Michael D. Rugg - US grants

DESCRIPTION (provided by applicant): The Eighth Conference on the Neurobiology of Learning and Memory is the eighth in a series of conferences organized by the Center for the Neurobiology of Learning and Memory at the University of California, Irvine. The theme of the conference is: Memory and Brain: Basic Mechanisms and Clinical Implications. It will be held in Irvine, California on March 11-14, 2006. The overall goals of the conference are to communicate and discuss recent research findings in five currently important topics in the neurobiology of learning and memory, to stimulate discussion about how basic findings might be translated into therapeutic or other applications, and to educate and inform researchers in the field. The 2006 meeting will include five sessions: 1) Mechanisms for acquisition and maintenance of reinforcement related behavior: Relation to addiction/compulsion, 2) Sensory and perceptual learning, 3) Memory and normal and abnormal aging, 4) Modulation of neuroplasticity and long-term memory, and 5) Molecular and cellular mechanisms of memory. To date, fifteen speakers have agreed to make presentations; we are planning a total of twenty. These speakers are among the world's leading investigators in the topics listed. The conference format emphasizes discussion by all participants. Chairs will be chosen for each session, to lead the interchange of ideas. The general sessions will take place at the Hyatt Regency Hotel in Irvine; a poster session (approximately 100 posters) will be held in the Herklotz Research Facility on the DC Irvine campus. We anticipate an attendance of 350-400 people, including faculty, postdoctoral researchers and graduate students from the U.S. and many foreign countries.

DESCRIPTION (provided by applicant): The capacity to acquire and retrieve memories of unique events is termed 'episodic memory'. Impairments of episodic memory are prominent in numerous neurological conditions. Episodic memory dysfunction is also found in major psychiatric disorders, including schizophrenia and depression. The characterization of episodic memory impairments, elucidation of their roles in the etiology of different disorders, and the development of remedial measures, require an understanding of the cognitive operations that support episodic memory and their neural underpinnings. The proposed research will contribute to this understanding by investigating episodic memory encoding-the processes engaged when an event is experienced that result in a durable memory for the event. Functional magnetic resonance imaging will be employed to investigate event-related neural activity that is predictive of whether or not the event will be later remembered. Such differences in neural activity are termed 'subsequent memory effects', and are candidate neural correlates of successful encoding. Experiments will be conducted to investigate: i) encoding of semantically vs. non-semantically mediated item-context associations; ii) encoding of single versus multiple contextual attributes; iii) study-test compatibility effects; iv) general vs. domain-specific interference with encoding; v) the relationship between pre- and post-stimulus subsequent memory effects.

The long-term objectives of this research are to characterize age-related changes in the neural correlates of episodic memory, determining which of these changes underlie the decline in episodic memory that accompanies aging, and which may reflect compensatory mechanisms that ameliorate such decline. The findings will provide information relevant to the understanding and remediation of memory decline in healthy aging, and facilitate future investigations of the more severe memory impairments that are associated with age-associated pathology such as Alzheimer's Disease. The proposed research will investigate the functional significance of recently reported age-associated differences in the neural correlates of episodic memory encoding and retrieval, employing samples of healthy young (18-30yrs) and older (65-75yrs) adults. The research will also extend earlier findings by contrasting the neural correlates of encoding and retrieval in healthy older adults according to their age (65-75 years versus 80-95 yrs, that is, 'young-old'versus 'old-old'). fMRI studies of memory encoding will investigate whether the more bilaterally distributed encoding-related activity found in the inferior lateral prefrontal cortex of young-old relative to young adults is associated with relatively preserved episodic memory function. A further encoding study will address the question whether the neural correlates of encoding differ between young-old and old-old individuals. ERPs will be used to follow up recent findings that young-old adults are less able to differentially process retrieval cues in service of different retrieval goals than are younger individuals. These studies will address the questions whether age-associated attenuation of differential cue processing varies according to episodic memory function, and whether amount of attenuation is sensitive to task demands. In a final study, fMRI will be employed to determine whether the neural correlates of successful episodic retrieval in young-old and old-old participants differ as a function of age.

DESCRIPTION (provided by applicant): The capacity to acquire and retrieve memories of unique events is termed 'episodic memory'. Disabling impairments of episodic memory are prominent in several common neurological conditions, including Alzheimer's disease and Traumatic Brain Injury, and it has been proposed that episodic memory dysfunction plays a role in common psychiatric disorders such as post-traumatic stress disorder and depression. The characterization of episodic memory impairment and dysfunction, and the development of rational remedial measures, require an understanding of the cognitive operations that support episodic memory and their neural underpinnings. The proposed research will contribute to this understanding through a cognitive neuroscience investigation of two aspects of episodic memory retrieval: the processes engaged i) when a cue is employed in an attempt to retrieve episodic information from memory, and ii) when a retrieval attempt is successful. The research will combine behavioral methods with two methods for non-invasive measurement of brain activity, event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI). Together, the methods will be employed to further understanding of cue processing and successful episodic retrieval. With regard to cue processing, issues to be addressed include: the circumstances under which individuals can bias cue processing (adopt a 'retrieval orientation') in service of a specific retrieval goal; the neural correlates of the maintenance of specific retrieval orientations; and the functional significance of differential neural activity elicited by cues employed in service of different retrieval goals. In the case of successful retrieval, issues include: the enerality of previously described neural correlates of episodic retrieval; the sensitivity of these neural correlates to the content and amount of information retrieved; and comparison of existing recognition-based procedures for investigating episodic retrieval to results obtained with a recall procedure.

DESCRIPTION (provided by applicant): The overarching goal of the proposed research is to understand, from a cognitive neuroscience perspective, how information about an event is successfully encoded into episodic memory. Functional magnetic resonance imaging (fMRI) will be employed to identify neural activity elicited during the successful encoding of experimental items such as words and pictures and their associations either with other items (item-item encoding), or with one or more contextual features (item-context encoding). The theoretical perspective guiding the proposed research derives from the proposals that an episodic memory is represented in terms of the processing engaged by an event as it is experienced, and that successful episodic encoding requires that the various features constituting an event are 'bound'or integrated into a cohesive memory representation. Guided by this perspective, experiments will address the roles of the cerebral cortex and the medial temporal lobe in the 'binding'of within- versus across- modality item-context and item-item associations. Other experiments will investigate the neural correlates of the formation of within- and across-modality associations between different contextual features. Another experiment will investigate the neural correlates of the formation of temporal associations between items presented at different times. In a second strand of the research, the focus will be on neural activity that appears to play a 'permissive'role in episodic encoding, rather than supporting processes engaged by a specific study task. Experiments will be conducted to elucidate i) the functional significance of the relative attenuation of neural activity elicited in some cortical regions by study items that are remembered rather than forgotten on a later memory test, and ii) modulations of pre-stimulus activity that also are predictive of later memory performance. Disabling impairments of episodic memory are prominent in several common neurological conditions, notably Alzheimer's disease and traumatic brain injury. Episodic memory dysfunction is also a significant component of several common psychiatric disorders, including schizophrenia, depression and post-traumatic stress disorder. In addition, episodic memory declines substantially and, relative to other kinds of memory, disproportionately, with increasing age. The proposed research will contribute to the detailed understanding of the neurocognitive processes that support normally-functioning episodic memory, an understanding that is necessary for the elucidation of different kinds of episodic memory disorders and the development of effective therapeutic interventions. PUBLIC HEALTH RELEVANCE: Disabling impairments of episodic memory - memory for unique events - are found in numerous neurological and psychiatric conditions. The proposed research will contribute to the detailed understanding of normally-functioning episodic memory that is necessary if different kinds of episodic memory disorders are to be fully understood and effectively treated.

DESCRIPTION (provided by applicant): Episodic memory declines substantially and, relative to most other forms of memory, disproportionately, with age, while a considerably more severe impairment of episodic memory is a prominent feature of several age-related neurodegenerative disorders. An understanding of the cognitive and neural bases of age-related episodic decline in healthy subjects is important because even the relatively modest impairment typical of healthy individuals entering their 70's is sufficient to have a detrimental impact on cognitive function. Thus, the development of interventions that ameliorate age-related memory decline would be of considerable value and would be much facilitated by increased understanding of its causes. Equally important, a full understanding of the more severe memory impairments characteristic of pathological conditions such as Alzheimer's Disease will be difficult to achieve without knowledge of how memory and its neural substrates change in the course of healthy aging. The overarching aim of the present research program is to elucidate the functional significance of age- related differences in the neural correlates of cognitive processes supporting episodic memory, determining which of these differences reflect processes that contribute to age-related decline in memory function, and which reflect compensatory mechanisms that ameliorate such decline. The focus of the program is on the neural correlates of episodic encoding and retrieval as indexed by fMRI 'subsequent memory' and 'retrieval success' effects. The program takes as its starting point findings indicating that, relative to individuals in their 20's, people in the 60's and 70's demonstrate characteristic differences in the magnitude and cortical distribution of subsequent memory and retrieval success effects. One of these differences takes the form of 'right frontal over-recruitment' - larger subsequent memory effects in the right prefrontal cortex in older relative to younger individuals. Recent findings indicate that right frontal over-recruitment of subsequent memory effects is associated with relatively poor levels of memory performance. Five experiments will be conducted that, together, will rigorously characterize the relationship between neural correlates of episodic encoding and retrieval and age, memory performance, and a variety of structural brain measures including white matter integrity. The studies include a large-scale investigation of encoding- and retrieval-related neural activity in young, middle-aged and older individuals, a longitudinal study permitting investigation of the relationship between encoding and retrieval effects and age-related memory decline, a study to investigate how subsequent memory effects vary with the difficulty of the study task in older people, and an experiment aimed at testing the hypothesis that the neural activity elicited during successful episodic retrieval carries less well- differentiated information in older than in young individuals.

Episodic memory declines substantially and, relative to other forms of memory, disproportionately, with age. Understanding the cognitive and neural bases of age-related episodic decline in healthy subjects is important because even the modest impairment (by clinical standards) typical of healthy individuals entering their 70?s is sufficient to have a detrimental impact on quality of life. Identifying the specific cognitive processes, and their neural substrates, which are most responsible for age-related memory decline is a crucial precursor to the development of potential rehabilitative interventions. Equally important, a full understanding of the much more severe memory impairments characteristic of age-related neurodegenerative diseases such as Alzheimer?s Disease will be difficult to achieve without knowledge of how memory and its neural substrates vary over the course of the healthy lifespan. The aim of the present research program is to investigate the possible role in age-related differences in episodic memory performance of the ?post-retrieval monitoring? processes that support evaluation of the products of an episodic retrieval attempt with respect to their relevance for current behavioral goals. The program takes as its starting point highly consistent findings from two experiments conducted as part of an ongoing research program. In both experiments fMRI contrasts between test items imposing high versus low demands on post-retrieval monitoring identified differential activity in regions of the prefrontal cortex previously implicated in monitoring and other cognitive control processes. The magnitude of these putative ?fMRI monitoring effects? did not differ between young adults in their 20s and older adults in their mid-60s to mid-70s, and correlated significantly with episodic memory performance. The findings are intriguing given the widely held view that cognitive functions supported by the PFC are especially vulnerable to increasing age. It is proposed that the findings can be understood from the assumption that older adults require more neural resources than young adults to achieve equivalent levels of performance, and thus that older adults will suffer resource depletion at lower levels of cognitive demand than the young. It is therefore predicted that the seeming age invariance in the neural correlates of post-retrieval monitoring and their relationship with memory performance will break down when the demands placed upon monitoring are especially high, or when the cognitive resources available to support monitoring are depleted. Two experiments, one involving fMRI, and one involving TMS, are proposed. If the predictions are fulfilled, the findings would support the proposal that, with increasing age, post-retrieval monitoring becomes more vulnerable to disruption when cognitive demands are high or neural resources are depleted. These findings would suggest that the processes supporting monitoring would be worth targeting in interventions aimed at ameliorating age-related memory decline. Equally important, failure of the predictions would strongly suggest that, although an important determinant of memory performance, monitoring is unlikely to be a significant cause of age-related memory decline.

Episodic memory declines more steeply with increasing age than other types of memory, and is severely impaired in Alzheimer?s Disease. Even the modest memory impairment typical of healthy people in their 70?s can negatively impact quality of life. Moreover, changes in memory function that harbinger Alzheimer?s Disease (AD) onset years before the emergence of symptoms. This prodromal period provides a window for disease- modifying interventions and places a premium on early detection of trajectories of ?unsuccessful? brain aging. Thus, it is important to understand the neurocognitive bases of the effects of age on episodic memory. The aim of the present research is to elucidate the functional significance of age-related differences in neural activity underpinning episodic memory. We aim to determine which of these differences reflect processes that contribute to age-related memory decline, which reflect compensatory mechanisms that ameliorate decline, and which differences are indicative of memory pathology. The focus of the program is on the neural correlates of episodic encoding and retrieval as these are indexed by fMRI. In one strand of the research, subjects will be people in their 60s and 70s with amnestic mild cognitive impairment (aMCI), a significant risk factor for AD, along with healthy aged-matched controls aged around 70 yrs, and healthy adults in their 80s. The goal is to identify which of the neural correlates of successful episodic encoding and retrieval previously identified in healthy people are also evident in aMCI, which correlates are shared with healthy older individuals with broadly comparable memory abilities, and which are specific to aMCI, especially to individuals at high risk for AD. In two studies we will examine the neural correlates of associative encoding and retrieval, and recollection-related cortical reinstatement, respectively. We will also continue to advance our recent work on healthy aging and episodic encoding. We have described several neural measures of encoding that are predictive of memory performance in people aged around 65-75 yrs, but not in middle-aged (45-55 yrs) or younger people. One of these measures - the ?right frontal subsequent memory effect? ? correlated positively with memory performance in a recent study, but correlated negatively with performance in an earlier study. We shall examine the hypothesis that the direction of the relationship depends upon the conditions under which memory is tested. In another experiment, we will investigate the effects of age on ?pre-stimulus? subsequent memory effects ? neural activity predictive of subsequent memory performance that precedes a study event. We predict that pre-stimulus effects will be attenuated in older subjects. Should this be so, it will constitute a novel mechanism by which memory encoding is compromised in later life. In a final experiment, we will assess whether age-invariance in the neural correlates of successful retrieval extends to circumstances where retrieved information must be retained in working memory for a period prior to being used to guide response selection.

Project Summary Episodic memory declines substantially and, relative to other forms of memory, disproportionately, with age. Understanding the cognitive and neural bases of age-related episodic decline in healthy subjects is important because even the modest impairment (by clinical standards) typical of healthy individuals entering their 70?s is sufficient to have a detrimental impact on quality of life. Identifying the specific cognitive processes, and their neural substrates, which are most responsible for age-related memory decline is a crucial precursor to the development of potential rehabilitative interventions. Equally important, a full understanding of the much more severe memory impairments characteristic of age-related neurodegenerative diseases like Alzheimer?s Disease will be difficult to achieve without knowledge of how memory and its neural substrates vary over the course of the healthy lifespan. The aim of the present research program is to investigate the possible role in age-related memory decline of the recently identified process of ?retrieval gating?, a process that controls the content of recollection in light of the retrieval goal. The program takes as its starting point findings from three experiments employing fMRI that converge to indicate that healthy young adults are able to ?gate? or ?suppress? recollection of goal-irrelevant features of a prior episode, along with preliminary findings indicating that, as a group, healthy older adults do not engage retrieval gating under the same conditions. Two experiments are proposed. In the first, which will employ groups of young and older adults, the effects on retrieval gating of varying the strength of goal-irrelevant memories will be examined. The experiment will examine the hypothesis that older adults require a greater incentive (more intrusive goal-irrelevant memories) than young subjects to adopt a retrieval gating strategy, but that they are capable of doing so when sufficiently incentivized. The second experiment will employ young subjects only and will utilize a divided attention manipulation to examine the hypothesis that retrieval gating is a resource-limited process, and hence is increasingly vulnerable to disruption with age.