Biology subjects

Murphy, P. R.

Publications and source records attributed to Murphy, P. R..

13 recordsLinked to original sources

bioRxiv2026

Change-point oddball elicits pupil-linked signatures of Bayesian belief updating

The auditory oddball protocol is widely used to study neural responses to unexpected events. In conventional designs, however, stimulus statistics are stationary: deviants do not indicate environmental change and therefore should not drive learning. Here, we introduce change-point oddball, a passive, no-report protocol in which the standard-oddball mapping reverses at unpredictable change points, requiring inference over latent environmental states. We measured pupil-linked arousal in three human cohorts. Pupil responses were larger for state-specific oddballs than standards, decayed across newly established standards after state changes, and scaled with model-derived change-point probability. A many-standards control experiment implicated a prediction-based rather than repetition-based mechanism. Finally, within participants, stronger pupil encoding of change-point probability during the passive task was associated with greater change-point-sensitive belief updating in a separate active navigation task. Thus, passive change-point oddball preserves core signatures of adaptive belief updating, enabling cross-species and clinical investigations.

neuroscience↗

bioRxiv2024

Dissociable encoding of evolving beliefs and momentary belief updates in distinct neural decision signals

Making accurate decisions in noisy or otherwise uncertain environments requires integrating evidence over time. Using simple tasks requiring rapid evaluation of a stationary sensory feature, two human neurophysiological signals have been found to evolve with similar integration dynamics, with one (centroparietal positivity; CPP) appearing to compute the running integral and continuously feed it to the other (motor beta lateralisation; MBL). However, it remains unknown whether and how these signals serve more distinct functional roles in more complex scenarios where information arrives discontinuously and requires more computational steps to form appropriate belief updates. We employed a volatile expanded judgement task that permits dissociation of the encoding of raw sensory information in each of a series of discrete stimuli ( objective evidence), the appropriately transformed belief updates from that information ( effective evidence), and the evolving belief itself (accumulated evidence). Whereas MBL traced the evolving belief across stimuli, the CPP was found only to locally encode the effective evidence associated with each individual stimulus. Furthermore, fluctuations in CPP amplitude after each single stimulus could account for variability in the encoding of accumulated evidence in MBL. These results suggest a flexible computational hierarchy in which effective evidence can be computed sample-by-sample at an intermediate processing level to drive downstream belief updates for protracted decisions about discrete stimuli.

neuroscience↗

bioRxiv2024

Individual Differences in Belief Updating and Phasic Arousal Are Related to Psychosis Proneness

Many decisions entail the updating of beliefs about the state of the environment, a process that may go awry in psychosis. When environments are subject to hidden changes in their state, optimal belief updating requires non-linear modulation of sensory evidence, which may be subserved by pupil-linked, phasic arousal. Here, we analyzed behavior and pupil responses during evidence accumulation in a changing environment in a community sample of human participants and assessed their subclinical psychotic experiences (psychosis proneness). Subjects most prone to psychosis showed overall less flexible belief updating profiles, with diminished weighting of late evidence. These same subjects also exhibited overall smaller pupil responses and less reliable pupil encoding of computational variables governing the adaptive belief updating. The observed changes in belief updating and arousal dynamics may account for the emergence of cognitive biases in psychotic psychopathology. Our results open a new window on the pathophysiology of mental disorders.

neuroscience↗

bioRxiv2023

Brainstem arousal systems adaptively shape large-scale cortical interactions for flexible decision-making

Most perceptual decisions entail a flexible mapping from sensory input to motor output. Flexible input-output mapping is reflected in correlated variability within the cortical network involved in perceptual decisions. Here, we tested the idea that brainstem arousal systems are involved in flexible input-output mapping and changes in cortical correlated variability. We combined brainstem fMRI, pupillometry, and time-resolved assessment of the intrinsic correlations between cortical population codes for stimulus and action. Human participants reported the orientation of visual stimuli by button presses, while the required stimulus-response mapping rule could undergo hidden and unpredictable changes. Rule switches evoked brainstem and pupil responses as well as changes in computational model-inferred, latent variables. These variables governed participants rule-switching behavior and pupil responses. Brainstem activity and pupil dilation preceded increases in the strength of correlations between cortical stimulus and action codes. Brainstem arousal systems may promote the reorganization of sensorimotor cortical pathways for flexible decisions.

neuroscience↗

bioRxiv2023

Linking cognitive integrity to working memory dynamics in the aging human brain

Aging is accompanied by a decline of multiple cognitive capacities, including working memory: the ability to maintain information online for the flexible control of behavior. Working memory involves stimulus-selective neural activity, persisting after stimulus presentation in widely distributed cortical areas. Here, we unraveled the mechanisms of working memory in healthy older adults and patients with mild cognitive impairment (MCI), a condition associated with increased risk of developing dementia. We studied a sample of 19 older adults diagnosed with MCI and 20 older healthy controls using a combination of model-based behavioral psychophysics, neuropsychological assessment, and magnetoencephalographic (MEG) recordings of brain activity. Twenty-one younger healthy adults were studied with model-based behavioral psychophysics only. All subjects performed a visuo-spatial delayed-match-to-sample working memory task under systematic manipulation of the temporal delay and the spatial distance between successively presented sample and test stimuli. We developed a computational model of the latent dynamics underlying task behavior and fit this to individual behavior. In the model, working memory representations diffused over time, a threshold was applied to produce a match/non-match decision about sample and test locations, and occasional lapses produced random decisions. For the older participants, we related the individual model parameters to a summary measure of individual cognitive integrity obtained from a large neuropsychological test battery, as well as to cortical MEG activity during the delay interval of the working memory task. For all groups, task accuracy decreased with delay duration and sample-test distance. When sample/test distances were small, older adults exhibited larger false alarm rates than younger adults. The behavioral effects were well captured by the model, which explained the age-related differences in terms of a deterioration of the quality of working memory representations, rather than differences in task strategy (i.e., threshold parameter). Task accuracy as well as the parameters governing behavioral stochasticity (diffusion noise and lapse rate combined) were correlated with overall cognitive integrity in the MCI group, but not in the older healthy controls. Individual task accuracy and stochasticity parameters (diffusion noise and lapse rate) were also correlated with stimulus-selective cortical activity during the delay interval, as assessed by decoding of the MEG signals, corroborating their validity as markers of cortical working memory mechanisms. Our findings provide insight into the mechanistic basis of aging-related changes in working memory maintenance and reveal a link between individual working memory dynamics and cognitive integrity in MCI.

neuroscience↗

bioRxiv2022

Large-Scale Circuit Configuration for Flexible Sensory-Motor Decisions

Humans and non-human primates can flexibly switch between different arbitrary mappings from sensation to action to solve a cognitive task. It has remained unknown how the brain implements such flexible sensory-motor mapping rules. Here, we uncovered a dynamic reconfiguration of task-specific correlated variability between sensory and motor brain regions. Human participants switched between two rules for reporting visual orientation judgments during fMRI recordings. Rule switches were either signaled explicitly or inferred by the participants from ambiguous cues. We used behavioral modeling to reconstruct the time course of their belief about the active rule. In both contexts, the patterns of correlations between ongoing fluctuations in stimulus- and action-selective activity across visual and action-related brain regions tracked participants belief about the active rule. The rule-specific correlation patterns broke down around the time of behavioral errors. We conclude that internal beliefs about task state are instantiated in brain-wide, selective patterns of correlated variability.

neuroscience↗

bioRxiv2020

Tasmanian devil CD28 and CTLA4 capture CD80 and CD86 from adjacent cells

Immune checkpoint immunotherapy is a pillar of human oncology with potential for non-human species. The first checkpoint immunotherapy approved for human cancers targeted the CTLA4 protein. CTLA4 can inhibit T cell activation by capturing and internalizing CD80 and CD86 from antigen presenting cells, a process called trans-endocytosis. Similarly, CD28 can capture CD80 and CD86 via trogocytosis and retain the captured ligands on the surface of the CD28-expressing cells. The Tasmanian devil (Sarcophilus harrisii) population has declined by 77% due to transmissible cancers that evade immune defenses despite genetic mismatches between the host and tumours. We used a live cell-based assay to demonstrate that devil CTLA4 and CD28 can capture CD80 and CD86. Mutation of evolutionarily conserved motifs in CTLA4 altered functional interactions with CD80 and CD86 in accordance with patterns observed in other species. These results suggest the potential for checkpoint immunotherapies can be translated to evolutionarily divergent species.

immunology↗

bioRxiv2020

Peripheral tolerance checkpoints imposed by ubiquitous antigen expression limit antigen-specific B-cell responses under strongly immunogenic conditions

A series of layered peripheral checkpoints maintain self-reactive B cells in an unresponsive state. Autoantibody production occurs when these checkpoints are breached, however, when and how this occurs is largely unknown. In particular, how self-reactive B cells are restrained during bystander inflammation in otherwise healthy individuals is poorly understood. A weakness has been the unavailability of methods capable of dissecting physiologically-relevant B-cell responses, without the use of an engineered B-cell receptor. Resolving this will provide insights that decipher how this process goes awry during autoimmunity or could be exploited for therapy. Here we use a strong adjuvant to provide bystander innate and adaptive signals that promote B-cell responsiveness, in conjunction with newly developed B cell detection tools to study in detail the ways that peripheral tolerance mechanisms limit the expansion and function of self-reactive B cells activated under these conditions. We show that although autoreactive B cells are recruited into the germinal centre, their development does not proceed, possibly through rapid counter-selection. Consequently, differentiation of plasma cells is blunted, and autoantibody responses are transient and devoid of affinity maturation. We propose this approach and these tools can be more widely applied to track antigen-specific B cell responses to more disease relevant antigens, without the need for BCR transgenic mice, in settings where tolerance pathways are compromised or have been genetically manipulated to drive stronger insights into the biology underlying B cell-mediated autoimmunity.

immunology↗

bioRxiv2020

Disentangling Decision-related Feedforward and Feedback Signals in Human Cortex

Perceptual decisions entail the accumulation of sensory evidence for a particular choice towards an action plan. An influential framework holds that sensory cortical areas encode the instantaneous sensory evidence and downstream, action-related regions accumulate this evidence. The large-scale distribution of this computation across the cerebral cortex has remained largely elusive. We developed a regionally-specific magnetoencephalography decoding approach to exhaustively map the dynamics of stimulus- and choice-specific signals across the human cortical surface during a visual decision. Comparison with the evidence accumulation dynamics inferred from behavior enabled us to disentangle stimulus-dependent and endogenous components of choice-predictive activity across the visual cortical hierarchy. The endogenous component was present in primary visual cortex, expressed in a low (< 20 Hz) frequency-band, and its time course tracked, with delay, the build-up of choice-predictive activity in (pre-)motor regions. Our results are consistent with choice-specific cortical feedback signaling in a specific frequency channel during decision formation.

neuroscience↗

bioRxiv2020

Temporal expectation hastens sensory encoding but does not affect evidence quality

The ability to predict the timing of forthcoming events, known as temporal expectation, has a strong impact on human information processing. Although there is growing consensus that temporal expectations enhance the speed and accuracy of perceptual decisions, it remains unclear whether they affect the decision process itself, or non-decisional (sensory / motor) processes. Here, healthy human participants (N = 21; 18 female) used predictive auditory cues to anticipate the timing of low-contrast visual stimuli they were required to detect. Modelling of the behavioral data using a prominent sequential sampling model indicated that temporal expectations speeded up non-decisional processes but had no effect on decision formation. Electrophysiological recordings confirmed and extended this result: temporal expectations hastened the onset of a neural signature of decision formation, but had no effect on its build-up rate. Anticipatory alpha-band power was modulated by temporal expectation, and co-varied with intrinsic trial-by-trial variability in behavioral and neural signatures of the onset latency of the decision process. These findings highlight how temporal predictions optimize our interaction with unfolding sensory events. SIGNIFICANCE STATEMENTTemporal expectation enhances performance, but the locus of this effect remains debated. Here, we contrasted the two dominant accounts: enhancement through (1) expedited decision onset, or (2) an increase in the quality of sensory evidence. We manipulated expectations about the onset of a dim visual target using a temporal cueing paradigm, and probed the locus of the expectation effect with two complementary approaches: drift diffusion modeling of behavior, and estimation of the onset and progression of the decision process from a supramodal accumulation-to-bound signal in simultaneously measured EEG signals. Behavioral modeling and neural data provided strong, converging evidence for an account in which temporal expectations enhance perception by speeding up decision onset, without affecting evidence quality.

neuroscience↗

bioRxiv2020

Normative Circuit Dynamics Across Human Cortex During Evidence Accumulation in Changing Environments

Many decisions under uncertainty entail the temporal accumulation of evidence that informs about the state of the environment. When environments are subject to hidden changes in their state, maximizing accuracy and reward requires non-linear accumulation of the evidence. How this adaptive, non-linear computation is realized in the brain is unknown. We analyzed human behavior and cortical population activity (measured with magnetoencephalography) recorded during visual evidence accumulation in a changing environment. Behavior and decision-related activity in cortical regions involved in action planning exhibited hallmarks of adaptive evidence accumulation, which could also be implemented by a recurrent cortical microcircuit. Decision dynamics in action-encoding parietal and frontal regions were mirrored in a frequency-specific modulation of the state of visual cortex that depended on pupil-linked arousal and the expected probability of change. These findings link normative decision computations to recurrent cortical circuit dynamics and highlight the adaptive nature of decision-related feedback to sensory cortex.

neuroscience↗

bioRxiv2019

Immune checkpoint proteins are conserved across 160 million years of evolution and are expressed on transmissible cancers

Immune checkpoint immunotherapy has revolutionized medicine, but translational success for new treatments remains low. Around 40% of humans and Tasmanian devils (Sarcophilus harrisii) develop cancer in their lifetime, compared to less than 10% for most species. Additionally, devils are affected by two of the three known transmissible cancers in mammals. Unfortunately, little is known about of immune checkpoints in devils and other non-model species, largely due to a lack of species-specific reagents. We developed a simple cut-and-paste reagent development method applicable to any vertebrate species and show that immune checkpoint interactions are conserved across 160 million years of evolution. The inhibitory checkpoint molecule CD200 is highly expressed on devil facial tumor cells. We are the first to demonstrate that co-expression of CD200R1 can block CD200 expression. The evolutionarily conserved pathways suggest that naturally occurring cancers in devils and other species can serve as models for understanding cancer and immunological tolerance. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/831404v3_ufig1.gif" ALT="Figure 1"> View larger version (108K): org.highwire.dtl.DTLVardef@14ff10eorg.highwire.dtl.DTLVardef@15acfd4org.highwire.dtl.DTLVardef@102a37dorg.highwire.dtl.DTLVardef@3b726c_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2018

A post-decisional neural marker of confidence predicts information-seeking

Theoretical work predicts that decisions made with low confidence should lead to increased information-seeking. This is an adaptive strategy because it can increase the quality of a decision, and previous behavioral work has shown that decision-makers engage in such confidence-driven information seeking. The present study aimed to characterize the neural markers that mediate the relationship between confidence and information-seeking. A paradigm was used in which human participants made an initial perceptual decision, and then decided whether or not they wanted to sample more evidence before committing to a final decision and confidence judgment. Pre-decisional and post-decisional ERP components were similarly modulated by the level of confidence and by information-seeking choices. Time-resolved multivariate decoding of scalp EEG signals first revealed that information-seeking choices could be decoded from the time of the initial decision to the time of the subsequent information-seeking choice (within-condition decoding). No above-chance decoding was visible in the pre-response time window. Crucially, a classifier trained to decode high versus low confidence predicted information-seeking choices after the initial perceptual decision (across-condition decoding). This time window corresponds to that of a post-decisional neural marker of confidence. Collectively, our findings demonstrate for the first time that neural indices of confidence are functionally involved in information-seeking decisions.

neuroscience↗