David J. Madden, Ph.D. - US grants

The long-term objective of the experiments proposed in the present application is to investigate adult age differences in several components of reading, ranging from word identification to sentence memory. All of the proposed experiments require young and older adult subjects to make a series of choice responses regarding visually presented words and sentences. The amount of time required to make these responses is the dependent variable of primary interest. Experiments 1-4 will all involve versions of the lexical decision paradigm, which requires that subjects decide, on each trial, whether or not a visually presented "target" letter string forms a real word. In Experiment 1, each letter string will be presesnted individually, and the type of information (e.g., pronounceability versus meaning) that is sufficient for making the lexical decision will be varied. A measure of basic visual functioning, contrast sensitivity to gratings of various spatial frequencies, will also be obtained in Experiment 1, and the relationship between contrast sensitivity and word identification time will be examined. Experiments 2-4 will use the lexical decision task to investigate identification of words in the context of sentences. Experiment 2 will examine the effect of the rate of presentation of the sentence context on word identification. Experiment 3 will vary the visual quality of the target letter string. In Experiment 4, the amount of time intervening between the context sentence and the target letter string will be varied. Experiments 2-4 will also investigate the ways in which word identification is affected by both the meaning of the context sentence and the difficulty (i.e., length and familiarity) of the target word. Experiment 5 will examine subjects' ability to make decisions about whole sentences rather than individual words. Experiments 6 and 7 will investigate aspects of recognition memory for visually presented text, by measuring the time required to decide whether particular words and sentences occurred in previously presented paragraphs. The proposed experiments are designed to determine whether an age-related slowing in the speed of information processing can account for age differences in component processes of reading, and to suggest ways in which text presentation can be best adapted for older adults.

DESCRIPTION (adapted from Investigator's abstract): The goal of this project is to determine, in the context of visual search and classification tasks, the degree of age-related change in different forms of attentional functioning. The project is also concerned with the potential contribution of mild essential hypertension to age-related cognitive changes. The proposed experiments will involve measuring subjects' reaction time and accuracy for decisions regarding different types of visual displays. Experiments 1-6 will test the hypothesis that, as perceptual load is increased, disruption of performance from task-irrelevant information (flankers) will decline more for young adults that for older adults. This hypothesis will be assessed under conditions of varying display size (Experiment 1), perceptual discriminability (Experiment 2) memory load (Experiment 3), target location predictability (Experiment 4), and response-correlated flankers (Experiments 5 and 6). Experiments 7-13 will investigate the allocation of attention. Experiments 7-8 will determine whether there is an age-related change in the spatial distribution of attention. Experiments 9-12 will use the subadditivity diagnostic and analysis of different levels of stochastic dominance to test a model in which the shift of attention between display positions is serial but distance-independent. Experiment 13 will examine age differences in the ability to guide search on the basis of target-relevant features. Experiment 14 will compare the performance of hypertensive and normotensive individuals in visual search performance, to test the hypothesis that the interaction between age and hypertensive status is related to the memory demands of the task. Data from the present project will contribute to an improved account of the age-related changes in attentional functioning in healthy individuals, and of the potential role of hypertension in age-related cognitive change.

DESCRIPTION (provided by applicant): The long-term goal of this project is to identify the patterns of age-related change and constancy in the functioning of neural systems that mediate cognitive abilities, especially attention and memory. Recent findings from the present project, based on measures of neural activation obtained from positron emission tomography, suggest that aging is associated with both decreases and increases in regional activation. The proposed research will test healthy, community-dwelling younger and older adults, using event-related functional magnetic resonance imaging (fMRI), to address the following issues: age differences in the shape of the neural hemodynamic response (HDR) waveform, measured from fMRI, in various brain regions (Experiment 1); the role of strategy and memory demands in eliciting age-related increases in prefrontal activation (Experiments 2-3); the relative contributions of top-down and bottom-up attentional processing to age differences in visual search performance (Experiments 4-5); age-related changes in the neural basis of inhibition of response-incompatible information (Experiments 6-7); the differential pattern of prefrontal activation for episodic and semantic memory retrieval processes (Experiment 8); and the neural correlates of age-related declines in episodic encoding and retrieval success (Experiments 9-10). Across all of the experiments, analyses of the temporal characteristics of the HDR functions will be conducted, which will assist the interpretation of age differences within task conditions, as well as the characterization of the relation between neural activation and cognitive performance. The project is designed to provide new information regarding the age-related changes in neural functioning that occur independently of significant disease. The findings will be relevant to the development of functional neuroimaging techniques that can aid in the diagnosis of significant and abnormal cognitive impairment.

DESCRIPTION: The long-term objective of this project is to identify the pattern of age-related change and constancy in the functioning of neural systems mediating cognitive abilities. Positron emission tomography (PET) will be used to measure changes in regional cerebral blood flow (rCBF) during subjects' performance of specific cognitive tasks. The general hypothesis to be tested is that rCBF activation, as defined by the pattern of change in the PET voxel map between two task conditions, will be significantly lower and less regionally specific for older adults than for young adults. For each subject, the PET images will be registered to MRI. The project is designed to provide new data regarding the age-related changes in neural functioning that occur independently of the presence of significant disease.

This study is part of a multi-study research grant, "Age and Selective Attention in Visual Search," (R37 AG02163) funded by the National Institute on Aging. Purpose: The overall goal of the project is to determine the pattern of age-related change and constancy in the use of attention during the performance of visual search and classification tasks. Although the primary focus of the project is on the age-related changes that occur in the absence of significant disease, the project is also concerned with the potential role of one aspect of health status, mild essential hypertension, in mediating age-related changes in attention and cognition. All of the studies in the project involve measuring subjects' reaction time and accuracy for decisions regarding different types of visual displays. In the study conducted in the GCRC, we are comparing the performance of hypertensive and normotensive individuals in visual search performance, to test the hypothesis that the interaction and age and hypertensive status is related the memory demands of the task. In a previously conducted experiment we found that there was an interaction of age group and blood pressure group in the error rate data, such that for subjects less than 60 years of age, the error rate was higher for hypertensives than for normotensives. The reaction time data, in contrast, did not indicate substantial effects of hypertension. Thus, hypertension- related changes in cognitive performance may not be evident unless the memory demands of the task exceed some critical level. Our hypothesis is that the effects of hypertension will be most clearly evident in the exponential component of the reaction time distribution, especially when memory-set size is varied. Methods: The present experiment will use a visual search task in which the number of target items held in memory (memory-set size) and the number of items in the display (display size) are varied independently. To examine the attentional demands of the task we will analyze the complete distribution of reaction time data. Previous experiments using this approach have indicated that reaction time distributions actually represent a convolution of two component distributions, one characterized by an exponential function (representing task- specific decision processes) and one characterized by a Gaussian function (representing sensory encoding and response processes). Results: At the present time we are still in the subject recruitment phase and have not completed any manuscripts or abstracts. Future plans: Our plan is to continue recruiting hypertensive and normotensive subjects. This is a multi-year study and it is possible that a year or more may be required before sufficient data are available for analysis. Significance: The significance of the study is the improvement in the scientific understanding of the potential role of hypertension in age-related cognitive change, which will be important for distinguishing the effects of aging from those of disease.

Previous neuroimaging research suggests that age-related decline in the functioning of specific neural systems contributes to decline in cognitive performance, even in the absence of significant disease. Previous imaging studies, however, have typically focused on the magnitude of mean activation, rather than functional connectivity (FC) of activated regions, and have relied on extreme-group designs comparing younger and older adults. Building on the findings from the previous project period, we propose to investigate age-related differences in visual attention with a multimodal imaging methodology comprising both resting-state and task- related FC, as well as white matter integrity as assessed by diffusion tensor imaging (DTI). Each of four experiments will include 90 healthy, community-dwelling adults sampled continuously across the age range of 18-79 years. Critically, the research will use graph theoretical analyses of structural connectivity (SC) and FC, which will provide a unifying methodology and specific metrics (e.g., strength of FC within and between network modules) that can be applied to both structural and functional imaging. Each of the four experiments will involve a visual search task, and behavioral assessments of visual search performance will implement a mathematical model of reaction time that yields separate parameter estimates for the rate of information accumulation towards a decision (drift rate), as distinct from visual encoding and response execution processes (nondecision time). We propose to elicit differential engagement of functional modules, by varying the attentional demands of the search task related to: the enhancement of target information versus suppression of irrelevant but salient information (Exp. 1), the spatial selectivity of attention (Exp. 2), the activation of a motor response (Exp. 3), and the response to visually degraded targets (Exp. 4). Graph theoretical analyses of the structural and functional imaging data will test the overall scientific premise of this project: that aging is associated with a shift in the dynamic balance of within-module and between-module task-related FC (Aim 1), that this pattern is related to the degradation of visual information as reflected in SC and FC of visual sensory regions (Aim 2), and that task-related FC will reflect the participation of specific modules as a function of attentional task demands (Aim 3). We expect an age-related decline in the graph theoretical measures of within-module connectivity, but an increase with age in measures of between- module connectivity. Further, we hypothesize that the increase in between-module FC with age will be more prominent during task performance, relative to a resting-state, reflecting older adults? increased reliance on top- down attention to support task performance. The four studies and associated network analyses, with healthy adults, are designed to improve current theories of neurocognitive aging and provide information relevant for diagnosis and treatment of neurodegenerative disease.

DESCRIPTION (provided by applicant): Cognitive impairment frequently occurs in late-life depression (LLD), which increases the risk of dementia, mortality, and medical comorbidity. While cognitive impairment secondary to depression may resolve after successful treatment, persistent cognitive impairment or cognitive decline may occur in some patients even after remission from depressive symptoms. Individuals with cognitive decline over years have an increased risk of developing either Alzheimer's disease or vascular dementia. Identifying individuals who are at risk for developing cognitive decline is vital for early intervention strategies. Therefore, the long-term goals of the proposed project are to better understand the neural mechanisms linking depression and cognitive impairment, to establish biomarkers for early identification of depressed individuals at risk for cognitive impairment, and to understand the neural plasticity of LLD with and without cognitive impairment following prevention programs and clinical interventions. Our preliminary study indicates that reduced dorsal anterior cingulate (dACC) activation during target detection is associated with future cognitive decline in LLD. Reduced dACC- hippocampus connectivity is also found in LLD patients with cognitive impairment. Given that the dACC is one of the regions that is involved in both AD and depression, and because deficits in this region can result in broad abnormalities in functional connectivity across affective and cognitive networks in depression, we hypothesize that aberrant dACC activity (i.e., reduced dACC activation and reduced hippocampus-dACC connectivity) will predict cognitive decline in LLD. To test this hypothesis, we propose a two-year longitudinal neuroimaging study in 140 medication-free LLD patients. The objectives of this proposal are to investigate the neural mechanisms in LLD associated with cognitive decline and to examine whether our proposed imaging marker can predict which individuals are at a high risk of cognitive decline. All participants will be scanned during a resting state and during a simple target detection task at baseline, and at year 2. Our specific aims are: 1) to characterize the cognitive profile associated with reduced dACC activity in patients with acute LLD; 2) to examine whether reduced dACC activity at baseline predicts two-year cognitive decline; and 3) to examine the association between two-year changes in cognition with two-year changes in brain activation and functional connectivity in LLD patients. We hypothesize that LLD patients with reduced dACC activity will have lower cognitive function at baseline and greater cognitive decline over the two-year follow-up period. The proposed research is innovative because we plan to characterize a clinical profile in LLD based on functional activation pattern. The approach will stimulate future brain-based classification studies to predict individuals' clinica status based upon brain activation. The proposed research is significant because positive outcomes of the study will potentially assist clinical identification of LLD individuals who are at risk of cognitive decline. The dACC dysfunction pattern may also serve as a neural marker to monitor clinical intervention.

Iron concentration in deep gray matter (DGM) regions is associated with neurodegenerative disease, but DGM iron also increases with adult age, in the absence of disease. Previous studies have reported association between age-related DGM iron accumulation and decline in some aspects of neurocognitive function. However, previous studies have typically focused on a limited number of neurocognitive outcome measures, often biased towards motor functioning, and have relied on less than optimal MRI methods to estimate iron concentration, such as MRI relaxometry. Further, although decline in structural and functional brain connectivity appears to contribute to neurocognitive decline in healthy aging, the role of iron in this decline is not clear. In this project we test a model of the influence of age-related DGM iron accumulation on neurocognitive function, proposing that age-related DGM iron contributes to oxidative stress and consequently to a decline in network connectivity. The research will investigate the effects of DGM iron using Quantitative Susceptibility Mapping (QSM), a novel and validated technique that has several advantages over previous methods for estimating GM iron (e.g., relaxometry). This research comprises imaging and neurocognitive testing of 270 healthy, community-dwelling individuals, with 45 individuals in each of six age decades: 20s, 30s, 40s, 50s, 60s, and 70s. The participants in their 60s and 70s will be tested at two time points, approximately 3 years apart. Aim 1 will test the hypothesis that iron in the head of the caudate will have a greater mediating or moderating influence, on the relation between age and the neurocognitive measures, relative to other DGM regions, and that this influence will extend to measures of the efficiency of decision processes (drift rate). Aim 2 will test the hypothesis that age-related increase in DGM iron, particularly in the head of the caudate, influences structural and functional connectivity in a serial manner, with regionally specific associations among DGM iron, the white matter (WM) integrity of frontostriatal circuits, and the functional connectivity of associated resting-state networks (RSNs). Aim 3 will test the hypothesis that the age-related influences of DGM iron identified in Aims 1 and 2, in cross-sectional analyses, can be confirmed longitudinally, across a three-year interval. The project will consequently contribute to a more comprehensive theoretical model, than presently available, of the influence of DGM iron on the relation between age and neurocognitive performance. The findings will also be relevant to assessing the potential role of DGM iron as a biomarker of neurodegenerative disease.