Anthony Wagner

All Publications

• Representational integration and differentiation in the human hippocampus following goal-directed navigation. eLife Fernandez, C., Jiang, J., Wang, S., Choi, H. L., Wagner, A. D. 2023; 12

  Abstract

  As we learn, dynamic memory processes build structured knowledge across our experiences. Such knowledge enables the formation of internal models of the world that we use to plan, make decisions, and act. Recent theorizing posits that mnemonic mechanisms of differentiation and integration - which at one level may seem to be at odds - both contribute to the emergence of structured knowledge. We tested this possibility using fMRI as human participants learned to navigate within local and global virtual environments over the course of 3 days. Pattern similarity analyses on entorhinal cortical and hippocampal patterns revealed evidence that differentiation and integration work concurrently to build local and global environmental representations, and that variability in integration relates to differences in navigation efficiency. These results offer new insights into the neural machinery and the underlying mechanisms that translate experiences into structured knowledge that allows us to navigate to achieve goals.

  View details for DOI 10.7554/eLife.80281

  View details for PubMedID 36786678

• Readiness to remember: predicting variability in episodic memory. Trends in cognitive sciences Madore, K. P., Wagner, A. D. 2022

  Abstract

  Learning and remembering are fundamental to our lives, so what causes us to forget? Answers often highlight preparatory processes that precede learning, as well as mnemonic processes during the act of encoding or retrieval. Importantly, evidence now indicates that preparatory processes that precede retrieval attempts also have powerful influences on memory success or failure. Here, we review recent work from neuroimaging, electroencephalography, pupillometry, and behavioral science to propose an integrative framework of retrieval-period dynamics that explains variance in remembering in the moment and across individuals as a function of interactions among preparatory attention, goal coding, and mnemonic processes. Extending this approach, we consider how a 'readiness to remember' (R2R) framework explains variance in high-level functions of memory and mnemonic disruptions in aging.

  View details for DOI 10.1016/j.tics.2022.05.006

  View details for PubMedID 35786366

• When the ventral visual stream is not enough: A deep learning account of medial temporal lobe involvement in perception. Neuron Bonnen, T., Yamins, D. L., Wagner, A. D. 2021

  Abstract

  The medial temporal lobe (MTL) supports a constellation of memory-related behaviors. Its involvement in perceptual processing, however, has been subject to enduring debate. This debate centers on perirhinal cortex (PRC), an MTL structure at the apex of the ventral visual stream (VVS). Here we leverage a deep learning framework that approximates visual behaviors supported by the VVS (i.e., lacking PRC). We first apply this approach retroactively, modeling 30 published visual discrimination experiments: excluding non-diagnostic stimulus sets, there is a striking correspondence between VVS-modeled and PRC-lesioned behavior, while each is outperformed by PRC-intact participants. We corroborate and extend these results with a novel experiment, directly comparing PRC-intact human performance to electrophysiological recordings from the macaque VVS: PRC-intact participants outperform a linear readout of high-level visual cortex. By situating lesion, electrophysiological, and behavioral results within a shared computational framework, this work resolves decades of seemingly inconsistent findings surrounding PRC involvement in perception.

  View details for DOI 10.1016/j.neuron.2021.06.018

  View details for PubMedID 34265252

• Memory failure predicted by attention lapsing and media multitasking. Nature Madore, K. P., Khazenzon, A. M., Backes, C. W., Jiang, J., Uncapher, M. R., Norcia, A. M., Wagner, A. D. 2020

  Abstract

  With the explosion of digital media and technologies, scholars, educators and the public have become increasingly vocal about the role that an 'attention economy' has in our lives1. The rise of the current digital culture coincides with longstanding scientific questions about why humans sometimes remember and sometimes forget, and why some individuals remember better than others2-6. Here we examine whether spontaneous attention lapses-in the moment7-12, across individuals13-15 and as a function of everyday media multitasking16-19-negatively correlate with remembering. Electroencephalography and pupillometry measures of attention20,21 were recorded as eighty young adults (mean age, 21.7years) performed a goal-directed episodic encoding and retrieval task22. Trait-level sustained attention was further quantified using task-based23 and questionnaire measures24,25. Using trial-to-trial retrieval data, we show that tonic lapses in attention in the moment before remembering, assayed by posterior alpha power and pupil diameter, were correlated with reductions in neural signals of goal coding and memory, along with behavioural forgetting. Independent measures of trait-level attention lapsing mediated the relationship between neural assays of lapsing and memory performance, and between media multitasking and memory. Attention lapses partially account for why we remember or forget in the moment, and why some individuals remember better than others. Heavier media multitasking is associated with a propensity to have attention lapses and forget.

  View details for DOI 10.1038/s41586-020-2870-z

  View details for PubMedID 33116309

• Prefrontal reinstatement of contextual task demand is predicted by separable hippocampal patterns. Nature communications Jiang, J., Wang, S., Guo, W., Fernandez, C., Wagner, A. D. 2020; 11 (1): 2053

  Abstract

  Goal-directed behavior requires the representation of a task-set that defines the task-relevance of stimuli and guides stimulus-action mappings. Past experience provides one source of knowledge about likely task demands in the present, with learning enabling future predictions about anticipated demands. We examine whether spatial contexts serve to cue retrieval of associated task demands (e.g., context A and B probabilistically cue retrieval of task demands X and Y, respectively), and the role of the hippocampus and dorsolateral prefrontal cortex (dlPFC) in mediating such retrieval. Using 3D virtual environments, we induce context-task demand probabilistic associations and find that learned associations affect goal-directed behavior. Concurrent fMRI data reveal that, upon entering a context, differences between hippocampal representations of contexts (i.e., neural pattern separability) predict proactive retrieval of the probabilistically dominant associated task demand, which is reinstated in dlPFC. These findings reveal how hippocampal-prefrontal interactions support memory-guided cognitive control and adaptive behavior.

  View details for DOI 10.1038/s41467-020-15928-z

  View details for PubMedID 32345979

• Hippocampal and cortical mechanisms at retrieval explain variability in episodic remembering in older adults. eLife Trelle, A. N., Carr, V. A., Guerin, S. A., Thieu, M. K., Jayakumar, M. n., Guo, W. n., Nadiadwala, A. n., Corso, N. K., Hunt, M. P., Litovsky, C. P., Tanner, N. J., Deutsch, G. K., Bernstein, J. D., Harrison, M. B., Khazenzon, A. M., Jiang, J. n., Sha, S. J., Fredericks, C. A., Rutt, B. K., Mormino, E. C., Kerchner, G. A., Wagner, A. D. 2020; 9

  Abstract

  Age-related episodic memory decline is characterized by striking heterogeneity across individuals. Hippocampal pattern completion is a fundamental process supporting episodic memory. Yet, the degree to which this mechanism is impaired with age, and contributes to variability in episodic memory, remains unclear. We combine univariate and multivariate analyses of fMRI data from a large cohort of cognitively normal older adults (N=100) to measure hippocampal activity and cortical reinstatement during retrieval of trial-unique associations. Trial-wise analyses revealed that (a) hippocampal activity scaled with reinstatement strength, (b) cortical reinstatement partially mediated the relationship between hippocampal activity and associative retrieval, (c) older age weakened cortical reinstatement and its relationship to memory behaviour. Moreover, individual differences in the strength of hippocampal activity and cortical reinstatement explained unique variance in performance across multiple assays of episodic memory. These results indicate that fMRI indices of hippocampal pattern completion explain within- and across-individual memory variability in older adults.

  View details for DOI 10.7554/eLife.55335

  View details for PubMedID 32469308

• Stress Disrupts Human Hippocampal-Prefrontal Function during Prospective Spatial Navigation and Hinders Flexible Behavior. Current biology : CB Brown, T. I., Gagnon, S. A., Wagner, A. D. 2020

  Abstract

  The ability to anticipate and flexibly plan for the future is critical for achieving goal-directed outcomes. Extant data suggest that neural and cognitive stress mechanisms may disrupt memory retrieval and restrict prospective planning, with deleterious impacts on behavior. Here, we examined whether and how acute psychological stress influences goal-directed navigational planning and efficient, flexible behavior. Our methods combined fMRI, neuroendocrinology, and machine learning with a virtual navigation planning task. Human participants were trained to navigate familiar paths in virtual environments and then (concurrent with fMRI) performed a planning and navigation task that could be most efficiently solved by taking novel shortcut paths. Strikingly, relative to non-stressed control participants, participants who performed the planning task under experimentally induced acute psychological stress demonstrated (1) disrupted neural activity critical for mnemonic retrieval and mental simulation and (2) reduced traversal of shortcuts and greater reliance on familiar paths. These neural and behavioral changes under psychological stress were tied to evidence for disrupted neural replay of memory for future locations in the spatial environment, providing mechanistic insight into why and how stress can alter planning and foster inefficient behavior.

  View details for DOI 10.1016/j.cub.2020.03.006

  View details for PubMedID 32243859

• Stress Impairs Episodic Retrieval by Disrupting Hippocampal and Cortical Mechanisms of Remembering CEREBRAL CORTEX Gagnon, S. A., Waskom, M. L., Brown, T. I., Wagner, A. D. 2019; 29 (7): 2947–64

  View details for DOI 10.1093/cercor/bhy162

  View details for Web of Science ID 000477708300014

• Hippocampal pattern separation supports reinforcement learning. Nature communications Ballard, I. C., Wagner, A. D., McClure, S. M. 2019; 10 (1): 1073

  Abstract

  Animals rely on learned associations to make decisions. Associations can be based on relationships between object features (e.g., the three leaflets of poison ivy leaves) and outcomes (e.g., rash). More often, outcomes are linked to multidimensional states (e.g., poison ivy is green in summer but red in spring). Feature-based reinforcement learning fails when the values of individual features depend on the other features present. One solution is to assign value to multi-featural conjunctive representations. Here, we test if the hippocampus forms separable conjunctive representations that enables the learning of response contingencies for stimuli of the form: AB+, B-, AC-, C+. Pattern analyses on functional MRI data show the hippocampus forms conjunctive representations that are dissociable from feature components and that these representations, along with those of cortex, influence striatal prediction errors. Our results establish a novel role for hippocampal pattern separation and conjunctive representation in reinforcement learning.

  View details for PubMedID 30842581

• Minds and brains of media multitaskers: Current findings and future directions. Proceedings of the National Academy of Sciences of the United States of America Uncapher, M. R., Wagner, A. D. 2018; 115 (40): 9889–96

  Abstract

  Media and technology are ubiquitous elements of our daily lives, and their use can offer many benefits and rewards. At the same time, decisions about how individuals structure their use of media can be informed by consideration of whether, and if so how, the mind and brain are shaped by different use patterns. Here we review the growing body of research that investigates the cognitive and neural profiles of individuals who differ in the extent to which they simultaneously engage with multiple media streams, or ‟media multitasking." While the literature is still sparse, and is marked by both convergent and divergent findings, the balance of evidence suggests that heavier media multitaskers exhibit poorer performance in a number of cognitive domains, relative to lighter media multitaskers (although many studies find no performance differences between groups). When evidence points to a relationship between media multitasking level and cognition, it is often on tasks that require or are influenced by fluctuations in sustained goal-directed attention. Given the real-world significance of such findings, further research is needed to uncover the mechanistic underpinnings of observed differences, to determine the direction of causality, to understand whether remediation efforts are needed and effective, and to determine how measurement heterogeneity relates to variable outcomes. Such efforts will ultimately inform decisions about how to minimize the potential costs and maximize the many benefits of our ever-evolving media landscape.

  View details for PubMedID 30275312

• Individual differences in associative memory among older adults explained by hippocampal subfield structure and function PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Carr, V. A., Bernstein, J. D., Favila, S. E., Rutt, B. K., Kerchner, G. A., Wagner, A. D. 2017; 114 (45): 12075–80

  Abstract

  Older adults experience impairments in episodic memory, ranging from mild to clinically significant. Given the critical role of the medial temporal lobe (MTL) in episodic memory, age-related changes in MTL structure and function may partially account for individual differences in memory. Using ultra-high-field 7T structural MRI and high-resolution 3T functional MRI (hr-fMRI), we evaluated MTL subfield thickness and function in older adults representing a spectrum of cognitive health. Participants performed an associative memory task during hr-fMRI in which they encoded and later retrieved face-name pairs. Motivated by prior research, we hypothesized that differences in performance would be explained by the following: (i) entorhinal cortex (ERC) and CA1 apical neuropil layer [CA1-stratum radiatum lacunosum moleculare (SRLM)] thickness, and (ii) activity in ERC and the dentate gyrus (DG)/CA3 region. Regression analyses revealed that this combination of factors significantly accounted for variability in memory performance. Among these metrics, CA1-SRLM thickness was positively associated with memory, whereas DG/CA3 retrieval activity was negatively associated with memory. Furthermore, including structural and functional metrics in the same model better accounted for performance than did single-modality models. These results advance the understanding of how independent but converging influences of both MTL subfield structure and function contribute to age-related memory impairment, complementing findings in the rodent and human postmortem literatures.

  View details for PubMedID 29078387

• Distributed representation of context by intrinsic subnetworks in prefrontal cortex. Proceedings of the National Academy of Sciences of the United States of America Waskom, M. L., Wagner, A. D. 2017; 114 (8): 2030-2035

  Abstract

  Human prefrontal cortex supports goal-directed behavior by representing abstract information about task context. The organizational basis of these context representations, and of representations underlying other higher-order processes, is unknown. Here, we use multivariate decoding and analyses of spontaneous correlations to show that context representations are distributed across subnetworks within prefrontal cortex. Examining targeted prefrontal regions, we found that pairs of voxels with similar context preferences exhibited spontaneous correlations that were approximately twice as large as those between pairs with opposite context preferences. This subnetwork organization was stable across task-engaged and resting states, suggesting that abstract context representations are constrained by an intrinsic functional architecture. These results reveal a principle of fine-scaled functional organization in association cortex.

  View details for DOI 10.1073/pnas.1615269114

  View details for PubMedID 28174269

  View details for PubMedCentralID PMC5338424

• Prospective representation of navigational goals in the human hippocampus. Science Brown, T. I., Carr, V. A., LaRocque, K. F., Favila, S. E., Gordon, A. M., Bowles, B., Bailenson, J. N., Wagner, A. D. 2016; 352 (6291): 1323-1326

  Abstract

  Mental representation of the future is a fundamental component of goal-directed behavior. Computational and animal models highlight prospective spatial coding in the hippocampus, mediated by interactions with the prefrontal cortex, as a putative mechanism for simulating future events. Using whole-brain high-resolution functional magnetic resonance imaging and multi-voxel pattern classification, we tested whether the human hippocampus and interrelated cortical structures support prospective representation of navigational goals. Results demonstrated that hippocampal activity patterns code for future goals to which participants subsequently navigate, as well as for intervening locations along the route, consistent with trajectory-specific simulation. The strength of hippocampal goal representations covaried with goal-related coding in the prefrontal, medial temporal, and medial parietal cortex. Collectively, these data indicate that a hippocampal-cortical network supports prospective simulation of navigational events during goal-directed planning.

  View details for DOI 10.1126/science.aaf0784

  View details for PubMedID 27284194

• Electrocorticography reveals the temporal dynamics of posterior parietal cortical activity during recognition memory decisions PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Gonzalez, A., Hutchinson, J. B., Uncapher, M. R., Chen, J., LaRocque, K. F., Foster, B. L., Rangarajan, V., Parvizi, J., Wagner, A. D. 2015; 112 (35): 11066-11071

  Abstract

  Theories of the neurobiology of episodic memory predominantly focus on the contributions of medial temporal lobe structures, based on extensive lesion, electrophysiological, and imaging evidence. Against this backdrop, functional neuroimaging data have unexpectedly implicated left posterior parietal cortex (PPC) in episodic retrieval, revealing distinct activation patterns in PPC subregions as humans make memory-related decisions. To date, theorizing about the functional contributions of PPC has been hampered by the absence of information about the temporal dynamics of PPC activity as retrieval unfolds. Here, we leveraged electrocorticography to examine the temporal profile of high gamma power (HGP) in dorsal PPC subregions as participants made old/new recognition memory decisions. A double dissociation in memory-related HGP was observed, with activity in left intraparietal sulcus (IPS) and left superior parietal lobule (SPL) differing in time and sign for recognized old items (Hits) and correctly rejected novel items (CRs). Specifically, HGP in left IPS increased for Hits 300-700 ms poststimulus onset, and decayed to baseline ∼200 ms preresponse. By contrast, HGP in left SPL increased for CRs early after stimulus onset (200-300 ms) and late in the memory decision (from 700 ms to response). These memory-related effects were unique to left PPC, as they were not observed in right PPC. Finally, memory-related HGP in left IPS and SPL was sufficiently reliable to enable brain-based decoding of the participant's memory state at the single-trial level, using multivariate pattern classification. Collectively, these data provide insights into left PPC temporal dynamics as humans make recognition memory decisions.

  View details for DOI 10.1073/pnas.1510749112

  View details for Web of Science ID 000360383200069

• Cortical Reinstatement Mediates the Relationship Between Content-Specific Encoding Activity and Subsequent Recollection Decisions CEREBRAL CORTEX Gordon, A. M., Rissman, J., Kiani, R., Wagner, A. D. 2014; 24 (12): 3350-3364

  Abstract

  Episodic recollection entails the conscious remembrance of event details associated with previously encountered stimuli. Recollection depends on both the establishment of cortical representations of event features during stimulus encoding and the cortical reinstatement of these representations at retrieval. Here, we used multivoxel pattern analyses of functional magnetic resonance imaging data to examine how cortical and hippocampal activity at encoding and retrieval drive recollective memory decisions. During encoding, words were associated with face or scene source contexts. At retrieval, subjects were cued to recollect the source associate of each presented word. Neurally derived estimates of encoding strength and pattern reinstatement in occipitotemporal cortex were computed for each encoding and retrieval trial, respectively. Analyses demonstrated that (1) cortical encoding strength predicted subsequent memory accuracy and reaction time, (2) encoding strength predicted encoding-phase hippocampal activity, and (3) encoding strength and retrieval-phase hippocampal activity predicted the magnitude of cortical reinstatement. Path analyses further indicated that cortical reinstatement partially mediated both the effect of cortical encoding strength and the effect of retrieval-phase hippocampal activity on subsequent source memory performance. Taken together, these results indicate that memory-guided decisions are driven in part by a pathway leading from hippocampally linked cortical encoding of event attributes to hippocampally linked cortical reinstatement at retrieval.

  View details for DOI 10.1093/cercor/bht194

  View details for Web of Science ID 000345838300022

  View details for PubMedID 23921785

  View details for PubMedCentralID PMC4296124

• Frontoparietal representations of task context support the flexible control of goal-directed cognition. journal of neuroscience Waskom, M. L., Kumaran, D., Gordon, A. M., Rissman, J., Wagner, A. D. 2014; 34 (32): 10743-10755

  Abstract

  Cognitive control allows stimulus-response processing to be aligned with internal goals and is thus central to intelligent, purposeful behavior. Control is thought to depend in part on the active representation of task information in prefrontal cortex (PFC), which provides a source of contextual bias on perception, decision making, and action. In the present study, we investigated the organization, influences, and consequences of context representation as human subjects performed a cued sorting task that required them to flexibly judge the relationship between pairs of multivalent stimuli. Using a connectivity-based parcellation of PFC and multivariate decoding analyses, we determined that context is specifically and transiently represented in a region spanning the inferior frontal sulcus during context-dependent decision making. We also found strong evidence that decision context is represented within the intraparietal sulcus, an area previously shown to be functionally networked with the inferior frontal sulcus at rest and during task performance. Rule-guided allocation of attention to different stimulus dimensions produced discriminable patterns of activation in visual cortex, providing a signature of top-down bias over perception. Furthermore, demands on cognitive control arising from the task structure modulated context representation, which was found to be strongest after a shift in task rules. When context representation in frontoparietal areas increased in strength, as measured by the discriminability of high-dimensional activation patterns, the bias on attended stimulus features was enhanced. These results provide novel evidence that illuminates the mechanisms by which humans flexibly guide behavior in complex environments.

  View details for DOI 10.1523/JNEUROSCI.5282-13.2014

  View details for PubMedID 25100605

• Global Similarity and Pattern Separation in the Human Medial Temporal Lobe Predict Subsequent Memory JOURNAL OF NEUROSCIENCE LaRocque, K. F., Smith, M. E., Carr, V. A., Witthoft, N., Grill-Spector, K., Wagner, A. D. 2013; 33 (13): 5466-5474

  Abstract

  Intense debate surrounds the role of medial temporal lobe (MTL) structures in recognition memory. Using high-resolution fMRI and analyses of pattern similarity in humans, we examined the encoding computations subserved by MTL subregions. Specifically, we tested the theory that MTL cortex supports memory by encoding overlapping representations, whereas hippocampus supports memory by encoding pattern-separated representations. Consistent with this view, the relationship between encoding pattern similarity and subsequent memory dissociated MTL cortex and hippocampus: later memory was predicted by greater across-item pattern similarity in perirhinal cortex and in parahippocampal cortex, but greater pattern distinctiveness in hippocampus. Additionally, by comparing neural patterns elicited by individual stimuli regardless of subsequent memory, we found that perirhinal cortex and parahippocampal cortex exhibited differential content sensitivity for multiple stimulus categories, whereas hippocampus failed to demonstrate content sensitivity. These data provide novel evidence that complementary MTL encoding computations subserve declarative memory.

  View details for DOI 10.1523/JNEUROSCI.4293-12.2013

  View details for Web of Science ID 000316948600005

  View details for PubMedID 23536062

  View details for PubMedCentralID PMC3643502

• Distributed Representations in Memory: Insights from Functional Brain Imaging ANNUAL REVIEW OF PSYCHOLOGY, VOL 63 Rissman, J., Wagner, A. D. 2012; 63: 101-128

  Abstract

  Forging new memories for facts and events, holding critical details in mind on a moment-to-moment basis, and retrieving knowledge in the service of current goals all depend on a complex interplay between neural ensembles throughout the brain. Over the past decade, researchers have increasingly utilized powerful analytical tools (e.g., multivoxel pattern analysis) to decode the information represented within distributed functional magnetic resonance imaging activity patterns. In this review, we discuss how these methods can sensitively index neural representations of perceptual and semantic content and how leverage on the engagement of distributed representations provides unique insights into distinct aspects of memory-guided behavior. We emphasize that, in addition to characterizing the contents of memories, analyses of distributed patterns shed light on the processes that influence how information is encoded, maintained, or retrieved, and thus inform memory theory. We conclude by highlighting open questions about memory that can be addressed through distributed pattern analyses.

  View details for DOI 10.1146/annurev-psych-120710-100344

  View details for Web of Science ID 000299709900005

  View details for PubMedID 21943171

• Fidelity of neural reactivation reveals competition between memories PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kuhl, B. A., Rissman, J., Chun, M. M., Wagner, A. D. 2011; 108 (14): 5903-5908

  Abstract

  Remembering an event from the past is often complicated by the fact that our memories are cluttered with similar events. Though competition is a fundamental part of remembering, there is little evidence of how mnemonic competition is neurally represented. Here, we assessed whether competition between visual memories is captured in the relative degree to which target vs. competing memories are reactivated within the ventral occipitotemporal cortex (VOTC). To assess reactivation, we used multivoxel pattern analysis of fMRI data, quantifying the degree to which retrieval events elicited patterns of neural activity that matched those elicited during encoding. Consistent with recent evidence, we found that retrieval of visual memories was associated with robust VOTC reactivation and that the degree of reactivation scaled with behavioral expressions of target memory retrieval. Critically, competitive remembering was associated with more ambiguous patterns of VOTC reactivation, putatively reflecting simultaneous reactivation of target and competing memories. Indeed, the more weakly that target memories were reactivated, the more likely that competing memories were later remembered. Moreover, when VOTC reactivation indicated that conflict between target and competing memories was high, frontoparietal mechanisms were markedly engaged, revealing specific neural mechanisms that tracked competing mnemonic evidence. Together, these findings provide unique evidence that neural reactivation captures competition between individual memories, providing insight into how well target memories are retrieved in the present and how likely competing memories will be remembered in the future.

  View details for DOI 10.1073/pnas.1016939108

  View details for Web of Science ID 000289265300077

  View details for PubMedID 21436044

  View details for PubMedCentralID PMC3078372

• A Roadmap to Brain Mapping: Toward a Functional Map of Human Parietal Cortex NEURON Uncapher, M. R., Hutchinson, J. B., Wagner, A. D. 2010; 67 (1): 5-8

  Abstract

  In this issue of Neuron, Nelson and colleagues report a novel parcellation of human lateral parietal cortex based on task-induced response profiles and resting-state functional connectivity. Their findings inform current debates about the contributions of parietal cortex to cognition, including the retrieval of episodic memories.

  View details for DOI 10.1016/j.neuron.2010.06.025

  View details for Web of Science ID 000280221000003

  View details for PubMedID 20624586

• Detecting individual memories through the neural decoding of memory states and past experience PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Rissman, J., Greely, H. T., Wagner, A. D. 2010; 107 (21): 9849-9854

  Abstract

  A wealth of neuroscientific evidence indicates that our brains respond differently to previously encountered than to novel stimuli. There has been an upswell of interest in the prospect that functional MRI (fMRI), when coupled with multivariate data analysis techniques, might allow the presence or absence of individual memories to be detected from brain activity patterns. This could have profound implications for forensic investigations and legal proceedings, and thus the merits and limitations of such an approach are in critical need of empirical evaluation. We conducted two experiments to investigate whether neural signatures of recognition memory can be reliably decoded from fMRI data. In Exp. 1, participants were scanned while making explicit recognition judgments for studied and novel faces. Multivoxel pattern analysis (MVPA) revealed a robust ability to classify whether a given face was subjectively experienced as old or new, as well as whether recognition was accompanied by recollection, strong familiarity, or weak familiarity. Moreover, a participant's subjective mnemonic experiences could be reliably decoded even when the classifier was trained on the brain data from other individuals. In contrast, the ability to classify a face's objective old/new status, when holding subjective status constant, was severely limited. This important boundary condition was further evidenced in Exp. 2, which demonstrated that mnemonic decoding is poor when memory is indirectly (implicitly) probed. Thus, although subjective memory states can be decoded quite accurately under controlled experimental conditions, fMRI has uncertain utility for objectively detecting an individual's past experiences.

  View details for DOI 10.1073/pnas.1001028107

  View details for Web of Science ID 000278054700067

  View details for PubMedID 20457911

  View details for PubMedCentralID PMC2906873

• Resistance to forgetting associated with hippocampus-mediated reactivation during new learning NATURE NEUROSCIENCE Kuhl, B. A., Shah, A. T., DuBrow, S., Wagner, A. D. 2010; 13 (4): 501-U128

  Abstract

  One of the reasons why we forget past experiences is because we acquire new memories in the interim. Although the hippocampus is thought to be important for acquiring and retaining memories, there is little evidence linking neural operations during new learning to the forgetting (or remembering) of earlier events. We found that, during the encoding of new memories, responses in the human hippocampus are predictive of the retention of memories for previously experienced, overlapping events. This brain-behavior relationship is evident in neural responses to individual events and in differences across individuals. We found that the hippocampus accomplishes this function by reactivating older memories as new memories are formed; in this case, reactivating neural responses that represented monetary rewards associated with older memories. These data reveal a fundamental mechanism by which the hippocampus tempers the forgetting of older memories as newer memories are acquired.

  View details for DOI 10.1038/nn.2498

  View details for Web of Science ID 000276073500021

  View details for PubMedID 20190745

  View details for PubMedCentralID PMC2847013

• Imaging the Human Medial Temporal Lobe with High-Resolution fMRI NEURON Carr, V. A., Rissman, J., Wagner, A. D. 2010; 65 (3): 298-308

  Abstract

  High-resolution functional MRI (hr-fMRI) affords unique leverage on the functional properties of human medial temporal lobe (MTL) substructures. We review initial hr-fMRI efforts to delineate (1) encoding and retrieval processes within the hippocampal circuit, (2) hippocampal subfield contributions to pattern separation and pattern completion, and (3) the representational capabilities of distinct MTL subregions. Extant data reveal functional heterogeneity within human MTL and highlight the promise of hr-fMRI for bridging human, animal, and computational approaches to understanding MTL function.

  View details for DOI 10.1016/j.neuron.2009.12.022

  View details for Web of Science ID 000275185200004

  View details for PubMedID 20159444

  View details for PubMedCentralID PMC2844113

• Cognitive control in media multitaskers PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Ophir, E., Nass, C., Wagner, A. D. 2009; 106 (37): 15583-15587

  Abstract

  Chronic media multitasking is quickly becoming ubiquitous, although processing multiple incoming streams of information is considered a challenge for human cognition. A series of experiments addressed whether there are systematic differences in information processing styles between chronically heavy and light media multitaskers. A trait media multitasking index was developed to identify groups of heavy and light media multitaskers. These two groups were then compared along established cognitive control dimensions. Results showed that heavy media multitaskers are more susceptible to interference from irrelevant environmental stimuli and from irrelevant representations in memory. This led to the surprising result that heavy media multitaskers performed worse on a test of task-switching ability, likely due to reduced ability to filter out interference from the irrelevant task set. These results demonstrate that media multitasking, a rapidly growing societal trend, is associated with a distinct approach to fundamental information processing.

  View details for DOI 10.1073/pnas.0903620106

  View details for Web of Science ID 000269806600016

  View details for PubMedID 19706386

  View details for PubMedCentralID PMC2747164

• Integrating Memories in the Human Brain: Hippocampal-Midbrain Encoding of Overlapping Events NEURON Shohamy, D., Wagner, A. D. 2008; 60 (2): 378-389

  Abstract

  Decisions are often guided by generalizing from past experiences. Fundamental questions remain regarding the cognitive and neural mechanisms by which generalization takes place. Prior data suggest that generalization may stem from inference-based processes at the time of generalization. By contrast, generalization may emerge from mnemonic processes occurring while premise events are encoded. Here, participants engaged in a two-phase learning and generalization task, wherein they learned a series of overlapping associations and subsequently generalized what they learned to novel stimulus combinations. Functional MRI revealed that successful generalization was associated with coupled changes in learning-phase activity in the hippocampus and midbrain (ventral tegmental area/substantia nigra). These findings provide evidence for generalization based on integrative encoding, whereby overlapping past events are integrated into a linked mnemonic representation. Hippocampal-midbrain interactions support the dynamic integration of experiences, providing a powerful mechanism for building a rich associative history that extends beyond individual events.

  View details for DOI 10.1016/j.neuron.2008.09.023

  View details for Web of Science ID 000260549300019

  View details for PubMedID 18957228

  View details for PubMedCentralID PMC2628634

• Decreased demands on cognitive control reveal the neural processing benefits of forgetting NATURE NEUROSCIENCE Kuhl, B. A., Dudukovic, N. M., Kahn, I., Wagner, A. D. 2007; 10 (7): 908-914

  Abstract

  Remembering often requires the selection of goal-relevant memories in the face of competition from irrelevant memories. Although there is a cost of selecting target memories over competing memories (increased forgetting of the competing memories), here we report neural evidence for the adaptive benefits of forgetting--namely, reduced demands on cognitive control during future acts of remembering. Functional magnetic resonance imaging during selective retrieval showed that repeated retrieval of target memories was accompanied by dynamic reductions in the engagement of functionally coupled cognitive control mechanisms that detect (anterior cingulate cortex) and resolve (dorsolateral and ventrolateral prefrontal cortex) mnemonic competition. Strikingly, regression analyses revealed that this prefrontal disengagement tracked the extent to which competing memories were forgotten; greater forgetting of competing memories was associated with a greater decline in demands on prefrontal cortex during target remembering. These findings indicate that, although forgetting can be frustrating, memory might be adaptive because forgetting confers neural processing benefits.

  View details for DOI 10.1038/nn1918

  View details for Web of Science ID 000247560200022

  View details for PubMedID 17558403

• Left ventrolateral prefrontal cortex and the cognitive control of memory NEUROPSYCHOLOGIA Badre, D., Wagner, A. D. 2007; 45 (13): 2883-2901

  Abstract

  Cognitive control mechanisms permit memory to be accessed strategically, and so aid in bringing knowledge to mind that is relevant to current goals and actions. In this review, we consider the contribution of left ventrolateral prefrontal cortex (VLPFC) to the cognitive control of memory. Reviewed evidence supports a two-process model of mnemonic control, supported by a double dissociation among rostral regions of left VLPFC. Specifically, anterior VLPFC (approximately BA 47; inferior frontal gyrus pars orbitalis) supports controlled access to stored conceptual representations, whereas mid-VLPFC (approximately BA 45; inferior frontal gyrus pars triangularis) supports a domain-general selection process that operates post-retrieval to resolve competition among active representations. We discuss the contribution of these control mechanisms across a range of mnemonic domains, including semantic retrieval, recollection of contextual details about past events, resolution of proactive interference in working memory, and task switching. Finally, we consider open directions for future research into left VLPFC function and the cognitive control of memory.

  View details for DOI 10.1016/j.neuropsychologia.2007.06.015

  View details for Web of Science ID 000250257100001

  View details for PubMedID 17675110

• Computational and neurobiological mechanisms underlying cognitive flexibility PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Badre, D., Wagner, A. D. 2006; 103 (18): 7186-7191

  Abstract

  The ability to switch between multiple tasks is central to flexible behavior. Although switching between tasks is readily accomplished, a well established consequence of task switching (TS) is behavioral slowing. The source of this switch cost and the contribution of cognitive control to its resolution remain highly controversial. Here, we tested whether proactive interference arising from memory places fundamental constraints on flexible performance, and whether prefrontal control processes contribute to overcoming these constraints. Event-related functional MRI indexed neural responses during TS. The contributions of cognitive control and interference were made theoretically explicit in a computational model of task performance. Model estimates of two levels of proactive interference, "conceptual conflict" and "response conflict," produced distinct preparation-related profiles. Left ventrolateral prefrontal cortical activation paralleled model estimates of conceptual conflict, dissociating from that in left inferior parietal cortex, which paralleled model estimates of response conflict. These computationally informed neural measures specify retrieved conceptual representations as a source of conflict during TS and suggest that left ventrolateral prefrontal cortex resolves this conflict to facilitate flexible performance.

  View details for DOI 10.1073/pnas.0509550103

  View details for Web of Science ID 000237399900072

  View details for PubMedID 16632612

  View details for PubMedCentralID PMC1459038

• Dissociable controlled retrieval and generalized selection mechanisms in ventrolateral prefrontal cortex NEURON Badre, D., Poldrack, R. A., Pare-Blagoev, E. J., Insler, R. Z., Wagner, A. D. 2005; 47 (6): 907-918

  Abstract

  How does ventrolateral prefrontal cortex (VLPFC) control mnemonic processing? Alternative models propose that VLPFC guides top-down (controlled) retrieval of knowledge from long-term stores or selects goal-relevant products of retrieval from among competitors. A paucity of evidence supports a retrieval/selection distinction, raising the possibility that these models reduce to a common mechanism. Here, four manipulations varied semantic control demands during fMRI: judgment specificity, cue-target-associative strength, competitor dominance, and number of competitors. Factor analysis revealed evidence for a metafactor that accounted for common behavioral variance across manipulations and for functional variance in left mid-VLPFC. These data support a generalized control process that selects relevant knowledge from among competitors. By contrast, left anterior VLPFC and middle temporal cortex were sensitive to cue-target-associative strength, but not competition, consistent with a control process that retrieves knowledge stored in lateral temporal cortex. Distinct PFC mechanisms mediate top-down retrieval and postretrieval selection.

  View details for DOI 10.1016/j.neuron.2005.07.023

  View details for Web of Science ID 000232085000017

  View details for PubMedID 16157284

• Parietal lobe contributions to episodic memory retrieval TRENDS IN COGNITIVE SCIENCES Wagner, A. D., Shannon, B. J., Kahn, I., Buckner, R. L. 2005; 9 (9): 445-453

  Abstract

  Although the parietal lobe is not traditionally thought to support declarative memory, recent event-related fMRI studies of episodic retrieval have consistently revealed a range of memory-related influences on activation in lateral posterior parietal cortex (PPC) and precuneus extending into posterior cingulate and retrosplenial cortex. This article surveys the fMRI literature on PPC activation during remembering, a literature that complements earlier electroencephalography data. We consider these recent memory-related fMRI responses within the context of classical ideas about parietal function that emphasize space-based attention and motor intention. We conclude by proposing three hypotheses concerning how parietal cortex might contribute to memory.

  View details for DOI 10.1016/j.tics.2005.07.001

  View details for Web of Science ID 000232251000015

  View details for PubMedID 16054861

• Memory strength and repetition suppression: Multimodal imaging of medial temporal cortical contributions to recognition NEURON Gonsalves, B. D., Kahn, I., Curran, T., Norman, K. A., Wagner, A. D. 2005; 47 (5): 751-761

  Abstract

  Declarative memory permits an organism to recognize stimuli that have been previously encountered, discriminating them from those that are novel. One basis for recognition is item memory strength, which may support the perception of stimulus familiarity. Though the medial temporal lobes are known to be critical for declarative memory, at present the neural mechanisms supporting perceived differences in memory strength remain poorly specified. Here, functional MRI (fMRI) and anatomically constrained magnetoencephalography (MEG) indexed correlates of graded memory strength in the human brain, focusing on medial temporal cortex. fMRI revealed a decrease in medial temporal cortical activation that tracked parametric levels of perceived memory strength. Anatomically constrained MEG current estimates revealed that strength-dependent signal reductions onset within 150-300 ms. Memory strength appears to be rapidly signaled by medial temporal cortex through repetition suppression (activation reductions), providing a basis for the subjective perception of stimulus familiarity or novelty.

  View details for DOI 10.1016/j.neuron.2005.07.013

  View details for Web of Science ID 000231782700015

  View details for PubMedID 16129403

• Selection, integration, and conflict monitoring: Assessing the nature and generality of prefrontal cognitive control mechanisms NEURON Badre, D., Wagner, A. D. 2004; 41 (3): 473-487

  Abstract

  Prefrontal cortex (PFC) supports flexible behavior by mediating cognitive control, though the elemental forms of control supported by PFC remain a central debate. Dorsolateral PFC (DLPFC) is thought to guide response selection under conditions of response conflict or, alternatively, may refresh recently active representations within working memory. Lateral frontopolar cortex (FPC) may also adjudicate response conflict, though others propose that FPC supports higher order control processes such as subgoaling and integration. Anterior cingulate cortex (ACC) is hypothesized to upregulate response selection by detecting response conflict; it remains unclear whether ACC functions generalize beyond monitoring response conflict. The present fMRI experiment directly tested these competing theories regarding the functional roles of DLPFC, FPC, and ACC. Results reveal dissociable control processes in PFC, with mid-DLPFC selectively mediating resolution of response conflict and FPC further mediating subgoaling/integration. ACC demonstrated a broad sensitivity to control demands, suggesting a generalized role in modulating cognitive control.

  View details for Web of Science ID 000221457900017

  View details for PubMedID 14766185

• Multiple routes to memory: Distinct medial temporal lobe processes build item and source memories PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Davachi, L., Mitchell, J. P., Wagner, A. D. 2003; 100 (4): 2157-2162

  Abstract

  A central function of memory is to permit an organism to distinguish between stimuli that have been previously encountered and those that are novel. Although the medial temporal lobe (which includes the hippocampus and surrounding perirhinal, parahippocampal, and entorhinal cortices) is known to be crucial for recognition memory, controversy remains regarding how the specific subregions within the medial temporal lobe contribute to recognition. We used event-related functional MRI to examine the relation between activation in distinct medial temporal lobe subregions during memory formation and the ability (i) to later recognize an item as previously encountered (item recognition) and (ii) to later recollect specific contextual details about the prior encounter (source recollection). Encoding activation in hippocampus and in posterior parahippocampal cortex predicted later source recollection, but was uncorrelated with item recognition. In contrast, encoding activation in perirhinal cortex predicted later item recognition, but not subsequent source recollection. These outcomes suggest that the subregions within the medial temporal lobe subserve distinct, but complementary, learning mechanisms.

  View details for DOI 10.1073/pnas.0337195100

  View details for Web of Science ID 000181073000127

  View details for PubMedID 12578977

• Executive control during episodic retrieval: Multiple prefrontal processes subserve source memory NEURON Dobbins, I. G., Foley, H., Schacter, D. L., Wagner, A. D. 2002; 35 (5): 989-996

  Abstract

  During recognition, one may sense items as familiar (item memory) and additionally recollect specific contextual details of the earlier encounters (source memory). Cognitive theory suggests that, unlike item memory, source memory requires controlled cue specification and monitoring processes. Functional imaging suggests that such processes may depend on left prefrontal cortex (PFC). However, the nature and possible anatomical segregation of these processes remains unknown. Using functional magnetic resonance imaging, we isolated distinct response patterns in left PFC during source memory consistent with semantic analysis/cue specification (anterior ventrolateral), recollective monitoring (posterior dorsolateral and frontopolar), and phonological maintenance/rehearsal (posterior ventrolateral). Importantly, cue specification and recollective monitoring responses were not seen during item memory and were unaffected by retrieval success, demonstrating that the mere attempt to recollect episodic detail engages multiple control processes with different left PFC substrates.

  View details for Web of Science ID 000177779800019

  View details for PubMedID 12372291

• Observing the transformation of experience into memory TRENDS IN COGNITIVE SCIENCES Paller, K. A., Wagner, A. D. 2002; 6 (2): 93-102

  Abstract

  The ability to remember one's past depends on neural processing set in motion at the moment each event is experienced. Memory formation can be observed by segregating neural responses according to whether or not each event is recalled or recognized on a subsequent memory test. Subsequent memory analyses have been performed with various neural measures, including brain potentials extracted from intracranial and extracranial electroencephalographic recordings, and hemodynamic responses from functional magnetic resonance imaging. Neural responses can predict which events, and which aspects of those events, will be subsequently remembered or forgotten, thereby elucidating the neurocognitive processes that establish durable episodic memories.

  View details for Web of Science ID 000173740900012

  View details for PubMedID 15866193

• Recovering meaning: Left prefrontal cortex guides controlled semantic retrieval NEURON Wagner, A. D., Pare-Blagoev, E. J., Clark, J., Poldrack, R. A. 2001; 31 (2): 329-338

  Abstract

  Prefrontal cortex plays a central role in mnemonic control, with left inferior prefrontal cortex (LIPC) mediating control of semantic knowledge. One prominent theory posits that LIPC does not mediate semantic retrieval per se, but rather subserves the selection of task-relevant knowledge from amidst competing knowledge. The present event-related fMRI study provides evidence for an alternative hypothesis: LIPC guides controlled semantic retrieval irrespective of whether retrieval requires selection against competing representations. With selection demands held constant, LIPC activation increased with semantic retrieval demands and with the level of control required during retrieval. LIPC mediates a top-down bias signal that is recruited to the extent that the recovery of meaning demands controlled retrieval. Selection may reflect a specific instantiation of this mechanism.

  View details for Web of Science ID 000170277700016

  View details for PubMedID 11502262

• Building memories: Remembering and forgetting of verbal experiences as predicted by brain activity SCIENCE Wagner, A. D., Schacter, D. L., Rotte, M., Koutstaal, W., Maril, A., Dale, A. M., Rosen, B. R., Buckner, R. L. 1998; 281 (5380): 1188-1191

  Abstract

  A fundamental question about human memory is why some experiences are remembered whereas others are forgotten. Brain activation during word encoding was measured using blocked and event-related functional magnetic resonance imaging to examine how neural activation differs for subsequently remembered and subsequently forgotten experiences. Results revealed that the ability to later remember a verbal experience is predicted by the magnitude of activation in left prefrontal and temporal cortices during that experience. These findings provide direct evidence that left prefrontal and temporal regions jointly promote memory formation for verbalizable events.

  View details for Web of Science ID 000075531200052

  View details for PubMedID 9712582

• Parkinson's disease is characterized by vitamin B6-dependent inflammatory kynurenine pathway dysfunction. Research square Wilson, E., Umans, J., Swarovski, M., Minhas, P., Midttun, Ø., Ulvik, A. A., Shahid-Besanti, M., Linortner, P., Mhatre, S., Wang, Q., Channappa, D., Corso, N., Tian, L., Fredericks, C., Kerchner, G., Plowey, E., Cholerton, B., Ueland, P., Zabetian, C., Gray, N., Quinn, J., Montine, T., Sha, S., Longo, F., Wolk, D., Chen-Plotkin, A., Henderson, V., Wyss-Coray, T., Wagner, A., Mormino, E., Aghaeepour, N., Poston, K., Andreasson, K. 2024

  Abstract

  Parkinson's disease (PD) is a complex multisystem disorder clinically characterized by motor, non-motor, and premotor manifestations. Pathologically, PD involves neuronal loss in the substantia nigra, striatal dopamine deficiency, and accumulation of intracellular inclusions containing aggregates of α-synuclein. Recent studies demonstrate that PD is associated with dysregulated metabolic flux through the kynurenine pathway (KP), in which tryptophan is converted to kynurenine (KYN), and KYN is subsequently metabolized to neuroactive compounds quinolinic acid (QA) and kynurenic acid (KA). This multicenter study used highly sensitive liquid chromatography-tandem mass-spectrometry to compare blood and cerebral spinal fluid (CSF) KP metabolites between 158 unimpaired older adults and 177 participants with PD. Results indicate that increased neuroexcitatory QA/KA ratio in both plasma and CSF of PD participants associated with peripheral and cerebral inflammation and vitamin B6 deficiency. Furthermore, increased QA tracked with CSF tau and severity of both motor and non-motor PD clinical dysfunction. Importantly, plasma and CSF kynurenine metabolites classified PD participants with a high degree of accuracy (AUC = 0.897). Finally, analysis of metabolite data revealed subgroups with distinct KP profiles, and these were subsequently found to display distinct PD clinical features. Together, these data further support the hypothesis that the KP serves as a site of brain and periphery crosstalk, integrating B-vitamin status, inflammation and metabolism to ultimately influence PD clinical manifestation.

  View details for DOI 10.21203/rs.3.rs-4980210/v1

  View details for PubMedID 39399688

  View details for PubMedCentralID PMC11469709

• Cross-regional coordination of activity in the human brain during autobiographical self-referential processing. Proceedings of the National Academy of Sciences of the United States of America Stieger, J. R., Pinheiro-Chagas, P., Fang, Y., Li, J., Lusk, Z., Perry, C. M., Girn, M., Contreras, D., Chen, Q., Huguenard, J. R., Spreng, R. N., Edlow, B. L., Wagner, A. D., Buch, V., Parvizi, J. 2024; 121 (32): e2316021121

  Abstract

  For the human brain to operate, populations of neurons across anatomical structures must coordinate their activity within milliseconds. To date, our understanding of such interactions has remained limited. We recorded directly from the hippocampus (HPC), posteromedial cortex (PMC), ventromedial/orbital prefrontal cortex (OFC), and the anterior nuclei of the thalamus (ANT) during two experiments of autobiographical memory processing that are known from decades of neuroimaging work to coactivate these regions. In 31 patients implanted with intracranial electrodes, we found that the presentation of memory retrieval cues elicited a significant increase of low frequency (LF < 6 Hz) activity followed by cross-regional phase coherence of this LF activity before select populations of neurons within each of the four regions increased high-frequency (HF > 70 Hz) activity. The power of HF activity was modulated by memory content, and its onset followed a specific temporal order of ANTHPC/PMCOFC. Further, we probed cross-regional causal effective interactions with repeated electrical pulses and found that HPC stimulations cause the greatest increase in LF-phase coherence across all regions, whereas the stimulation of any region caused the greatest LF-phase coherence between that particular region and ANT. These observations support the role of the ANT in gating, and the HPC in synchronizing, the activity of cortical midline structures when humans retrieve self-relevant memories of their past. Our findings offer a fresh perspective, with high temporal fidelity, about the dynamic signaling and underlying causal connections among distant regions when the brain is actively involved in retrieving self-referential memories from the past.

  View details for DOI 10.1073/pnas.2316021121

  View details for PubMedID 39078679

• Florbetaben amyloid PET acquisition time: Influence on Centiloids and interpretation. Alzheimer's & dementia : the journal of the Alzheimer's Association Johns, E., Vossler, H. A., Young, C. B., Carlson, M. L., Winer, J. R., Younes, K., Park, J., Rathmann-Bloch, J., Smith, V., Harrison, T. M., Landau, S., Henderson, V., Wagner, A., Sha, S. J., Zeineh, M., Zaharchuk, G., Poston, K. L., Davidzon, G. A., Mormino, E. C. 2024

  Abstract

  Amyloid positron emission tomography (PET) acquisition timing impacts quantification.In florbetaben (FBB) PET scans of 245 adults with and without cognitive impairment, we investigated the impact of post-injection acquisition time on Centiloids (CLs) across five reference regions. CL equations for FBB were derived using standard methods, using FBB data collected between 90 and 110 min with paired Pittsburgh compound B data. Linear mixed models and t-tests evaluated the impact of acquisition time on CL increases.CL values increased significantly over the scan using the whole cerebellum, cerebellar gray matter, and brainstem as reference regions, particularly in amyloid-positive individuals. In contrast, CLs based on white matter-containing reference regions decreased across the scan.The quantification of CLs in FBB PET imaging is influenced by both the overall scan acquisition time and the choice of reference region. Standardized acquisition protocols or the application of acquisition time-specific CL equations should be implemented in clinical protocols.Acquisition timing affects florbetaben positron emission tomography (PET) scan quantification, especially in amyloid-positive participants. The impact of acquisition timing on quantification varies across common reference regions. Consistent acquisitions and/or appropriate post-injection adjustments are needed to ensure comparability of PET data.

  View details for DOI 10.1002/alz.13893

  View details for PubMedID 38962867

• Post-retrieval stress impairs subsequent memory depending on hippocampal memory trace reinstatement during reactivation. Science advances Heinbockel, H., Wagner, A. D., Schwabe, L. 2024; 10 (18): eadm7504

  Abstract

  Upon retrieval, memories can become susceptible to meaningful events, such as stress. Post-retrieval memory changes may be attributed to an alteration of the original memory trace during reactivation-dependent reconsolidation or, alternatively, to the modification of retrieval-related memory traces that impact future remembering. Hence, how post-retrieval memory changes emerge in the human brain is unknown. In a 3-day functional magnetic resonance imaging study, we show that post-retrieval stress impairs subsequent memory depending on the strength of neural reinstatement of the original memory trace during reactivation, driven by the hippocampus and its cross-talk with neocortical representation areas. Comparison of neural patterns during immediate and final memory testing further revealed that successful retrieval was linked to pattern-dissimilarity in controls, suggesting the use of a different trace, whereas stressed participants relied on the original memory representation. These representation changes were again dependent on neocortical reinstatement during reactivation. Our findings show disruptive stress effects on the consolidation of retrieval-related memory traces that support future remembering.

  View details for DOI 10.1126/sciadv.adm7504

  View details for PubMedID 38691596

• Comprehensive proteomics of CSF, plasma, and urine identify DDC and other biomarkers of early Parkinson's disease. Acta neuropathologica Rutledge, J., Lehallier, B., Zarifkar, P., Losada, P. M., Shahid-Besanti, M., Western, D., Gorijala, P., Ryman, S., Yutsis, M., Deutsch, G. K., Mormino, E., Trelle, A., Wagner, A. D., Kerchner, G. A., Tian, L., Cruchaga, C., Henderson, V. W., Montine, T. J., Borghammer, P., Wyss-Coray, T., Poston, K. L. 2024; 147 (1): 52

  Abstract

  Parkinson's disease (PD) starts at the molecular and cellular level long before motor symptoms appear, yet there are no early-stage molecular biomarkers for diagnosis, prognosis prediction, or monitoring therapeutic response. This lack of biomarkers greatly impedes patient care and translational research-L-DOPA remains the standard of care more than 50 years after its introduction. Here, we performed a large-scale, multi-tissue, and multi-platform proteomics study to identify new biomarkers for early diagnosis and disease monitoring in PD. We analyzed 4877 cerebrospinal fluid, blood plasma, and urine samples from participants across seven cohorts using three orthogonal proteomics methods: Olink proximity extension assay, SomaScan aptamer precipitation assay, and liquid chromatography-mass spectrometry proteomics. We discovered that hundreds of proteins were upregulated in the CSF, blood, or urine of PD patients, prodromal PD patients with DAT deficit and REM sleep behavior disorder or anosmia, and non-manifesting genetic carriers of LRRK2 and GBA mutations. We nominate multiple novel hits across our analyses as promising markers of early PD, including DOPA decarboxylase (DDC), also known as L-aromatic acid decarboxylase (AADC), sulfatase-modifying factor 1 (SUMF1), dipeptidyl peptidase 2/7 (DPP7), glutamyl aminopeptidase (ENPEP), WAP four-disulfide core domain 2 (WFDC2), and others. DDC, which catalyzes the final step in dopamine synthesis, particularly stands out as a novel hit with a compelling mechanistic link to PD pathogenesis. DDC is consistently upregulated in the CSF and urine of treatment-naïve PD, prodromal PD, and GBA or LRRK2 carrier participants by all three proteomics methods. We show that CSF DDC levels correlate with clinical symptom severity in treatment-naïve PD patients and can be used to accurately diagnose PD and prodromal PD. This suggests that urine and CSF DDC could be a promising diagnostic and prognostic marker with utility in both clinical care and translational research.

  View details for DOI 10.1007/s00401-024-02706-0

  View details for PubMedID 38467937

  View details for PubMedCentralID 3995906

• Extended Realities and the Future of Knowledge Work: Opportunities and Challenges Queiroz, A. M., Bailenson, J. N., Blair, K., Schwartz, D. L., Thille, C., Wagner, A., IEEE COMPUTER SOC IEEE COMPUTER SOC. 2024: 662-666

  View details for DOI 10.1109/VRW62533.2024.00130

  View details for Web of Science ID 001239375400124

• Post-translational modifications linked to preclinical Alzheimer's disease-related pathological and cognitive changes. Alzheimer's & dementia : the journal of the Alzheimer's Association Abiose, O., Rutledge, J., Moran-Losada, P., Belloy, M. E., Wilson, E. N., He, Z., Trelle, A. N., Channappa, D., Romero, A., Park, J., Yutsis, M. V., Sha, S. J., Andreasson, K. I., Poston, K. L., Henderson, V. W., Wagner, A. D., Wyss-Coray, T., Mormino, E. C. 2023

  Abstract

  In this study, we leverage proteomic techniques to identify communities of proteins underlying Alzheimer's disease (AD) risk among clinically unimpaired (CU) older adults.We constructed a protein co-expression network using 3869 cerebrospinal fluid (CSF) proteins quantified by SomaLogic, Inc., in a cohort of participants along the AD clinical spectrum. We then replicated this network in an independent cohort of CU older adults and related these modules to clinically-relevant outcomes.We discovered modules enriched for phosphorylation and ubiquitination that were associated with abnormal amyloid status, as well as p-tau181 (M4: β = 2.44, p < 0.001, M7: β = 2.57, p < 0.001) and executive function performance (M4: β = -2.00, p = 0.005, M7: β = -2.39, p < 0.001).In leveraging CSF proteomic data from individuals spanning the clinical spectrum of AD, we highlight the importance of post-translational modifications for early cognitive and pathological changes.

  View details for DOI 10.1002/alz.13576

  View details for PubMedID 38146099

• Organ aging signatures in the plasma proteome track health and disease. Nature Oh, H. S., Rutledge, J., Nachun, D., Pálovics, R., Abiose, O., Moran-Losada, P., Channappa, D., Urey, D. Y., Kim, K., Sung, Y. J., Wang, L., Timsina, J., Western, D., Liu, M., Kohlfeld, P., Budde, J., Wilson, E. N., Guen, Y., Maurer, T. M., Haney, M., Yang, A. C., He, Z., Greicius, M. D., Andreasson, K. I., Sathyan, S., Weiss, E. F., Milman, S., Barzilai, N., Cruchaga, C., Wagner, A. D., Mormino, E., Lehallier, B., Henderson, V. W., Longo, F. M., Montgomery, S. B., Wyss-Coray, T. 2023; 624 (7990): 164-172

  Abstract

  Animal studies show aging varies between individuals as well as between organs within an individual1-4, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20-50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer's disease (AD) progression independently from and as strongly as plasma pTau-181 (ref. 5), the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects.

  View details for DOI 10.1038/s41586-023-06802-1

  View details for PubMedID 38057571

  View details for PubMedCentralID PMC10700136

• A 3' UTR Deletion Is a Leading Candidate Causal Variant at the TMEM106B Locus Reducing Risk for FTLD-TDP. medRxiv : the preprint server for health sciences Chemparathy, A., Le Guen, Y., Zeng, Y., Gorzynski, J., Jensen, T., Kasireddy, N., Talozzi, L., Belloy, M. E., Stewart, I., Gitler, A. D., Wagner, A. D., Mormino, E., Henderson, V. W., Wyss-Coray, T., Ashley, E., Greicius, M. D. 2023

  Abstract

  Single nucleotide variants (SNVs) near TMEM106B have been associated with risk of frontotemporal lobar dementia with TDP pathology (FTLD-TDP) but the causal variant at this locus has not yet been isolated. The initial leading FTLD-TDP genome-wide association study (GWAS) hit at this locus, rs1990622, is intergenic and is in linkage disequilibrium (LD) with a TMEM106B coding SNV, rs3173615. We developed a long-read sequencing (LRS) dataset of 407 individuals in order to identify structural variants associated with neurodegenerative disorders. We identified a prevalent 322 base pair deletion on the TMEM106B 3' untranslated region (UTR) that was in perfect linkage with rs1990622 and near-perfect linkage with rs3173615 (genotype discordance in two of 274 individuals who had LRS and short-read next-generation sequencing). In Alzheimer's Disease Sequencing Project (ADSP) participants, this deletion was in greater LD with rs1990622 (R2=0.920916, D'=0.963472) than with rs3173615 (R2=0.883776, D'=0.963575). rs1990622 and rs3173615 are less closely linked (R2=0.7403, D'=0.9915) in African populations. Among African ancestry individuals in the ADSP, the deletion is in even greater LD with rs1990622 (R2=0.936841, D'=0.976782) than with rs3173615 (R2=0.764242, D'=0.974406). Querying publicly available genetic datasets with associated mRNA expression and protein levels, we confirmed that rs1990622 is consistently a protein quantitative trait locus but not an expression quantitative trait locus, consistent with a causal variant present on the TMEM106B 3'UTR. In summary, the TMEM106B 3' UTR deletion is a large genetic variant on the TMEM106B transcript that is in higher LD with the leading GWAS hit rs1990622 than rs3173615 and may mediate the protective effect of this locus in neurodegenerative disease.

  View details for DOI 10.1101/2023.07.06.23292312

  View details for PubMedID 37461476

  View details for PubMedCentralID PMC10350161

• Neural Evidence for Advantaged Representation of First Items in Memory. NeuroImage Poker, G., Oren, N., Bezalel, V., Abecasis, D., Hendler, T., Fried, I., Wagner, A. D., Shapira-Lichter, I. 2023: 120239

  Abstract

  Visual areas activated during perception can retain specific information held in memory without the presence of the physical stimuli, via distributed activity patterns. Neuroimaging studies have shown that delay-period representation of information in visual areas is modulated by factors such as memory load and task demands, raising the possibility of serial position as another potential modulator. Specifically, enhanced representation of first items during the post-encoding delay period, may serve as a mechanism underlying the well-established but not well-understood primacy effect - the mnemonic advantage of first items. To test this hypothesis, 13 males and 16 females performed a human fMRI task, wherein each trial consisted of the sequential encoding of two stimuli (a famous face and landscape, order counterbalanced), followed by a distracting task, a delay period, and then cued recall of one of the items. Participants exhibited the expected behavioral primacy effect, manifested as faster recall of the first items. In order to elucidate the still debated neural underpinnings of this effect, using multivariatedecoding, a classifier was trained on data collected during encoding to differentiate stimulus category (i.e., faces vs. landscapes) and was tested on data collected during the post-encoding period. Greater reactivation of first versus second items was observed in the ventral occipito-temporal cortex during the entire post-encoding period but not during encoding. Moreover, trial-level analyses revealed that the degree of first-item neural advantage during the post-encoding delay predicted the behavioral primacy effect. These findings highlight the role of item reinstatement in ventral occipito-temporal cortex in the primacy effect and are discussed in the context of the uniqueness of the very first item and event boundaries, illuminating putative neural mechanisms underlying the effect.

  View details for DOI 10.1016/j.neuroimage.2023.120239

  View details for PubMedID 37348626

• Metrologically Traceable Quantification of 3 Apolipoprotein E Isoforms in Cerebrospinal Fluid. Clinical chemistry Huynh, H., Kuch, K., Orquillas, A., Forrest, K., Barahona-Carrillo, L., Keene, D., Henderson, V. W., Wagner, A. D., Poston, K. L., Montine, T. J., Lin, A., Tian, L., MacCoss, M. J., Emrick, M. A., Hoofnagle, A. N. 2023

  Abstract

  BACKGROUND: APOE genotype is associated with Alzheimer disease. Thus, the concentration of apolipoprotein E (apoE) isoforms in cerebrospinal fluid (CSF) could be altered in dementia. However, conflicting results have been obtained in different studies. Carefully validated and standardized assays could improve the interpretation of research findings, allow their replication in other laboratories, and generalize their application.METHODS: To evaluate this hypothesis, we aimed to develop, validate, and standardize a new measurement procedure using LC-MS/MS. Purified recombinant apoE protein standards (E2, E3, E4) were thoroughly characterized and used to assign the concentration of a matrix-matched calibration material that contained each apoE isoform, which ensured the metrological traceability of results.RESULTS: The assay of each isoform in human CSF was precise (≤11%CV) and of moderate throughput (approximately 80 samples per day). It demonstrated good linearity and parallelism for lumbar CSF, ventricular CSF, and bovine CSF. The use of an SI-traceable matrix-matched calibrator enabled precise and accurate measurements. There was no association observed between total apoE concentration and the number of Ɛ4 alleles in a cohort of 322 participants. However, the concentration of each isoform was significantly different in heterozygotes, with E4 > E3 > E2. Isoform concentrations were associated with cognitive and motor symptoms but contributed negligibly to a predictive model of cognitive impairment that included established CSF biomarkers.CONCLUSIONS: Our method simultaneously measures each apoE isoform in human CSF with excellent precision and accuracy. A secondary matrix-matched material has been developed and is available to other laboratories to improve interlaboratory agreement.

  View details for DOI 10.1093/clinchem/hvad056

  View details for PubMedID 37279935

• Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment. Cell Piehl, N., van Olst, L., Ramakrishnan, A., Teregulova, V., Simonton, B., Zhang, Z., Tapp, E., Channappa, D., Oh, H., Losada, P. M., Rutledge, J., Trelle, A. N., Mormino, E. C., Elahi, F., Galasko, D. R., Henderson, V. W., Wagner, A. D., Wyss-Coray, T., Gate, D. 2022

  Abstract

  Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with aging or neurodegenerative disease. Here, we performed single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years old. We uncovered an upregulation of lipid transport genes in monocytes with age. We then compared this cohort with 14 cognitively impaired subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred concomitantly with altered cytokine signaling to CD8 Tcells. Clonal CD8T effector memory cells upregulated C-X-C motif chemokine receptor 6 (CXCR6) in cognitively impaired subjects. The CXCR6 ligand, C-X-C motif chemokine ligand 16 (CXCL16), was elevated in the CSF of cognitively impaired subjects, suggesting CXCL16-CXCR6 signaling as a mechanism for antigen-specific Tcell entry into the brain. Cumulatively, these results reveal cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.

  View details for DOI 10.1016/j.cell.2022.11.019

  View details for PubMedID 36516855

• Performance of a fully-automated Lumipulse plasma phospho-tau181 assay for Alzheimer's disease. Alzheimer's research & therapy Wilson, E. N., Young, C. B., Ramos Benitez, J., Swarovski, M. S., Feinstein, I., Vandijck, M., Le Guen, Y., Kasireddy, N. M., Shahid, M., Corso, N. K., Wang, Q., Kennedy, G., Trelle, A. N., Lind, B., Channappa, D., Belnap, M., Ramirez, V., Skylar-Scott, I., Younes, K., Yutsis, M. V., Le Bastard, N., Quinn, J. F., van Dyck, C. H., Nairn, A., Fredericks, C. A., Tian, L., Kerchner, G. A., Montine, T. J., Sha, S. J., Davidzon, G., Henderson, V. W., Longo, F. M., Greicius, M. D., Wagner, A. D., Wyss-Coray, T., Poston, K. L., Mormino, E. C., Andreasson, K. I. 2022; 14 (1): 172

  Abstract

  BACKGROUND: The recent promise of disease-modifying therapies for Alzheimer's disease (AD) has reinforced the need for accurate biomarkers for early disease detection, diagnosis and treatment monitoring. Advances in the development of novel blood-based biomarkers for AD have revealed that plasma levels of tau phosphorylated at various residues are specific and sensitive to AD dementia. However, the currently available tests have shortcomings in access, throughput, and scalability that limit widespread implementation.METHODS: We evaluated the diagnostic and prognostic performance of a high-throughput and fully-automated Lumipulse plasma p-tau181 assay for the detection of AD. Plasma from older clinically unimpaired individuals (CU, n = 463) and patients with mild cognitive impairment (MCI, n = 107) or AD dementia (n = 78) were obtained from the longitudinal Stanford University Alzheimer's Disease Research Center (ADRC) and the Stanford Aging and Memory Study (SAMS) cohorts. We evaluated the discriminative accuracy of plasma p-tau181 for clinical AD diagnosis, association with amyloid beta peptides and p-tau181 concentrations in CSF, association with amyloid positron emission tomography (PET), and ability to predict longitudinal cognitive and functional change.RESULTS: The assay showed robust performance in differentiating AD from control participants (AUC 0.959, CI: 0.912 to 0.990), and was strongly associated with CSF p-tau181, CSF Abeta42/Abeta40 ratio, and amyloid-PET global SUVRs. Associations between plasma p-tau181 with CSF biomarkers were significant when examined separately in Abeta+ and Abeta- groups. Plasma p-tau181 significantly increased over time in CU and AD diagnostic groups. After controlling for clinical diagnosis, age, sex, and education, baseline plasma p-tau181 predicted change in MoCA overall and change in CDR Sum of Boxes in the AD group over follow-up of up to 5 years.CONCLUSIONS: This fully-automated and available blood-based biomarker assay therefore may be useful for early detection, diagnosis, prognosis, and treatment monitoring of AD.

  View details for DOI 10.1186/s13195-022-01116-2

  View details for PubMedID 36371232

• Thalamic nuclei atrophy at high and heterogenous rates during cognitively unimpaired human aging. NeuroImage Choi, E. Y., Tian, L., Su, J. H., Radovan, M. T., Tourdias, T., Tran, T. T., Trelle, A. N., Mormino, E., Wagner, A. D., Rutt, B. K. 2022: 119584

  Abstract

  The thalamus is a central integration structure in the brain, receiving and distributing information among the cerebral cortex, subcortical structures, and the peripheral nervous system. Prior studies clearly show that the thalamus atrophies in cognitively unimpaired aging. However, the thalamus is comprised of multiple nuclei involved in a wide range of functions, and the age-related atrophy of individual thalamic nuclei remains unknown. Using a recently developed automated method of identifying thalamic nuclei (3T or 7T MRI with white-matter-nulled MPRAGE contrast and THOMAS segmentation) and a cross-sectional design, we evaluated the age-related atrophy rate for 10 thalamic nuclei (AV, CM, VA, VLA, VLP, VPL, pulvinar, LGN, MGN, MD) and an epithalamic nucleus (habenula). We also used T1-weighted images with the FreeSurfer SAMSEG segmentation method to identify and measure age-related atrophy for 11 extra-thalamic structures (cerebral cortex, cerebral white matter, cerebellar cortex, cerebellar white matter, amygdala, hippocampus, caudate, putamen, nucleus accumbens, pallidum, and lateral ventricle). In 198 cognitively unimpaired participants with ages spanning 20-88 years, we found that the whole thalamus atrophied at a rate of 0.45% per year, and that thalamic nuclei had widely varying age-related atrophy rates, ranging from 0.06% to 1.18% per year. A functional grouping analysis revealed that the thalamic nuclei involved in cognitive (AV, MD; 0.53% atrophy per year), visual (LGN, pulvinar; 0.62% atrophy per year), and auditory/vestibular (MGN; 0.64% atrophy per year) functions atrophied at significantly higher rates than those involved in motor (VA, VLA, VLP, and CM; 0.37% atrophy per year) and somatosensory (VPL; 0.32% atrophy per year) functions. A proximity-to-CSF analysis showed that the group of thalamic nuclei situated immediately adjacent to CSF atrophied at a significantly greater atrophy rate (0.59% atrophy per year) than that of the group of nuclei located farther from CSF (0.36% atrophy per year), supporting a growing hypothesis that CSF-mediated factors contribute to neurodegeneration. We did not find any significant hemispheric differences in these rates of change for thalamic nuclei. Only the CM thalamic nucleus showed a sex-specific difference in atrophy rates, atrophying at a greater rate in male versus female participants. Roughly half of the thalamic nuclei showed greater atrophy than all extra-thalamic structures examined (0% to 0.54% per year). These results show the value of white-matter-nulled MPRAGE imaging and THOMAS segmentation for measuring distinct thalamic nuclei and for characterizing the high and heterogeneous atrophy rates of the thalamus and its nuclei across the adult lifespan. Collectively, these methods and results advance our understanding of the role of thalamic substructures in neurocognitive and disease-related changes that occur with aging.

  View details for DOI 10.1016/j.neuroimage.2022.119584

  View details for PubMedID 36007822

• Encoding Contexts Are Incidentally Reinstated During Competitive Retrieval and Track the Temporal Dynamics of Memory Interference. Cerebral cortex (New York, N.Y. : 1991) Bramao, I., Jiang, J., Wagner, A. D., Johansson, M. 1800

  Abstract

  The ability to remember an episode from our past is often hindered by competition from similar events. For example, if we want to remember the article a colleague recommended during the last lab meeting, we may need to resolve interference from other article recommendations from the same colleague. This study investigates if the contextual features specifying the encoding episodes are incidentally reinstated during competitive memory retrieval. Competition between memories was created through the AB/AC interference paradigm. Individual word-pairs were presented embedded in a slowly drifting real-word-like context. Multivariate pattern analysis (MVPA) of high temporal-resolution electroencephalographic (EEG) data was used to investigate context reactivation during memory retrieval. Behaviorally, we observed proactive (but not retroactive) interference; that is, performance for AC competitive retrieval was worse compared with a control DE noncompetitive retrieval, whereas AB retrieval did not suffer from competition. Neurally, proactive interference was accompanied by an early reinstatement of the competitor context and interference resolution was associated with the ensuing reinstatement of the target context. Together, these findings provide novel evidence showing that the encoding contexts of competing discrete events are incidentally reinstated during competitive retrieval and that such reinstatement tracks retrieval competition and subsequent interference resolution.

  View details for DOI 10.1093/cercor/bhab529

  View details for PubMedID 35106538

• Association of CSF Biomarkers with Hippocampal-dependent Memory in Preclinical Alzheimer Disease. Neurology Trelle, A. N., Carr, V. A., Wilson, E. N., Swarovski, M. S., Hunt, M. P., Toueg, T. N., Tran, T. T., Channappa, D. n., Corso, N. K., Thieu, M. K., Jayakumar, M. n., Nadiadwala, A. n., Guo, W. n., Tanner, N. J., Bernstein, J. D., Litovsky, C. P., Guerin, S. A., Khazenzon, A. M., Harrison, M. B., Rutt, B. K., Deutsch, G. K., Chin, F. T., Davidzon, G. A., Hall, J. N., Sha, S. J., Fredericks, C. A., Andreasson, K. I., Kerchner, G. A., Wagner, A. D., Mormino, E. C. 2021

  Abstract

  To determine if memory tasks with demonstrated sensitivity to hippocampal function can detect variance related to preclinical Alzheimer's disease (AD) biomarkers, we examined associations between performance in three memory tasks and CSF Aβ42/Aβ40 and p-tau181 in cognitively unimpaired older adults (CU).CU enrolled in the Stanford Aging and Memory Study (N=153; age 68.78 ± 5.81 yrs; 94 female) completed a lumbar puncture and memory assessments. CSF Aβ42, Aβ40, and phosopho-tau181 (p-tau181) were measured with the automated Lumipulse G system in a single-batch analysis. Episodic memory was assayed using a standardized delayed recall composite, paired associate (word-picture) cued recall, and a mnemonic discrimination task that involves discrimination between studied 'target' objects, novel 'foil' objects, and perceptually similar 'lure' objects. Analyses examined cross-sectional relationships between memory performance, age, and CSF measures, controlling for sex and education.Age and lower Aβ42/Aβ40 were independently associated with elevated p-tau181. Age, Aβ42/Aβ40, and p-tau181 were each associated with a) poorer associative memory and b) diminished improvement in mnemonic discrimination performance across levels of decreased task difficulty (i.e., target-lure similarity). P-tau mediated the effect of Aβ42/Aβ40 on memory. Relationships between CSF proteins and delayed recall were similar but non-significant. CSF Aβ42 was not significantly associated with p-tau181 or memory.Tests designed to tax hippocampal function are sensitive to subtle individual differences in memory among CU, and correlate with early AD-associated biomarker changes in CSF. These tests may offer utility for identifying cognitively unimpaired older adults with preclinical AD pathology.

  View details for DOI 10.1212/WNL.0000000000011477

  View details for PubMedID 33408146

• Visual Read Protocols for Clinicians Analyzing 18F-PI-2620 tau PET/MRI Images Koran, M., Shams, S., Adams, P., Toueg, T., Azevedo, C., Hall, J., Corso, N., Sha, S., Fredericks, C., Greicius, M., Wagner, A., Zaharchuk, G., Davidzon, G., Chin, F., Mormino, E. SOC NUCLEAR MEDICINE INC. 2020

  View details for Web of Science ID 000568290501466

• Temporal Dynamics of Memory-guided Cognitive Control and Generalization of Control via Overlapping Associative Memories. The Journal of neuroscience : the official journal of the Society for Neuroscience Jiang, J., Bramao, I., Khazenzon, A., Wang, S., Johansson, M., Wagner, A. D. 2020

  Abstract

  Goal-directed behavior can benefit from proactive adjustments of cognitive control that occur in anticipation of forthcoming cognitive control demands (CCD). Predictions of forthcoming CCD are thought to depend on learning and memory in two ways: First, through direct experience, associative encoding may link previously experienced CCD to its triggering item, such that subsequent encounters with the item serve to cue retrieval of (i.e., predict) the associated CCD. Second, in the absence of direct experience, pattern completion and mnemonic integration mechanisms may allow CCD to be generalized from its associated item to other items related in memory. While extant behavioral evidence documents both types of CCD prediction, the neurocognitive mechanisms giving rise to these predictions remain largely unexplored. Here, we tested two hypotheses: (1) memory-guided predictions about CCD precede control adjustments due to the actual CCD required to perform, and (2) generalization of CCD can be accomplished through integration mechanisms that link partially overlapping CCD-item and item-item associations in memory. Supporting these hypotheses, the temporal dynamics of theta and alpha power in human electroencephalography data (n=43, 26 females) revealed that an associative CCD effect emerges earlier than interaction effects involving actual CCD. Furthermore, generalization of CCD from one item (X) to another item (Y) was predicted by a decrease in alpha power following the presentation of the X-Y pair. These findings advance understanding of the mechanisms underlying memory-guided adjustments of cognitive control.SIGNIFICANCE STATEMENTCognitive control adaptively regulates information processing to align with task goals. Experience-based expectations enable adjustments of control, leading to improved performance when expectations match the actual control demand required. Using EEG, we demonstrate that memory for past cognitive control demand proactively guides the allocation of cognitive control, preceding adjustments of control triggered by the demands of the present environment. Furthermore, we demonstrate that learned cognitive control demands can be generalized through mnemonic integration processes, enabling the spread of expectations about cognitive control demands to items associated in memory. We reveal that this generalization is linked to decreased alpha oscillation in medial frontal channels. Collectively, these findings provide new insights into how memory-control interactions facilitate goal-directed behavior.

  View details for DOI 10.1523/JNEUROSCI.1869-19.2020

  View details for PubMedID 32019830

• Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease. Nature Gate, D., Saligrama, N., Leventhal, O., Yang, A. C., Unger, M. S., Middeldorp, J., Chen, K., Lehallier, B., Channappa, D., De Los Santos, M. B., McBride, A., Pluvinage, J., Elahi, F., Tam, G. K., Kim, Y., Greicius, M., Wagner, A. D., Aigner, L., Galasko, D. R., Davis, M. M., Wyss-Coray, T. 2020

  Abstract

  Alzheimer's disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function1. However, little is known about the contribution of the adaptive immune response in Alzheimer's disease2. Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer's disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer's disease that consists of increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. In a second cohort, we found that CD8+ TEMRA cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8+ TEMRA cells in the cerebrospinal fluid of patients with Alzheimer's disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer's disease to two separate Epstein-Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer's disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.

  View details for DOI 10.1038/s41586-019-1895-7

  View details for PubMedID 31915375

• Tau PET imaging with 18F-PI-2620 in aging and neurodegenerative diseases. European journal of nuclear medicine and molecular imaging Mormino, E. C., Toueg, T. N., Azevedo, C. n., Castillo, J. B., Guo, W. n., Nadiadwala, A. n., Corso, N. K., Hall, J. N., Fan, A. n., Trelle, A. N., Harrison, M. B., Hunt, M. P., Sha, S. J., Deutsch, G. n., James, M. n., Fredericks, C. A., Koran, M. E., Zeineh, M. n., Poston, K. n., Greicius, M. D., Khalighi, M. n., Davidzon, G. A., Shen, B. n., Zaharchuk, G. n., Wagner, A. D., Chin, F. T. 2020

  Abstract

  In vivo measurement of the spatial distribution of neurofibrillary tangle pathology is critical for early diagnosis and disease monitoring of Alzheimer's disease (AD).Forty-nine participants were scanned with 18F-PI-2620 PET to examine the distribution of this novel PET ligand throughout the course of AD: 36 older healthy controls (HC) (age range 61 to 86), 11 beta-amyloid+ (Aβ+) participants with cognitive impairment (CI; clinical diagnosis of either mild cognitive impairment or AD dementia, age range 57 to 86), and 2 participants with semantic variant primary progressive aphasia (svPPA, age 66 and 78). Group differences in brain regions relevant in AD (medial temporal lobe, posterior cingulate cortex, and lateral parietal cortex) were examined using standardized uptake value ratios (SUVRs) normalized to the inferior gray matter of the cerebellum.SUVRs in target regions were relatively stable 60 to 90 min post-injection, with the exception of very high binders who continued to show increases over time. Robust elevations in 18F-PI-2620 were observed between HC and Aβ+ CI across all AD regions. Within the HC group, older age was associated with subtle elevations in target regions. Mildly elevated focal uptake was observed in the anterior temporal pole in one svPPA patient.Preliminary results suggest strong differences in the medial temporal lobe and cortical regions known to be impacted in AD using 18F-PI-2620 in patients along the AD trajectory. This work confirms that 18F-PI-2620 holds promise as a tool to visualize tau aggregations in AD.

  View details for DOI 10.1007/s00259-020-04923-7

  View details for PubMedID 32572562

• Content tuning in the medial temporal lobe cortex: Voxels that perceive, retrieve. eNeuro Schultz, H., Tibon, R., LaRocque, K. F., Gagnon, S. A., Wagner, A. D., Staresina, B. P. 2019

  Abstract

  How do we recall vivid details from our past based only on sparse cues? Research suggests that the phenomenological reinstatement of past experiences is accompanied by neural reinstatement of the original percept. This process critically depends on the medial temporal lobe (MTL). Within the MTL, perirhinal cortex (PRC) and parahippocampal cortex (PHC) are thought to support encoding and recall of objects and scenes, respectively, with the hippocampus (HC) serving as a content-independent hub. If the fidelity of recall indeed arises from neural reinstatement of perceptual activity, then successful recall should preferentially draw upon those neural populations within content-sensitive MTL cortex that are tuned to the same content during perception. We tested this hypothesis by having eighteen human participants undergo functional magnetic resonance imaging (fMRI) while they encoded and recalled objects and scenes paired with words. Critically, recall was cued with the words only. While HC distinguished successful from unsuccessful recall of both objects and scenes, PRC and PHC were preferentially engaged during successful vs. unsuccessful object and scene recall, respectively. Importantly, within PRC and PHC, this content-sensitive recall was predicted by content tuning during perception: Across PRC voxels, we observed a positive relationship between object tuning during perception and successful object recall, while across PHC voxels, we observed a positive relationship between scene tuning during perception and successful scene recall. Our results thus highlight content-based roles of MTL cortical regions for episodic memory and reveal a direct mapping between content-specific tuning during perception and successful recall.Significance Statement Episodic memory, our ability to encode and later recall experiences, involves neural overlap between perceptual and recall activity. Research has shown that this phenomenon depends on the medial temporal lobe (MTL). Within MTL, perirhinal (PRC) and parahippocampal cortex (PHC) are engaged during encoding and recall of objects and scenes, respectively, linked by content-independent hippocampus (HC). Here, we find that within MTL cortex, content tuning during perception predicts successful recall of that content: We observe a positive relationship between object tuning and object recall across PRC voxels, and between scene tuning and scene recall across PHC voxels. These results highlight the role of stimulus content for understanding MTL, and demonstrate a clear mapping between content tuning and content recall.

  View details for DOI 10.1523/ENEURO.0291-19.2019

  View details for PubMedID 31451605

• Hippocampal CA1 subfield predicts episodic memory impairment in Parkinson's disease. NeuroImage. Clinical La, C. n., Linortner, P. n., Bernstein, J. D., Ua Cruadhlaoich, M. A., Fenesy, M. n., Deutsch, G. K., Rutt, B. K., Tian, L. n., Wagner, A. D., Zeineh, M. n., Kerchner, G. A., Poston, K. L. 2019; 23: 101824

  Abstract

  Parkinson's disease (PD) episodic memory impairments are common; however, it is not known whether these impairments are due to hippocampal pathology. Hippocampal Lewy-bodies emerge by Braak stage 4, but are not uniformly distributed. For instance, hippocampal CA1 Lewy-body pathology has been specifically associated with pre-mortem episodic memory performance in demented patients. By contrast, the dentate gyrus (DG) is relatively free of Lewy-body pathology. In this study, we used ultra-high field 7-Tesla to measure hippocampal subfields in vivo and determine if these measures predict episodic memory impairment in PD during life.We studied 29 participants with PD (age 65.5 ± 7.8 years; disease duration 4.5 ± 3.0 years) and 8 matched-healthy controls (age 67.9 ± 6.8 years), who completed comprehensive neuropsychological testing and MRI. With 7-Tesla MRI, we used validated segmentation techniques to estimate CA1 stratum pyramidale (CA1-SP) and stratum radiatum lacunosum moleculare (CA1-SRLM) thickness, dentate gyrus/CA3 (DG/CA3) area, and whole hippocampus area. We used linear regression, which included imaging and clinical measures (age, duration, education, gender, and CSF), to determine the best predictors of episodic memory impairment in PD.In our cohort, 62.1% of participants with PD had normal cognition, 27.6% had mild cognitive impairment, and 10.3% had dementia. Using 7-Tesla MRI, we found that smaller CA1-SP thickness was significantly associated with poorer immediate memory, delayed memory, and delayed cued memory; by contrast, whole hippocampus area, DG/CA3 area, and CA1-SRLM thickness did not significantly predict memory. Age-adjusted linear regression models revealed that CA1-SP predicted immediate memory (beta[standard error]10.895[4.215], p < .05), delayed memory (12.740[5.014], p < .05), and delayed cued memory (12.801[3.991], p < .05). In the fully-adjusted models, which included all five clinical measures as covariates, only CA1-SP remained a significant predictor of delayed cued memory (13.436[4.651], p < .05).In PD, we found hippocampal CA1-SP subfield thickness estimated on 7-Tesla MRI scans was the best predictor of episodic memory impairment, even when controlling for confounding clinical measures. Our results imply that ultra-high field imaging could be a sensitive measure to identify changes in hippocampal subfields and thus probe the neuroanatomical underpinnings of episodic memory impairments in patients with PD.

  View details for PubMedID 31054380

• Hippocampal CA1 subfield predicts episodic memory impairment in Parkinson's disease NEUROIMAGE-CLINICAL La, C., Linortner, P., Bernstein, J. D., Cruadhlaoich, M., Fenesy, M., Deutsch, G. K., Rutt, B. K., Tian, L., Wagner, A. D., Zeineh, M., Kerchner, G. A., Poston, K. L. 2019; 23

  View details for DOI 10.1016/j.nicl.2019.101824

  View details for Web of Science ID 000485804400029

• Learned Spatial Schemas and Prospective Hippocampal Activity Support Navigation After One-Shot Learning FRONTIERS IN HUMAN NEUROSCIENCE van Kesteren, M. R., Brown, T. I., Wagner, A. D. 2018; 12

  View details for DOI 10.3389/fnhum.2018.00486

  View details for Web of Science ID 000452123600001

• Learned Spatial Schemas and Prospective Hippocampal Activity Support Navigation After One-Shot Learning. Frontiers in human neuroscience van Kesteren, M. T., Brown, T. I., Wagner, A. D. 2018; 12: 486

  Abstract

  Prior knowledge structures (or schemas) confer multiple behavioral benefits. First, when we encounter information that fits with prior knowledge structures, this information is generally better learned and remembered. Second, prior knowledge can support prospective planning. In humans, memory enhancements related to prior knowledge have been suggested to be supported, in part, by computations in prefrontal and medial temporal lobe (MTL) cortex. Moreover, animal studies further implicate a role for the hippocampus in schema-based facilitation and in the emergence of prospective planning signals following new learning. To date, convergence across the schema-enhanced learning and memory literature may be constrained by the predominant use of hippocampally dependent spatial navigation paradigms in rodents, and non-spatial list-based learning paradigms in humans. Here, we targeted this missing link by examining the effects of prior knowledge on human navigational learning in a hippocampally dependent virtual navigation paradigm that closely relates to foundational studies in rodents. Outside the scanner, participants overlearned Old Paired Associates (OPA- item-location associations) in multiple spatial environments, and they subsequently learned New Paired Associates (NPA-new item-location associations) in the environments while undergoing fMRI. We hypothesized that greater OPA knowledge precision would positively affect NPA learning, and that the hippocampus would be instrumental in translating this new learning into prospective planning of navigational paths to NPA locations. Behavioral results revealed that OPA knowledge predicted one-shot learning of NPA locations, and neural results indicated that one-shot learning was predicted by the rapid emergence of performance-predictive prospective planning signals in hippocampus. Prospective memory relationships were not significant in parahippocampal cortex and were marginally dissociable from the primary hippocampal effect. Collectively, these results extend understanding of how schemas impact learning and performance, showing that the precision of prior spatial knowledge is important for future learning in humans, and that the hippocampus is involved in translating this knowledge into new goal-directed behaviors.

  View details for DOI 10.3389/fnhum.2018.00486

  View details for PubMedID 30564110

  View details for PubMedCentralID PMC6288548

• Integrated externally and internally generated task predictions Jointly guide cognitive control in prefrontal cortex. eLife Jiang, J., Wagner, A. D., Egner, T. 2018; 7

  Abstract

  Cognitive control proactively configures information processing to suit expected task demands. Predictions of forthcoming demand can be driven by explicit external cues or be generated internally, based on past experience (cognitive history). However, it is not known whether and how the brain reconciles these two sources of information to guide control. Pairing a probabilistic task-switching paradigm with computational modeling, we found that external and internally generated predictions jointly guide task preparation, with a bias for internal predictions. Using model-based neuroimaging, we then show that the two sources of task prediction are integrated in dorsolateral prefrontal cortex, and jointly inform a representation of the likelihood of a change in task demand, encoded in frontoparietal cortex. Upon task-stimulus onset, dorsomedial prefrontal cortex encoded the need for reactive task-set adjustment. These data reveal how the human brain integrates external cues and cognitive history to prepare for an upcoming task.

  View details for PubMedID 30113310

• Stress Impairs Episodic Retrieval by Disrupting Hippocampal and Cortical Mechanisms of Remembering. Cerebral cortex (New York, N.Y. : 1991) Gagnon, S. A., Waskom, M. L., Brown, T. I., Wagner, A. D. 2018

  Abstract

  Despite decades of science investigating the neural underpinnings of episodic memory retrieval, a critical question remains: how does stress influence remembering and the neural mechanisms of recollection in humans? Here, we used functional magnetic resonance imaging and multivariate pattern analyses to examine the effects of acute stress during retrieval. We report that stress reduced the probability of recollecting the details of past experience, and that this impairment was driven, in part, by a disruption of the relationship between hippocampal activation, cortical reinstatement, and memory performance. Moreover, even memories expressed with high confidence were less accurate under stress, and this stress-induced decline in accuracy was explained by reduced posterior hippocampal engagement despite similar levels of category-level cortical reinstatement. Finally, stress degraded the relationship between the engagement of frontoparietal control networks and retrieval decision uncertainty. Collectively, these findings demonstrate the widespread consequences of acute stress on the neural systems of remembering.

  View details for PubMedID 30060134

• Differential Medial Temporal Lobe and Parietal Cortical Contributions to Real-world Autobiographical Episodic and Autobiographical Semantic Memory SCIENTIFIC REPORTS Brown, T. I., Rissman, J., Chow, T. E., Uncapher, M. R., Wagner, A. D. 2018; 8: 6190

  Abstract

  Autobiographical remembering can depend on two forms of memory: episodic (event) memory and autobiographical semantic memory (remembering personally relevant semantic knowledge, independent of recalling a specific experience). There is debate about the degree to which the neural signals that support episodic recollection relate to or build upon autobiographical semantic remembering. Pooling data from two fMRI studies of memory for real-world personal events, we investigated whether medial temporal lobe (MTL) and parietal subregions contribute to autobiographical episodic and semantic remembering. During scanning, participants made memory judgments about photograph sequences depicting past events from their life or from others' lives, and indicated whether memory was based on episodic or semantic knowledge. Results revealed several distinct functional patterns: activity in most MTL subregions was selectively associated with autobiographical episodic memory; the hippocampal tail, superior parietal lobule, and intraparietal sulcus were similarly engaged when memory was based on retrieval of an autobiographical episode or autobiographical semantic knowledge; and angular gyrus demonstrated a graded pattern, with activity declining from autobiographical recollection to autobiographical semantic remembering to correct rejections of novel events. Collectively, our data offer insights into MTL and parietal cortex functional organization, and elucidate circuitry that supports different forms of real-world autobiographical memory.

  View details for PubMedID 29670138

• Memory, Numbers, and Action Decision in Human Posterior Parietal Cortex NEURON Parvizi, J., Wagner, A. D. 2018; 97 (1): 7–10

  Abstract

  Human lateral PPC demonstrates rich, functional heterogeneity across its subregions, including during mnemonic and numerical decision tasks. In this issue of Neuron, Rutishauser et al. (2018) report striking local heterogeneity within a small patch of anterior IPS at the neuronal level during memory-based decisions.

  View details for PubMedID 29301107

• Media Multitasking and Cognitive, Psychological, Neural, and Learning Differences PEDIATRICS Uncapher, M. R., Lin, L., Rosen, L. D., Kirkorian, H. L., Baron, N. S., Bailey, K., Cantor, J., Strayer, D. L., Parsons, T. D., Wagner, A. D. 2017; 140: S62–S66

  Abstract

  American youth spend more time with media than any other waking activity: an average of 7.5 hours per day, every day. On average, 29% of that time is spent juggling multiple media streams simultaneously (ie, media multitasking). This phenomenon is not limited to American youth but is paralleled across the globe. Given that a large number of media multitaskers (MMTs) are children and young adults whose brains are still developing, there is great urgency to understand the neurocognitive profiles of MMTs. It is critical to understand the relation between the relevant cognitive domains and underlying neural structure and function. Of equal importance is understanding the types of information processing that are necessary in 21st century learning environments. The present review surveys the growing body of evidence demonstrating that heavy MMTs show differences in cognition (eg, poorer memory), psychosocial behavior (eg, increased impulsivity), and neural structure (eg, reduced volume in anterior cingulate cortex). Furthermore, research indicates that multitasking with media during learning (in class or at home) can negatively affect academic outcomes. Until the direction of causality is understood (whether media multitasking causes such behavioral and neural differences or whether individuals with such differences tend to multitask with media more often), the data suggest that engagement with concurrent media streams should be thoughtfully considered. Findings from such research promise to inform policy and practice on an increasingly urgent societal issue while significantly advancing our understanding of the intersections between cognitive, psychosocial, neural, and academic factors.

  View details for PubMedID 29093034

  View details for PubMedCentralID PMC5658797

• Neural Correlates of Impaired Removal of Negative Information From Working Memory are Associated With Rumination and Reappraisal in Individuals Diagnosed With Major Depressive Disorder Davis, E., Uncapher, M., Camacho, M., Sacchet, M., Wagner, A., Gotlib, I. NATURE PUBLISHING GROUP. 2017: S562–S563

  View details for Web of Science ID 000416846303135

• Cognitive control, attention, and the other race effect in memory PLOS ONE Brown, T. I., Uncapher, M. R., Chow, T. E., Eberhardt, J. L., Wagner, A. D. 2017; 12 (3)

  Abstract

  People are better at remembering faces from their own race than other races-a phenomenon with significant societal implications. This Other Race Effect (ORE) in memory could arise from different attentional allocation to, and cognitive control over, same- and other-race faces during encoding. Deeper or more differentiated processing of same-race faces could yield more robust representations of same- vs. other-race faces that could support better recognition memory. Conversely, to the extent that other-race faces may be characterized by lower perceptual expertise, attention and cognitive control may be more important for successful encoding of robust, distinct representations of these stimuli. We tested a mechanistic model in which successful encoding of same- and other-race faces, indexed by subsequent memory performance, is differentially predicted by (a) engagement of frontoparietal networks subserving top-down attention and cognitive control, and (b) interactions between frontoparietal networks and fusiform cortex face processing. European American (EA) and African American (AA) participants underwent fMRI while intentionally encoding EA and AA faces, and ~24 hrs later performed an "old/new" recognition memory task. Univariate analyses revealed greater engagement of frontoparietal top-down attention and cognitive control networks during encoding for same- vs. other-race faces, stemming particularly from a failure to engage the cognitive control network during processing of other-race faces that were subsequently forgotten. Psychophysiological interaction (PPI) analyses further revealed that OREs were characterized by greater functional interaction between medial intraparietal sulcus, a component of the top-down attention network, and fusiform cortex during same- than other-race face encoding. Together, these results suggest that group-based face memory biases at least partially stem from differential allocation of cognitive control and top-down attention during encoding, such that same-race memory benefits from elevated top-down attentional engagement with face processing regions; conversely, reduced recruitment of cognitive control circuitry appears more predictive of memory failure when encoding out-group faces.

  View details for DOI 10.1371/journal.pone.0173579

  View details for Web of Science ID 000396091800053

  View details for PubMedID 28282414

• Adaptive Engagement of Cognitive Control in Context-Dependent Decision Making CEREBRAL CORTEX Waskom, M. L., Frank, M. C., Wagner, A. D. 2017; 27 (2): 1270-1284

  Abstract

  Many decisions require a context-dependent mapping from sensory evidence to action. The capacity for flexible information processing of this sort is thought to depend on a cognitive control system in frontoparietal cortex, but the costs and limitations of control entail that its engagement should be minimized. Here, we show that humans reduce demands on control by exploiting statistical structure in their environment. Using a context-dependent perceptual discrimination task and model-based analyses of behavioral and neuroimaging data, we found that predictions about task context facilitated decision making and that a quantitative measure of context prediction error accounted for graded engagement of the frontoparietal control network. Within this network, multivariate analyses further showed that context prediction error enhanced the representation of task context. These results indicate that decision making is adaptively tuned by experience to minimize costs while maintaining flexibility.

  View details for DOI 10.1093/cercor/bhv333

  View details for Web of Science ID 000397257600030

• Cognitive and neural consequences of memory suppression in major depressive disorder COGNITIVE AFFECTIVE & BEHAVIORAL NEUROSCIENCE Sacchet, M. D., Levy, B. J., Hamilton, J. P., Maksimovskiy, A., Hertel, P. T., Joormann, J., Anderson, M. C., Wagner, A. D., Gotlib, I. H. 2017; 17 (1): 77-93

  Abstract

  Negative biases in cognition have been documented consistently in major depressive disorder (MDD), including difficulties in the ability to control the processing of negative material. Although negative information-processing biases have been studied using both behavioral and neuroimaging paradigms, relatively little research has been conducted examining the difficulties of depressed persons with inhibiting the retrieval of negative information from long-term memory. In this study, we used the think/no-think paradigm and functional magnetic resonance imaging to assess the cognitive and neural consequences of memory suppression in individuals diagnosed with depression and in healthy controls. The participants showed typical behavioral forgetting effects, but contrary to our hypotheses, there were no differences between the depressed and nondepressed participants or between neutral and negative memories. Relative to controls, depressed individuals exhibited greater activity in right middle frontal gyrus during memory suppression, regardless of the valence of the suppressed stimuli, and differential activity in the amygdala and hippocampus during memory suppression involving negatively valenced stimuli. These findings indicate that depressed individuals are characterized by neural anomalies during the suppression of long-term memories, increasing our understanding of the brain bases of negative cognitive biases in MDD.

  View details for DOI 10.3758/s13415-016-0464-x

  View details for Web of Science ID 000393772800004

• Cognitive and neural consequences of memory suppression in major depressive disorder. Cognitive, affective & behavioral neuroscience Sacchet, M. D., Levy, B. J., Hamilton, J. P., Maksimovskiy, A., Hertel, P. T., Joormann, J., Anderson, M. C., Wagner, A. D., Gotlib, I. H. 2016: -?

  Abstract

  Negative biases in cognition have been documented consistently in major depressive disorder (MDD), including difficulties in the ability to control the processing of negative material. Although negative information-processing biases have been studied using both behavioral and neuroimaging paradigms, relatively little research has been conducted examining the difficulties of depressed persons with inhibiting the retrieval of negative information from long-term memory. In this study, we used the think/no-think paradigm and functional magnetic resonance imaging to assess the cognitive and neural consequences of memory suppression in individuals diagnosed with depression and in healthy controls. The participants showed typical behavioral forgetting effects, but contrary to our hypotheses, there were no differences between the depressed and nondepressed participants or between neutral and negative memories. Relative to controls, depressed individuals exhibited greater activity in right middle frontal gyrus during memory suppression, regardless of the valence of the suppressed stimuli, and differential activity in the amygdala and hippocampus during memory suppression involving negatively valenced stimuli. These findings indicate that depressed individuals are characterized by neural anomalies during the suppression of long-term memories, increasing our understanding of the brain bases of negative cognitive biases in MDD.

  View details for PubMedID 27649971

• Knowledge Acquisition during Exam Preparation Improves Memory and Modulates Memory Formation JOURNAL OF NEUROSCIENCE Brod, G., Lindenberger, U., Wagner, A. D., Shing, Y. L. 2016; 36 (31): 8103-8111

  Abstract

  According to the schema-relatedness hypothesis, new experiences that make contact with existing schematic knowledge are more easily encoded and remembered than new experiences that do not. Here we investigate how real-life gains in schematic knowledge affect the neural correlates of episodic encoding, assessing medical students 3 months before and immediately after their final exams. Human participants were scanned with functional magnetic resonance imaging while encoding associative information that varied in relatedness to medical knowledge (face-diagnosis vs face-name pairs). As predicted, improvements in memory performance over time were greater for face-diagnosis pairs (high knowledge-relevance) than for face-name pairs (low knowledge-relevance). Improved memory for face-diagnosis pairs was associated with smaller subsequent memory effects in the anterior hippocampus, along with increased functional connectivity between the anterior hippocampus and left middle temporal gyrus, a region important for the retrieval of stored conceptual knowledge. The decrease in the anterior hippocampus subsequent memory effect correlated with knowledge accumulation, as independently assessed by a web-based learning platform with which participants studied for their final exam. These findings suggest that knowledge accumulation sculpts the neural networks associated with successful memory formation, and highlight close links between knowledge acquired during studying and basic neurocognitive processes that establish durable memories.In a sample of medical students, we tracked knowledge accumulation via a web-based learning platform and investigated its effects on memory formation before and after participants' final medical exam. Knowledge accumulation led to significant gains in memory for knowledge-related events and predicted a selective decrease in hippocampal activation for successful memory formation. Furthermore, enhanced functional connectivity was found between hippocampus and semantic processing regions. These findings (1) demonstrate that knowledge facilitates binding in the hippocampus by enhancing its communication with the association cortices, (2) highlight close links between knowledge induced in the real world and basic neurocognitive processes that establish durable memories, and (3) exemplify the utility of combining laboratory-based cognitive neuroscience research with real-world educational technology for the study of memory.

  View details for DOI 10.1523/JNEUROSCI.0045-16.2016

  View details for Web of Science ID 000382304000009

  View details for PubMedID 27488631

• Media multitasking and memory: Differences in working memory and long-term memory. Psychonomic bulletin & review Uncapher, M. R., K Thieu, M., Wagner, A. D. 2016; 23 (2): 483-490

  Abstract

  Increasing access to media in the 21st century has led to a rapid rise in the prevalence of media multitasking (simultaneous use of multiple media streams). Such behavior is associated with various cognitive differences, such as difficulty filtering distracting information and increased trait impulsivity. Given the rise in media multitasking by children, adolescents, and adults, a full understanding of the cognitive profile of media multitaskers is imperative. Here we investigated the relationship between chronic media multitasking and working memory (WM) and long-term memory (LTM) performance. Four key findings are reported (1) heavy media multitaskers (HMMs) exhibited lower WM performance, regardless of whether external distraction was present or absent; (2) lower performance on multiple WM tasks predicted lower LTM performance; (3) media multitasking-related differences in memory reflected differences in discriminability rather than decision bias; and (4) attentional impulsivity correlated with media multitasking behavior and reduced WM performance. These findings suggest that chronic media multitasking is associated with a wider attentional scope/higher attentional impulsivity, which may allow goal-irrelevant information to compete with goal-relevant information. As a consequence, heavy media multitaskers are able to hold fewer or less precise goal-relevant representations in WM. HMMs' wider attentional scope, combined with their diminished WM performance, propagates forward to yield lower LTM performance. As such, chronic media multitasking is associated with a reduced ability to draw on the past-be it very recent or more remote-to inform present behavior.

  View details for DOI 10.3758/s13423-015-0907-3

  View details for PubMedID 26223469

  View details for PubMedCentralID PMC4733435

• Decoding fMRI Signatures of Real-world Autobiographical Memory Retrieval JOURNAL OF COGNITIVE NEUROSCIENCE Rissman, J., Chow, T. E., Reggente, N., Wagner, A. D. 2016; 28 (4): 604-620

  Abstract

  Extant neuroimaging data implicate frontoparietal and medial-temporal lobe regions in episodic retrieval, and the specific pattern of activity within and across these regions is diagnostic of an individual's subjective mnemonic experience. For example, in laboratory-based paradigms, memories for recently encoded faces can be accurately decoded from single-trial fMRI patterns [Uncapher, M. R., Boyd-Meredith, J. T., Chow, T. E., Rissman, J., & Wagner, A. D. Goal-directed modulation of neural memory patterns: Implications for fMRI-based memory detection. Journal of Neuroscience, 35, 8531-8545, 2015; Rissman, J., Greely, H. T., & Wagner, A. D. Detecting individual memories through the neural decoding of memory states and past experience. Proceedings of the National Academy of Sciences, U.S.A., 107, 9849-9854, 2010]. Here, we investigated the neural patterns underlying memory for real-world autobiographical events, probed at 1- to 3-week retention intervals as well as whether distinct patterns are associated with different subjective memory states. For 3 weeks, participants (n = 16) wore digital cameras that captured photographs of their daily activities. One week later, they were scanned while making memory judgments about sequences of photos depicting events from their own lives or events captured by the cameras of others. Whole-brain multivoxel pattern analysis achieved near-perfect accuracy at distinguishing correctly recognized events from correctly rejected novel events, and decoding performance did not significantly vary with retention interval. Multivoxel pattern classifiers also differentiated recollection from familiarity and reliably decoded the subjective strength of recollection, of familiarity, or of novelty. Classification-based brain maps revealed dissociable neural signatures of these mnemonic states, with activity patterns in hippocampus, medial PFC, and ventral parietal cortex being particularly diagnostic of recollection. Finally, a classifier trained on previously acquired laboratory-based memory data achieved reliable decoding of autobiographical memory states. We discuss the implications for neuroscientific accounts of episodic retrieval and comment on the potential forensic use of fMRI for probing experiential knowledge.

  View details for DOI 10.1162/jocn_a_00920

  View details for Web of Science ID 000371600700006

  View details for PubMedID 26741803

• Adaptive Engagement of Cognitive Control in Context-Dependent Decision Making. Cerebral cortex Waskom, M. L., Frank, M. C., Wagner, A. D. 2016

  Abstract

  Many decisions require a context-dependent mapping from sensory evidence to action. The capacity for flexible information processing of this sort is thought to depend on a cognitive control system in frontoparietal cortex, but the costs and limitations of control entail that its engagement should be minimized. Here, we show that humans reduce demands on control by exploiting statistical structure in their environment. Using a context-dependent perceptual discrimination task and model-based analyses of behavioral and neuroimaging data, we found that predictions about task context facilitated decision making and that a quantitative measure of context prediction error accounted for graded engagement of the frontoparietal control network. Within this network, multivariate analyses further showed that context prediction error enhanced the representation of task context. These results indicate that decision making is adaptively tuned by experience to minimize costs while maintaining flexibility.

  View details for PubMedID 26733531

• Acute stress and episodic memory retrieval: neurobiological mechanisms and behavioral consequences YEAR IN COGNITIVE NEUROSCIENCE Gagnon, S. A., Wagner, A. D. 2016; 1369: 55-75

  Abstract

  Episodic retrieval allows people to access memories from the past to guide current thoughts and decisions. In many real-world situations, retrieval occurs under conditions of acute stress, either elicited by the retrieval task or driven by other, unrelated concerns. Memory under such conditions may be hindered, as acute stress initiates a cascade of neuromodulatory changes that can impair episodic retrieval. Here, we review emerging evidence showing that dissociable stress systems interact over time, influencing neural function. In addition to the adverse effects of stress on hippocampal-dependent retrieval, we consider how stress biases attention and prefrontal cortical function, which could further affect controlled retrieval processes. Finally, we consider recent data indicating that stress at retrieval increases activity in a network of brain regions that enable reflexive, rapid responding to upcoming threats, while transiently taking offline regions supporting flexible, goal-directed thinking. Given the ubiquity of episodic memory retrieval in everyday life, it is critical to understand the theoretical and applied implications of acute stress. The present review highlights the progress that has been made, along with important open questions.

  View details for DOI 10.1111/nyas.12996

  View details for Web of Science ID 000376588900004

  View details for PubMedID 26799371

• Interactions between Memory and New Learning: Insights from fMRI Multivoxel Pattern Analysis. Frontiers in systems neuroscience van Kesteren, M. T., Brown, T. I., Wagner, A. D. 2016; 10: 46-?

  View details for DOI 10.3389/fnsys.2016.00046

  View details for PubMedID 27303274

  View details for PubMedCentralID PMC4880566

• Electrocorticography reveals the temporal dynamics of posterior parietal cortical activity during recognition memory decisions. Proceedings of the National Academy of Sciences of the United States of America Gonzalez, A., Hutchinson, J. B., Uncapher, M. R., Chen, J., LaRocque, K. F., Foster, B. L., Rangarajan, V., Parvizi, J., Wagner, A. D. 2015; 112 (35): 11066-11071

  Abstract

  Theories of the neurobiology of episodic memory predominantly focus on the contributions of medial temporal lobe structures, based on extensive lesion, electrophysiological, and imaging evidence. Against this backdrop, functional neuroimaging data have unexpectedly implicated left posterior parietal cortex (PPC) in episodic retrieval, revealing distinct activation patterns in PPC subregions as humans make memory-related decisions. To date, theorizing about the functional contributions of PPC has been hampered by the absence of information about the temporal dynamics of PPC activity as retrieval unfolds. Here, we leveraged electrocorticography to examine the temporal profile of high gamma power (HGP) in dorsal PPC subregions as participants made old/new recognition memory decisions. A double dissociation in memory-related HGP was observed, with activity in left intraparietal sulcus (IPS) and left superior parietal lobule (SPL) differing in time and sign for recognized old items (Hits) and correctly rejected novel items (CRs). Specifically, HGP in left IPS increased for Hits 300-700 ms poststimulus onset, and decayed to baseline ∼200 ms preresponse. By contrast, HGP in left SPL increased for CRs early after stimulus onset (200-300 ms) and late in the memory decision (from 700 ms to response). These memory-related effects were unique to left PPC, as they were not observed in right PPC. Finally, memory-related HGP in left IPS and SPL was sufficiently reliable to enable brain-based decoding of the participant's memory state at the single-trial level, using multivariate pattern classification. Collectively, these data provide insights into left PPC temporal dynamics as humans make recognition memory decisions.

  View details for DOI 10.1073/pnas.1510749112

  View details for PubMedID 26283375

• Prediction strength modulates responses in human area CA1 to sequence violations JOURNAL OF NEUROPHYSIOLOGY Chen, J., Cook, P. A., Wagner, A. D. 2015; 114 (2): 1227-1238

  Abstract

  Emerging human, animal, and computational evidence suggest that, within the hippocampus, stored memories are compared with current sensory input to compute novelty, i.e., detecting when inputs deviate from expectations. Hippocampal subfield CA1 is thought to detect mismatches between past and present, and detected novelty is thought to modulate encoding processes, providing a mechanism for gating the entry of information into memory. Using high-resolution functional MRI, we examined human hippocampal subfield and medial temporal lobe cortical activation during prediction violations within a sequence of events unfolding over time. Subjects encountered sequences of four visual stimuli that were then reencountered in the same temporal order (Repeat) or a rearranged order (Violation). Prediction strength was manipulated by varying whether the sequence was initially presented once (Weak) or thrice (Strong) prior to the critical Repeat or Violation sequence. Analyses of blood oxygen level-dependent signals revealed that task-responsive voxels in anatomically defined CA1, CA23/dentate gyrus, and perirhinal cortex were more active when expectations were violated than when confirmed. Additionally, stronger prediction violations elicited greater activity than weaker violations in CA1, and CA1 contained the greatest proportion of voxels displaying this prediction violation pattern relative to other medial temporal lobe regions. Finally, a memory test with a separate group of subjects showed that subsequent recognition memory was superior for items that had appeared in prediction violation trials than in prediction confirmation trials. These findings indicate that CA1 responds to temporal order prediction violations, and that this response is modulated by prediction strength.

  View details for DOI 10.1152/jn.00149.2015

  View details for Web of Science ID 000360554100043

  View details for PubMedCentralID PMC4725111

• Prediction strength modulates responses in human area CA1 to sequence violations. Journal of neurophysiology Chen, J., Cook, P. A., Wagner, A. D. 2015; 114 (2): 1227-38

  Abstract

  Emerging human, animal, and computational evidence suggest that, within the hippocampus, stored memories are compared with current sensory input to compute novelty, i.e., detecting when inputs deviate from expectations. Hippocampal subfield CA1 is thought to detect mismatches between past and present, and detected novelty is thought to modulate encoding processes, providing a mechanism for gating the entry of information into memory. Using high-resolution functional MRI, we examined human hippocampal subfield and medial temporal lobe cortical activation during prediction violations within a sequence of events unfolding over time. Subjects encountered sequences of four visual stimuli that were then reencountered in the same temporal order (Repeat) or a rearranged order (Violation). Prediction strength was manipulated by varying whether the sequence was initially presented once (Weak) or thrice (Strong) prior to the critical Repeat or Violation sequence. Analyses of blood oxygen level-dependent signals revealed that task-responsive voxels in anatomically defined CA1, CA23/dentate gyrus, and perirhinal cortex were more active when expectations were violated than when confirmed. Additionally, stronger prediction violations elicited greater activity than weaker violations in CA1, and CA1 contained the greatest proportion of voxels displaying this prediction violation pattern relative to other medial temporal lobe regions. Finally, a memory test with a separate group of subjects showed that subsequent recognition memory was superior for items that had appeared in prediction violation trials than in prediction confirmation trials. These findings indicate that CA1 responds to temporal order prediction violations, and that this response is modulated by prediction strength.

  View details for DOI 10.1152/jn.00149.2015

  View details for PubMedID 26063773

  View details for PubMedCentralID PMC4725111

• Goal-Directed Modulation of Neural Memory Patterns: Implications for fMRI-Based Memory Detection. The Journal of neuroscience : the official journal of the Society for Neuroscience Uncapher, M. R., Boyd-Meredith, J. T., Chow, T. E., Rissman, J., Wagner, A. D. 2015; 35 (22): 8531-45

  Abstract

  Remembering a past event elicits distributed neural patterns that can be distinguished from patterns elicited when encountering novel information. These differing patterns can be decoded with relatively high diagnostic accuracy for individual memories using multivoxel pattern analysis (MVPA) of fMRI data. Brain-based memory detection--if valid and reliable--would have clear utility beyond the domain of cognitive neuroscience, in the realm of law, marketing, and beyond. However, a significant boundary condition on memory decoding validity may be the deployment of "countermeasures": strategies used to mask memory signals. Here we tested the vulnerability of fMRI-based memory detection to countermeasures, using a paradigm that bears resemblance to eyewitness identification. Participants were scanned while performing two tasks on previously studied and novel faces: (1) a standard recognition memory task; and (2) a task wherein they attempted to conceal their true memory state. Univariate analyses revealed that participants were able to strategically modulate neural responses, averaged across trials, in regions implicated in memory retrieval, including the hippocampus and angular gyrus. Moreover, regions associated with goal-directed shifts of attention and thought substitution supported memory concealment, and those associated with memory generation supported novelty concealment. Critically, whereas MVPA enabled reliable classification of memory states when participants reported memory truthfully, the ability to decode memory on individual trials was compromised, even reversing, during attempts to conceal memory. Together, these findings demonstrate that strategic goal states can be deployed to mask memory-related neural patterns and foil memory decoding technology, placing a significant boundary condition on their real-world utility.

  View details for DOI 10.1523/JNEUROSCI.5145-14.2015

  View details for PubMedID 26041920

• Goal-Directed Modulation of Neural Memory Patterns: Implications for fMRI-Based Memory Detection JOURNAL OF NEUROSCIENCE Uncapher, M. R., Boyd-Meredith, J. T., Chow, T. E., Rissman, J., Wagner, A. D. 2015; 35 (22): 8531-8545

  Abstract

  Remembering a past event elicits distributed neural patterns that can be distinguished from patterns elicited when encountering novel information. These differing patterns can be decoded with relatively high diagnostic accuracy for individual memories using multivoxel pattern analysis (MVPA) of fMRI data. Brain-based memory detection--if valid and reliable--would have clear utility beyond the domain of cognitive neuroscience, in the realm of law, marketing, and beyond. However, a significant boundary condition on memory decoding validity may be the deployment of "countermeasures": strategies used to mask memory signals. Here we tested the vulnerability of fMRI-based memory detection to countermeasures, using a paradigm that bears resemblance to eyewitness identification. Participants were scanned while performing two tasks on previously studied and novel faces: (1) a standard recognition memory task; and (2) a task wherein they attempted to conceal their true memory state. Univariate analyses revealed that participants were able to strategically modulate neural responses, averaged across trials, in regions implicated in memory retrieval, including the hippocampus and angular gyrus. Moreover, regions associated with goal-directed shifts of attention and thought substitution supported memory concealment, and those associated with memory generation supported novelty concealment. Critically, whereas MVPA enabled reliable classification of memory states when participants reported memory truthfully, the ability to decode memory on individual trials was compromised, even reversing, during attempts to conceal memory. Together, these findings demonstrate that strategic goal states can be deployed to mask memory-related neural patterns and foil memory decoding technology, placing a significant boundary condition on their real-world utility.

  View details for DOI 10.1523/JNEUROSCI.5145-14.2015

  View details for Web of Science ID 000358247900015

• Quantitative comparison of 21 protocols for labeling hippocampal subfields and parahippocampal subregions in in vivo MRI: Towards a harmonized segmentation protocol NEUROIMAGE Yushkevich, P. A., Amaral, R. S., Augustinack, J. C., Bender, A. R., Bernstein, J. D., Boccardi, M., Bocchetta, M., Burggren, A. C., Carr, V. A., Chakravarty, M. M., Chetelat, G., Daugherty, A. M., Davachi, L., Ding, S., Ekstrom, A., Geerlings, M. I., Hassan, A., Huang, Y., Iglesias, J. E., La Joie, R., Kerchner, G. A., LaRocque, K. F., Libby, L. A., Malykhin, N., Mueller, S. G., Olsen, R. K., Palombo, D. J., Parekh, M. B., Pluta, J. B., Preston, A. R., Pruessner, J. C., Ranganath, C., Raz, N., Schlichting, M. L., Schoemaker, D., Singh, S., Stark, C. E., Suthana, N., Tompary, A., Turowski, M. M., Van Leemput, K., Wagner, A. D., Wang, L., Winterburn, J. L., Wisse, L. E., Yassa, M. A., Zeineh, M. M. 2015; 111: 526-541

  Abstract

  An increasing number of human in vivo magnetic resonance imaging (MRI) studies have focused on examining the structure and function of the subfields of the hippocampal formation (the dentate gyrus, CA fields 1-3, and the subiculum) and subregions of the parahippocampal gyrus (entorhinal, perirhinal, and parahippocampal cortices). The ability to interpret the results of such studies and to relate them to each other would be improved if a common standard existed for labeling hippocampal subfields and parahippocampal subregions. Currently, research groups label different subsets of structures and use different rules, landmarks, and cues to define their anatomical extents. This paper characterizes, both qualitatively and quantitatively, the variability in the existing manual segmentation protocols for labeling hippocampal and parahippocampal substructures in MRI, with the goal of guiding subsequent work on developing a harmonized substructure segmentation protocol.MRI scans of a single healthy adult human subject were acquired both at 3 T and 7 T. Representatives from 21 research groups applied their respective manual segmentation protocols to the MRI modalities of their choice. The resulting set of 21 segmentations was analyzed in a common anatomical space to quantify similarity and identify areas of agreement.The differences between the 21 protocols include the region within which segmentation is performed, the set of anatomical labels used, and the extents of specific anatomical labels. The greatest overall disagreement among the protocols is at the CA1/subiculum boundary, and disagreement across all structures is greatest in the anterior portion of the hippocampal formation relative to the body and tail.The combined examination of the 21 protocols in the same dataset suggests possible strategies towards developing a harmonized subfield segmentation protocol and facilitates comparison between published studies.

  View details for DOI 10.1016/j.neuroimage.2015.01.004

  View details for PubMedID 25596463

• Synaptic Proteins in the Hippocampus Indicative of Increased Neuronal Activity in CA3 in Schizophrenia AMERICAN JOURNAL OF PSYCHIATRY Li, W., Ghose, S., Gleason, K., Begovic, A., Perez, J., Bartko, J., Russo, S., Wagner, A. D., Selemon, L., Tamminga, C. A. 2015; 172 (4): 373-382

  Abstract

  In schizophrenia, hippocampal perfusion is increased and declarative memory function is degraded. Based on an a priori model of hippocampal dysfunction in schizophrenic psychosis, the authors postulated molecular and cellular changes in CA3 consistent with increased NMDA receptor signaling.Postmortem hippocampal subfield tissue (CA3, CA1) from subjects with schizophrenia and nonpsychiatric comparison subjects was analyzed using Western blotting and Golgi histochemistry to examine the hypothesized outcomes.The GluN2B-containing NMDA receptors (GluN2B/GluN1) and their associated postsynaptic membrane protein PSD95 were both increased in schizophrenia in CA3 tissue, but not in CA1 tissue. Quantitative analyses of Golgi-stained hippocampal neurons showed an increase in spine density on CA3 pyramidal cell apical dendrites (stratum radiatum) and an increase in the number of thorny excrescences.The hippocampal data are consistent with increased excitatory signaling in CA3 and/or with an elevation in silent synapses in CA3, a state that may contribute to an increase in long-term potentiation in CA3 with subsequent stimulation and "unsilencing." These changes are plausibly associated with increased associational activity in CA3, with degraded declarative memory function, and with formation of false memories with psychotic content. The influence of these hyperactive hippocampal projections on targets in the limbic neocortex could contribute to components of schizophrenia manifestations in other cerebral regions.

  View details for DOI 10.1176/appi.ajp.2014.14010123

  View details for Web of Science ID 000352117600013

  View details for PubMedID 25585032

  View details for PubMedCentralID PMC4457341

• Noninvasive Functional and Anatomical Imaging of the Human Medial Temporal Lobe COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY Brown, T. I., Staresina, B. P., Wagner, A. D. 2015; 7 (4)

  Abstract

  The ability to remember life's events, and to leverage memory to guide behavior, defines who we are and is critical for everyday functioning. The neural mechanisms supporting such mnemonic experiences are multiprocess and multinetwork in nature, which creates challenges for studying them in humans and animals. Advances in noninvasive neuroimaging techniques have enabled the investigation of how specific neural structures and networks contribute to human memory at its many cognitive and mechanistic levels. In this review, we discuss how functional and anatomical imaging has provided novel insights into the types of information represented in, and the computations performed by, specific medial temporal lobe (MTL) regions, and we consider how interactions between the MTL and other cortical and subcortical structures influence what we learn and remember. By leveraging imaging, researchers have markedly advanced understanding of how the MTL subserves declarative memory and enables navigation of our physical and mental worlds.

  View details for DOI 10.1101/cshperspect.a021840

  View details for Web of Science ID 000355194500013

  View details for PubMedID 25780085

• Noninvasive functional and anatomical imaging of the human medial temporal lobe. Cold Spring Harbor perspectives in biology Brown, T. I., Staresina, B. P., Wagner, A. D. 2015; 7 (4)

  Abstract

  The ability to remember life's events, and to leverage memory to guide behavior, defines who we are and is critical for everyday functioning. The neural mechanisms supporting such mnemonic experiences are multiprocess and multinetwork in nature, which creates challenges for studying them in humans and animals. Advances in noninvasive neuroimaging techniques have enabled the investigation of how specific neural structures and networks contribute to human memory at its many cognitive and mechanistic levels. In this review, we discuss how functional and anatomical imaging has provided novel insights into the types of information represented in, and the computations performed by, specific medial temporal lobe (MTL) regions, and we consider how interactions between the MTL and other cortical and subcortical structures influence what we learn and remember. By leveraging imaging, researchers have markedly advanced understanding of how the MTL subserves declarative memory and enables navigation of our physical and mental worlds.

  View details for DOI 10.1101/cshperspect.a021840

  View details for PubMedID 25780085

• PATTERN SEPARATION DEFICIT IN SCHIZOPHRENIA: BEHAVIOUR AND IMAGING FINDINGS Das, T., Ivleva, E. I., Stark, C. L., Wagner, A. D., Tamminga, C. A. OXFORD UNIV PRESS. 2015: S221

  View details for Web of Science ID 000353548200585

• Increased functional connectivity between dorsal posterior parietal and ventral occipitotemporal cortex during uncertain memory decisions. Neurobiology of learning and memory Hutchinson, J. B., Uncapher, M. R., Wagner, A. D. 2015; 117: 71-83

  Abstract

  Retrieval of episodic memories is a multi-component act that relies on numerous operations ranging from processing the retrieval cue, evaluating retrieved information, and selecting the appropriate response given the demands of the task. Motivated by a rich functional neuroimaging literature, recent theorizing about various computations at retrieval has focused on the role of posterior parietal cortex (PPC). In a potentially promising line of research, recent neuroimaging findings suggest that different subregions of dorsal PPC respond distinctly to different aspects of retrieval decisions, suggesting that better understanding of their contributions might shed light on the component processes of retrieval. In an attempt to understand the basic operations performed by dorsal PPC, we used functional MRI and functional connectivity analyses to examine how activation in, and connectivity between, dorsal PPC and ventral temporal regions representing retrieval cues varies as a function of retrieval decision uncertainty. Specifically, participants made a five-point recognition confidence judgment for a series of old and new visually presented words. Consistent with prior studies, memory-related activity patterns dissociated across left dorsal PPC subregions, with activity in the lateral IPS tracking the degree to which participants perceived an item to be old, whereas activity in the SPL increased as a function of decision uncertainty. Importantly, whole-brain functional connectivity analyses further revealed that SPL activity was more strongly correlated with that in the visual word-form area during uncertain relative to certain decisions. These data suggest that the involvement of SPL during episodic retrieval reflects, at least in part, the processing of the retrieval cue, perhaps in service of attempts to increase the mnemonic evidence elicited by the cue.

  View details for DOI 10.1016/j.nlm.2014.04.015

  View details for PubMedID 24825621

  View details for PubMedCentralID PMC4226743

• Loss of pattern separation performance in schizophrenia suggests dentate gyrus dysfunction SCHIZOPHRENIA RESEARCH Das, T., Ivleva, E. I., Wagner, A. D., Stark, C. E., Tamminga, C. A. 2014; 159 (1): 193-197

  Abstract

  Motivated by evidence that the dentate gyrus differentially mediates the pattern separation (PS) component of declarative memory function and that dentate gyrus harbors molecular and cellular pathologies in schizophrenia, we examined whether PS performance is altered in volunteers with schizophrenia (SZV) relative to healthy volunteers (HV). In groups of well-characterized SZV (n=14) and HV (n=15), we contrasted performance on the Behavioral Pattern Separation (BPS) Task, acquiring two outcome measures, a PS parameter and a Recognition Memory (RM) parameter, as well as specific recognition data by stimulus type. The SZVs showed a significant decrement in PS performance relative to HV (mean ± SEM, SZV: 3.1 ± 2.7%; HV: 17.1 ± 5.8%; p=0.039, d'=0.86); whereas SZV and HV did not significantly differ in RM performance (SZV: 50.1 ± 8.1%; HV: 59.3 ± 5.5%; p=0.350, d'=0.36). Moreover, the SZVs showed a selective defect in correctly identifying similar lure items (SZV: 24.0 ± 3.7%; HV: 41.2 ± 4.6%; p<0.05), but demonstrated no impairment in identifying targets and novel foils. These data suggest that the dentate gyrus is dysfunctional in schizophrenia, a feature that could contribute to declarative memory impairment in the disorder and possibly to psychosis, a conclusion consistent with the considerable molecular pathology in the dentate gyrus in schizophrenia.

  View details for DOI 10.1016/j.schres.2014.05.006

  View details for Web of Science ID 000343107400032

  View details for PubMedID 25176349

  View details for PubMedCentralID PMC4177293

• What do differences between multi-voxel and univariate analysis mean? How subject-, voxel-, and trial-level variance impact fMRI analysis NEUROIMAGE Davis, T., LaRocque, K. F., Mumford, J. A., Norman, K. A., Wagner, A. D., Poldrack, R. A. 2014; 97: 271-283

  Abstract

  Multi-voxel pattern analysis (MVPA) has led to major changes in how fMRI data are analyzed and interpreted. Many studies now report both MVPA results and results from standard univariate voxel-wise analysis, often with the goal of drawing different conclusions from each. Because MVPA results can be sensitive to latent multidimensional representations and processes whereas univariate voxel-wise analysis cannot, one conclusion that is often drawn when MVPA and univariate results differ is that the activation patterns underlying MVPA results contain a multidimensional code. In the current study, we conducted simulations to formally test this assumption. Our findings reveal that MVPA tests are sensitive to the magnitude of voxel-level variability in the effect of a condition within subjects, even when the same linear relationship is coded in all voxels. We also find that MVPA is insensitive to subject-level variability in mean activation across an ROI, which is the primary variance component of interest in many standard univariate tests. Together, these results illustrate that differences between MVPA and univariate tests do not afford conclusions about the nature or dimensionality of the neural code. Instead, targeted tests of the informational content and/or dimensionality of activation patterns are critical for drawing strong conclusions about the representational codes that are indicated by significant MVPA results.

  View details for DOI 10.1016/j.neuroimage.2014.04.037

  View details for Web of Science ID 000337988700028

  View details for PubMedCentralID PMC4115449

• What do differences between multi-voxel and univariate analysis mean? How subject-, voxel-, and trial-level variance impact fMRI analysis. NeuroImage Davis, T., LaRocque, K. F., Mumford, J. A., Norman, K. A., Wagner, A. D., Poldrack, R. A. 2014; 97: 271-283

  Abstract

  Multi-voxel pattern analysis (MVPA) has led to major changes in how fMRI data are analyzed and interpreted. Many studies now report both MVPA results and results from standard univariate voxel-wise analysis, often with the goal of drawing different conclusions from each. Because MVPA results can be sensitive to latent multidimensional representations and processes whereas univariate voxel-wise analysis cannot, one conclusion that is often drawn when MVPA and univariate results differ is that the activation patterns underlying MVPA results contain a multidimensional code. In the current study, we conducted simulations to formally test this assumption. Our findings reveal that MVPA tests are sensitive to the magnitude of voxel-level variability in the effect of a condition within subjects, even when the same linear relationship is coded in all voxels. We also find that MVPA is insensitive to subject-level variability in mean activation across an ROI, which is the primary variance component of interest in many standard univariate tests. Together, these results illustrate that differences between MVPA and univariate tests do not afford conclusions about the nature or dimensionality of the neural code. Instead, targeted tests of the informational content and/or dimensionality of activation patterns are critical for drawing strong conclusions about the representational codes that are indicated by significant MVPA results.

  View details for DOI 10.1016/j.neuroimage.2014.04.037

  View details for PubMedID 24768930

• Law and neuroscience: recommendations submitted to the President's Bioethics Commission JOURNAL OF LAW AND THE BIOSCIENCES Jones, O. D., Bonnie, R. J., Casey, B. J., Davis, A., Faigman, D. L., Hoffman, M., Montague, R., Morse, S. J., Raichle, M. E., Richeson, J. A., Scott, E., Steinberg, L., Taylor-Thompson, K., Wagner, A., Yaffe, G. 2014; 1 (2): 224–27

  View details for PubMedID 27774166

• Comments of The MacArthur Foundation Research Network on Law and Neuroscience to The Presidential Commission for the Study of Bioethical Issues of the Department of Health and Human Services Comments on the Ethical Considerations of Neuroscience Research and the Application of Neuroscience Research Findings JOURNAL OF LAW AND THE BIOSCIENCES Jones, O. D., Bonnie, R. J., Casey, B. J., Davis, A., Faigman, D. L., Hoffman, M., Montague, R., Morse, S. J., Raichle, M. E., Richeson, J. A., Scott, E., Steinberg, L., Taylor-Thompson, K., Wagner, A., Yaffe, G. 2014; 1 (2): 228–36

  View details for Web of Science ID 000218521100012

• Functional MRI-based lie detection: scientific and societal challenges NATURE REVIEWS NEUROSCIENCE Farah, M. J., Hutchinson, J. B., Phelps, E. A., Wagner, A. D. 2014; 15 (2): 123-131

  Abstract

  Functional MRI (fMRI)-based lie detection has been marketed as a tool for enhancing personnel selection, strengthening national security and protecting personal reputations, and at least three US courts have been asked to admit the results of lie detection scans as evidence during trials. How well does fMRI-based lie detection perform, and how should the courts, and society more generally, respond? Here, we address various questions — some of which are based on a meta-analysis of published studies — concerning the scientific state of the art in fMRI-based lie detection and its legal status, and discuss broader ethical and societal implications. We close with three general policy recommendations.

  View details for DOI 10.1038/nrn3665

  View details for Web of Science ID 000329984700011

  View details for PubMedID 24588019

• Human hippocampal increases in low-frequency power during associative prediction violations. Neuropsychologia Chen, J., Dastjerdi, M., Foster, B. L., LaRocque, K. F., Rauschecker, A. M., Parvizi, J., Wagner, A. D. 2013; 51 (12): 2344-2351

  Abstract

  Environmental cues often trigger memories of past events (associative retrieval), and these memories are a form of prediction about imminent experience. Learning is driven by the detection of prediction violations, when the past and present diverge. Using intracranial electroencephalography (iEEG), we show that associative prediction violations elicit increased low-frequency power (in the slow-theta range) in human hippocampus, that this low-frequency power increase is modulated by whether conditions allow predictions to be generated, that the increase rapidly onsets after the moment of violation, and that changes in low-frequency power are not present in adjacent perirhinal cortex. These data suggest that associative mismatch is computed within hippocampus when cues trigger predictions that are violated by imminent experience.

  View details for DOI 10.1016/j.neuropsychologia.2013.03.019

  View details for PubMedID 23571081

• NEUROSCIENCE AND THE LAW - SCIENCE AND SOCIETY Neuroscientists in court NATURE REVIEWS NEUROSCIENCE Jones, O. D., Wagner, A. D., Faigman, D. L., Raichle, M. E. 2013; 14 (10): 730-736

  Abstract

  Neuroscientific evidence is increasingly being offered in court cases. Consequently, the legal system needs neuroscientists to act as expert witnesses who can explain the limitations and interpretations of neuroscientific findings so that judges and jurors can make informed and appropriate inferences. The growing role of neuroscientists in court means that neuroscientists should be aware of important differences between the scientific and legal fields, and, especially, how scientific facts can be easily misunderstood by non-scientists, including judges and jurors.

  View details for DOI 10.1038/nrn3585

  View details for Web of Science ID 000325195200015

• Content Representation in the Human Medial Temporal Lobe CEREBRAL CORTEX Liang, J. C., Wagner, A. D., Preston, A. R. 2013; 23 (1): 80-96

  Abstract

  Current theories of medial temporal lobe (MTL) function focus on event content as an important organizational principle that differentiates MTL subregions. Perirhinal and parahippocampal cortices may play content-specific roles in memory, whereas hippocampal processing is alternately hypothesized to be content specific or content general. Despite anatomical evidence for content-specific MTL pathways, empirical data for content-based MTL subregional dissociations are mixed. Here, we combined functional magnetic resonance imaging with multiple statistical approaches to characterize MTL subregional responses to different classes of novel event content (faces, scenes, spoken words, sounds, visual words). Univariate analyses revealed that responses to novel faces and scenes were distributed across the anterior-posterior axis of MTL cortex, with face responses distributed more anteriorly than scene responses. Moreover, multivariate pattern analyses of perirhinal and parahippocampal data revealed spatially organized representational codes for multiple content classes, including nonpreferred visual and auditory stimuli. In contrast, anterior hippocampal responses were content general, with less accurate overall pattern classification relative to MTL cortex. Finally, posterior hippocampal activation patterns consistently discriminated scenes more accurately than other forms of content. Collectively, our findings indicate differential contributions of MTL subregions to event representation via a distributed code along the anterior-posterior axis of MTL that depends on the nature of event content.

  View details for DOI 10.1093/cercor/bhr379

  View details for Web of Science ID 000312106300009

  View details for PubMedID 22275474

  View details for PubMedCentralID PMC3513952

• FMRI-BASED MEMORY AND LIE DECTION Wagner, A. MIT PRESS. 2013: 29–30

  View details for Web of Science ID 000317030500043

• Measuring Memory Reactivation With Functional MRI: Implications for Psychological Theory. Perspectives on psychological science : a journal of the Association for Psychological Science Levy, B. J., Wagner, A. D. 2013; 8 (1): 72-8

  Abstract

  Environmental cues often remind us of earlier experiences by triggering the reactivation of memories of events past. Recent evidence suggests that memory reactivation can be observed using functional MRI and that distributed pattern analyses can even provide evidence of reactivation on individual trials. The ability to measure memory reactivation offers unique and powerful leverage on theoretical issues of long-standing interest in cognitive psychology, providing a means to address questions that have proven difficult to answer with behavioral data alone. In this article, we consider three instances. First, reactivation measures can indicate whether memory-based inferences (i.e., generalization) arise through the encoding of integrated cross-event representations or through the flexible expression of separable event memories. Second, online measures of memory reactivation may inform theories of forgetting by providing information about when competing memories are reactivated during competitive retrieval situations. Finally, neural reactivation may provide a window onto the role of replay in memory consolidation. The ability to track memory reactivation, including at the individual trial level, provides unique leverage that is not afforded by behavioral measures and thus promises to shed light on such varied topics as generalization, integration, forgetting, and consolidation.

  View details for DOI 10.1177/1745691612469031

  View details for PubMedID 25484909

  View details for PubMedCentralID PMC4254794

• CROSS-FREQUENCY DYNAMICS IN HUMAN PARIETAL CORTEX DURING RECOGNITION MEMORY DECISIONS 20th Annual Meeting of the Cognitive-Neuroscience-Society Gonzalez, A., Hutchinson, J. B., Uncapher, M. R., Foster, B. L., Rangarajan, V., Parvizi, J., Wagner, A. D. MIT PRESS. 2013: 109–109

  View details for Web of Science ID 000317030500413

• Measuring Memory Reactivation With Functional MRI: Implications for Psychological Theory PERSPECTIVES ON PSYCHOLOGICAL SCIENCE Levy, B. J., Wagner, A. D. 2013; 8 (1): 72-78

  Abstract

  Environmental cues often remind us of earlier experiences by triggering the reactivation of memories of events past. Recent evidence suggests that memory reactivation can be observed using functional MRI and that distributed pattern analyses can even provide evidence of reactivation on individual trials. The ability to measure memory reactivation offers unique and powerful leverage on theoretical issues of long-standing interest in cognitive psychology, providing a means to address questions that have proven difficult to answer with behavioral data alone. In this article, we consider three instances. First, reactivation measures can indicate whether memory-based inferences (i.e., generalization) arise through the encoding of integrated cross-event representations or through the flexible expression of separable event memories. Second, online measures of memory reactivation may inform theories of forgetting by providing information about when competing memories are reactivated during competitive retrieval situations. Finally, neural reactivation may provide a window onto the role of replay in memory consolidation. The ability to track memory reactivation, including at the individual trial level, provides unique leverage that is not afforded by behavioral measures and thus promises to shed light on such varied topics as generalization, integration, forgetting, and consolidation.

  View details for DOI 10.1177/1745691612469031

  View details for Web of Science ID 000313817400009

  View details for PubMedCentralID PMC4254794

• Toward open sharing of task-based fMRI data: the OpenfMRI project FRONTIERS IN NEUROINFORMATICS Poldrack, R. A., Barch, D. M., Mitchell, J. P., Wager, T. D., Wagner, A. D., Devlin, J. T., Cumba, C., Koyejo, O., Milham, M. P. 2013; 7

  Abstract

  The large-scale sharing of task-based functional neuroimaging data has the potential to allow novel insights into the organization of mental function in the brain, but the field of neuroimaging has lagged behind other areas of bioscience in the development of data sharing resources. This paper describes the OpenFMRI project (accessible online at http://www.openfmri.org), which aims to provide the neuroimaging community with a resource to support open sharing of task-based fMRI studies. We describe the motivation behind the project, focusing particularly on how this project addresses some of the well-known challenges to sharing of task-based fMRI data. Results from a preliminary analysis of the current database are presented, which demonstrate the ability to classify between task contrasts with high generalization accuracy across subjects, and the ability to identify individual subjects from their activation maps with moderately high accuracy. Clustering analyses show that the similarity relations between statistical maps have a somewhat orderly relation to the mental functions engaged by the relevant tasks. These results highlight the potential of the project to support large-scale multivariate analyses of the relation between mental processes and brain function.

  View details for DOI 10.3389/fninf.2013.00012

  View details for Web of Science ID 000209207300011

  View details for PubMedCentralID PMC3703526

• Glutamate Dysfunction in Hippocampus: Relevance of Dentate Gyrus and CA3 Signaling SCHIZOPHRENIA BULLETIN Tamminga, C. A., Southcott, S., Sacco, C., Wagner, A. D., Ghose, S. 2012; 38 (5): 927-935

  Abstract

  Synaptic glutamate signaling in brain is highly complex and includes multiple interacting receptors, modulating cotransmitters and distinct regional dynamics. Medial temporal lobe (MTL) memory structures receive excitatory inputs from neocortical sensory and associational projections: afferents from neocortex pass to parahippocampal cortex, then to layers II/III of entorhinal cortex, and then onto hippocampal subfields. Principles of Hebbian plasticity govern synaptic encoding of memory signals, and homeostatic plasticity processes influence the activity of the memory system as a whole. Hippocampal imaging studies in schizophrenia have identified 2 alterations in MTL--increases in baseline blood perfusion and decreases in task-related activation. These observations along with converging postsynaptic hippocampal protein changes suggest that homeostatic plasticity mechanisms might be altered in schizophrenia hippocampus. If hippocampal pattern separation is diminished due to partial dentate gyrus failure (resulting in 'spurious associations') and also if pattern completion is accelerated and increasingly inaccurate due to increased CA3 associational activity, then it is conceivable that associations could be false and, especially if driven by anxiety or stress, could generate psychotic content, with the mistaken associations being laid down in memory, despite their psychotic content, especially delusions and thought disorder.

  View details for DOI 10.1093/schbul.sbs062

  View details for Web of Science ID 000309027900010

  View details for PubMedID 22532703

  View details for PubMedCentralID PMC3446225

• Hippocampal novelty activations in schizophrenia: Disease and medication effects SCHIZOPHRENIA RESEARCH Tamminga, C. A., Thomas, B. P., Chin, R., Mihalakos, P., Youens, K., Wagner, A. D., Preston, A. R. 2012; 138 (2-3): 157-163

  Abstract

  We examined hippocampal activation in schizophrenia (SZ) with fMRI BOLD in response to the presentation of novel and familiar scenes. Voxel-wise analysis showed no group differences. However, anatomical region-of-interest analyses contrasting normal (NL), SZ-on-medication (SZ-ON), SZ-off-medication (SZ-OFF) showed substantial differences in MTL-based novelty responding, accounted for by the reduction in novelty responses in the SZ-OFF predominantly in the anterior hippocampus and parahippocampal cortex. These differences in novelty-based activation in the SZ-OFF group represent disease characteristics of schizophrenia without confounding effects of antipsychotic medication and illustrate the tendency of antipsychotic drug treatment to improve memory functions in schizophrenia.

  View details for DOI 10.1016/j.schres.2012.03.019

  View details for Web of Science ID 000305279400008

  View details for PubMedID 22480957

• Multi-voxel patterns of visual category representation during episodic encoding are predictive of subsequent memory NEUROPSYCHOLOGIA Kuhl, B. A., Rissman, J., Wagner, A. D. 2012; 50 (4): 458-469

  Abstract

  Successful encoding of episodic memories is thought to depend on contributions from prefrontal and temporal lobe structures. Neural processes that contribute to successful encoding have been extensively explored through univariate analyses of neuroimaging data that compare mean activity levels elicited during the encoding of events that are subsequently remembered vs. those subsequently forgotten. Here, we applied pattern classification to fMRI data to assess the degree to which distributed patterns of activity within prefrontal and temporal lobe structures elicited during the encoding of word-image pairs were diagnostic of the visual category (Face or Scene) of the encoded image. We then assessed whether representation of category information was predictive of subsequent memory. Classification analyses indicated that temporal lobe structures contained information robustly diagnostic of visual category. Information in prefrontal cortex was less diagnostic of visual category, but was nonetheless associated with highly reliable classifier-based evidence for category representation. Critically, trials associated with greater classifier-based estimates of category representation in temporal and prefrontal regions were associated with a higher probability of subsequent remembering. Finally, consideration of trial-by-trial variance in classifier-based measures of category representation revealed positive correlations between prefrontal and temporal lobe representations, with the strength of these correlations varying as a function of the category of image being encoded. Together, these results indicate that multi-voxel representations of encoded information can provide unique insights into how visual experiences are transformed into episodic memories.

  View details for DOI 10.1016/j.neuropsychologia.2011.09.002

  View details for Web of Science ID 000301898200003

  View details for PubMedID 21925190

  View details for PubMedCentralID PMC3357999

• Dissociable Effects of Top-Down and Bottom-Up Attention during Episodic Encoding JOURNAL OF NEUROSCIENCE Uncapher, M. R., Hutchinson, J. B., Wagner, A. D. 2011; 31 (35): 12613-12628

  Abstract

  It is well established that the formation of memories for life's experiences-episodic memory-is influenced by how we attend to those experiences, yet the neural mechanisms by which attention shapes episodic encoding are still unclear. We investigated how top-down and bottom-up attention contribute to memory encoding of visual objects in humans by manipulating both types of attention during fMRI of episodic memory formation. We show that dorsal parietal cortex-specifically, intraparietal sulcus (IPS)-was engaged during top-down attention and was also recruited during the successful formation of episodic memories. By contrast, bottom-up attention engaged ventral parietal cortex-specifically, temporoparietal junction (TPJ)-and was also more active during encoding failure. Functional connectivity analyses revealed further dissociations in how top-down and bottom-up attention influenced encoding: while both IPS and TPJ influenced activity in perceptual cortices thought to represent the information being encoded (fusiform/lateral occipital cortex), they each exerted opposite effects on memory encoding. Specifically, during a preparatory period preceding stimulus presentation, a stronger drive from IPS was associated with a higher likelihood that the subsequently attended stimulus would be encoded. By contrast, during stimulus processing, stronger connectivity with TPJ was associated with a lower likelihood the stimulus would be successfully encoded. These findings suggest that during encoding of visual objects into episodic memory, top-down and bottom-up attention can have opposite influences on perceptual areas that subserve visual object representation, suggesting that one manner in which attention modulates memory is by altering the perceptual processing of to-be-encoded stimuli.

  View details for DOI 10.1523/JNEUROSCI.0152-11.2011

  View details for Web of Science ID 000294451900024

  View details for PubMedID 21880922

  View details for PubMedCentralID PMC3172893

• Associative retrieval processes in the human medial temporal lobe: Hippocampal retrieval success and CA1 mismatch detection LEARNING & MEMORY Chen, J., Olsen, R. K., Preston, A. R., Glover, G. H., Wagner, A. D. 2011; 18 (8): 523-528

  Abstract

  Hippocampal subfields CA(3) and CA(1) are hypothesized to differentially support the generation of associative predictions and the detection of associative mismatches, respectively. Using high-resolution functional MRI, we examined hippocampal subfield activation during associative retrieval and during subsequent comparisons of memory to matching or mismatching decision probes. Activity in the dentate gyrus/CA(2/3), CA(1), and other medial temporal lobe subregions tracked associative retrieval success, whereas activity in CA(1) and the perirhinal cortex tracked the presence of associative mismatches. These data support the hypothesis that CA(1) acts as a "comparator," detecting when memory for the past and sensory input in the present diverge.

  View details for DOI 10.1101/lm.2135211

  View details for Web of Science ID 000293858000004

  View details for PubMedID 21775513

  View details for PubMedCentralID PMC3256570

• Reduced hippocampal activity during encoding in cognitively normal adults carrying the APOE epsilon 4 allele NEUROPSYCHOLOGIA Adamson, M. M., Hutchinson, J. B., Shelton, A. L., Wagner, A. D., Taylor, J. L. 2011; 49 (9): 2448-2455

  Abstract

  Apolipoprotein (APOE) ɛ4-related differences in memory performance have been detected before age 65. The hippocampus and the surrounding medial temporal lobe (MTL) structures are the first site affected by Alzheimer's disease (AD) and the MTL is the seat of episodic memory, including visuo-spatial memory. While reports of APOE ɛ4-related differences in these brain structures are not consistent in either cross-sectional or longitudinal structural and functional magnetic resonance imaging (fMRI) studies, there is increasing evidence that brain activity at baseline (defined as activity during fixation or rest) may differ in APOE ɛ4 carriers compared to non-carriers. In this fMRI study, cognitively normal APOE ɛ4 carriers and non-carriers engaged in a perspective-dependent spatial learning task (Shelton & Gabrieli, 2002) previously shown to activate MTL structures in older participants (Borghesani et al., 2008). A low-level, visually engaging dot-control task was used for comparison, in addition to fixation. APOE ɛ4 carriers showed less activation than non-carriers in the hippocampus proper during encoding. Specifically, when spatial encoding was contrasted against the dot-control task, encoding-related activation was significantly lower in carriers than non-carriers. By contrast, no ɛ4-related differences in the hippocampus were found when spatial encoding was compared with fixation. Lower activation, however, was not global since encoding-related activation in early visual cortex (left lingual gyrus) was not different between APOE ɛ4 carriers and non-carriers. The present data document APOE ɛ4-related differences in the hippocampus proper during encoding and underscore the role of low-level control contrasts for complex encoding tasks. These results have implications for fMRI studies that investigate the default-mode network (DMN) in middle-aged to older APOE ɛ4 carriers to help evaluate AD risk in this otherwise cognitively normal population.

  View details for DOI 10.1016/j.neuropsychologia.2011.04.022

  View details for Web of Science ID 000293611600018

  View details for PubMedID 21549723

  View details for PubMedCentralID PMC3137687

• Expected value information improves financial risk taking across the adult life span SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE Samanez-Larkin, G. R., Wagner, A. D., Knutson, B. 2011; 6 (2): 207-217

  Abstract

  When making decisions, individuals must often compensate for cognitive limitations, particularly in the face of advanced age. Recent findings suggest that age-related variability in striatal activity may increase financial risk-taking mistakes in older adults. In two studies, we sought to further characterize neural contributions to optimal financial risk taking and to determine whether decision aids could improve financial risk taking. In Study 1, neuroimaging analyses revealed that individuals whose mesolimbic activation correlated with the expected value estimates of a rational actor made more optimal financial decisions. In Study 2, presentation of expected value information improved decision making in both younger and older adults, but the addition of a distracting secondary task had little impact on decision quality. Remarkably, provision of expected value information improved the performance of older adults to match that of younger adults at baseline. These findings are consistent with the notion that mesolimbic circuits play a critical role in optimal choice, and imply that providing simplified information about expected value may improve financial risk taking across the adult life span.

  View details for DOI 10.1093/scan/nsq043

  View details for Web of Science ID 000291543100006

  View details for PubMedID 20501485

  View details for PubMedCentralID PMC3073388

• High-resolution fMRI Reveals Match Enhancement and Attentional Modulation in the Human Medial Temporal Lobe JOURNAL OF COGNITIVE NEUROSCIENCE Dudukovic, N. M., Preston, A. R., Archie, J. J., Glover, G. H., Wagner, A. D. 2011; 23 (3): 670-682

  Abstract

  A primary function of the medial temporal lobe (MTL) is to signal prior encounter with behaviorally relevant stimuli. MTL match enhancement--increased activation when viewing previously encountered stimuli--has been observed for goal-relevant stimuli in nonhuman primates during delayed-match-to-sample tasks and in humans during more complex relational memory tasks. Match enhancement may alternatively reflect (a) an attentional response to familiar relative to novel stimuli or (b) the retrieval of contextual details surrounding the past encounter with familiar stimuli. To gain leverage on the functional significance of match enhancement in the hippocampus, high-resolution fMRI of human MTL was conducted while participants attended, ignored, or passively viewed face and scene stimuli in the context of a modified delayed-match-to-sample task. On each "attended" trial, two goal-relevant stimuli were encountered before a probe that either matched or mismatched one of the attended stimuli, enabling examination of the consequences of encountering one of the goal-relevant stimuli as a match probe on later memory for the other (nonprobed) goal-relevant stimulus. fMRI revealed that the hippocampus was insensitive to the attentional manipulation, whereas parahippocampal cortex was modulated by scene-directed attention, and perirhinal cortex showed more subtle and general effects of attention. By contrast, all hippocampal subfields demonstrated match enhancement to the probe, and a postscan test revealed more accurate recognition memory for the nonprobed goal-relevant stimulus on match relative to mismatch trials. These data suggest that match enhancement in human hippocampus reflects retrieval of other goal-relevant contextual details surrounding a stimulus's prior encounter.

  View details for Web of Science ID 000285160700014

  View details for PubMedID 20433244

• CA3 SUBFIELD-SPECIFIC INCREASES IN RCBV IN SCHIZOPHRENIA WHICH CORRELATE WITH PSYCHOSIS 13th International Congress on Schizophrenia Research (ICSR) Sacco, C., Fang, Y., Mihalakos, P., Uh, J., Lu, H., Wagner, A., Tamminga, C. OXFORD UNIV PRESS. 2011: 151–151

  View details for Web of Science ID 000287746000428

• HIPPOCAMPAL-DEPENDENT MEMORY IN TREATED AND UNTREATED SCHIZOPHRENIA 13th International Congress on Schizophrenia Research (ICSR) Mihalakos, P., Thomas, B., Fang, Y., Preston, A., Shohamy, D., Chen, J., Wagner, A., Tamminga, C. A. OXFORD UNIV PRESS. 2011: 221–222

  View details for Web of Science ID 000287746000626

• Cognitive control and right ventrolateral prefrontal cortex: reflexive reorienting, motor inhibition, and action updating YEAR IN COGNITIVE NEUROSCIENCE Levy, B. J., Wagner, A. D. 2011; 1224: 40-62

  Abstract

  Delineating the functional organization of the prefrontal cortex is central to advancing models of goal-directed cognition. Considerable evidence indicates that specific forms of cognitive control are associated with distinct subregions of the left ventrolateral prefrontal cortex (VLPFC), but less is known about functional specialization within the right VLPFC. We report a functional MRI meta-analysis of two prominent theories of right VLPFC function: stopping of motor responses and reflexive orienting to abrupt perceptual onsets. Along with a broader review of right VLPFC function, extant data indicate that stopping and reflexive orienting similarly recruit the inferior frontal junction (IFJ), suggesting that IFJ supports the detection of behaviorally relevant stimuli. By contrast, other right VLPFC subregions are consistently active during motor inhibition, but not reflexive reorienting tasks, with posterior-VLPFC being active during the updating of action plans and mid-VLPFC responding to decision uncertainty. These results highlight the rich functional heterogeneity that exists within right VLPFC.

  View details for DOI 10.1111/j.1749-6632.2011.05958.x

  View details for Web of Science ID 000290238100004

  View details for PubMedID 21486295

  View details for PubMedCentralID PMC3079823

• The Hippocampal Formation in Schizophrenia AMERICAN JOURNAL OF PSYCHIATRY Tamminga, C. A., Stan, A. D., Wagner, A. D. 2010; 167 (10): 1178-1193

  Abstract

  The hippocampal formation is one of the most extensively studied regions of the brain, with well-described anatomy and basic physiology; moreover, aspects of human memory mediated by the hippocampus are well characterized. In schizophrenia, alterations in hippocampal anatomy, perfusion, and activation are consistently reported; impairments in declarative memory function, especially in the flexible use of event memories (e.g., in the service of memory-based inference), are common. Postmortem molecular changes suggest a selective reduction in glutamate transmission in the dentate gyrus and in its efferent fibers, the mossy fiber pathway. A reduction in dentate gyrus glutamatergic output and in its information processing functions could generate two co-occurring outcomes in the hippocampus: 1) a change in homeostatic plasticity processes in cornu ammonis 3 (CA3), accompanied by increased activity due to reduced afferent stimulation from the dentate gyrus onto CA3 neurons, a process that could increase the pattern completion functions of CA3, and 2) the loss of mnemonic functions specific to the dentate gyrus, namely pattern separation, a change that could increase the prevalence of illusory pattern completion and reduce discrimination between present and past experiences in memory. The resulting increase in "runaway" CA3-mediated pattern completion could result in cognitive "mistakes," generating psychotic associations and resulting in memories with psychotic content. Tests of this model could result in novel approaches to the treatment of psychosis and declarative memory alterations and in novel animal preparations for basic schizophrenia research.

  View details for DOI 10.1176/appi.ajp.2010.09081187

  View details for Web of Science ID 000282374700010

  View details for PubMedID 20810471

• Multiple Forms of Learning Yield Temporally Distinct Electrophysiological Repetition Effects CEREBRAL CORTEX Race, E. A., Badre, D., Wagner, A. D. 2010; 20 (7): 1726-1738

  Abstract

  Prior experience with a stimulus leads to multiple forms of learning that facilitate subsequent behavior (repetition priming) and neural processing (repetition suppression). Learning can occur at the level of stimulus-specific features (stimulus learning), associations between stimuli and selected decisions (stimulus-decision learning), and associations between stimuli and selected responses (stimulus-response learning). Although recent functional magnetic resonance imaging results suggest that these distinct forms of learning are associated with repetition suppression (neural priming) in dissociable regions of frontal and temporal cortex, a critical question is how these different forms of learning influence cortical response dynamics. Here, electroencephalography (EEG) measured the temporal structure of neural responses when participants classified novel and repeated stimuli, using a design that isolated the effects of distinct levels of learning. Event-related potential and spectral EEG analyses revealed electrophysiological effects due to stimulus, stimulus-decision, and stimulus-response learning, demonstrating experience-dependent cortical modulation at multiple levels of representation. Stimulus-level learning modulated cortical dynamics earlier in the temporal-processing stream relative to stimulus-decision and stimulus-response learning. These findings indicate that repeated stimulus processing, including the mapping of stimuli to decisions and actions, is influenced by stimulus-level and associative learning mechanisms that yield multiple forms of experience-dependent cortical plasticity.

  View details for DOI 10.1093/cercor/bhp233

  View details for Web of Science ID 000278690800020

  View details for PubMedID 19915094

  View details for PubMedCentralID PMC2912654

• Learning and Generalization in Schizophrenia: Effects of Disease and Antipsychotic Drug Treatment BIOLOGICAL PSYCHIATRY Shohamy, D., Mihalakos, P., Chin, R., Thomas, B., Wagner, A. D., Tamminga, C. 2010; 67 (10): 926-932

  Abstract

  Schizophrenia involves alterations in hippocampal function. The implications of these alterations for memory function in the illness remain poorly understood. Furthermore, it remains unknown how memory is impacted by drug treatments for schizophrenia. The goal of this study was to delineate specific memory processes that are disrupted in schizophrenia and explore how they are affected by medication. We specifically focus on memory generalization--the ability to flexibly generalize memories in novel situations.Individuals with schizophrenia (n = 56) and healthy control subjects (n = 20) were tested on a computerized memory generalization paradigm. Participants first engaged in trial-by-error associative learning. They were then asked to generalize what they learned by responding to novel stimulus combinations. Individuals with schizophrenia were tested on or off antipsychotic medication, using a between-subject design in order to eliminate concerns about learning-set effects.Individuals with schizophrenia were selectively impaired in their ability to generalize knowledge, despite having intact learning and memory accuracy. This impairment was found only in individuals tested off medication. Individuals tested on medication generalized almost as well as healthy control subjects. This between-group difference was selective to memory generalization.These findings suggest that individuals with schizophrenia have a selective alteration in the ability to flexibly generalize past experience toward novel learning environments. This alteration is unaccompanied by global memory impairments. Additionally, the results indicate a robust generalization difference on the basis of medication status. These results suggest that hippocampal abnormalities in schizophrenia might be alleviated with antipsychotic medication, with important implications for understanding adaptive memory-guided behavior.

  View details for DOI 10.1016/j.biopsych.2009.10.025

  View details for Web of Science ID 000277629900005

  View details for PubMedID 20034612

• High-resolution fMRI of Content-sensitive Subsequent Memory Responses in Human Medial Temporal Lobe JOURNAL OF COGNITIVE NEUROSCIENCE Preston, A. R., Bornstein, A. M., Hutchinson, J. B., Gaare, M. E., Glover, G. H., Wagner, A. D. 2010; 22 (1): 156-173

  Abstract

  The essential role of the medial temporal lobe (MTL) in long-term memory for individual events is well established, yet important questions remain regarding the mnemonic functions of the component structures that constitute the region. Within the hippocampus, recent functional neuroimaging findings suggest that formation of new memories depends on the dentate gyrus and the CA(3) field, whereas the contribution of the subiculum may be limited to retrieval. During encoding, it has been further hypothesized that structures within MTL cortex contribute to encoding in a content-sensitive manner, whereas hippocampal structures may contribute to encoding in a more domain-general manner. In the current experiment, high-resolution fMRI techniques were utilized to assess novelty and subsequent memory effects in MTL subregions for two classes of stimuli--faces and scenes. During scanning, participants performed an incidental encoding (target detection) task with novel and repeated faces and scenes. Subsequent recognition memory was indexed for the novel stimuli encountered during scanning. Analyses revealed voxels sensitive to both novel faces and novel scenes in all MTL regions. However, similar percentages of voxels were sensitive to novel faces and scenes in perirhinal cortex, entorhinal cortex, and a combined region comprising the dentate gyrus, CA(2), and CA(3), whereas parahippocampal cortex, CA(1), and subiculum demonstrated greater sensitivity to novel scene stimuli. Paralleling these findings, subsequent memory effects in perirhinal cortex were observed for both faces and scenes, with the magnitude of encoding activation being related to later memory strength, as indexed by a graded response tracking recognition confidence, whereas subsequent memory effects were scene-selective in parahippocampal cortex. Within the hippocampus, encoding activation in the subiculum correlated with subsequent memory for both stimulus classes, with the magnitude of encoding activation varying in a graded manner with later memory strength. Collectively, these findings suggest a gradient of content sensitivity from posterior (parahippocampal) to anterior (perirhinal) MTL cortex, with MTL cortical regions differentially contributing to successful encoding based on event content. In contrast to recent suggestions, the present data further indicate that the subiculum may contribute to successful encoding irrespective of event content.

  View details for Web of Science ID 000272352100012

  View details for PubMedID 19199423

• The functional neuroimaging of forgetting FORGETTING Levy, B. J., Kuhl, B. A., Wagner, A. D., Sala, S. D. 2010: 135–63

  View details for Web of Science ID 000290092900008

• Attention during memory retrieval enhances future remembering MEMORY & COGNITION Dudukovic, N. M., DuBrow, S., Wagner, A. D. 2009; 37 (7): 953-961

  Abstract

  Memory retrieval is a powerful learning event that influences whether an experience will be remembered in the future. Although retrieval can succeed in the presence of distraction, dividing attention during retrieval may reduce the power of remembering as an encoding event. In the present experiments, participants studied pictures of objects under full attention and then engaged in item recognition and source memory retrieval under full or divided attention. Two days later, a second recognition and source recollection test assessed the impact of attention during initial retrieval on long-term retention. On this latter test, performance was superior for items that had been tested initially under full versus divided attention. More importantly, even when items were correctly recognized on the first test, divided attention reduced the likelihood of subsequent recognition on the second test. The same held true for source recollection. Additionally, foils presented during the first test were also less likely to be later recognized if they had been encountered initially under divided attention. These findings demonstrate that attentive retrieval is critical for learning through remembering.

  View details for DOI 10.3758/MC.37.7.953

  View details for Web of Science ID 000270516700002

  View details for PubMedID 19744935

  View details for PubMedCentralID PMC2776078

• Performance-Related Sustained and Anticipatory Activity in Human Medial Temporal Lobe during Delayed Match-to-Sample JOURNAL OF NEUROSCIENCE Olsen, R. K., Nichols, E. A., Chen, J., Hunt, J. F., Glover, G. H., Gabrieli, J. D., Wagner, A. D. 2009; 29 (38): 11880-11890

  Abstract

  The medial temporal lobe (MTL)-hippocampus and surrounding perirhinal, parahippocampal, and entorhinal cortical areas-has long been known to be critical for long-term memory for events. Recent functional neuroimaging and neuropsychological data in humans performing short-delay tasks suggest that the MTL also contributes to performance even when retention intervals are brief, and single-unit data in rodents reveal sustained, performance-related delay activity in the MTL during delayed-non-match-to-sample tasks. The current study used functional magnetic resonance imaging to examine the relationship between activation in human MTL subregions and performance during a delayed-match-to-sample task with repeated (non-trial-unique) stimuli. On critical trials, the presentation of two faces was followed by a 30 s delay period, after which participants performed two-alternative forced-choice recognition. Functional magnetic resonance imaging revealed significant delay period activity in anterior hippocampus, entorhinal cortex, and perirhinal cortex over the 30 s retention interval, with the magnitude of activity being significantly higher on subsequently correct compared with subsequently incorrect trials. In contrast, posterior hippocampus, parahippocampal cortex, and fusiform gyrus activity linearly increased across the 30 s delay, suggesting an anticipatory response, and activity in parahippocampal cortex and hippocampus was greater during the probe period on correct compared with incorrect trials. These results indicate that at least two patterns of MTL delay period activation-sustained and anticipatory-are present during performance of short-delay recognition memory tasks, providing novel evidence that multiple processes govern task performance. Implications for understanding the role of the hippocampus and surrounding MTL cortical areas in recognition memory after short delays are discussed.

  View details for DOI 10.1523/JNEUROSCI.2245-09.2009

  View details for Web of Science ID 000270102000018

  View details for PubMedID 19776274

  View details for PubMedCentralID PMC2775810

• It's In My Eyes, but It Doesn't Look that Way to Me NEURON Kumaran, D., Wagner, A. D. 2009; 63 (5): 561-563

  Abstract

  In this issue of Neuron, Hannula and Ranganath provide striking evidence that hippocampal activity predicts eye movements that reveal memory for the past even when participants' overt memory decisions are in error. Their findings bear on an ongoing debate about the relationship between mnemonic awareness and hippocampal function.

  View details for DOI 10.1016/j.neuron.2009.08.027

  View details for Web of Science ID 000269852300002

  View details for PubMedID 19755098

• Neural Priming in Human Frontal Cortex: Multiple Forms of Learning Reduce Demands on the Prefrontal Executive System JOURNAL OF COGNITIVE NEUROSCIENCE Race, E. A., Shanker, S., Wagner, A. D. 2009; 21 (9): 1766-1781

  Abstract

  Past experience is hypothesized to reduce computational demands in PFC by providing bottom-up predictive information that informs subsequent stimulus-action mapping. The present fMRI study measured cortical activity reductions ("neural priming"/"repetition suppression") during repeated stimulus classification to investigate the mechanisms through which learning from the past decreases demands on the prefrontal executive system. Manipulation of learning at three levels of representation-stimulus, decision, and response-revealed dissociable neural priming effects in distinct frontotemporal regions, supporting a multiprocess model of neural priming. Critically, three distinct patterns of neural priming were identified in lateral frontal cortex, indicating that frontal computational demands are reduced by three forms of learning: (a) cortical tuning of stimulus-specific representations, (b) retrieval of learned stimulus-decision mappings, and (c) retrieval of learned stimulus-response mappings. The topographic distribution of these neural priming effects suggests a rostrocaudal organization of executive function in lateral frontal cortex.

  View details for Web of Science ID 000270740200010

  View details for PubMedID 18823245

• Posterior parietal cortex and episodic retrieval: Convergent and divergent effects of attention and memory LEARNING & MEMORY Hutchinson, J. B., Uncapher, M. R., Wagner, A. D. 2009; 16 (6): 343-356

  Abstract

  Functional neuroimaging studies of humans engaged in retrieval from episodic memory have revealed a surprisingly consistent pattern of retrieval-related activity in lateral posterior parietal cortex (PPC). Given the well-established role of lateral PPC in subserving goal-directed and reflexive attention, it has been hypothesized that PPC activation during retrieval reflects the recruitment of parietal attention mechanisms during remembering. Here, we evaluate this hypothesis by considering the anatomical overlap of retrieval and attention effects in lateral PPC. We begin by briefly reviewing the literature implicating dorsal PPC in goal-directed attention and ventral PPC in reflexive attention. We then discuss the pattern of dorsal and ventral PPC activation during episodic retrieval, and conclude with consideration of the degree of anatomical convergence across the two domains. This assessment revealed that predominantly divergent subregions of lateral PPC are engaged during acts of episodic retrieval and during goal-directed and reflexive attention, suggesting that PPC retrieval effects reflect functionally distinct mechanisms from these forms of attention. Although attention must play a role in aspects of retrieval, the data reviewed here suggest that further investigation into the relationship between processes of attention and memory, as well as alternative accounts of PPC contributions to retrieval, is warranted.

  View details for DOI 10.1101/lm.919109

  View details for Web of Science ID 000266565400001

  View details for PubMedID 19470649

  View details for PubMedCentralID PMC2704099

• Integrative Encoding AMERICAN JOURNAL OF PSYCHIATRY Shohamy, D., Wagner, A. D. 2009; 166 (3): 284-284

  View details for DOI 10.1176/appi.ajp.2009.09020150

  View details for Web of Science ID 000263842400007

  View details for PubMedID 19255050

• Posterior parietal cortex and episodic encoding: Insights from fMRI subsequent memory effects and dual-attention theory NEUROBIOLOGY OF LEARNING AND MEMORY Uncapher, M. R., Wagner, A. D. 2009; 91 (2): 139-154

  Abstract

  The formation of episodic memories--memories for life events--is affected by attention during event processing. A leading neurobiological model of attention posits two separate yet interacting systems that depend on distinct regions in lateral posterior parietal cortex (PPC). From this dual-attention perspective, dorsal PPC is thought to support the goal-directed allocation of attention, whereas ventral PPC is thought to support reflexive orienting to information that automatically captures attention. To advance understanding of how parietal mechanisms may impact event encoding, we review functional MRI studies that document the relationship between lateral PPC activation during encoding and subsequent memory performance (e.g., later remembering or forgetting). This review reveals that (a) encoding-related activity is frequently observed in human lateral PPC, (b) increased activation in dorsal PPC is associated with later memory success, and (c) increased activation in ventral PPC predominantly correlates with later memory failure. From a dual-attention perspective, these findings suggest that allocating goal-directed attention during event processing increases the probability that the event will be remembered later, whereas the capture of reflexive attention during event processing may have negative consequences for event encoding. The prevalence of encoding-related activation in parietal cortex suggests that neurobiological models of episodic memory should consider how parietal-mediated attentional mechanisms regulate encoding.

  View details for DOI 10.1016/j.nlm.2008.10.011

  View details for Web of Science ID 000263608600006

  View details for PubMedID 19028591

  View details for PubMedCentralID PMC2814803

• CNTRICS Final Task Selection: Long-Term Memory SCHIZOPHRENIA BULLETIN Ragland, J. D., Cools, R., Frank, M., Pizzagalli, D. A., Preston, A., Ranganath, C., Wagner, A. D. 2009; 35 (1): 197-212

  Abstract

  Long-term memory (LTM) is a multifactorial construct, composed of different stages of information processing and different cognitive operations that are mediated by distinct neural systems, some of which may be more responsible for the marked memory problems that limit the daily function of individuals with schizophrenia. From the outset of the CNTRICS initiative, this multidimensionality was appreciated, and an effort was made to identify the specific memory constructs and task paradigms that hold the most promise for immediate translational development. During the second CNTRICS meeting, the LTM group identified item encoding and retrieval and relational encoding and retrieval as key constructs. This article describes the process that the LTM group went through in the third and final CNTRICS meeting to select nominated tasks within the 2 LTM constructs and within a reinforcement learning construct that were judged most promising for immediate development. This discussion is followed by each nominating authors' description of their selected task paradigm, ending with some thoughts about future directions.

  View details for DOI 10.1093/schbul/sbn134

  View details for Web of Science ID 000261682700020

  View details for PubMedID 18927344

  View details for PubMedCentralID PMC2643960

• Overcoming suppression in order to remember: Contributions from anterior cingulate and ventrolateral prefrontal cortex COGNITIVE AFFECTIVE & BEHAVIORAL NEUROSCIENCE Kuhl, B. A., Kahn, I., Dudukovic, N. M., Wagner, A. D. 2008; 8 (2): 211-221

  Abstract

  The ability to remember is often compromised by competition from irrelevant memories. However, acts of selective remembering can alter the competitive relationship between memories; memories that are selected against are weakened, whereas those that are retrieved are strengthened. Whereas the weakening of selected-against memories is typically evidenced by subsequently poorer recall of these memories, the present study tested the hypothesis that when previously selected-against memories can subsequently be successfully retrieved, such acts of successful retrieval are associated with engagement of neurobiological mechanisms that serve to detect and overcome competition. Consistent with this hypothesis, fMRI revealed that anteriorcingulate cortex and right ventrolateral prefrontal cortex are differentially engaged during successful retrieval of previously selected-against memories, and that their engagement is directly related to the magnitude of weakening that is induced by prior acts of selecting against these memories.

  View details for DOI 10.3758/CABN.8.2.211

  View details for Web of Science ID 000257221500009

  View details for PubMedID 18589510

  View details for PubMedCentralID PMC2490713

• The interface between neuroscience and psychological science CURRENT DIRECTIONS IN PSYCHOLOGICAL SCIENCE Poldrack, R. A., Wagner, A. D. 2008; 17 (2): 61

  View details for DOI 10.1111/j.1467-8721.2008.00549.x

  View details for Web of Science ID 000254807700001

• Goal-dependent modulation of declarative memory: Neural correlates of temporal recency decisions and novelty detection NEUROPSYCHOLOGIA Dudukovic, N. M., Wagner, A. D. 2007; 45 (11): 2608-2620

  Abstract

  Declarative memory allows an organism to discriminate between previously encountered and novel items, and to place past encounters in time. Numerous imaging studies have investigated the neural processes supporting item recognition, whereas few have examined retrieval of temporal information. In the present study, functional magnetic resonance imaging (fMRI) was conducted while subjects engaged in temporal recency and item novelty decisions. Subjects encountered three-alternative forced-choice retrieval trials, each consisting of two words from a preceding study phase and one novel word, and were instructed to either identify the novel item (Novelty trials) or the more recently presented study item (Recency trials). Relative to correct Novelty decisions, correct Recency decisions elicited greater activation in a network of left-lateralized regions, including frontopolar and dorsolateral prefrontal cortex and intraparietal sulcus. A conjunction analysis revealed that these left-lateralized regions overlapped with those previously observed to be engaged during source recollection versus novelty detection, suggesting that during Recency trials subjects attempted to recollect event details. Consistent with this interpretation, correct Recency decisions activated posterior hippocampus and parahippocampal cortex, whereas incorrect Recency decisions elicited greater anterior cingulate activation. The magnitude of this latter effect positively correlated with activation in right dorsolateral prefrontal cortex. Finally, correct Novelty decisions activated the anterior medial temporal lobe to a greater extent than did correct Recency decisions, suggesting that medial temporal novelty responses are not obligatory but rather can be modulated by the goal-directed allocation of attention. Collectively, these findings advance understanding of how subjects strategically engage frontal and parietal mechanisms in the service of attempting to remember the temporal order of events, and how retrieval goals impact novelty processing within the medial temporal lobe.

  View details for DOI 10.1016/j.neuropsychologia.2007.02.025

  View details for Web of Science ID 000247865800021

  View details for PubMedID 17499318

• Attending to remember and remembering to attend NEURON Duclukovic, N. M., Wagner, A. D. 2006; 49 (6): 784-787

  Abstract

  Attention and memory are intimately linked. Two functional imaging studies in this issue of Neuron provide novel evidence for this powerful, reciprocal relationship. Turk-Browne and colleagues report that attention simultaneously facilitates the formation of both implicit and explicit memories, while Summerfield and colleagues demonstrate that memory for the past can guide the allocation of attention in the present. Together, these elegant studies reveal bidirectional interactions between attention and memory.

  View details for DOI 10.1016/j.neuron.2006.03.008

  View details for Web of Science ID 000236227500005

  View details for PubMedID 16543125

• Frontal lobe mechanisms that resolve proactive interference CEREBRAL CORTEX Badre, D., Wagner, A. D. 2005; 15 (12): 2003-2012

  Abstract

  Memory of a past experience can interfere with processing during a subsequent experience, a phenomenon termed proactive interference (PI). Neuroimaging and neuropsychological evidence implicate the left mid-ventrolateral prefrontal cortex (mid-VLPFC) in PI resolution during short-term item recognition, though the precise mechanisms await specification. The present functional magnetic resonance imaging (fMRI) experiment sought to further constrain theorizing regarding PI resolution. On each trial, subjects maintained a target set of words, and then decided if a subsequent probe was contained in the target set (positive) or not (negative). Importantly, for half of the negative and half of the positive trials, the probe had been contained in the previous target set (recent). Relative to non-recent trials, negative-recent trials produced an increase in response times and error rates, behavioral markers of PI. In fMRI measures, negative recency was associated with increased activation in the left mid-VLPFC, as well as in the bilateral fronto-polar cortex, providing evidence for multiple components in PI resolution. Furthermore, recency effects were evident during both negative and positive trials, with the magnitude of the recency effect in the mid-VLPFC being greater on negative trials. Collectively, these results serve to specify and constrain proposed models of PI resolution.

  View details for DOI 10.1093/cercor/bhi075

  View details for Web of Science ID 000233217300014

  View details for PubMedID 15788702

• Domain-general and domain-sensitive prefrontal mechanisms for recollecting events and detecting novelty CEREBRAL CORTEX Dobbins, I. G., Wagner, A. D. 2005; 15 (11): 1768-1778

  Abstract

  Recollecting the past and discriminating novel from familiar memoranda depend on poorly understood prefrontal cortical (PFC) mechanisms hypothesized to vary according to memory task (e.g. recollection versus novelty detection) and domain of targeted memories (e.g. perceptual versus conceptual). Using event-related fMRI, we demonstrate that recollecting conceptual or perceptual details surrounding object encounters similarly recruits left frontopolar and posterior PFC compared with detecting novel stimuli, suggesting that a domain-general control network is engaged during contextual remembering. In contrast, left anterior ventrolateral PFC coactivated with a left middle temporal region associated with semantic representation, and right ventrolateral PFC with bilateral occipito-temporal cortices associated with representing object form, depending on whether recollections were conceptual or perceptual. These PFC/posterior cortical dissociations suggest that during recollection, lateralized ventrolateral PFC mechanisms bias posterior conceptual or perceptual feature representations as a function of memory relevance, potentially improving the gain of bottom-up memory signals. Supporting this domain-sensitive biasing hypothesis, novelty detection also recruited right ventrolateral PFC and bilateral occipito-temporal cortices compared with conceptual recollection, suggesting that searching for novel objects heavily relies upon perceptual feature processing. Collectively, these data isolate task- from domain-sensitive PFC control processes strategically recruited in the service of episodic memory.

  View details for DOI 10.1093/cercor/bhi054

  View details for Web of Science ID 000232595700013

  View details for PubMedID 15728740

• Transient disruption of ventrolateral prefrontal cortex during verbal encoding affects subsequent memory performance JOURNAL OF NEUROPHYSIOLOGY Kahn, I., Pascual-Leone, A., Theoret, H., Fregni, F., Clark, D., Wagner, A. D. 2005; 94 (1): 688-698

  Abstract

  Episodic memory supports conscious remembrance of everyday experience. Prior functional neuroimaging data indicate that episodic encoding during phonological task performance is correlated with activation in bilateral posterior ventrolateral prefrontal cortex (pVLPFC), although uncertainty remains regarding whether these prefrontal regions make necessary contributions to episodic memory formation. Using functional MRI data to guide application of single-pulse transcranial magnetic stimulation (spTMS), this study examined the necessity of left and right pVLPFC for episodic encoding (as expressed through subsequent memory performance). To assess the timing of critical computations, pVLPFC function was transiently disrupted at different poststimulus onset times while subjects made syllable decisions about visually presented familiar and unfamiliar words; subsequent memory for these stimuli was measured. Results revealed that left pVLPFC disruption during encoding of familiar words impaired subsequent memory, expressed as a decline in recognition confidence, with disruption being maximal at 380 ms after stimulus onset. In contrast, right pVLPFC disruption facilitated subsequent memory for familiar words, expressed as an increase in medium confidence recognition, with this facilitation being maximal at 380 ms. Finally, phonological (syllable) decision accuracy was facilitated by right pVLPFC disruption, with this effect being maximal at 340 ms, but was unaffected by left pVLPFC disruption. These findings suggest that left pVLPFC mechanisms onset between 300 and 400 ms during phonological processing of words, with these mechanisms appearing necessary for effective episodic encoding. In contrast, disruption of correlated mechanisms in right pVLPFC facilitates encoding, perhaps by inducing a functional shift in the mechanisms engaged during learning.

  View details for DOI 10.1152/jn.01335.2004

  View details for Web of Science ID 000230135500061

  View details for PubMedID 15758048

• Hippocampal function, declarative memory, and schizophrenia: anatomic and functional neuroimaging considerations. Current neurology and neuroscience reports Preston, A. R., Shohamy, D., Tamminga, C. A., Wagner, A. D. 2005; 5 (4): 249-256

  View details for PubMedID 15987607

• Analogical reasoning and prefrontal cortex: Evidence for separable retrieval and integration mechanisms CEREBRAL CORTEX Bunge, S. A., Wendelken, C., Badre, D., Wagner, A. D. 2005; 15 (3): 239-249

  Abstract

  The present study examined the contributions of prefrontal cortex (PFC) subregions to two component processes underlying verbal analogical reasoning: semantic retrieval and integration. Event-related functional magnetic resonance imaging data were acquired while subjects performed propositional analogy and semantic decision tasks. On each trial, subjects viewed a pair of words (pair 1), followed by an instructional cue and a second word pair (pair 2). On analogy trials, subjects evaluated whether pair 2 was semantically analogous to pair 1. On semantic trials, subjects indicated whether the pair 2 words were semantically related to each other. Thus, analogy--but not semantic--trials required integration across multiple retrieved relations. To identify regions involved in semantic retrieval, we manipulated the associative strength of pair 1 words in both tasks. Anterior left inferior PFC (aLIPC) was modulated by associative strength, consistent with a role in controlled semantic retrieval. Left frontopolar cortex was insensitive to associative strength, but was more sensitive to integration demands than was aLIPC, consistent with a role in integrating the products of semantic retrieval to evaluate whether distinct representations are analogous. Right dorsolateral PFC exhibited a profile consistent with a role in response selection rather than retrieval or integration. These findings indicate that verbal analogical reasoning depends on multiple, PFC-mediated computations.

  View details for DOI 10.1093/cercor/bhh126

  View details for Web of Science ID 000227128300001

  View details for PubMedID 15238433

• Conceptual and perceptual novelty effects in human medial temporal cortex HIPPOCAMPUS O'Kane, G., Insler, R. Z., Wagner, A. D. 2005; 15 (3): 326-332

  Abstract

  Medial temporal lobe (MTL) structures often respond to stimulus repetition with a reduction in neural activity. Such novelty/familiarity responses reflect the mnemonic consequences of initial stimulus encounter, although the aspects of initial processing that lead to novelty/familiarity responses remain unspecified. The current functional magnetic resonance imaging (fMRI) experiment examined the sensitivity of MTL to changes in the semantic representations/processes engaged across stimulus repetitions. During initial study blocks, words were visually presented, and participants made size, shape, or composition judgments about the named referents. During repeated study blocks, the initial words were visually re-presented along with novel words, and participants made size judgments for all items. Behaviorally, responses were faster to repeated words in which the same task was performed at initial and repeated exposure (i.e., size-->size) relative to repeated words in which the tasks differed (i.e., composition-->size and shape-->size). fMRI measures revealed activation reductions in left parahippocampal cortex following same-task and different-task repetition; numerically, the effect was larger in the same-task condition. Accordingly, left parahippocampal cortex demonstrates sensitivity to perceptual novelty/familiarity, and it remains unclear whether this region also is sensitive to novelty/familiarity in the conceptual domain. In left perirhinal cortex, a novelty/familiarity effect was observed in the same-task condition but not in the different-task condition, thus revealing sensitivity to the degree of semantic overlap across exposures but insensitivity to perceptual repetition of the visual word form. Perirhinal sensitivity to semantic repetition and insensitivity to perceptual repetition suggests that human perirhinal cortex receives conceptual inputs, with perirhinal contributions to declarative memory perhaps partially stemming from its role in processing semantic aspects of experiences.

  View details for DOI 10.1002/hipo.20053

  View details for Web of Science ID 000228421600005

  View details for PubMedID 15490462

• Prefrontal and hippocampal contributions to visual associative recognition: Interactions between cognitive control and episodic retrieval BRAIN AND COGNITION Bunge, S. A., Burrows, B., Wagner, A. D. 2004; 56 (2): 141-152

  Abstract

  The ability to recover episodic associations is thought to depend on medial-temporal lobe mnemonic mechanisms and frontal lobe cognitive control processes. The present study examined the neural circuitry underlying non-verbal associative retrieval, and considered the consequences of successful retrieval on cognitive control demands. Event-related fMRI data were acquired while subjects retrieved strongly or weakly associated pairs of novel visual patterns in a two-alternative forced choice associative recognition paradigm. Behaviorally, successful retrieval of strongly associated relative to weakly associated pairs was more likely to be accompanied by conscious recollection of the pair's prior co-occurrence. At the neural level, right ventrolateral prefrontal cortex (VLPFC) and hippocampus were more active during successful retrieval of Strong than of Weak associations, consistent with a role in visual associative recollection. By contrast, Weak trials elicited greater activation in right anterior cingulate cortex (ACC), which may detect conflict between the similarly familiar target and foil stimuli in the absence of recollection. Consistent with this interpretation, stronger ACC activity was associated with weaker hippocampal and stronger right dorsolateral PFC (DLPFC) responses. Thus, recollection of relevant visual associations (hippocampus and VLPFC) results in lower levels of mnemonic conflict (ACC) and decreased familiarity-based monitoring demands (DLPFC). These findings highlight the interplay between cognitive control and episodic retrieval.

  View details for DOI 10.1016/j.bandc.2003.08.001

  View details for Web of Science ID 000225113600002

  View details for PubMedID 15518931

• What can neuroimaging tell us about the mind? Insights from prefrontal cortex CURRENT DIRECTIONS IN PSYCHOLOGICAL SCIENCE Poldrack, R. A., Wagner, A. D. 2004; 13 (5): 177-181

  View details for Web of Science ID 000224169100002

• Functional-neuroanatomic correlates of recollection: Implications for models of recognition memory JOURNAL OF NEUROSCIENCE Kahn, I., Davachi, L., Wagner, A. D. 2004; 24 (17): 4172-4180

  Abstract

  Recognition decisions can be based on familiarity, the sense that an item was encountered previously (item memory), and on recollection, the conscious recovery of contextual information surrounding a previous encounter with the item (e.g., source memory). Recognition with recollection is thought to depend on multiple mechanisms, including prefrontal "control" processes that guide retrieval and recapitulation mechanisms that reactivate posterior neocortical representations that were present at encoding. However, uncertainty remains regarding the precise nature of prefrontal contributions to recollection and the selectivity of recapitulation to veridical recollection. The present event-related functional magnetic resonance imaging study sought to examine whether regions showing "old-new" effects support processes sensitive to recollection success or recollection attempt and whether recapitulation of neocortical representations emerge during veridical recollection as well as during false recognition (i.e., false alarms) or whether false recognition resembles familiarity-based responding. Results revealed that multiple left prefrontal cortical regions were engaged during attempts to recollect previous contextual (source) details, regardless of the nature of the to-be-recollected details and of source recollection outcome (successful vs unsuccessful). Recapitulation effects were observed in regions sensitive to the encoding task, suggesting that veridical recollection entails the reactivation of processes or representations present during encoding. Importantly, in contrast to leading models of recognition memory, false alarms also appeared to be based partially on recollection, as revealed through false recapitulation effects. Implications for neural and cognitive models of recognition are considered.

  View details for DOI 10.1523/JNEUROSCI.0624-04.2004

  View details for Web of Science ID 000221195100008

  View details for PubMedID 15115812

• Item- and task-level processes in the left inferior prefrontal cortex: positive and negative correlates of encoding NEUROIMAGE Reynolds, J. R., Donaldson, D. I., Wagner, A. D., Braver, T. S. 2004; 21 (4): 1472-1483

  Abstract

  Activity in the left inferior prefrontal cortex (LIPC) is often thought to reflect processes that support episodic encoding. Functional magnetic resonance imaging (fMRI) was used to test whether processes subserved by LIPC could be negatively related to subsequent memory performance. Specifically, the current experiment explicitly tested the hypothesis that LIPC processing would positively impact encoding when primarily focused towards specific target items (item-level processing), whereas it would negatively impact encoding when primarily focused on the retrieval and instantiation of current task instructions (task-level processing). Two methods were used to identify regions that were sensitive to the two types of processes: a block-level manipulation of encoding task that influenced subsequent memory, and a back-sort procedure. LIPC was sensitive to item- and task-level processing, but not in a way that always facilitates encoding. LIPC was more active for subsequently remembered words than subsequently forgotten words, but it was also more active in a task that emphasized task-level processing relative to a task that emphasized item-level processing, although this former condition led to poorer subsequent memory performance. This pattern indicates that processes subserved by LIPC are not always positively correlated with episodic encoding. Rather, LIPC processes can support both the controlled semantic processing of items and the controlled retrieval of relevant semantic task context. When devoted to the latter, the diversion of LIPC processes to the task level can have a negative consequence for item-level analysis and encoding.

  View details for DOI 10.1016/j.neuroimage.2003.10.033

  View details for Web of Science ID 000220723900026

  View details for PubMedID 15050572

• Cognitive Control, Semantic Memory, and Priming: Contributions from Prefrontal Cortex Conference of the Summer-Institute-in-Cognitive-Neuroscience Wagner, A. D., Bunge, S. A., Badre, D. MIT PRESS. 2004: 709–725

  View details for Web of Science ID 000279844100055

• Neural circuits subserving the retrieval and maintenance of abstract rules JOURNAL OF NEUROPHYSIOLOGY Bunge, S. A., Kahn, I., Wallis, J. D., Miller, E. K., Wagner, A. D. 2003; 90 (5): 3419-3428

  Abstract

  Behavior is often governed by abstract rules or instructions for behavior that can be abstracted from one context and applied to another. Prefrontal cortex (PFC) is thought to be important for representing rules, although the contributions of ventrolateral (VLPFC) and dorsolateral (DLPFC) regions remain under-specified. In the present study, event-related fMRI was used to examine abstract rule representation in humans. Prior to scanning, subjects learned to associate unfamiliar shapes and nonwords with particular rules. During each fMRI trial, presentation of one of these cues was followed by a delay and then by sample and probe stimuli. Match and non-match rules required subjects to indicate whether or not the sample and probe matched; go rules required subjects to make a response that was not contingent on the sample/probe relation. Left VLPFC, parietal cortex, and pre-SMA exhibited sensitivity to rule type during the cue and delay periods. Delay-period activation in these regions, but not DLPFC, was greater when subjects had to maintain response contingencies (match, non-match) relative to when the cue signaled a specific response (go). In contrast, left middle temporal cortex exhibited rule sensitivity during the cue but not delay period. These results support the hypothesis that VLPFC interacts with temporal cortex to retrieve semantic information associated with a cue and with parietal cortex to retrieve and maintain relevant response contingencies across delays. Future investigations of cross-regional interactions will enable full assessment of this account. Collectively, these results demonstrate that multiple, neurally separable processes are recruited during abstract rule representation.

  View details for DOI 10.1152/jn.00910.2002

  View details for Web of Science ID 000186547600052

  View details for PubMedID 12867532

• Neural mechanisms of visual object priming: evidence for perceptual and semantic distinctions in fusiform cortex NEUROIMAGE Simons, J. S., Koutstaal, W., Prince, S., Wagner, A. D., Schacter, D. L. 2003; 19 (3): 613-626

  Abstract

  Previous functional imaging studies have shown that facilitated processing of a visual object on repeated, relative to initial, presentation (i.e., repetition priming) is associated with reductions in neural activity in multiple regions, including fusiform/lateral occipital cortex. Moreover, activity reductions have been found, at diminished levels, when a different exemplar of an object is presented on repetition. In one previous study, the magnitude of diminished priming across exemplars was greater in the right relative to the left fusiform, suggesting greater exemplar specificity in the right. Another previous study, however, observed fusiform lateralization modulated by object viewpoint, but not object exemplar. The present fMRI study sought to determine whether the result of differential fusiform responses for perceptually different exemplars could be replicated. Furthermore, the role of the left fusiform cortex in object recognition was investigated via the inclusion of a lexical/semantic manipulation. Right fusiform cortex showed a significantly greater effect of exemplar change than left fusiform, replicating the previous result of exemplar-specific fusiform lateralization. Right fusiform and lateral occipital cortex were not differentially engaged by the lexical/semantic manipulation, suggesting that their role in visual object recognition is predominantly in the visual discrimination of specific objects. Activation in left fusiform cortex, but not left lateral occipital cortex, was modulated by both exemplar change and lexical/semantic manipulation, with further analysis suggesting a posterior-to-anterior progression between regions involved in processing visuoperceptual and lexical/semantic information about objects. The results are consistent with the view that the right fusiform plays a greater role in processing specific visual form information about objects, whereas the left fusiform is also involved in lexical/semantic processing.

  View details for DOI 10.1016/S1053-8119(03)00096-X

  View details for Web of Science ID 000184485400012

  View details for PubMedID 12880792

• Assembling and encoding word representations: fMRI subsequent memory effects implicate a role for phonological control NEUROPSYCHOLOGIA Clark, D., Wagner, A. D. 2003; 41 (3): 304-317

  Abstract

  Novel word learning is central to the flexibility inherent in the human language capacity. Word learning may partially depend on long-term memory formation during the assembly of phonological representations from orthographic inputs. In the present study, event-related functional magnetic resonance imaging (fMRI) examined the contributions of phonological control-a component of the verbal working memory system-to phonological assembly and word learning. Subjects were scanned while making syllable decisions about visually presented familiar (English) and novel (pseudo-English and Foreign) words, a task that required retrieval and analysis of existing phonological codes or the assembly and analysis of novel representations. Results revealed that left inferior prefrontal cortex (LIPC) and bilateral parietal cortices were differentially engaged during the processing of novel words, suggesting that this circuit is recruited during phonological assembly. A subsequent memory analysis that examined the relation between fMRI signal and the subject's ability to later remember the words (a measure of effective memory formation) revealed that the magnitude of activation in LIPC, bilateral superior parietal, and left inferior parietal cortices was positively correlated with later memory. Moreover, although the magnitude of the subsequent memory effect in parietal cortex was not significantly affected by word type, this effect was greater in posterior LIPC for novel (pseudo-English) than for familiar (English) words. In the course of subserving the assembly of novel word representations, the phonological (articulatory) control component of the phonological system appears to play a central role in the encoding of novel words into long-term memory.

  View details for Web of Science ID 000179889700008

  View details for PubMedID 12457756

• Memory orientation and success: separable neurocognitive components underlying episodic recognition NEUROPSYCHOLOGIA Dobbins, I. G., Rice, H. J., Wagner, A. D., Schacter, D. L. 2003; 41 (3): 318-333

  Abstract

  Episodic recognition can be based on recollection of contextual details, on a sense of recent encounter, or some combination of the two. According to several cognitive models, selectively attending to these distinct aspects of memory may require different retrieval orientations and result in different neural responses depending upon whether or not retrieval is successful. Using event-related fMRI, we examined retrieval orientation by having subjects discriminate between two test words in one of two manners. During source recollection, they selected the member of the pair previously associated with a particular encoding task. In contrast, recency judgment required selection of the most recently encountered item of the pair, regardless of how it had been encoded. Furthermore, successful and unsuccessful trials within each retrieval task were contrasted to determine whether retrieval success effects occurred in overlapping or dissimilar neural populations compared to those associated with each retrieval orientation. The results revealed distinct lateral prefrontal and parietal activations that distinguished attempted source recollection from judgments of relative recency; these orientation effects were largely independent of retrieval success. In contrast, medial temporal lobe structures (hippocampus and parahippocampal gyrus) were differentially more active during successful recollection of encoding context, showing similar reduced responses during failed source recollection and judgments of recency. These results indicate that different memory orientations recruit distinct prefrontal and parietal networks and that the recovery of episodic context is associated with the hippocampus and surrounding medial temporal cortices.

  View details for Web of Science ID 000179889700009

  View details for PubMedID 12457757

• Semantic retrieval, mnemonic control, and prefrontal cortex. Behavioral and cognitive neuroscience reviews Badre, D., Wagner, A. D. 2002; 1 (3): 206-218

  Abstract

  Accessing stored knowledge is a fundamental function of the cognitive and neural architectures of memory. Here, the authors review evidence from cognitive-behavioral paradigms, neuropsychological studies of patients with focal neural insult, and functional brain imaging concerning the mechanisms underlying retrieval of semantic knowledge and their association with prefrontal cortex. First, the authors examine behavioral and neuropsychological evidence distinguishing between controlled and automatic semantic retrieval. Then the authors review the subregions of prefrontal cortex that functional neuroimaging has associated with semantic retrieval across a range of memory demanding tasks. Finally, two hypotheses concerning the nature of processing in these brain regions--the controlled semantic retrieval and selection hypotheses--are critically examined, and a possible synthesis is proposed.

  View details for PubMedID 17715593

• Hippocampal contributions to episodic encoding: Insights from relational and item-based learning JOURNAL OF NEUROPHYSIOLOGY Davachi, L., Wagner, A. D. 2002; 88 (2): 982-990

  Abstract

  The integrity of the hippocampus and surrounding medial-temporal cortices is critical for episodic memory, with the hippocampus being posited to support relational or configural associative learning. The present event-related functional magnetic resonance imaging (fMRI) study investigated the role of specific medial-temporal lobe structures in learning during relational and item-based processing, as well as the extent to which these structures are engaged during item-based maintenance of stimuli in working memory. fMRI indexed involvement of the hippocampus and underlying cortical regions during performance of two verbal encoding conditions, one that required item-based maintenance of word triplets in working memory and the other that entailed the formation of inter-item associations across the words in each triplet. Sixteen subjects were scanned using a rapid event-related fMRI design while they encountered the item-based and relational processing trials. To examine the correlation between fMRI signal in medial-temporal structures during learning and the subject's subsequent ability to remember the stimuli (a measure of effective memory formation), subjects were administered a yes-no recognition memory test following completion of the encoding scans. Results revealed that the hippocampus proper was engaged during both relational and item-based processing, with relational processing resulting in a greater hippocampal response. By contrast, entorhinal and parahippocampal gyri were differentially engaged during item-based processing, providing strong evidence for a functional neuroanatomic distinction between hippocampal and parahippocampal structures. Analysis of the neural correlates of subsequent memory revealed that activation in the bilateral hippocampus was reliably correlated with behavioral measures of effective memory formation only for those stimuli that were encoded in a relational manner. Taken together, these data provide evidence that the hippocampus, while engaged during item-based working memory maintenance, differentially subserves the relational binding of items into an integrated memory trace so that the experience can be later remembered.

  View details for DOI 10.1152/jn00046.2002

  View details for Web of Science ID 000177276100039

  View details for PubMedID 12163547

• Synchronicity: when you're gone I'm lost without a trace? NATURE NEUROSCIENCE Wagner, A. D. 2001; 4 (12): 1159-1160

  View details for Web of Science ID 000172525000005

  View details for PubMedID 11723457

• Prefrontal contributions to executive control: fMRI evidence for functional distinctions within lateral prefrontal cortex NEUROIMAGE Wagner, A. D., Maril, A., Bjork, R. A., Schacter, D. L. 2001; 14 (6): 1337-1347

  Abstract

  The prefrontal cortex (PFC) plays a fundamental role in internally guided behavior. Although it is generally accepted that PFC subserves working memory and executive control operations, it remains unclear whether the subregions within lateral PFC support distinct executive control processes. An event-related fMRI study was implemented to test the hypothesis that ventrolateral and dorsolateral PFC are functionally distinct, as well as to assess whether functional specialization exists within ventrolateral PFC. Participants performed two executive control tasks that differed in the types of control processes required. During rote rehearsal, participants covertly rehearsed three words in the order presented, thus requiring phonological access and maintenance. During elaborative rehearsal, participants made semantic comparisons between three words held in working memory, reordering them from least to most desirable. Thus, in addition to maintenance, elaborative rehearsal required goal-relevant coding of items in working memory ("monitoring") and selection from among the items to implement their reordering. Results revealed that left posterior ventrolateral PFC was active during performance of both tasks, whereas right dorsolateral PFC was differentially engaged during elaborative rehearsal. The temporal characteristics of the hemodynamic responses further suggested that dorsolateral activation lagged ventrolateral activation. Finally, differential activation patterns were observed within left ventrolateral PFC, distinguishing between posterior and anterior regions. These data suggest that anatomically separable subregions within lateral PFC may be functionally distinct and are consistent with models that posit a hierarchical relationship between dorsolateral and ventrolateral regions such that the former monitors and selects goal-relevant representations being maintained by the latter.

  View details for DOI 10.1006/nimg.2001.0936

  View details for Web of Science ID 000172524500010

  View details for PubMedID 11707089

• Cognitive neuroscience: Forgetting of things past CURRENT BIOLOGY Wagner, A. D., Davachi, L. 2001; 11 (23): R964-R967

  Abstract

  Recent functional imaging and electrophysiological results indicate that failure to remember experiences can result from a decreased recruitment of encoding processes that build effective memories and an increased recruitment of alternative mechanisms that may impair effective learning.

  View details for Web of Science ID 000172475700009

  View details for PubMedID 11728323

• When keeping in mind supports later bringing to mind: Neural markers of phonological rehearsal predict subsequent remembering JOURNAL OF COGNITIVE NEUROSCIENCE Davachi, L., Maril, A., Wagner, A. D. 2001; 13 (8): 1059-1070

  Abstract

  The ability to bring to mind a past experience depends on the cognitive and neural processes that are engaged during the experience and that support memory formation. A central and much debated question is whether the processes that underlie rote verbal rehearsal-that is, working memory mechanisms that keep information in mind-impact memory formation and subsequent remembering. The present study used event-related functional magnetic resonance imaging (fMRI) to explore the relation between working memory maintenance operations and long-term memory. Specifically, we investigated whether the magnitude of activation in neural regions supporting the on-line maintenance of verbal codes is predictive of subsequent memory for words that were rote-rehearsed during learning. Furthermore, during rote rehearsal, the extent of neural activation in regions associated with semantic retrieval was assessed to determine the role that incidental semantic elaboration may play in subsequent memory for rote-rehearsed items. Results revealed that (a) the magnitude of activation in neural regions previously associated with phonological rehearsal (left prefrontal, bilateral parietal, supplementary motor, and cerebellar regions) was correlated with subsequent memory, and (b) while rote rehearsal did not--on average--elicit activation in an anterior left prefrontal region associated with semantic retrieval, activation in this region was greater for trials that were subsequently better remembered. Contrary to the prevalent view that rote rehearsal does not impact learning, these data suggest that phonological maintenance mechanisms, in addition to semantic elaboration, support the encoding of an experience such that it can be later remembered.

  View details for Web of Science ID 000172629900003

  View details for PubMedID 11784444

• On the tip of the tongue: An event-related fMRI study of semantic retrieval failure and cognitive conflict NEURON Maril, A., Wagner, A. D., Schacter, D. L. 2001; 31 (4): 653-660

  Abstract

  The tip of the tongue (TOT) state refers to a temporary inaccessibility of information that one is sure exists in long-term memory and is on the verge of recovering. Using event-related fMRI, we assessed the neural correlates of this semantic retrieval failure to determine whether the anterior cingulate-lateral prefrontal neural circuit posited to mediate conflict resolution is engaged during metacognitive conflicts that arise during the TOT. Results revealed that, relative to successful retrieval or unsuccessful retrieval not accompanied by a TOT, retrieval failures accompanied by TOTs elicited a selective response in anterior cingulate-prefrontal cortices. During a TOT, cognitive control mechanisms may be recruited in attempts to resolve the conflict and retrieval failure that characterize this state.

  View details for Web of Science ID 000170759200018

  View details for PubMedID 11545723

• Can medial temporal lobe regions distinguish true from false? An event-related functional MRI study of veridical and illusory recognition memory PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Cabeza, R., Rao, S. M., Wagner, A. D., Mayer, A. R., Schacter, D. L. 2001; 98 (8): 4805-4810

  Abstract

  To investigate the types of memory traces recovered by the medial temporal lobe (MTL), neural activity during veridical and illusory recognition was measured with the use of functional MRI (fMRI). Twelve healthy young adults watched a videotape segment in which two speakers alternatively presented lists of associated words, and then the subjects performed a recognition test including words presented in the study lists (True items), new words closely related to studied words (False items), and new unrelated words (New items). The main finding was a dissociation between two MTL regions: whereas the hippocampus was similarly activated for True and False items, suggesting the recovery of semantic information, the parahippocampal gyrus was more activated for True than for False items, suggesting the recovery of perceptual information. The study also yielded a dissociation between two prefrontal cortex (PFC) regions: whereas bilateral dorsolateral PFC was more activated for True and False items than for New items, possibly reflecting monitoring of retrieved information, left ventrolateral PFC was more activated for New than for True and False items, possibly reflecting semantic processing. Precuneus and lateral parietal regions were more activated for True and False than for New items. Orbitofrontal cortex and cerebellar regions were more activated for False than for True items. In conclusion, the results suggest that activity in anterior MTL regions does not distinguish True from False, whereas activity in posterior MTL regions does.

  View details for Web of Science ID 000168059700096

  View details for PubMedID 11287664

• Prefrontal regions supporting spontaneous and directed application of verbal learning strategies - Evidence from PET BRAIN Savage, C. R., Deckersbach, T., Heckers, S., Wagner, A. D., Schacter, D. L., Alpert, N. M., Fischman, A. J., Rauch, S. L. 2001; 124: 219-231

  Abstract

  The prefrontal cortex has been implicated in strategic memory processes, including the ability to use semantic organizational strategies to facilitate episodic learning. An important feature of these strategies is the way they are applied in novel or ambiguous situations-failure to initiate effective strategies spontaneously in unstructured settings is a central cognitive deficit in patients with frontal lobe disorders. The current study examined strategic memory with PET and a verbal encoding paradigm that manipulated semantic organization in three encoding conditions: spontaneous, directed and unrelated. During the spontaneous condition, subjects heard 24 words that were related in four categories but presented in mixed order, and they were not informed of this structure beforehand. Any semantic reorganization was, therefore, initiated spontaneously by the subject. In the directed condition, subjects were given a different list of 24 related words and explicitly instructed to notice relationships and mentally group related words together to improve memory. The unrelated list consisted of 24 unrelated words. Behavioural measures included semantic clustering, which assessed active regrouping of words into semantic categories during free recall. In graded PET contrasts (directed > spontaneous > unrelated), two distinct activations were found in left inferior prefrontal cortex (inferior frontal gyrus) and left dorsolateral prefrontal cortex (middle frontal gyrus), corresponding to levels of semantic clustering observed in the behavioural data. Additional covariate analyses in the first spontaneous condition indicated that blood flow in orbitofrontal cortex (OFC) was strongly correlated with semantic clustering scores during immediate free recall. Thus, blood flow in OFC during encoding predicted which subjects would spontaneously initiate effective strategies during free recall. Our findings indicate that OFC performs an important, and previously unappreciated, role in strategic memory by supporting the early mobilization of effective behavioural strategies in novel or ambiguous situations. Once initiated, lateral regions of left prefrontal cortex control verbal semantic organization.

  View details for Web of Science ID 000166619900019

  View details for PubMedID 11133799

• Perceptual specificity in visual object priming: functional magnetic resonance imaging evidence for a laterality difference in fusiform cortex NEUROPSYCHOLOGIA Koutstaal, W., Wagner, A. D., Rotte, M., Maril, A., Buckner, R. L., Schacter, D. L. 2001; 39 (2): 184-199

  Abstract

  Seeing an object on one occasion may facilitate or prime processing of the same object if it is later again encountered. Such priming may also be found -- but at a reduced level -- for different but perceptually similar objects that are alternative exemplars or 'tokens' of the initially presented object. We explored the neural correlates of this perceptual specificity using event-related functional magnetic resonance imaging (fMRI) procedures, contrasting neural activity when participants made object classification decisions (size judgments) regarding previously presented objects (repeated same), alternative exemplars of previously presented objects (repeated different), or entirely new objects (novel). Many frontal regions (including bilateral frontal operculum, bilateral posterior inferior frontal/precentral, left anterior inferior frontal, and superior frontal cortices) and multiple late visual and posterior regions (including middle occipital, fusiform, fusiform-parahippocampal, precuneus, and posterior cingulate, all bilaterally), demonstrated reduced neural activity for repeated compared to novel objects. Greater repetition-induced reductions were observed for same than for different exemplars in several of these regions (bilateral posterior inferior frontal, right precuneus, bilateral middle occipital, bilateral fusiform, bilateral parahippocampal and bilateral superior parietal). Additionally, right fusiform (occipitotemporal) cortex showed significantly less priming for different versus same exemplars than did left fusiform. These findings converge with behavioral evidence from divided visual field studies and with neuropsychological evidence underscoring the key role of right occipitotemporal cortex in processing specific visual form information; possible differences in the representational-functional role of left fusiform are discussed.

  View details for Web of Science ID 000166054800008

  View details for PubMedID 11163375

• Task-specific repetition priming in left inferior prefrontal cortex CEREBRAL CORTEX Wagner, A. D., Koutstaal, W., Maril, A., Schacter, D. L., Buckner, R. L. 2000; 10 (12): 1176-1184

  Abstract

  Previous neuroimaging studies have shown that activation in left inferior prefrontal cortices (LIPC) is reduced during repeated (primed) relative to initial (unprimed) stimulus processing. These reductions in anterior (approximately BA 45/47) and posterior (approximately BA 44/6) LIPC activation have been interpreted as reflecting implicit memory for initial semantic or phonological processing. However, prior studies do not unambiguously indicate that LIPC priming effects are specific to the recapitulation of higher-level (semantic and/or phonological), rather than lower-level (perceptual), processes. Moreover, no prior study has shown that the patterns of priming in anterior and posterior LIPC regions are dissociable. To address these issues, the present fMRI study examined the nature of priming in LIPC by examining the task-specificity of these effects. Participants initially processed words in either a semantic or a nonsemantic manner. Subsequently, participants were scanned while they made semantic decisions about words that had been previously processed in a semantic manner (within-task repetition), words that had been previously processed in a nonsemantic manner (across-task repetition), and words that had not been previously processed (novel words). Behaviorally, task-specific priming was observed: reaction times to make the semantic decision declined following prior semantic processing but not following prior nonsemantic processing of a word. Priming in anterior LIPC paralleled these results with signal reductions being observed following within-task, but not following across-task, repetition. Importantly, neural priming in posterior LIPC demonstrated a different pattern: priming was observed following both within-task and across-task repetition, with the magnitude of priming tending to be greater in the within-task condition. Direct comparison between anterior and posterior LIPC regions revealed a significant interaction. These findings indicate that anterior and posterior LIPC demonstrate distinct patterns of priming, with priming in the anterior region being task-specific, suggesting that this facilitation derives from repeated semantic processing of a stimulus.

  View details for Web of Science ID 000165526700003

  View details for PubMedID 11073867

• Early detection of Alzheimer's disease: An fMRI marker for people at risk? NATURE NEUROSCIENCE Wagner, A. D. 2000; 3 (10): 973-974

  View details for Web of Science ID 000167177500012

  View details for PubMedID 11017166

• Prefrontal-temporal circuitry for episodic encoding and subsequent memory JOURNAL OF NEUROSCIENCE Kirchhoff, B. A., Wagner, A. D., Maril, A., Stern, C. E. 2000; 20 (16): 6173-6180

  Abstract

  Humans encounter and form memories for multiple types of experiences that differ in content, novelty, and memorability. Critical for understanding memory is determining (1) how the brain supports the encoding of events with differing content and (2) whether neural regions that are sensitive to novelty also influence whether stimuli will be subsequently remembered. This event-related functional magnetic resonance imaging (fMRI) study crossed content (picture/word), novelty (novel/repeated), and subsequent memory (remembered/forgotten) to examine prefrontal and temporal lobe contributions to encoding. Results revealed three patterns of encoding-related activation in anatomically connected inferior prefrontal and lateral temporal structures that appeared to vary depending on whether visuospatial/visuo-object, phonological/lexical, or semantic attributes were processed. Event content also modulated medial temporal lobe activity; word encoding predominantly activated the left hemisphere, whereas picture encoding activated both hemispheres. Critically, in prefrontal and temporal regions that were modulated by novelty, the magnitude of encoding activation also predicted whether an event would be subsequently remembered. These results suggest that (1) regions that demonstrate a sensitivity to novelty may actively support encoding processes that impact subsequent explicit memory and (2) multiple content-dependent prefrontal-temporal circuits support event encoding. The similarities between prefrontal and lateral temporal encoding responses raise the possibility that prefrontal modulation of posterior cortical representations is central to encoding.

  View details for Web of Science ID 000088676400034

  View details for PubMedID 10934267

• Interactions between forms of memory: When priming hinders new episodic learning JOURNAL OF COGNITIVE NEUROSCIENCE Wagner, A. D., Maril, A., Schacter, D. L. 2000; 12: 52-60

  Abstract

  Human memory consists of multiple forms, including priming and explicit memory. Although considerable evidence indicates that priming and explicit memory are functionally and neuroanatomically distinct, little is know about when and how these different forms of memory interact. Here, behavioral and functional magnetic resonance imaging (fMRI) methods were used to examine a novel and counterintuitive hypothesis: Priming during episodic encoding may be negatively associated with subsequent explicit memory. Using an experimental design that exploited known properties of spacing or lag effects, the magnitudes of behavioral and neural priming during a second study episode were varied and the relation between these magnitudes of priming during re-encoding and performance on a subsequent explicit memory test was examined. Results revealed that greater behavioral priming (reduced reaction times) and neural priming (reduced left inferior prefrontal brain activation) during re-encoding were associated with lower levels of subsequent explicit memory. Moreover, those subjects who demonstrated greater behavioral and neural priming effects during re-encoding following a long lag tended to demonstrate the least benefit in subsequent explicit memory due to this second study episode. These findings suggest that priming for past experiences can hinder new episodic encoding.

  View details for Web of Science ID 000166194100006

  View details for PubMedID 11506647

• Convergent cortical representation of semantic processing in bilinguals BRAIN AND LANGUAGE Illes, J., Francis, W. S., Desmond, J. E., Gabrieli, J. D., Glover, G. H., Poldrack, R., Lee, C. J., Wagner, A. D. 1999; 70 (3): 347-363

  Abstract

  This study examined whether semantic processes in two languages (English and Spanish) are mediated by a common neural system in fluent bilinguals who acquired their second language years after acquiring their first language. Functional magnetic resonance imaging was performed while bilingual participants made semantic and nonsemantic decisions about words in Spanish and English. There was greater activation for semantic relative to nonsemantic decisions in left and right frontal regions, with greater left frontal activation. The locations of activations were similar for both languages, and no differences were found when semantic decisions for English and Spanish words were compared directly. These results demonstrate a shared frontal lobe system for semantic analysis of the languages and are consistent with cognitive research on bilingualism indicating that the two languages of a bilingual person access a common semantic system.

  View details for Web of Science ID 000084152700003

  View details for PubMedID 10600225

• Perspectives: Neuroscience - Remembrance of things past SCIENCE Schacter, D. L., Wagner, A. D. 1999; 285 (5433): 1503-1504

  View details for Web of Science ID 000082359500038

  View details for PubMedID 10498535

• When encoding yields remembering: insights from event-related neuroimaging PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES Wagner, A. D., Koutstaal, W., Schacter, D. L. 1999; 354 (1387): 1307-1324

  Abstract

  To understand human memory, it is important to determine why some experiences are remembered whereas others are forgotten. Until recently, insights into the neural bases of human memory encoding, the processes by which information is transformed into an enduring memory trace, have primarily been derived from neuropsychological studies of humans with select brain lesions. The advent of functional neuroimaging methods, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), has provided a new opportunity to gain additional understanding of how the brain supports memory formation. Importantly, the recent development of event-related fMRI methods now allows for examination of trial-by-trial differences in neural activity during encoding and of the consequences of these differences for later remembering. In this review, we consider the contributions of PET and fMRI studies to the understanding of memory encoding, placing a particular emphasis on recent event-related fMRI studies of the Dm effect: that is, differences in neural activity during encoding that are related to differences in subsequent memory. We then turn our attention to the rich literature on the Dm effect that has emerged from studies using event-related potentials (ERPs). It is hoped that the integration of findings from ERP studies, which offer higher temporal resolution, with those from event-related fMRI studies, which offer higher spatial resolution, will shed new light on when and why encoding yields subsequent remembering.

  View details for Web of Science ID 000081832800015

  View details for PubMedID 10466153

• Functional specialization for semantic and phonological processing in the left inferior prefrontal cortex NEUROIMAGE Poldrack, R. A., Wagner, A. D., Prull, M. W., Desmond, J. E., Glover, G. H., Gabrieli, J. D. 1999; 10 (1): 15-35

  Abstract

  Neuroimaging and neuropsychological studies have implicated left inferior prefrontal cortex (LIPC) in both semantic and phonological processing. In this study, functional magnetic resonance imaging was used to examine whether separate LIPC regions participate in each of these types of processing. Performance of a semantic decision task resulted in extensive LIPC activation compared to a perceptual control task. Phonological processing of words and pseudowords in a syllable-counting task resulted in activation of the dorsal aspect of the left inferior frontal gyrus near the inferior frontal sulcus (BA 44/45) compared to a perceptual control task, with greater activation for nonwords compared to words. In a direct comparison of semantic and phonological tasks, semantic processing preferentially activated the ventral aspect of the left inferior frontal gyrus (BA 47/45). A review of the literature demonstrated a similar distinction between left prefrontal regions involved in semantic processing and phonological/lexical processing. The results suggest that a distinct region in the left inferior frontal cortex is involved in semantic processing, whereas other regions may subserve phonological processes engaged during both semantic and phonological tasks.

  View details for Web of Science ID 000081454800003

  View details for PubMedID 10385578

• Medial temporal lobe activations in fMRI and PET studies of episodic encoding and retrieval HIPPOCAMPUS Schacter, D. L., Wagner, A. D. 1999; 9 (1): 7-24

  Abstract

  Early neuroimaging studies often failed to obtain evidence of medial temporal lobe (MTL) activation during episodic encoding or retrieval, but a growing number of studies using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) have provided such evidence. We review data from fMRI studies that converge on the conclusion that posterior MTL is associated with episodic encoding; too few fMRI studies of retrieval have reported MTL activations to allow firm conclusions about their exact locations. We then turn to a recent meta-analysis of PET studies (Lepage et al., Hippocampus 1998;8:313-322) that appears to contradict the fMRI encoding data. Based on their analysis of the rostrocaudal distribution of activations reported during episodic encoding or retrieval, Lepage et al. (1998) concluded that anterior MTL is strongly associated with episodic encoding, whereas posterior MTL is strongly associated with episodic retrieval. After considering the evidence reviewed by Lepage et al. (1998) along with additional studies, we conclude that PET studies of encoding reveal both anterior and posterior MTL activations. These observations indicate that the contradiction between fMRI and PET studies of encoding was more apparent than real. However, PET studies have reported anterior MTL encoding activations more frequently than have fMRI studies. We consider possible sources of these differences.

  View details for Web of Science ID 000079002000002

  View details for PubMedID 10088896

• Working memory contributions to human learning and remembering NEURON Wagner, A. D. 1999; 22 (1): 19-22

  View details for Web of Science ID 000078410300008

  View details for PubMedID 10027285

• Material-specific lateralization of prefrontal activation during episodic encoding and retrieval NEUROREPORT Wagner, A. D., Poldrack, R. A., Eldridge, L. L., Desmond, J. E., Glover, G. H., Gabrieli, J. D. 1998; 9 (16): 3711-3717

  Abstract

  Although numerous neuroimaging studies have examined the functional neuroanatomy supporting episodic memory for verbal material, there have been few investigations of non-verbal episodic encoding and retrieval. We used fMRI to directly compare prefrontal activation elicited by verbal and non-verbal material during encoding and during retrieval. Regardless of the mnemonic operation (encoding/retrieval), inferior prefrontal activation lateralized based on material type. Verbal encoding and retrieval resulted in greater left inferior prefrontal activation, whereas non-verbal encoding and retrieval resulted in greater right inferior prefrontal activation. The similarity between inferior prefrontal activity during encoding and during retrieval indicates that these mnemonic operations depend on shared processes mediated by inferior prefrontal regions.

  View details for Web of Science ID 000077493400030

  View details for PubMedID 9858384

• Prefrontal cortex and recognition memory - Functional-MRI evidence for context-dependent retrieval processes BRAIN Wagner, A. D., Desmond, J. E., Glover, G. H., Gabrieli, J. D. 1998; 121: 1985-2002

  Abstract

  Functional neuroimaging studies of episodic recognition memory consistently demonstrate retrieval-associated activation in right prefrontal regions, including the right anterior and right dorsolateral prefrontal cortices. In theory, these activations could reflect processes associated with retrieval success, retrieval effort or retrieval attempt; each of these hypotheses has some support from previous studies. In Experiment 1, we examined these functional interpretations using functional MRI to measure prefrontal activation across multiple levels of recognition performance. Results revealed similar patterns of right prefrontal activation across varying levels of retrieval success and retrieval effort, suggesting that these activations reflect retrieval attempt. Retrieval attempt may include initiation of retrieval search or evaluation of the products of retrieval, such as scrutiny of specific attributes of the test item in an effort to determine whether it was encountered previously. In Experiment 2, we examined whether engagement of retrieval attempt is context-dependent by varying the context in which retrieval was performed; this was done by changing test instructions. Importantly, study and test stimuli were held constant, with only the test instructions varying across conditions. Results revealed that the pattern of right prefrontal activation varied across retrieval contexts. Collectively, these experiments suggest that right prefrontal regions mediate processes associated with retrieval attempt, with the probability of engaging these regions depending upon the retrieval context. Conflicting results across previous studies may be reconciled if the influence of retrieval context on the adopted retrieval strategy is considered. Finally, these results suggest that right prefrontal regions activated during recognition are not critical for successful performance as similar magnitudes of activation were present across multiple levels of performance. These findings reconcile imaging results with the selective effects of prefrontal lesions on retrieval-intensive episodic memory tests.

  View details for Web of Science ID 000076550700013

  View details for PubMedID 9798751

• Neuropsychological dissociation between recognition familiarity and perceptual priming in visual long-term memory CORTEX Wagner, A. D., Stebbins, G. T., Masciari, F., Fleischman, D. A., Gabrieli, J. D. 1998; 34 (4): 493-511

  Abstract

  The present study examined whether the same brain region mediates visual-perceptual repetition priming and a familiarity component of visual recognition memory. In two experiments, familiarity-based recognition was measured in an individual (M.S.) with impaired visual repetition priming due to a lesion of right occipital cortex. In both experiments, M.S. demonstrated intact recognition familiarity despite his visual nondeclarative memory impairment. These results converge with other behavioral results to indicate that recognition familiarity does not depend on the same memory system that mediates perceptual priming.

  View details for Web of Science ID 000076443900002

  View details for PubMedID 9800086

• Functional-anatomic study of episodic retrieval using fMRI I. Retrieval effort versus retrieval success NEUROIMAGE Buckner, R. L., Koutstaal, W., Schacter, D. L., Wagner, A. D., Rosen, B. R. 1998; 7 (3): 151-162

  Abstract

  A number of recent functional imaging studies have identified brain areas activated during tasks involving episodic memory retrieval. The identification of such areas provides a foundation for targeted hypotheses regarding the more specific contributions that these areas make to episodic retrieval. As a beginning effort toward such an endeavor, whole-brain functional magnetic resonance imaging (fMRI) was used to examine 14 subjects during episodic word recognition in a block-designed fMRI experiment. Study conditions were manipulated by presenting either shallow or deep encoding tasks. This manipulation yielded two recognition conditions that differed with regard to retrieval effort and retrieval success: shallow encoding yielded low levels of recognition success with high levels of retrieval effort, and deep encoding yielded high levels of recognition success with low levels of effort. Many brain areas were activated in common by these two recognition conditions compared to a low-level fixation condition, including left and right prefrontal regions often detected during PET episodic retrieval paradigms (e.g., R. L. Buckner et al., 1996, J. Neurosci. 16, 6219-6235) thereby generalizing these findings to fMRI. Characterization of the activated regions in relation to the separate recognition conditions showed (1) bilateral anterior insular regions and a left dorsal prefrontal region were more active after shallow encoding, when retrieval demanded greatest effort, and (2) right anterior prefrontal cortex, which has been implicated in episodic retrieval, was most active during successful retrieval after deep encoding. We discuss these findings in relation to component processes involved in episodic retrieval and in the context of a companion study using event-related fMRI.

  View details for Web of Science ID 000073589600001

  View details for PubMedID 9597657

• On the relationship between recognition familiarity and perceptual fluency: Evidence for distinct mnemonic processes ACTA PSYCHOLOGICA Wagner, A. D., Gabrieli, J. D. 1998; 98 (2-3): 211-230

  Abstract

  Fluent reprocessing of perceptual aspects of recently experienced stimuli is thought to support repetition priming effects on implicit perceptual memory tests. Although behavioral and neuropsychological dissociations demonstrate that separable mnemonic processes and neural substrates mediate implicit and explicit test performance, dual-process theories of memory posit that explicit recognition memory judgments may be based on familiarity derived from the same perceptual fluency that yields perceptual priming. Here we consider the relationship between familiarity-based recognition memory and implicit perceptual memory. A select review of the literature demonstrates that the fluency supporting implicit perceptual memory is functionally and anatomically distinct from that supporting recognition memory. In contrast to perceptual fluency, recognition familiarity is more sensitive to conceptual than to perceptual processing, and does not depend on modality-specific sensory cortices. Alternative possible relationships between familiarity in explicit memory and fluency in implicit memory are discussed.

  View details for Web of Science ID 000073902500006

  View details for PubMedID 9621831

• Recognition memory in the inclusion-exclusion paradigm: An FMRI study. Dorfman, J., Wagner, A. D., Stebbins, G. T., Dirksen, C., Turner, D., Glover, G. H., Desmond, J. E., Gabrielli, D. E. MIT PRESS. 1998: 51–51

  View details for Web of Science ID 000073196500146

• Lobular patterns of cerebellar activation in verbal working-memory and finger-tapping tasks as revealed by functional MRI JOURNAL OF NEUROSCIENCE Desmond, J. E., Gabrieli, J. D., Wagner, A. D., GINIER, B. L., Glover, G. H. 1997; 17 (24): 9675-9685

  Abstract

  The lobular distributions of functional activation of the cerebellum during verbal working-memory and finger movement tasks were investigated using functional magnetic resonance imaging (fMRI). Relative to a rest control, finger tapping of the right hand produced ipsilateral-increased activation in HIV/HV [Roman numeral designations based on Larsell's () nomenclature] and HVI and weaker activation in HVIII that was stronger on the ipsilateral side. For a working-memory task, subjects were asked to remember six (high load) or one (low load) visually presented letters across a brief delay. To assess the motoric aspects of rehearsal in the absence of working memory, we asked the subjects to repeatedly read subvocally six or one letters at a rate that approximated the internally generated rehearsal of working memory (motoric rehearsal task). For both tasks, bilateral regions of the superior cerebellar hemispheres (left superior HVIIA and right HVI) and portions of posterior vermis (VI and superior VIIA) exhibited increased activation during high relative to low load conditions. In contrast, the right inferior cerebellar hemisphere (HVIIB) exhibited this load effect only during the working-memory task. We hypothesize that HVI and superior HVIIA activation represents input from the articulatory control system of working memory from the frontal lobes and that HVIIB activation is derived from the phonological store in temporal and parietal regions. From these inputs, the cerebellum could compute the discrepancy between actual and intended phonological rehearsal and use this information to update a feedforward command to the frontal lobes, thereby facilitating the phonological loop.

  View details for Web of Science ID A1997YK82200028

  View details for PubMedID 9391022

• Semantic repetition priming for verbal and pictorial knowledge: A functional MRI study of left inferior prefrontal cortex JOURNAL OF COGNITIVE NEUROSCIENCE Wagner, A. D., Desmond, J. E., Demb, J. B., Glover, G. H., Gabrieli, J. D. 1997; 9 (6): 714-726

  Abstract

  Functional neuroimaging studies of single-word processing have demonstrated decreased activation in left inferior prefrontal cortex (LIPC) during repeated semantic processing relative to initial semantic processing. This item-specific memory effect occurs under implicit test instructions and represents word-toword semantic repetition priming. The present study examined the stimulus generality of LIPC function by measuring prefrontal cortical activation during repeated relative to initial semantic processing of words (word-to-word semantic repetition priming) and of pictures (picture-to-picture semantic repetition priming). For both words and pictures, LIPC activation decreased with repetition, suggesting that this area subserves semantic analysis of stimuli regardless of perceptual form. Decreased activation was greater in extent for words than for pictures. The LIPC area may act as a semantic executive system that mediates on-line retrieval of long-term conceptual knowledge necessary for guiding task performance.

  View details for Web of Science ID 000071078700002

  View details for PubMedID 23964594

• Dissociations between familiarity processes in explicit recognition and implicit perceptual memory Meeting of the Cognitive-Neuroscience-Society Wagner, A. D., Gabrieli, J. D., Verfaellie, M. AMER PSYCHOLOGICAL ASSOC. 1997: 305–23

  Abstract

  Dual-process theories of recognition posit that a perceptual familiarity process contributes to both explicit recognition and implicit perceptual memory. This putative single familiarity process has been indexed by inclusion-exclusion, remember-know, and repetition priming measures. The present studies examined whether these measures identify a common familiarity process. Familiarity-based explicit recognition (as indexed by the inclusion-exclusion and the independence remember-know procedures) increased with conceptual processing. In contrast, implicit word-identification priming and familiarity-based word-stem completion (as indexed by inclusion-exclusion) increased with study-test perceptual similarity. These dissociations indicate that familiarity-based explicit recognition may be more sensitive to conceptual than to perceptual processing and is functionally distinct from the perceptual familiarity process mediating implicit perceptual memory.

  View details for Web of Science ID A1997WP84700003

  View details for PubMedID 9080006

• Functional magnetic resonance imaging of semantic memory processes in the frontal lobes PSYCHOLOGICAL SCIENCE Gabrieli, J. D., Desmond, J. E., Demb, J. B., Wagner, A. D., Stone, M. V., Vaidya, C. J., Glover, G. H. 1996; 7 (5): 278-283

  View details for Web of Science ID A1996VF83300004

• Does recoding interfering material improve recall? JOURNAL OF EXPERIMENTAL PSYCHOLOGY-LEARNING MEMORY AND COGNITION Bower, G. H., Wagner, A. D., Newman, S. E., Randle, J. D., Hodges, M. J. 1996; 22 (1): 240-245

  Abstract

  In 4 experiments, the authors attempted to replicate an improvement in recall of target memories produced by a post-learning clue enabling participants to reorganize and segregate interfering material, as shown by G. H. Bower and T. Mann (1992). The 1st three experiments studied retroactive interference (RI) in free recall of an initial word list after participants were informed post-learning of a way to categorize a second, interfering list. In each case, the reorganizing clue failed to reduce RI. In the 4th experiment, interference during serial recall of an initial list of letters from a 2nd list was examined. Again, the reorganizing clue given after learning failed to reduce RI. Clearly, if the post-information effect is genuine, then better experimental arrangements will be required to demonstrate it more reliably.

  View details for Web of Science ID A1996TT57200015

  View details for PubMedID 8648287

• Functional MRI measurement of language lateralization in Wada-tested patients BRAIN Desmond, J. E., Sum, J. M., Wagner, A. D., Demb, J. B., Shear, P. K., Glover, G. H., Gabrieli, J. D., Morrell, M. J. 1995; 118: 1411-1419

  Abstract

  In this study the use of functional MRI (fMRI) for measuring language lateralization non-invasively was examined. The subjects were seven patients with histories of temporal lobe epilepsy who had undergone Wada testing for pre-surgical evaluation. Four patients were left-hemisphere-dominant and three were right-hemisphere-dominant for language. They received fMRI scans while they made semantic or perceptual judgments about visually presented words. Regions of the inferior frontal gyrus (pars triangularis and pars orbitalis) and neighbouring orbital cortex, corresponding to portions of Brodmann areas 45, 46 and 47, exhibited significant increases in activation during semantic relative to perceptual judgments. Lateralization of the increases in activation were consistent with the Wada test assessments of hemispheric language dominance in each of the seven patients. These results suggest that, in addition to providing a tool for investigating human cognitive processes, fMRI has significant clinical potential as a non-invasive measure of language lateralization.

  View details for Web of Science ID A1995TQ33300004

  View details for PubMedID 8595473

• SEMANTIC ENCODING AND RETRIEVAL IN THE LEFT INFERIOR PREFRONTAL CORTEX - A FUNCTIONAL MRI STUDY OF TASK-DIFFICULTY AND PROCESS SPECIFICITY JOURNAL OF NEUROSCIENCE Demb, J. B., Desmond, J. E., Wagner, A. D., Vaidya, C. J., Glover, G. H., Gabrieli, J. D. 1995; 15 (9): 5870-5878

  Abstract

  Prefrontal cortical function was examined during semantic encoding and repetition priming using functional magnetic resonance imaging (fMRI), a noninvasive technique for localizing regional changes in blood oxygenation, a correlate of neural activity. Words studied in a semantic (deep) encoding condition were better remembered than words studied in both easier and more difficult nonsemantic (shallow) encoding conditions, with difficulty indexed by response time. The left inferior prefrontal cortex (LIPC) (Brodmann's areas 45, 46, 47) showed increased activation during semantic encoding relative to nonsemantic encoding regardless of the relative difficulty of the nonsemantic encoding task. Therefore, LIPC activation appears to be related to semantic encoding and not task difficulty. Semantic encoding decisions are performed faster the second time words are presented. This represents semantic repetition priming, a facilitation in semantic processing for previously encoded words that is not dependent on intentional recollection. The same LIPC area activated during semantic encoding showed decreased activation during repeated semantic encoding relative to initial semantic encoding of the same words. This decrease in activation during repeated encoding was process specific; it occurred when words were semantically reprocessed but not when words were nonsemantically reprocessed. The results were apparent in both individual and averaged functional maps. These findings suggest that the LIPC is part of a semantic executive system that contributes to the on-line retrieval of semantic information.

  View details for Web of Science ID A1995RU10800002

  View details for PubMedID 7666172