Anthony D. Wagner - US grants

illusions; memory disorders; aging; discrimination learning; functional magnetic resonance imaging; human subject; behavioral /social science research tag; clinical research;

[unreadable] DESCRIPTION (provided by applicant): Declarative memory permits an organism to bridge the past with the present, providing information about prior events that serves to inform present decisions and action. Declarative memory critically depends on the medial temporal lobe (MIL), which is composed of the hippocampal formation (dentate gyrus, fields of cornu Ammonis, and subiculum) and the surrounding entorhinal, perirhinal, and parahippocampal cortices. Though decades of research have aimed to characterize the role of MIL in declarative memory, fundamental questions remain regarding the functional contributions of specific MTL substructures. Recent advances in functional imaging have now made it possible to begin to address these questions in humans. The proposed research will use high-resolution functional MRI and anatomically-based analysis methods to delineate the role of specific MTL cortical and hippocampal subfields in declarative memory. The proposed experiments will test anatomically-informed theory-driven hypotheses regarding the nature of declarative memory and its dependence on MTL function. Expts 1-3 will examine novelty-encoding processes in the anterior/posterior and coronal axes of MTL, focusing on whether content-sensitive encoding effects are present within distinct MTL cortices and hippocampal subfields. Expts 4-9 will explore the function of MTL substructures and their interactions during declarative memory encoding and retrieval, focusing on decomposition of mechanisms that support conjunctive and item memory. Expts 10-12 will test hypotheses about the nature of MTL retrieval mechanisms signaling item familiarity and temporal recency, including their dependence on study- test perceptual similarity. Expts 13-14 will examine how hippocampal and MTL cortical encoding mechanisms that encode item and conjunctive memories are impacted by goal-directed attention, including attention-dependent enhancement and suppression of MTL responses. The basic knowledge to be gained from this programmatic effort to test theory-driven hypotheses of declarative memory and MTL substructure function promises to yield new insights into the nature of learning and memory impairments in clinical populations. Declarative memory deficits accompany a number of clinical conditions, including schizophrenia, mild cognitive impairment, and Alzheimer's disease. We will directly translate the obtained outcomes to inform our collaborative studies of MTL dysfunction in schizophrenia. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): This proposal aims to examine the neurobiological mechanisms that subserve distinct forms of long-term memory, and to explore the relationship between them. Episodic memory refers to conscious memory for new events, and depends on the medial temporal lobe (MTL). Incremental stimulus-response learning refers to gradual learning of stimulus-response regularities over many trials, and is thought to depend on the basal ganglia (BG). While initial evidence has suggested that the neural substrates of these forms of memory operate as distinct and independent memory systems, recent data alternately suggest that the MTL and BG may jointly contribute to both forms of knowledge or that there may be a competitive interaction between these neural systems. Beyond MTL and BG, other data indicate that the acquisition and expression of both of these forms of memory are modulated by prefrontal cortex (PFC). The proposed research will address fundamental questions regarding the nature of MTL, BG, and PFC contributions to episodic and incremental learning, and the relationship between them. We will use fMRI to examine the temporal dynamics of activity within, and between, each system over the course of learning. We specifically aim to understand how the temporal profile of neural activity during learning relates to changes in memory performance (Expts 1-3). We will subsequently examine the nature of the relationship between the systems more directly, by determining how modulation of each system impacts activity and performance of the other. These fMRI studies will test whether functional coupling or competition exists between these systems, how such interactions change over time, and whether putative between-system interactions are direct or mediated (Expts 4-6). Finally, we will specifically examine the role of PFC in incremental and episodic learning, and in mediating putative between-system interactions during learning, combining electroencephalography (EEG) and transcranial magnetic stimulation (TMS). EEG will specify the temporal profile of PFC contributions to episodic and incremental learning (Expts 7-8), and the obtained fMRI and EEG data will guide TMS disruption of PFC function to test the necessity of PFC mechanisms for learning (Expts 9-10). Collectively, the proposed research will advance understanding of the temporal and spatial characteristics of MTL, BG, and PFC involvement in episodic and incremental learning, including whether and how interactions between these neural systems impact memory. The resulting knowledge will provide a foundation for understanding memory impairments in various neurological diseases and mental disorders that are associated with MTL, BG, and PFC dysfunction, including schizophrenia. Indeed, while not part of this proposal, we will draw directly on the outcomes from these studies to inform our investigations of memory deficits in schizophrenia (in collaboration with Dr. Carol Tamminga). [unreadable] [unreadable] [unreadable]

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).

This award permits Dr. Brian Wandell and his collaborators at Stanford University to purchase a 3T functional magnetic resonance imaging scanner. The shared instrument will be the centerpiece of a new facility, The Center for Neurobiological Imaging, designed to advance scientific research and training on topics spanning human decision-making, cognition, perception, child development, education and emotion. The instrument will be used to support research that advances understanding of the human brain and also offer the opportunity to integrate teaching about brain functions and systems into the curricula of students in a variety of fields. The instrument will increase the efficiency and quality of a broad array of scientific research efforts that aim to understand human brain function, and ultimately apply this new knowledge to the development of effective social, economic, educational and legal systems. The research approach involves a partnership between basic scientists and engineers. The advances in imaging over the last fifteen years are still in an early phase and within the next ten years, scientists believe, it should be possible to measure the distributions of particular molecules within the brain, trace brain development in detail and measure properties of the neuroglia. The close proximity in the laboratory between magnetic resonance physicists, statisticians, psychologists and other social scientists will make it possible to explore collaboratively new imaging modalities and transform technical advances into scientific insights. The instrument and related software and analysis tools will also be used to train graduate students and post-doctoral fellows in advanced methods for understanding the human brain.

DESCRIPTION (provided by applicant): This proposal aims to examine the neurobiological mechanisms that subserve distinct forms of long-term memory, and to explore the relationship between them. Episodic memory refers to conscious memory for new events, and depends on the medial temporal lobe (MTL). Incremental stimulus-response learning refers to gradual learning of stimulus-response regularities over many trials, and is thought to depend on the basal ganglia (BG). While initial evidence has suggested that the neural substrates of these forms of memory operate as distinct and independent memory systems, recent data alternately suggest that the MTL and BG may jointly contribute to both forms of knowledge or that there may be a competitive interaction between these neural systems. Beyond MTL and BG, other data indicate that the acquisition and expression of both of these forms of memory are modulated by prefrontal cortex (PFC). The proposed research will address fundamental questions regarding the nature of MTL, BG, and PFC contributions to episodic and incremental learning, and the relationship between them. We will use fMRI to examine the temporal dynamics of activity within, and between, each system over the course of learning. We specifically aim to understand how the temporal profile of neural activity during learning relates to changes in memory performance (Expts 1-3). We will subsequently examine the nature of the relationship between the systems more directly, by determining how modulation of each system impacts activity and performance of the other. These fMRI studies will test whether functional coupling or competition exists between these systems, how such interactions change over time, and whether putative between-system interactions are direct or mediated (Expts 4-6). Finally, we will specifically examine the role of PFC in incremental and episodic learning, and in mediating putative between-system interactions during learning, combining electroencephalography (EEG) and transcranial magnetic stimulation (TMS). EEG will specify the temporal profile of PFC contributions to episodic and incremental learning (Expts 7-8), and the obtained fMRI and EEG data will guide TMS disruption of PFC function to test the necessity of PFC mechanisms for learning (Expts 9-10). Collectively, the proposed research will advance understanding of the temporal and spatial characteristics of MTL, BG, and PFC involvement in episodic and incremental learning, including whether and how interactions between these neural systems impact memory. The resulting knowledge will provide a foundation for understanding memory impairments in various neurological diseases and mental disorders that are associated with MTL, BG, and PFC dysfunction, including schizophrenia. Indeed, while not part of this proposal, we will draw directly on the outcomes from these studies to inform our investigations of memory deficits in schizophrenia (in collaboration with Dr. Carol Tamminga).

Functional magnetic resonance imaging (fMRI) has become the most common tool for cognitive neuroscience, because it provides a safe, non-invasive, and powerful means to image human brain function. Based on recent rates of publication, there are currently more than 2000 fMRI studies being performed every year worldwide. The aggregation of data across multiple studies can provide the ability to answer questions that cannot be answered based on a single study. For example, using datasets from multiple domains one can start to investigate to what degree a region is selectively engaged in relation to a particular mental process, as opposed to being generally engaged across a broad range of tasks and processes. In addition, it provides the ability to integrate across specific tasks to obtain stronger empirical generalizations about mind-brain relationships, and to better understand the nature of individual variability across different measures. Recent work in neuroimaging analysis has focused on the application of methods such as machine learning techniques to understand the coding of information at the macroscopic level, and network analysis techniques to understand the interactions inherent in large-scale neural systems. The availability of a large testbed of high-quality fMRI data from published studies would also provide an important resource for the development of these and other new analytic techniques for fMRI data. However, sharing of raw fMRI data is challenging due to the large size of the datasets and the complexity of the associated metadata, and there is currently no infrastructure for the open sharing of new fMRI datasets.

This project, OpenfMRI, will provide a new infrastructure for the broad dissemination of raw data within cognitive neuroscience, addressing a critical need by providing an open data sharing resource for neuroimaging. The initial project is already online at http://www.openfmri.org with a limited number of datasets. The full project will greatly expand this repository by providing access to a large number of fMRI datasets from several prominent neuroimaging labs, spanning across a broad range of cognitive domains. Utilizing the substantial computational resources of the Texas Advanced Computing Center, the project will also perform standard fMRI analyses on all data in the repository using a common analysis pipeline, thus providing directly comparable analysis results for all of the studies in the database. The OpenfMRI project will support the development of infrastructural elements to make sharing of data by additional investigators more straightforward.

The repository of data that will be created by the OpenfMRI project will also serve as an important resource for teaching by providing students with the ability to replicate the analyses from published studies using the same data. By providing any researcher in the world with the ability to acquire large fMRI datasets, it will also provide all researchers with the ability to work with the same state-of-the-art datasets, regardless of institution. By creating the infrastructure for open sharing of research data, the project will also enhance the impact of other NSF-funded neuroimaging research projects by providing an infrastructure that can be used to make their data available. The planned work has the potential to benefit society by improving education, health, and human productivity through an increased understanding of mental function and its relationship to brain function.

DESCRIPTION (provided by applicant): Information gating-the ability to filter out task-irrelevant information-is central to a broad range of cognition. Individuals vary in their ability o gate distracting information, and this difference relates to differences in goal- directed behavior and memory. Recent evidence indicates that one factor that correlates with the ability to gate distractors is individual differences in chronic multitasking behavior with media ('media multitasking'). Relative to individuals who engage less frequently with multiple streams of media in daily life, heavy media multitaskers (HMMs) appear more susceptible to distractors, whether external (from the environment) or internal (from memory). Given the rising prevalence of media multitasking (MM) behavior, it is increasingly important to understand the relationship between MM behavior and neurocognitive function. To this end, we aim to (a) delineate the relationship between MM behavior, filtering ability, and neural function, and (b) examine whether poor information gating gives rise to positive and negative consequences for memory. We will use task-based and resting-state fMRI to test the hypothesis that decreased distractor filtering in HMMs relative to light MMs (LMMs) relates to differential engagement of bottom-up and top-down attention networks, as well as differences in large-scale connectivity within and between these networks. We will examine how distraction affects memory for task-relevant and irrelevant information, and we will relate differences in memory outcomes to differences in neural activation during distraction (using univariate and multivoxel pattern analyses [MVPA]) and during rest (measuring large-scale network coherence). Aim 1 will examine MM-related differences in perceptual filtering and the consequences for memory, testing the hypotheses that (a) MM-related differences in gating irrelevant perceptual information are associated with differential functioning of the dorsal (top-down) and ventral (bottom-up) frontoparietal attention networks, and (b) these differences impact memory encoding of task-relevant and irrelevant information, as expressed by later remembering or forgetting. Aim 2 will examine MM-related differences in mnemonic filtering and the consequences for the ability to generalize knowledge across events, testing the hypothesis that one benefit of failures to gate distracting internal representations may be increased across-event generalization, because reinstatement of 'distracting' memories may support the building of integrated representations of overlapping experiences. In addition to informing neurocognitive theories of attention, memory, and attention-memory interactions, the proposed research has significant mental health relevance as it will provide some of the first evidence bearing on whether and how media multitasking relates to the function of large-scale neural systems of attention and memory. Moreover, by advancing understanding of the relationship between multitasking behavior and attention, the proposed research may prove informative for assessment and intervention in clinical conditions of attention, such as attention deficit hyperactivity disorder (ADHD) and schizophrenia. PUBLIC HEALTH RELEVANCE: The prevalence of media multitasking has markedly increased in recent years, raising public health questions about potential consequences for cognitive and neural function. This innovative research program will provide critical evidence addressing the relationship between media multitasking behavior and the function of neural systems of attention and memory. By addressing this important but under-explored issue, the planned research will also yield new insights into interactions between attention and memory, which may inform strategies for assessment and remediation of attention deficits in clinical populations, such as ADHD and schizophrenia.

DESCRIPTION (provided by applicant): Memory decline is a frequent symptom among aging adults. A substantial literature points to an age-related deterioration of episodic memory (the capacity to encode and subsequently retrieve memories for events). The hippocampus is critical for episodic memory, and comprises multiple subfields thought to contribute differentially to pattern separation and pattern completion - fundamental mechanisms of memory -- and to exhibit differential vulnerability to age. In particular, selective changes in hippocampal subfield structure and function may drive age-related changes in memory performance, and these changes may relate, in part, to preclinical evidence of Alzheimer's disease (AD) pathology. Recent developments in high-resolution magnetic resonance imaging (MRI), including (a) high-resolution functional MRI (hr-fMRI) combined with powerful multivariate analysis methods and (b) ultra-high field 7T structural MRI, provide a means to study human hippocampal subfields in vivo and to examine hippocampal mechanisms of memory. Here, we propose to apply these innovative MRI techniques to a large, 200-person cross-sectional population of healthy older adults (e60 years) to test the following central hypothesis: In older adults, selective changes in hippocampal subfield function and structure drive mechanistic changes in pattern separation and pattern completion, which relate to age-related decline in associative recollection (a central form of episodic memory) and, in part, to preclinical AD pathology. In Aim 1, we will use hr-fMRI at 3T, along with representational similarity analysis and multivoxel pattern analysis, to quantitatively estimate hippocampal pattern separation at encoding and pattern completion at retrieval, with the latter indexed by cortical reinstatement; we further aim to relate these quantitative measures of hippocampal function to associative recollection and item recognition memory performance. In Aim 2, we will use high-resolution structural MRI at 7T to quantify hippocampal subfield structural atrophy, and we will relate these structural measures to our quantitative hr-fMRI indices of pattern separation and cortical reinstatement, as well as to memory behavior. In Aim 3, we will relate cerebrospinal fluid assays of AD biomarkers (Abeta42, tau, and phospho-tau proteins) to hr- fMRI functional metrics, 7T MRI hippocampal subfield structural metrics, and memory behavior. The novelty and power of the proposed research, which is grounded in strong preliminary data, derives from our ability to synthesize data across these Aims to discover how function, structure, and early pathology interact to affect episodic memory in aging. The project may ultimately inform diagnostic and intervention approaches for addressing age-related memory decline in unimpaired older adults, as well as those suffering from amnestic Mild Cognitive Impairment and AD.

DESCRIPTION (provided by applicant): A behavioral hallmark of Major Depressive Disorder (MDD) is impaired gating of negative, task-irrelevant information. In previous work we documented that people with MDD exhibit impairments in controlling the entry of irrelevant negative information into working memory (WM) and in removing no-longer-relevant information from WM. Given the high prevalence and enormous costs of MDD, it is critical that we gain a better under- standing of the neural mechanisms that underlie these cognitive difficulties. Although investigators have begun to examine neural correlates of impaired information-gating processes in MDD, we do not yet understand the functional significance of these activations or the nature of their relation to depression, or consequently, how to leverage this knowledge to develop and evaluate individualized treatments for this heterogeneous disorder. We propose to use cutting-edge neuroimaging techniques to elucidate the neural mechanisms that underlie impaired gating of negative information in MDD, conducting innovative analyses of fMRI data (multi-voxel pattern analyses [MVPA] and functional connectivity) in order to quantify on a moment-to-moment basis the degree to which negative irrelevant information is represented in WM. This approach will allow us to test hypotheses about (a) specific large-scale networks that are posited to underlie information-gating deficits in MDD; and (b) the contribution of these networks to various clinical characteristics of MDD. Specifically, in two experiments we will elucidate the cognitive and neural mechanisms that underlie impaired gating in MDD during the entry of negative stimuli into WM, and during the removal of negative information from WM. Moreover, given findings in nondepressed populations that individual differences in the ability to gate task- irrelevant information are related to variations in goal-directed behavior, we further propose to assess the relation of individual differences in information gating to specific aspects of depressive symptomatology. We hypothesize that impaired gating of negative irrelevant information in MDD is associated with anomalous functioning of dorsal frontoparietal (top-down attentional control) and subcortical (emotional appraisal) networks during both the entry of negative information into WM and the removal of negative information from WM. We further hypothesize that these abnormalities are related to the specific depressive characteristics of emotion dysregulation, rumination, and negative affect, and to the severity of depressive symptoms. Importantly, our novel quantification of neural representations of negative information will move beyond coarse group-level assays to a more fine-grained individual-subject and trial-level understanding of the dynamic nature of the neurocognitive mechanisms that underlie MDD. Together, the proposed studies promise to 1) advance understanding of mechanisms that underlie the control of affective information in MDD; 2) inform theoretical models of the interaction of attention and emotion; and 3) facilitate the ultimate development of more effective, patient-specific interventions (e.g., cognitive or neural training) for major depression.

Abstract American youth spend more time with media than in any other activity. Almost a third of this time is spent simultaneously engaging with (or switching between) multiple media streams (`media multitasking'; MMT). The rapid rise in MMT has generated considerable scientific and societal interest in determining whether, and if so how, MMT impacts cognition, psychosocial health, academic achievement, and brain structure and function. Given the prevalence of MMT in children and young adults, there is urgency to understand the neurocognitive profiles of media multitaskers. Mounting evidence (including new behavioral and neural findings generated in our exploratory grant R21MH099812) points to consistent MMT-related differences in attention and memory, yet the nature and extent of these cognitive differences, their neural underpinnings, and their emergence across the lifespan remain largely unknown. The proposed multi-modal research program will examine the neurocognitive differences associated with chronic MMT, and will explore how and when differences onset. In young adults (18-24yr), we will leverage sensitive behavioral paradigms, scalp EEG, and concurrent EEG-fMRI to test hypotheses about the nature and neural underpinnings of MMT-related attention and memory differences, and we will relate these cognitive and task-based neural differences to functional and structural connectivity in frontoparietal networks of attention and cognitive control. In children (7-12yr), we will use a large-sample, longitudinal design and a novel multi-domain cognitive assessment tool to measure working memory (WM), selective and sustained attention, and inhibitory control; we will relate these cognitive measures to MMT behavior and to EEG measures of attention- and memory-related neural function. We also will obtain measures of academic achievement for both age groups. Our aims are to: (Aim 1) delineate the nature of the WM and long-term memory (LTM) decrements associated with heavier MMT, and (Aim 2) test the hypothesis that increased attentional lapses and diminished attentional control contribute to these decrements; (Aim 3) test the hypothesis that the large-scale frontoparietal structural and functional networks that support attention and cognitive control vary with MMT; and (Aim 4) determine how and when MMT-related cognitive and neural differences arise in children (7-12yr), at the time when younger populations begin to engage in MMT. The proposed research will (a) delineate how memory, attention, and cognitive control, and their underlying neural systems, vary with MMT and relate to academic achievement in young adults and children, as well as (b) begin to shed light on whether chronic MMT is a cause or consequence of neurocognitive differences. Moreover, by leveraging an individual differences approach, we will advance mechanistic understanding of the interactions between four R-DoC cognitive constructs (attention, cognitive control, WM, and declarative memory) and their dependence on large-scale frontoparietal structural and functional networks.

Project Summary/Abstract Aging is accompanied by cognitive declines, including in declarative (episodic) memory and in cognitive control, which refers to a set of cognitive functions that align actions with internal goals. Extant evidence indicates that older adults exhibit difficulty in proactively adjusting cognitive control, failing to effectively adjust control based on contextual cues that signal upcoming cognitive control demand. This difficulty leads to reduced flexibility, impedes goal-directed behavior, and can profoundly impact older people?s daily lives, as contexts are common and powerful predictive cues to signal adjustment of cognitive control. For instance, viewing a usually busy traffic circle can serve as a cue to increase control demand in driving before entering the traffic circle. While age-related deficits in proactive control likely stem from disruptions in memory system and control system processes, and their interaction, little is known about the neurocognitive mechanisms supporting the formation and expression of associations between contexts and cognitive control demand and how these mechanisms change with aging. To answer these questions, three experiments are proposed using a combination of virtual reality behavioral methods and human functional magnetic resonance imaging. Specific Aim 1 will delineate the mechanisms supporting the encoding and retrieval of associations between context and cognitive control demand, enabling proactive control in young adults. This experiment will also lay the foundations for Specific Aims 2 and 3. Specific Aim 2 will determine whether and how context-control demand associations can be generalized to objects appearing in the context via the mechanism of memory replay. Finally, Specific Aim 3 will characterize whether reductions in proactive control in older adults are partially due to dysfunctional mnemonic mechanisms that build and express associations between contexts and cognitive control demands. Specific Aim 3 will further examine whether individual differences in hippocampal anatomical and cerebrospinal fluid biomarkers of elevated risk for Alzheimer?s disease relate to age-related differences in memory for context-control demand associations. In all proposed experiments, we will harness virtual reality techniques to present contextual stimuli (virtual rooms) in order to more closely simulate real life scenarios. FMRI univariate and multivariate pattern analyses will be combined to comprehensively interrogate age-related changes in neurocognitive mechanisms underlying associations between contexts and cognitive control demand. The proposed studies promise to advance understanding of memory?cognitive control interactions, including how memory of procedural processing features (e.g., past levels of control demand experienced in a context) can drive flexible adjustments of proactive control, and will provide valuable new insights into how decreased cognitive control in older adults may stem, in part, from multi-system (memory and control) dysfunction.

Structural and functional changes in neural networks of attention and goal-directed cognition likely contribute to age-related memory decline and impede daily living. While considerable progress has been made in specifying how changes in the medial temporal lobe affect memory, moment-to-moment and individual differences in attention and goal-state representation are also hypothesized to impact episodic encoding and retrieval in young and older adults, and to contribute to age-related memory change. Of equal importance, in asymptomatic (`healthy') older adults, preclinical Alzheimer's disease (AD) pathology may disrupt attention and goal coding, with deleterious consequences for memory. Here, we aim to use innovative functional, molecular, and structural measures to characterize interactions between attention, goal states, and memory, and to examine (a) their contributions to trial-level, subject-level, and group-level memory differences, and (b) their relation to AD pathology. We will leverage goal-directed episodic encoding and retrieval paradigms and cutting-edge cognitive neuroscience tools, including task-based EEG-fMRI with pupillometry in asymptomatic (`healthy') older (65-79 yrs) and young adults (18-30 yrs). Trial-level attentional lapses will be assayed via fluctuations of alpha and theta oscillatory power and pupil diameter; the strength of trial-level goal states will be quantified via multivariate analyses of frontoparietal BOLD patterns. Aims 1-2 will address: How do interactions in attention and goal-state representation affect cortical and hippocampal mechanisms of episodic encoding (Aim 1) and retrieval (Aim 2), and how do age-related changes in these interactions relate to memory differences across age? Moreover, we will examine how molecular and structural biomarkers of pathological aging (AD) in `healthy' older adults relate to neural, pupillometry, and behavioral assays of attention, goal states, memory, and their interactions. Via PET-MR, we will measure (a) global ?-amyloid (A?) burden and regional A? in frontoparietal cortex, and (b) locus coeruleus integrity, a core structure for attention, arousal, and goal-directed cognition, and an early site of AD pathology. Using categorical (A?+ vs. A?-) and continuous analyses, Aim 3 will address: Do molecular and structural biomarkers of pathology in preclinical aging predict differences in attentional lapses and goal coding, accounting for significant shared or unique variance in behavioral and neural measures of memory in asymptomatic individuals? The promise, feasibility, and novelty of the proposed research are grounded in strong preliminary data and derive from the use of multi-modal measures to discover how function, structure, and early pathology interact to affect attention, goal coding, and memory in aging. The project will advance understanding of (a) how moment-to- moment and individual differences in attention and goal coding affect learning and remembering in young and older adults, and (b) how these differences relate to memory decline in aging with and without AD pathology. The latter holds promise for revealing novel neurocognitive biomarkers of AD risk.