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.

[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): 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): 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.

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.