David A. Balota - US grants

It is well known that memory functioning suffers some deterioration with age, yet it is not entirely clear why this is the case. The proposed research is designed to investigate some underlying memory mechanisms which may be responsible for this age-related deficit. Specifically, the theoretical mechanisms of automatic spreading activation in the memory network, and attentional capacity in retrieving information from memory will be the focus of this research. The first series of experiments will address age-related differences in various characteristics of spreading activation (e.g., rate of buildup, decay, depth) in the memory network. This will be accomplished via a semantic priming task in which a prime item (e.g., cat) is presented followed by a target item (e.g., dog) and the latency to pronounce the target item is measured. The semantic relationship between the prime and target is varied, and response latency is used as an index of activation in the memory network. The second series of experiments will address age-related differences in the focusing of attention to specific areas of memory. This again will be accomplished in a semantic priming task in which the direction of attention is manipulated by varying the subjects' expectancies about which area of memory will be necessary for retrieval. In the third series of experiments, age-related differences in the retrieval of information from memory will be addressed by instantiating an episodic memory network in the context of the experiment. Subjects will be required to learn a list of sentences related to a topic. The number of sentences related to a topic, the integration of the memorized sentences, and the conditions under which the sentences are learned will be varied. The time to recognize the memorized sentences will be used as a measure of retrieval from an episodic memory network.

As the elderly population increases, senile dementia of the Alzheimer type (SDAT) is becoming one of the most devastating health problems facing society. Early in SDAT, individuals primarily produce memory deficits, however, these deficits are typically followed by widespread breakdowns in cognitive performance. The widespread involvement of cognitive processes in Alzheimer's disease suggests that there may be fundamental cognitive mechanisms involved in the progression of the disease. The goal of the present proposal is to continue our pursuit for such a fundamental mechanism. Specifically, the proposed studies all address the notion that SDAT individuals have difficulty inhibiting irrelevant information at different stages within the information processing system. Such a failure to inhibit the processing the irrelevant information has recently gained considerable attention in research addressing infants, children, and young and older adults. Recent evidence indicates that a breakdown in one's ability to inhibit irrelevant information can influence processes involved in perception, memory, comprehension, and even syntactic parsing. Furthermore, recent work completed in our lab (supported by Grant R01 AG03991) indicates that SDAT individuals fail to inhibit unbiased meanings of ambiguous words, and also fail to inhibit noncued locations in visual attentional tasks. In addition to providing information regarding failure to inhibit irrelevant information in SDAT individuals, the present work will also provide further information regarding the notion that healthy aged individuals produce some breakdown in their ability to inhibit irrelevant information. Each experiment will involve four groups of subjects (healthy young adults, healthy older adults, questionably demented individuals, and mildly demented individuals). The first experiments will address the phenomenon referred to as inhibition of return in a visual spatial processing task. The second experiment will address the negative impact of earlier ignored irrelevant information when it subsequently becomes relevant. Experiments 3 to 7 address processes involved in selecting meaning for ambiguous words in simple naming, word association, and in a relatedness judgement task. Each experiment will also include manipulations of stimulus onset asynchrony to track the time-course of inhibitory operations across the four groups of subjects. All experiments involve either simple key presses or vocal responses, and the resulting response latencies and error rates will be used to index underlying cognitive operations.

This award permits the Psychology Department at Washington University to purchase instrumentation to store and analyze functional magnetic resonance imaging and positron emission typography data. Currently cognitive scientists in the department conduct cognitive research using fMRI and PET machines located at the Washington University Medical School campus and they must analyze the resultant data there. This makes convenient and continuous access difficult both for senior researchers and students. The instrumentation provided will allow transmission of this information to the Psychology Department where it can be analyzed. The system includes: a server computer which will receive the large data structures and store the images for distribution to other work stations; an SGI Work Station that takes advantage of programs that have been developed to provide 2-dimensional surface reconstructrions of the human cortex; three work-stations; an eithernet hub; a color printing device; a half-time technician who will be responsible for the initial development and maintenance of the system. Two projects currently under way will make immediate use of the system. Both address the neural underpinnings of cognitive components of behavior. The first - PET Activation Studies of Words - addresses those areas of the brain which are actively engaged in processing distinct aspects of words and the neural underpinnings of the attentional control systems that coordinate such processes. The second project - Imaging Studies of Learning and Memory - addresses those brain areas which are involved in the distinct aspects of encoding and retrieval of information from episodic, semantic and procedural memory systems. This equipment will also be used for training graduate students and postdoctoral fellows in the area of cognitive neuroscience.

Senile dementia of the Alzheimer type (SDAT) is becoming one of the most devasting health problems facing society. In the initial stages of the disease, individuals experience some memory impairment followed later by widespread breakdown in most cognitive functions. In addition, although the deficits are not as severe and progressive, there is also evidence of cognitive breakdowns in healthy aged individuals. The goal of the present proposal is to examine a cognitive mechanism which may underlie the deficits exhibited in both healthy aged and in SDAT individuals, and to begin to develop a formal model which can account for these deficits. The specific target mechanism addressed in this proposal is the ability to inhibit partially activated and competitive information. Recent work from our lab (P01AG03991, Project 3) indicates that healthy aged individuals and to a greater extent SDAT individuals exhibit a breakdown in inhibitory aged individuals and to a greater extent SDAT individuals exhibit a breakdown in inhibitory control across a number of experimental paradigms. In the first series of proposed experiments (Experiments 1-7, Series I), the efficiency of inhibitory processes in healthy aging and SDAT will be examined at a number of distinct levels within the information processing system: perception, memory retrieval, lexical disambiguation, and sentence comprehension. In addition, these experiments will involve manipulations that will allow one to track changes in the time course of inhibitory processes across our subjects groups. The second series of experiments (Experiments 1-4, Series II) will extend to healthy aged and SDAT individuals a set of formal connectionist models that were developed by Cohen and Servan-Schreiber (1992) to account for breakdowns in the efficiency of inhibitory processes in schizophrenic individuals and also to simulate dopaminergic breakdowns in the prefrontal cortex. The proposed experiments will provide an empirical base for formally modelling cognitive changes that occur in healthy aged and SDAT individuals, and also provide a unique opportunity to compare changes in the specific model parameters that are necessary to account for changes in cognitive performance across three distinct populations (schizophrenic, healthy aged, and SDAT individuals). Hence, in collaboration with J. Cohen and D. Servan-Schreiber we intend to use a three-pronged attack utilizing basic cognitive theory, formal connectionist modelling, and neurological evidence to better understand the cognitive changes that are associated with healthy aging and Alzheimer's Disease.

The word is as central to human communication as the cell is to biology. In developing our understanding of how the brain processes words, researchers have relied heavily on tasks that measure the speed of processing words. These tasks are speeded naming, in which one measures how quickly a person can name a visually presented word aloud, and speeded lexical decision in which people are asked to decide if a letter string is a word or nonword. Unfortunately, research in this area has been somewhat hindered by the limited amount of data available for word processing in these tasks. The current project will fill this void.

The English Lexicon Project will amass a large set (over 25 million behavioral estimates) of speeded naming and lexical decision responses for 42,000 words across 1200 subjects. This will be accomplished via the coordination of six testing sites at major research institutions across the country. These data will be integrated within a larger database that will include estimates of variables (e.g., frequency of occurrence in the language) that have been central to our understanding of how the brain processes words. A high-speed server will then make this large database available to researchers worldwide via the Internet. Access and search of this data set will be facilitated by a flexible program, which will provide easy and fast access to any items or sets of items with specified constraints.

The audience for the English Lexicon Project will include the following researchers: First, computational modelers will now have a large standardized empirical database to provide tests of their models. Second, researchers (including those interested in reading educators) interested in effects of specific variables can easily test these in the database. Third, researchers who use words as their primary stimuli will be able to select better-controlled stimuli. This later targeted audience will include memory researchers, neuropsychologists, and researchers interested in brain imaging. Ultimately, the English Lexicon Project will provide the gold standard for our understanding of how the brain processes words.

Recent evidence suggests that components of attention may serve as early indicators of the onset of dementia of the Alzheimer type (DAT). For example, work from our current Project indicates that higher-level aspects of attentional control are deficient in the earliest stages of the disease, and that these control systems contribute to the observed memory changes. However, to date there has been relatively little work investigating systematic changes in the specific components of attention with age and DAT or the consistency of these components within individuals across different attentional measures and testing sessions. The goal of the present proposal is to target specific components of attention, and provide individual attentional profiles in an attempt to distinguish healthy aging from the earliest stages of Alzheimers Disease. The data obtained from these experiments will also be especially useful in evaluating recent evidence indicating that within-individual variability can serve as a marker for discriminating healthy aging from early stage DAT. In addition, recent evidence suggests that components of attention may be differentially affected by distinct personality types. Hence, personality traits based on the five-factor model of personality will be explored in relation to distinct attentional profiles, disease onset, and disease progression. The proposed experiments will isolate four distinct components of attention: maintenance, selection, switching, and divided attention. Based on the extant literature, three experiments will be designed to tap each of the four components of attention, yielding a battery of 12 attentional tests. Factor analytic procedures will be used to determine whether these tasks load on the predicted attentional components. In addition, we will include a brief standardized attention battery that has been recently developed (Attention Network Test) to investigate its relationship to the targeted components of attention in the present set of experiments. Seven groups of subjects will be tested during Years 1-3 in the proposed attention battery: young adults, middle-aged relatives of a DAT individual, middle-aged controls, healthy young-old adults (mean age 70 years), healthy old-old adults (mean age 85 years), very mild DAT (CDR 0.5) and mild DAT (CDR 1) individuals. In Years 4-5, approximately 70% of these individuals will be retested to provide a replication of the factor structure from Wave 1 testing and to examine the consistency of performance within individuals across testing sessions. In conjunction with data from the remaining Cores and Projects, the data from this project will serve as a cognitive marker to differentiate healthy aging from the earliest stages of the disease process.

Accumulating evidence indicates that specific cognitive deficits may be present several years prior to an initial clinical diagnosis in individuals who later develop Alzheimer's disease (AD). In particular, recent research examining specific components of attentional control systems may be potential early cognitive markers for AD. For example, deficits in spatial controlled attention, working memory, and prospective memory have been shown in healthy middle-aged adults, who have the ApoE e-4 gene compared to individuals who do not have the e-4 allele, even though these individuals do not produce deficits on more standard neuropsychological measures. There have not been any studies that have attempted to decompose the hypothesized theoretical components of attentional processing (maintenance, selection, switching, and divided attention) presumed to be deficient in early stage AD. Moreover, there is little evidence that the underlying components of attention are consistent within an individual across different attentional measures and across different testing sessions. The goal of the present proposal is to target specific components of attention, and provide individual attentional profiles in an attempt to identify early cognitive markers for Alzheimer's Disease. In addition, recent evidence suggests that components of attention may be differentially affected by distinct personality types, and that variability in behavior may be an important discriminator in early stage DAT. Hence, the proposed studies will also provide indices of personality and variability profiles. The proposed experiments will isolate four distinct components of attention: maintenance, selection, switching, and divided attention. Based on the extant literature, three experiments will be designed to tap each of the four components of attention, yielding a battery of 12 attentional tests. Two categories of individuals will be tested in this battery: individuals who have a biologic parent with DAT and control individuals who do not have a biologic parent with DAT. Within each of these two categories, 3 age groups will be included (ages 45-54 years; 55-64 years; 65-74 years). Approximately 120 subjects per category (40 per age group within each category) will be tested in the first wave of experiments. We anticipate that 70% of the total sample will be tested beginning in year four for a second wave. The goal of these multiple tests will be to provide a replication of the factor structure, and also to index the consistency of the within-subject profiles. Analyses will be conducted to determine the relation between the attentional, personality, and variability profiles of the individuals and the biomarkers from the remaining Projects, along with APOe4 status of the individuals.

This competitive renewal is to continue the Aging and Development Training Program in the Department of Psychological and Brain Sciences at Washington University. Because of the increased demands of an aging population on society along with the concomitant increased health risks, there is a critical need to train researchers to better understand what does and does not lead to successful aging. Requests are made to support the training of the next generation of researchers in aging at both the predoctoral level and at the postdoctoral level. There are currently 14 faculty who serve as the Preceptors (primary mentors) in this program along with 3 Affiliated (Other) faculty. This training program focuses on the Psychology of Aging, and emphasizes a multifaceted approach to individual differences in their aging trajectory including the following interrelated themes: cognitive aging, cognitive neuroscience in healthy and abnormal aging, personality and social aging, and translational science. Although trainees will develop depth within one of these themes, the program is designed to expose trainees to breadth across themes. The program trains candidates both in clinical and non-clinical areas of Psychology and benefits from the emphasis at Washington University on aging and age-related diseases, as reflected by the Charles F. and Joanne Knight Alzheimer's Disease Research Center and the Center for Aging. As described in the proposal, the Department continues its emphasis on the Psychology of Aging, with 5 of the last 7 faculty hires having substantive research focus in aging, which makes this program ideal for training. In this proposal we document the high quality of the program trainees and faculty, the structure of its well-established training program and its assessment, and the success of the training.

There is accumulating evidence that early stage Alzheimer's disease reflects a breakdown in attentional control systems that likely contribute to the changes in memory performance, along with other aspects of cognitive performance. Recent evidence indicates that tasks that place a maximum load on attentional systems are particularly useful in serving as a behavioral biomarker both in discriminating healthy aging from early stage DAT, and are correlated with other biomarkers in non-demented older adults. The proposed research plan will continue to longitudinally follow a set of healthy older adults and individuals in the early stages of the disease process, along with individuals who are at risk due to stroke, to better isolate the contributions of novel attentional control measures, and to investigate the extent to which these individuals respond to memory/attention training techniques. We will have three waves of testing, which will be separated by approximately 1.5 years. Each participant will be tested in a single session for each wave of testing, lasting approximately 2 hours. During each wave, we will continue to administer a small battery (no more than 40 minutes) of executive measures (computation span, Stroop, a retroactive interference exclusion measure, and a short switching task). This will afford the ability to continue to follow these individuals with the same set of measures for which we already have data. In addition to the executive control measures, we will also use experimental procedures to provide estimates of three different targeted components in each wave. These will include measures of (a) controlled and automatic processing via the processing dissociation procedure, (b) components of prospective memory performance, and (c) standard mnemonic manipulations (i.e., repeated testing, expanded retrieval, semantic encoding). We will continue to explore distinct measures of participant variability and the components of reaction time distributions that lead to any change in the observed variability estimates as a potential marker for cognitive changes in healthy aging and early stage DAT. In addition, because of recent evidence that certain personality traits (e.g., conscientiousness and neuroticism) predispose individuals for developing DAT, we will explore the modulatory role of personality characteristics in the cognitive markers, and susceptibility to mnemonic techniques. Moreover, we have recently found that personality characteristics are related to cognitive performance including variability estimates. Finally, the behavioral assays obtained in Project 3 will be correlated with the results from the biomarkers available from other projects and cores (e.g., CSF, PIB, genetics, and volumetric measures of targeted areas) to determine which composite measures afford the best behavioral biomarkers.

There is accumulating evidence of a breakdown in attentional control systems and consequent increases in reaction time (RT) variability that may reflect a prodromal stage of Alzheimer's disease (AD). Recent evidence indicates that tasks which place a high load on attentional systems are particularly useful in (a) serving as a behavioral marker in discriminafing healthy aging from early stage DAT, (b) predicfing later conversion in a group of healthy middle-aged/older adults, and (c) showing relafionships with other biomarkers in healthy control individuals. The proposed research will continue to longitudinally follow the adult child sample, who have well-characterized risk for developing symptomatic AD, to address the following issues: First, we will examine a set of cognitive tasks that target attentional selection, executive control, and attentional control contributions to memory performance and relate these measures to the accumulafing biomarkers from the other projects and cores (e.g., PIB, CSF measures, AP0E4 status, structural and resting state fMRI measures). Second, we will explore subtle characteristics of RT distribufional performance utilizing ex-Gaussian analyses and the diffusion model to examine the extent to which distinct parameters are useful prodromal markers for risk for developing AD. Third, we will use both a Sustained Attention to Respond task (SART) and a simple repetitive finger tapping task as behavioral markers for momentary fiuctuafions in task disengagement to irrelevant thoughts (i.e., mind wandering). Fourth, we will measure the task related neural response (via fMRI) in both a Stroop and Encoding Subsequent Memory paradigm to determine if attentional and/or default mode neural networks begin to be compromised before there is disruption in cognitive performance and relate these results to the biomarkers developing in the other projects, especially the resting state fcMRI studies in Project 4. Fifth, we will examine the extent to which personality characterisfics are related to the attenfional control mechanisms, and modulate the brain-behavior relafionships. The convergence across these aims, projects, and cores in the confinuing longitudinal study of the Adult Children Study cohort affords a unique opportunity to develop an understanding of the multi-faceted nature of the earliest bio-behavioral changes associated with AD.

Two decades ago, the National Science Foundation supported the development of the English Lexicon Project (ELP), a critical database for researchers exploring how people read. The ELP affords measures of word recognition for over 40,000 words across over 1200 participants that were collected at six universities. Importantly, these data are made available to the wider research community via a user-friendly website at elexicon.wust.edu. Using the database, researchers can select stimuli with specific characteristics for experiments exploring the nature of reading and its neural underpinnings. Moreover, the database has been important in identifying new variables that influence the reading process. The impact of this database on research is exemplified by the over 1600 (google scholar) citations to the original (2007) publication describing the project. The website is accessed approximately 250 times each week from researchers worldwide. This is a prime example of how big data can have a substantial impact on a theoretically important area that has clear applied implications, i.e., how individuals read words.

This ELP is being run on an outdated computer that has outlived its life expectancy and the original software interface is no longer supported. This proposal is to rewrite the programs for the user interface using current software supported by a virtual computer system within the Department of Psychological and Brain Sciences at Washington University. This will ensure the database remains available to the psycholinguistic community.