Biology subjects

Smith, D. E.

Publications and source records attributed to Smith, D. E..

14 recordsLinked to original sources

bioRxiv2025

Repeated extrinsic rewards following retrieval practice facilitate later memory

The anticipation of extrinsic reward facilitates memory formation. However, it is unclear how reward following memory retrieval influences the information that is retrieved and later remembered. Here, we conducted four behavioral experiments (N=42 male/female young adults per experiment) in which we manipulated retrieval practice reward delivery. Across all experiments, participants studied word-image pairs and then completed two rounds of retrieval practice, followed by a final recognition test. Participants made vividness judgments during retrieval practice and in three of four experiments each response had a 50% chance of yielding positive feedback. We find that repeated rewards following retrieval practice facilitate later memory whereas low vivid retrieval practice impairs later memory. Together, these results suggest that the benefit of both retrieval practice and reward may be dependent on the strength of the memory that is retrieved.

neuroscience↗

bioRxiv2024

Mnemonic brain state engagement is diminished in healthy aging

Healthy older adults typically show impaired episodic memory - memory for when and where an event oc-curred - but intact semantic memory - knowledge for general information and facts. As older adults also have difficulty inhibiting the retrieval of prior knowledge from memory, their selective decline in episodic memory may be due to a tendency to over engage the retrieval state, a brain state in which attention is focused internally in an attempt to access prior knowledge. The retrieval state trades off with the encoding state, a brain state which supports the formation of new memories. Therefore, episodic memory declines in older adults may be the result of differential engagement in mnemonic brain states. Our hypothesis is that older adults are biased toward a retrieval state. We recorded scalp electroencephalography while young, middle-aged and older adults performed a memory task in which they were explicitly directed to either encode the currently presented object stimulus or retrieve a previously presented, categorically-related object stimulus. We used multivariate pattern analysis of spectral activity to decode engagement in the retrieval vs. encoding state. We find that all three age groups can follow top-down instructions to selectively engage in encoding or retrieval and that we can decode mnemonic states for all age groups. However, we find that mnemonic brain state engagement is diminished for older adults relative to middle-aged adults. Our interpretation is that a combination of executive control deficits and a modest bias to retrieve modulates older adults mnemonic state engagement. Together, these findings suggest that dif-ferential mnemonic state engagement may underlie age-related memory changes.

neuroscience↗

bioRxiv2024

Successful retrieval is its own reward

The ability to successfully remember past events is critical to our daily lives, yet the neural mechanisms underlying the motivation to retrieve is unclear. Although reward-system activity and feedback-related signals have been observed during memory retrieval, whether this signal reflects intrinsic reward or goal-attainment is unknown. Adjudicating between these two alternatives is crucial for understanding how individuals are motivated to engage in retrieval and how retrieval supports later remembering. To test these two accounts, we conducted between-subjects recognition memory tasks on human participants undergoing scalp electroencephalography and varied test-phase goals (recognize old vs. detect new items). We used an independently validated feedback classifier to measure positive feedback evidence. We find positive feedback following successful retrieval regardless of task goals. Together, these results suggest that successful retrieval is intrinsically rewarding. Such a feedback signal may promote future retrieval attempts as well as bolster later memory for the successfully retrieved events.

neuroscience↗

bioRxiv2024

Top-down task goals induce the retrieval state

Engaging the retrieval state (Tulving, 1983) impacts processing and behavior (Long & Kuhl, 2019, 2021; Smith, Moore, & Long, 2022), but the extent to which top-down factors - explicit instructions and goals - vs. bottom-up factors - stimulus properties such as repetition and similarity - jointly or independently induce the retrieval state is unclear. Identifying the impact of bottom-up and top-down factors on retrieval state engagement is critical for understanding how control of task-relevant vs. task-irrelevant brain states influence cognition. We conducted between-subjects recognition memory tasks on male and female human participants in which we varied test phase goals. We recorded scalp electroencephalography and used an independently validated mnemonic state classifier (Long, 2023) to measure retrieval state engagement as a function of top-down task goals (recognize old vs. detect new items) and bottom-up stimulus repetition (hits vs. correct rejections). We find that whereas the retrieval state is engaged for hits regardless of top-down goals, the retrieval state is only engaged during correct rejections when the top-down goal is to recognize old items. Furthermore, retrieval state engagement is greater for low compared to high confidence hits when the task goal is to recognize old items. Together, these results suggest that top-down demands to recognize old items induce the retrieval state independent from bottom-up factors, potentially reflecting the recruitment of internal attention to enable access of a stored representation. Significance StatementBoth top-down goals and automatic bottom-up influences may lead us into a retrieval brain state - a whole-brain pattern of activity that supports our ability to remember the past. Here we tested the extent to which top-down vs. bottom-up factors independently influence the retrieval state by manipulating participants goals and stimulus repetition during a memory test. We find that in response to the top-down goal to recognize old items, the retrieval state is engaged for both old and new probes, suggesting that top-down and bottom-up factors independently engage the retrieval state. Our interpretation is that top-down demands recruit internal attention in service of the attempt to access a stored representation.

neuroscience↗

bioRxiv2024

Response-locked theta dissociations reveal potential feedback signal following successful retrieval

Successful memory retrieval relies on memory processes to access an internal representation and decision processes to evaluate and respond to the accessed representation, both of which are supported by fluctuations in theta (4-8Hz) activity. However, the extent to which decision making processes are engaged following a memory response is unclear. Here, we recorded scalp electroencephalography (EEG) while human participants performed a recognition memory task. We focused on response-locked data, allowing us to investigate the processes that occur prior to and following a memory response. We replicate previous work and find that prior to a memory response theta power is greater for identification of previously studied items (hits) relative to rejection of novel lures (correct rejections; CRs). Following the memory response, the theta power dissociation flips whereby theta power is greater for CRs relative to hits. We find that the post-response flip is more robust for hits that are committed quickly, potentially reflecting a positive feedback signal for strongly remembered experiences. Our findings suggest that there are potentially distinct processes occurring before and after a memory response that are modulated by successful memory retrieval.

neuroscience↗

bioRxiv2023

Cerebrospinal Fluid Flow Extends to Peripheral Nerves

Cerebrospinal fluid (CSF) is an aqueous solution responsible for nutrient delivery and waste removal for the central nervous system (CNS). The three-layer meningeal coverings of the CNS support CSF flow. Peripheral nerves have an analogous three-layer covering consisting of the epineurium, perineurium, and endoneurium. Peripheral axons, located in the inner endoneurium, are bathed in "endoneurial fluid" similar to CSF but of undefined origin. CSF flow in the peripheral nervous system has not been demonstrated. Here we show CSF flow extends beyond the CNS to peripheral nerves in a contiguous flowing system. Utilizing gold nanoparticles, we identified that CSF is continuous with the endoneurial fluid and reveal the endoneurial space as the likely site of CSF flow in the periphery. Nanogold distribution along entire peripheral nerves and within their axoplasm suggests CSF plays a role in nutrient delivery and waste clearance, fundamental aspects of peripheral nerve health and disease. One Sentence SummaryCerebrospinal fluid unites the nervous system by extending beyond the central nervous system into peripheral nerves.

neuroscience↗

bioRxiv2023

Role of DNA-DNA sliding friction and non-equilibrium dynamics in viral genome ejection and packaging

Many viruses eject their DNA via a nanochannel in the viral shell, driven by internal forces arising from the high-density genome packing. The speed of DNA exit is controlled by friction forces that limit the molecular mobility, but the nature of this friction is unknown. We introduce a method to probe the mobility of the tightly confined DNA by measuring DNA exit from phage phi29 capsids with optical tweezers. We measure extremely low initial exit velocity, a regime of exponentially increasing velocity, stochastic pausing that dominates the kinetics, and large dynamic heterogeneity. Measurements with variable applied force provide evidence that the initial velocity is controlled by DNA-DNA sliding friction, consistent with a Frenkel-Kontorova model for nanoscale friction. We confirm several aspects of the ejection dynamics predicted by theoretical models. Features of the pausing suggest it is connected to the phenomenon of "clogging" in soft-matter systems. Our results provide evidence that DNA-DNA friction and clogging control the DNA exit dynamics, but that this friction does not significantly affect DNA packaging.

biophysics↗

bioRxiv2022

Regulation of the Phage Lambda Viral Packaging Motor's Grip and DNA End-clamp Mechanism

Many dsDNA viruses utilize ATP-powered "terminase" motors to package their genomes into procapsid shells. Here we use a single-molecule DNA grip/slip assay with rapid solution exchange to probe effects of nucleotide binding/dissociation in phage lambda motors containing both the large (TerL) and small (TerS) terminase subunits. Both subunits are required for packaging in vivo, but for some viruses (e.g., phages T4, HK97) packaging can be measured in vitro with only the catalytic TerL subunit. TerS facilitates initiation of packaging in vivo, but it has remained unclear if it plays any role during translocation. Surprisingly we measure frequent DNA gripping and high motor-DNA friction even in the absence of nucleotide. Such behavior was not observed in phage T4 motors containing only TerL, for which motor-DNA interactions were measured to be much weaker and significant gripping and friction was only observed with nucleotide present. For the lambda TerL/TerS holoenzyme, binding of nucleotide (ATP analogs or ADP) further increases gripping and friction, indicating there are both nucleotide independent and dependent interactions. Our findings suggest that TerS plays an important role in motor processivity, and that ATP-independent DNA gripping explains pausing observed during lambda packaging. We propose TerS acts as a "sliding clamp" to limit back slipping when TerL loses grip. Additionally, we show that the lambda packaging complex has a "DNA end clamp" mechanism that prevents the viral genome from completely exiting the capsid once packaging has initiated.

biophysics↗

bioRxiv2022

Spatiotemporal dynamics of memory encoding and memory retrieval states

Memory encoding and memory retrieval are neurally distinct brain states that can be differentiated on the basis of cortical network activity. However, it is unclear whether sustained engagement of one network or fluctuations between multiple networks give rise to these memory states. The spatiotemporal dynamics of memory states may have important implications for memory behavior and cognition; however, measuring temporally resolved signals of cortical networks poses a challenge. Here we recorded scalp electroencephalography from subjects performing a mnemonic state task in which they were biased toward memory encoding or retrieval. We performed a microstate analysis in order to measure the temporal dynamics of cortical networks throughout this mnemonic state task. We find that microstate E, a putative analog of the default mode network, shows temporally sustained dissociations between memory encoding and retrieval, with greater engagement during retrieve compared to encode trials. We further show that decreased engagement of microstate E is a general property of encoding, rather than a reflection of retrieval suppression. Together, these findings show that memory states are supported by sustained engagement of a particular cortical network. Memory success, as well as cognition more broadly, may be influenced by the ability to engage or disengage microstate E in a goal-dependent manner.

neuroscience↗

bioRxiv2021

Spatiotemporal context modulates encoding and retrieval of overlapping events

Overlap between events can lead to interference due to a tradeoff between encoding the present event and retrieving the past event. Temporal context information - when something occurred, a defining feature of episodic memory - can cue retrieval of a past event. However, the influence of temporal overlap, or proximity in time, on the mechanisms of interference are unclear. Here, by identifying brain states using scalp electroencephalography (EEG) from male and female human subjects, we show the extent to which temporal overlap promotes interference and induces retrieval. In this experiment, subjects were explicitly directed to either encode the present event or retrieve a past, overlapping event while perceptual input was held constant. We find that the degree of temporal overlap between events leads to selective interference. Specifically, greater temporal overlap between two events leads to impaired memory for the past event selectively when the top-down goal is to encode the present event. Using pattern classification analyses to measure neural evidence for a retrieval state, we find that greater temporal overlap leads to automatic retrieval of a past event, independent of top-down goals. Critically, the retrieval evidence we observe likely reflects a general retrieval mode, rather than retrieval success or effort. Collectively, our findings provide insight into the role of temporal overlap on interference and memory formation.

neuroscience↗

bioRxiv2019

Targeted stimulation of human orbitofrontal networks disrupts outcome-guided behavior

Outcome-guided behavior requires knowledge about the current value of expected outcomes. Such behavior can be isolated in the reinforcer devaluation task, which assesses the ability to infer the current value of rewards after devaluation. Animal lesion studies demonstrate that orbitofrontal cortex (OFC) is necessary for normal behavior in this task, but a causal role for human OFC in outcome-guided behavior has not been established. Here we used sham-controlled non-invasive continuous theta-burst stimulation (cTBS) to temporarily disrupt human OFC network activity prior to devaluation of food odor rewards in a between-subjects design. Subjects in the sham group appropriately avoided Pavlovian cues associated with devalued food odors. However, subjects in the stimulation group persistently chose those cues, even though devaluation of food odors themselves was unaffected by cTBS. This behavioral impairment was mirrored in changes in resting-stated functional magnetic resonance imaging (rs-fMRI) activity, such that subjects in the stimulation group exhibited reduced global OFC network connectivity after cTBS, and the magnitude of this reduction was correlated with choices after devaluation. These findings demonstrate the feasibility of indirectly targeting the human OFC with non-invasive cTBS, and indicate that OFC is specifically required for inferring the value of expected outcomes.

neuroscience↗

bioRxiv2019

Development of a Prediction Model for Incident Atrial Fibrillation using Machine Learning Applied to Harmonized Electronic Health Record Data

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, whose early detection could lead to significant improvements in outcomes through appropriate prescription of anticoagulation. Although a variety of methods exist for screening for AF, there is general agreement that a targeted approach would be preferred. Implicit within this approach is the need for an efficient method for identification of patients at risk. In this investigation, we examined the strengths and weaknesses of an approach based on application of machine-learning algorithms to electronic health record (EHR) data that has been harmonized to the Observational Medical Outcomes Partnership (OMOP) common data model. We examined data from a total of 2.3M individuals, of whom 1.16% developed incident AF over designated 6-month time intervals. We examined and compared several approaches for data reduction, sample balancing (re-sampling) and predictive modeling using cross-validation for hyperparameter selection, and out-of-sample testing for validation. Although no approach provided outstanding classification accuracy, we found that the optimal approach for prediction of 6-month incident AF used a random forest classifier, raw features (no data reduction), and synthetic minority oversampling technique (SMOTE) resampling (F1 statistic 0.12, AUC 0.65). This model performed better than a predictive model based only on known AF risk factors, and highlighted the importance of using resampling methods to optimize ML approaches to imbalanced data as exists in EHRs. Further studies using EHR data in other medical systems are needed to validate the clinical applicability of these findings.

epidemiology↗

bioRxiv2018

ciftify: A framework for surface-based analysis of legacy MR acquisitions

The preprocessing pipelines of the Human Connectome Project (HCP) were made publicly available for the neuroimaging community to apply the HCP analytic approach to data from non-HCP sources. The HCP analytic approach is surface-based for the cerebral cortex, uses the CIFTI "grayordinate" file format, provides greater statistical sensitivity than traditional volume-based analysis approaches, and allows for a more neuroanatomically-faithful representation of data. However, the HCP pipelines require the acquisition of specific images (namely T2w and field map) that historically have often not been acquired. Massive amounts of this legacy data could benefit from the adoption of HCP-style methods. However, there is currently no published framework, to our knowledge, for adapting HCP preprocessing to "legacy" data. Here we present the ciftify project, a parsimonious analytic framework for adapting key modules from the HCP pipeline into existing structural workflows using FreeSurfers recon_all structural and existing functional preprocessing workflows. Within this framework, any functional dataset with an accompanying (i.e. T1w) anatomical data can be analyzed in CIFTI format. To simplify usage for new data, the workflow has been bundled with fMRIPrep following the BIDS-app framework. Finally, we present the package and comment on future neuroinformatics advances that may accelerate the movement to a CIFTI-based grayordinate framework. HIGHLIGHTSO_LIthe ciftify package allows for grayordinate-based (CIFTI format) analysis of non-Human Connectome Project (i.e. legacy) MR acquisitions C_LIO_LIThe workflow and dependencies are distributed as a Docker container, following the BIDS-app interface C_LIO_LIAdditional ciftify utilities aid in downstream analysis of CIFTI images C_LIO_LIWe intend for this work to offer bridging solution for legacy data that will allow many researchers to adopt CIFTI format analyses C_LI

neuroscience↗

bioRxiv2017

Personalized intrinsic network topography mapping and functional connectivity deficits in Autism Spectrum Disorder

BackgroundRecent advances demonstrate individually specific variation in brain architecture in healthy individuals using fMRI data. To our knowledge, the effects of individually specific variation in complex brain disorders have not been previously reported.\n\nMethodsWe developed a novel approach (Personalized Intrinsic Network topography, PINT) for localizing individually specific resting state networks using conventional resting state fMRI scans. Using cross-sectional data from participants with ASD (n=393) and TD controls (n=496) across 15 sites we tested: 1) effect of diagnosis and age on the variability of intrinsic network locations and 2) whether prior findings of functional connectivity differences in ASD as compared to TD remain after PINT application.\n\nResultsWe found greater variability in the spatial locations of resting state networks within individuals with ASD as compared to TD. In TD participants, variability decreased from childhood into adulthood, and increased again in late-life, following a U-shaped pattern, which was not present in those with ASD. Comparison of intrinsic connectivity between groups revealed that the application of PINT decreased the number of hypo-connected regions in ASD.\n\nConclusionsOur results provide a new framework for measuring altered brain functioning in neurodevelopmental disorders that may have implications for tracking developmental course, phenotypic heterogeneity, and ultimately treatment response. We underscore the importance of accounting for individual variation in the study of complex brain disorders.

neuroscience↗