effects of aging on visual processing and cognitive functions, such as memory, have typically been investigated independently of each other. Filling this void, the proposed neuroimaging studies focus on the interactions between age effects on visual and memory processes, and the brain regions mediating these processes. This significant goal is combined with an innovative multi-measure methodological approach which assesses age effects (1) on visual and memory performance using behavioral tests; (2) on brain activity in occipito-temporal, medial temporal, prefrontal regions using functional MRI (fMRI); (3) on the interactions among these regions using functional connectivity (fCON); and (4) on the integrity of the white- matter fiber tracts connecting these regions using diffusion tensor imaging (DTI). Most importantly, these different measures are directly linked to each other. The multi-measure approach is applied to three specific aims. Specific Aim 1 is to investigate the role of peripheral and top-down modulation deficits in visual memory impairments in older adults. Older adults show reduced activity and selectivity (dedifferentiation) in occipito-temporal cortex, which may reflect peripheral or top-down modulation deficits. Study 1 compares the effects of divided attention, which interferes with top-down modulation, and stimulus degradation, which mimics age-related peripheral visual deficits. Study 2 employs overlapping face-house stimuli to examine selective attention deficits. Specific Aim 2 is to investigate the role of perceptual and conceptual processing deficits in visual memory impairments in older adults. Conceptual processing enhances memory for meaningful visual stimuli such as objects but, when combined with perceptual processing deficits, can lead to false memories. Study 3 investigates age effects on conceptual vs. perceptual processing during the encoding of meaningful objects. Study 4 examines age effects on encoding leading to true vs. false memory for objects. Specific Aim 3 is to investigate the role of retrieval reactivation deficits in visual memory impairments in older adults. Visual memory depends not only on visual cortex activations during learning but also on visual cortex reactivations when visual events are remembered. Study 5 investigates age effects on the reactivation of memories for familiar faces and objects. Linking with Specific Aim 2, Study 6 investigates the reactivation of perceptual and conceptual representations. The proposed studies will be the first to systematically investigate the neural mechanisms of age-related visual memory decline. Their results will have direct implications for the development of treatments for memory decline in healthy aging. Moreover, given that visual memory decline predicts Alzheimer's disease a decade before diagnosis, the results will also have implications for the early detection and treatment of this disease.

? DESCRIPTION (provided by applicant): Cognitive decline and dementia have become important public health issues in our time as medical science has increased lifespan and our society becomes progressively older. A great deal of the cognitive decline due to aging can be explained by decline in working memory (WM), a mental function central to cognition in which aging deficits appear almost universally. Attempts to use WM training to increase WM ability in older adults has had some success, but the transfer of performance enhancements caused by this training to other cognitive skills is controversial. Another intervention that shows much promise is noninvasive stimulation of cerebral cortex using transcranial magnetic stimulation (TMS), which has been shown to increase performance in many cognitive tasks. In previous work we developed a paradigm using fMRI-guided TMS in which we identified a cortical network sensitive to the effects of sleep deprivation and to WM and targeted it with TMS, almost completely remediating the deficits in WM performance caused by the sleep deprivation, and whose effects outlasted TMS stimulation by at least a day. We then applied this paradigm to healthy young and older adults, to assess the effects of aging on WM. Stimulation to the left lateral occipital complex, a region involved in the maintenance of visual information, enhanced WM performance in both young and older groups. Here we propose to use our fMRI-guided TMS enhancement paradigm to stimulate dorsolateral prefrontal cortex (DLPFC), a region involved not only in the maintenance of items in WM, but also in their manipulation, in order to create WM performance enhancements that will be long lasting and that will transfer to other cognitive tasks as well. This will be achieved through three studies. In the first we will stimulat both old and young healthy adults while they perform different WM tasks that will increasingly engage DLPFC in order to demonstrate enhancement of WM performance that is greater in the older adults. In the second and third studies, older adults will receive active or sham TMS over two weeks of daily sessions while they perform the WM tasks. In the second study, we hope to demonstrate that the cumulative effect of multiple TMS sessions, in tandem with the synergistic effects of simultaneous TMS + WM training, create WM performance enhancements greater than those found with WM training alone, whose effects are long-lasting, continuing a month following the course of TMS sessions. In the third, we will investigate whether the WM enhancements generated by the two- weeks of TMS sessions will generalize to other cognitive tasks. Success of these studies will provide proof in principle for long-lasting, transferable effects of TMS in remediating WM and more general cognitive deficits due to aging, and point to a possible non-invasive brain stimulation therapy for cognitive decline in healthy aging and in dementia.

Effects of aging on episodic memory-dependent decision making Most studies of human decision making use tasks in which information relevant to the decision is either completely available or never available. Yet, in many real-life scenarios decision making requires retrieving in- formation from specific past events, or episodic memory. Clarifying the role of episodic memory in decision making is critical for understanding decision making deficits in healthy older adults, who show significant epi- sodic memory decline. Our overarching goal is to clarify how episodic memory impairments in older age con- tribute to decision making. In particular, we focus on the neural mechanisms of age differences in decision making using functional MRI measures of brain activity and connectivity and diffusion tensor imaging measures of white-matter integrity. We investigate two decision-making tasks, the multi-attribute choice task and the time discounting task, and have 3 specific aims. Our first aim is to investigate age differences in mul- ti-attribute decision making as function of episodic memory demands and decision making demands. In Study 1, we manipulate episodic memory demands by varying whether or not the decision amount requires retrieving previously learned information, and decision making demands by instructing participants to using a simple or a more elaborate decision strategy. Study 1 focuses on remembering the past but episodic memory is also nec- essary for for thinking about the future. Our second aim is to examine age differences in the time discounting task as a function of episodic future thinking, which is known to be impaired in older adults Study 2 investi- gates the effects of episodic tags on monetary intertemporal decision making. Finally, our third aim is to spec- ify how individual differences in brain integrity modulate age differences in episodic memory-dependent deci- sion making. Individual differences in episodic memory in older age have been linked to an executive factor as- sociated with the frontal lobes, and a memory factor associated with the medial temporal lobes. We examine how these two factors account for individual differences in white-matter integrity among older adults and how these individual differences modulate the results of Studies 1 and 2. In sum, the proposed studies investigate the neural mechanisms of age differences in episodic memory-dependent decisions, which are common in eve- ryday life. The research will link two previously disconnected areas of research, the cognitive neuroscience of aging and neuroeconomics of aging. The studies will contribute to a more comprehensive scientific under- standing of brain aging that is more easily translatable to critical behavior in everyday life. The work has the potential to identify mechanisms to improve episodic memory-dependent choice across all stages of adulthood, which will contribute to improving health and well-being in old age.

Training autobiographical memory in older adults using novel lifelogging technology Memory for personally experienced past events, or episodic memory, is the cognitive ability most impaired by healthy aging and the first one to decline in Alzheimer's Disease. Therefore, it is not surprising that episodic memory has been a primary target of cognitive training studies in these populations. Yet, most of these studies have focused on episodic memory for laboratory stimuli (such as lists of words or pictures), rather than on episodic memory as it typically operates in the real world?namely autobiographical memory. Autobiographical memory refers to memory of events in our own life, such as what we did last weekend or where we parked the car in the morning. Although it is usually assumed that training memory using word or pictures should transfer to everyday memory, transfer is often small because of the large differences between these memory tasks. One way to address this important issue is to train memory abilities that are closer to the way memory is used in the real world. Thus, instead of training memory for laboratory stimuli, we propose to train autobiographical memory. This approach is novel as no previous memory training study in older adults has focused on autobiographical memory. One of the reasons for this gap in research is that, until recently, it has been very difficult to train autobiographical memory and accurately measure its improvement. This situation has recently changed due to the creation of novel wearable technology such as lifelogging cameras. These cameras can continuously and automatically take photos from a first-person perspective without user intervention. Preliminary studies have shown that lifelogging camera photos can dramatically enhance remembering in amnesics. The proposed studies will train autobiographical memory in older adults using lifelogging camera photos and movies created from them, which will also allow accurate measures of memory improvement. We have three specific aims. (1) Demonstrate that autobiographical memory training yields transfer to software-based untrained autobiographical memory and laboratory memory tasks. (2) Show that autobiographical memory training yields significant transfer to everyday memory measures. (3) Prove that autobiographical memory training effects persist for several months. In sum, the proposed study will investigate an innovative memory training approach based on training autobiographical memory instead of the traditional approach of training that uses laboratory stimuli. Taking advantage of novel lifelogging technology, we will train memory in healthy OAs using participants' own memories, which is likely to enhance transfer to memory in everyday life. The results will provide critical pilot data for a future R01 application focused on using our novel approach to rehabilitate episodic memory in early Alzheimer's Disease.

Project Summary This is an application for an Administrative Supplement award to an existing project, using fMRI-guided TMS to increase central executive function in older adults. This award will provide our team with the support necessary to extend our existing fMRI-TMS paradigm to patients with a prodromal form of Alzheimer?s Disease (AD) known as amnestic Mild Cognitive Impairment (MCI), and investigate the role of brain health factors in mediating the TMS-related memory performance benefits associated with communication between a network of frontoparietal brain regions in these populations. To achieve these goals, we have developed a plan to expand our existing project and augmented our scientific team to add Dr. Richard O?Brien, Chair of the Neurology Department at Duke, and Dr. Jeffrey Browndyke, who both have extensive experience conducting multimethodological investigations of aging and neurodegenerative disease, including AD and MCI, the population examined in the current proposal. The focus on focal neurostimulation at only a single site represents a fundamental gap in the approach of memory-based neurostimulation therapies. Neurostimulation affects multiple sites within a cortical network, but these global effects have not been used as targets for stimulation because of limited knowledge about what influence these localized sites have on global changes in brain state. To address this problem, we will use multimodal neuroimaging tools and network modeling approaches developed though the parent U01 project, to demonstrate how focal neurostimulation improves the efficacy of TMS for enhancing memory function. These goals will be addressed in the Administrative Supplement under our two specific aims. First, we will use network-guided TMS to optimize memory success based in the frontoparietal network (FPN) in a new group of MCI patients. We will implement a new form of TMS targeting that involves modeling of the global network to understand how the controllability of a stimulation site evokes changes in widespread brain networks. Second, we will identify structural and functional factors affecting the efficacy of individualized network-guided TMS to ameliorate deficits in MCI. By creating a multimodal model of neural deficits related to MCI, we will adjust network-guided TMS to demonstrate how the MCI brain might compensate for these neural deficits. The parent U01 project has made foundational advances towards these goals, as we have demonstrated the ability of to selectively enhance and reduce working memory performance in healthy older adults. In the current Administrative Supplement we will extend this paradigm to a group of MCI participants in order to test the hypothesis that excitatory rTMS to the working memory network can provide positive outcomes for patients with pre-clinical AD. The proposed work will provide an important tool for studying the stability and controllability of network connectivity of memory states in the aging brain, as well as new information on the effectiveness of brain stimulation technologies as a therapeutic approach for cognitive decline.

Alzheimer?s Disease (AD) impairs not only cognitive abilities, such as memory, but also sensory functions, such as vision. The current project investigates memory-vision interactions in the early stage of AD known as amnestic Mild Cognitive Impairment (aMCI), as well as in healthy aging. We focus on memory for visual stimuli, which declines substantially in AD, predicting dementia more than a decade before diagnosis. We propose 3 functional MRI (fRMI) studies, each including 3 groups of participants: aMCI, older adults, and younger adults. Whereas most fMRI studies on memory and aMCI investigated memory processes, we focus on the quality of the information used by these processes or memory representations. To our knowledge, no fMRI study has examined the quality of memory representations in MCI. Our first aim is to investigate the effects of healthy aging and aMCI on visual vs. semantic features of memory representations. There is evidence that healthy aging impairs visual representations in posterior occipito-temporal cortex (OTC) and medial temporal lobe (MTL) regions, but we have preliminary that it spares semantic representations in anterior OTC/MTL. In contrast, aMCIs are impaired in semantic processing and anterior temporal function. We test the hypothesis that visual representations in posterior OTC/MTL are impaired in both aMCI and healthy older adults, whereas semantic representations in anterior OTC/MTL are impaired in aMCI but not in healthy older adults (Hypothesis 1). This dissociation between healthy and pathological aging has important implications for the early diagnosis of AD. Our second aim is to examine the semantic support effect on memory representations in healthy older adults and aMCIs. The semantic support effect refers to the reliable finding that conditions that allow or promote the use of preexistent semantic knowledge tend to attenuate age-related cognitive deficits, including memory deficits. The semantic support effect is weaker in aMCIs, consistent with their semantic processing deficits. Each of the 3 studies investigates a different form of the semantic support effect (levels of processing, schema congruency, and conceptual attention). We test the hypothesis that the semantic support effect enhances the quality of visual memory representations and subsequent visual memory to a greater extent in healthy older adults than in aMCIs (Hypothesis 2). This finding has implications for the use of the semantic support in memory training in these populations. In sum, the proposed studies will systematically examine the neural mechanisms of visual memory deficits in MCI and healthy aging. They will use novel representational similarity analyses that have not been used yet to investigate memory representations in aMCI. The expected results will contribute to methods for diagnosing AD early in the disease and to rehabilitating memory in aMCI and healthy aging, and are hence, highly significant.