bioRxiv Science⌕ Search

Biology subjects

Donner, T. H.

Publications and source records attributed to Donner, T. H..

At least 19 recordsLinked to original sources

Interplay of pupil-linked arousal and cortical decision computations in mice

Influential frameworks hold that brainstem neuromodulatory systems are rapidly recruited in a top-down manner during decision-making, adapting brain-wide activity and cognitive behavior in real time. Here, we examined the relationship between decision-related frontal cortical activity and pupil responses (a peripheral proxy of neuromodulatory activity) in mice accumulating fluctuating auditory evidence to choose among two options. We found two components of preparatory activity during decision formation, prior to motor action: a non-selective component shared between hemispheres and a choice-selective component that reflected decision uncertainty. Both components were mirrored in pupil responses during the task, which, in turn, scaled with decision uncertainty during decision formation and with uncertainty-modulated prediction errors after experiencing the outcome. Pupil responses also predicted an adjustment of choice behavior at the next trial. Our results point to a recurrent interplay between cortical decision computation and pupil-linked neuromodulation. HIGHLIGHTSO_LIMice switch between evidence integration and heuristic strategies during auditory-informed decisions C_LIO_LIPupil responses track decision uncertainty and uncertainty-modulated prediction errors C_LIO_LIDecision-related frontal cortical activity is coupled with pupil responses C_LIO_LIPupil responses predict an adjustment of future choice behavior C_LI IN SHORTMaheu et al. show that the phasic transitions in the arousal state mirror distinct components of cortical activity, including one directly involved in decision computations. In turn, these pupil-linked arousal responses predicted the strategy adopted at the next trial.

neuroscience↗

Impaired Sensory-motor Reconfiguration and Pupil-linked Arousal in Aging

Mounting evidence indicates impairments of decision-making and brainstem arousal systems in aging. To shed light on the relationship between these phenomena, we compared behavior and dynamics of pupil-linked arousal between older and younger adults during compositionally structured tasks. The main task required continuous online inference about hidden changes in the stimulus-response mappings required for reporting a perceptual categorization judgment. Accuracy in that task was reduced in older compared to younger adults, impairment specifically reflecting objective and subjective difficulty in switching between stimulus-response mappings: there was no age difference in tasks requiring only the online inference or only the perceptual categorization under stable stimulus-response mappings. Participant[s] pupils reliably dilated during the categorization judgment as well as moments of high probability of switches in the online inference process in both age groups. But only when the switches prompted a change in stimulus-response association in the main task, were these pupil responses deteriorated in older compared to younger adults. We propose that impaired cognitive engagement of arousal in aging might limit the sensory-motor reconfigurations required for behavioral flexibility. SIGNIFICANCE STATEMENTAging affects decision-making, but the computational and physiological basis of these alterations are poorly understood. Here, we show that older people are impaired in switching the association between sensation and action to support flexible decision-making. This flexible switching process recruits pupil-linked arousal systems of the brainstem in a manner that is altered in older compared to younger individuals. By contrast, we find that several other computational processes required for complex decision-making, including rapid online inference about uncertain environments, and the associated pupil-linked arousal responses, are largely unaffected in older people. Our findings implicate an aberrant cognitive recruitment of brainstem arousal systems in age-related problems in decision-making.

neuroscience↗

The resource-rational dynamics of evidence accumulation

Evidence accumulation is a fundamental aspect of human decision-making. However, how the precise temporal structure of evidence shapes the accumulation process has not been systematically studied. As a result, current understanding of evidence accumulation remains largely limited to its time-averaged behavior. We tested human subjects in a visual estimation task in which they inferred the angular position of an unknown source from a noisy stimulus sequence. Introducing systematic temporal perturbations, i.e., breaks of different durations and at different positions in the otherwise regular evidence sequence, revealed that subjects actively compensated for the memory loss endured during the break by dynamically enhancing evidence integration and memory maintenance immediately after the break. We derived a new time-continuous Bayesian updating model that is dynamically constrained by optimal performance-effort trade-offs. With two free parameters determining the overall resource-efficiencies of encoding and memory maintenance, the model accurately predicts the rich dependencies of subjects accumulation behavior on the evidence schedule, including subjects individual tendencies to emphasize either early (primacy) or late (recency) samples in the evidence sequence. Our results suggest that evidence accumulation is a non-stationary, dynamically controlled process that optimally balances the information gained from incoming evidence against the cognitive effort required to acquire and maintain it. The proposed model is general and should apply broadly across many task domains.

animal behavior and cognition↗

History-dependent Biases in Perceptual Decisions Depend on NMDA Receptors

Perceptual decisions are governed not only by current sensory input but also by the history of previous stimuli, choices, or outcomes. Such history-dependent biases evolve across multiple timescales ranging from seconds to minutes. Synaptic plasticity is one possible mechanism mediating such effects. The by N-methyl-aspartate (NMDA) glutamate receptor is critical for synaptic plasticity, and indirect evidence points to its role in the generation of history-dependent biases. Here, we pharmacologically blocked NMDA receptors in healthy human participants performing a two-alternative visual decision-making task. Participants choices were biased by the accumulation of fluctuating sensory evidence within each trial as well as the accumulation of across-trial sequences of stimuli, which enabled them to adapt to changing stimulus statistics across blocks. NMDA receptor blockade reduced the task-adaptive across trials, history-dependent biases. In contrast, enhancing GABA-A receptor activity in the same participants increased the transiency of the within-trial evidence accumulation dynamics. Our findings provide direct evidence for the importance of NMDA receptor function in history-dependent biases in the human brain.

neuroscience↗

Task-irrelevant stimuli boost phasic pupil-linked arousal but not memory formation

AO_SCPLOWBSTRACTC_SCPLOWBrainstem arousal systems including the locus coeruleus noradrenaline system, respond transiently to behaviorally relevant events. Locus coeruleus activity also drives dilations of the pupil, which are often observed during cognitive tasks. The strength of pupil responses during encoding of stimulus material predicts the success of its later retrieval, which might reflect the impact of noradrenaline on synaptic plasticity and memory formation. The pupil also dilates in response to task-irrelevant sounds, which could therefore serve as a valuable tool for investigating causal effects of phasic, pupil-linked arousal on cognition. Here, we evaluated whether task-irrelevant white noise sounds affect memory formation and memory-based decisions. These sounds were played before, during or after the presentation of memoranda (images or spoken words). Memory success was measured in recognition and free recall tasks the day after. Trial-to-trial variations in the amplitude of pupil dilations during word encoding without task-irrelevant sounds predicted memory success. Task-irrelevant white-noise sounds also robustly dilated the pupil but did not improve memory formation for the words or the images. We conclude that pupil-linked arousal processes triggered by task-irrelevant sounds differ from those recruited endogenously during memory formation, for example in states of increased emotionality or attention.

neuroscience↗

Cortex-wide Dynamics of Internal Decisions About Behavioral Context

Many human decisions manifest in the outside world as motor actions. Correspondingly, neural signals reflecting decision formation are expressed in neural populations encoding the final action. Some decisions, however, are internal, shaping overt behavior indirectly through the selection of policies or rules that guide elementary sensory-motor decisions. We studied the human brain dynamics underlying internal decisions about the stimulus-response mapping rule for reporting visual orientation judgments. The rule changed unpredictably in a hidden fashion, and participants tracked it by accumulating ambiguous sensory cues. Computational model-based decoding of source-level magnetoencephalography data uncovered representations of the internal belief about the active rule in many areas, including occipital cortex. These representations exhibited profiles as predicted by normative models and as observed in action-related frontal areas during overt decisions. We conclude that a widely distributed network of cortical areas implements evidence accumulation for internal decisions, and that even visual cortex may represent high-level beliefs.

neuroscience↗

Inter-areal coupling for cognition through coincident oscillatory transients

How do large-scale functional brain networks dynamically emerge to enable cognition? Correlated oscillations, a mechanism for inter-areal interactions, can be expressed as phase coherence or correlated amplitude fluctuations. While the functional role of phase coherence has been addressed in the past, it remains unknown how large-scale amplitude coupling dynamically supports the rapid network reconfigurations necessary for adaptive behavior. Here, we demonstrate that cognitive processing relies on the temporal alignment of brief, high-amplitude oscillatory events across distant cortical regions, rather than sustained coupling of oscillations. Capitalizing on the spatio-temporal resolution of magnetoencephalography (MEG) during a task probing attention and decision-making, we show that oscillatory event coincidences form functionally relevant, transient networks: First, coincidences of high-amplitude oscillatory events in the alpha and beta frequency range increase prior to correct decisions within a parieto-frontal network. Second, transient theta/alpha oscillatory event coincidences within a medial parietal, temporo-parietal junction and lateral prefrontal network track the dynamics of spontaneous, covert spatial attention reallocation. In contrast, transient aperiodic and sustained network components exhibit only weak functional modulations, revealing a spatial and spectral dissociation between transient and sustained amplitude coupling. Overall, our findings demonstrate that efficient cognition relies on large-scale interactions rapidly formed through co-occurring transient oscillatory events. We propose that the brain-wide orchestration of high-amplitude oscillatory events can provide a new framework for understanding how the brain dynamically integrates information to guide flexible behavior.

neuroscience↗

Competing Neural Decision Variables in Human Frontal Cortex Shape Decision Confidence

Theories of the neural basis of decision-making postulate a competition between choice-selective populations of neurons that are distributed across many brain areas. We hypothesized that agents sense of confidence in a choice is shaped by the consensus among these distributed decision signals. To test this idea, we simultaneously tracked the dynamics of choice-selective signals within each of many cortical areas via magnetoencephalography, while human participants formed difficult decisions. Signals within premotor cortex that supported the choice option selected on a given trial, or the alternative, exhibited a signature of intra-cortical competition. Both competing neural signals made opposing and unique contributions to confidence. Critically, the number and strength of choice-selective signals in associative cortical areas supporting the selected option on each trial made an additional contribution to confidence. We conclude that confidence emerges from cortex-wide, competitive dynamics, through a mechanism that monitors the consensus across many local decision modules.

neuroscience↗

Serotonergic and noradrenergic interactions in pupil-linked arousal

Changes in central arousal state shape cortical computations underlying perception, thought, and action. Variations in arousal are accompanied by fluctuations in pupil size. In turn, pupil dynamics are often used as a marker of noradrenaline release from neurons of the locus coeruleus. The serotonergic system of the dorsal raphe also contributes to the brainstem control of waking states. However, little is known about its relationship to noradrenergic activity and arousal dynamics in awake animals. Here, we simultaneously accessed both systems in awake mice and unraveled their unique and joint contributions to pupil-linked arousal. Serotonergic and noradrenergic systems co-fluctuated, and serotonergic dorsal raphe neurons affected pupil size partly via noradrenergic populations in the locus coeruleus. Yet, part of the serotonergic control of pupil dynamics was independent of the locus coeruleus. Our findings challenge common assumptions about the neuromodulatory control of pupil dynamics and illuminate the interplay between distinct neurochemical systems within the arousal network of the brainstem.

neuroscience↗

Catecholamines reduce choice history biases

Theoretical accounts postulate that the catecholaminergic neuromodulator noradrenaline shapes cognition and behavior by reducing the impact of prior expectations on learning, inference, and decision-making. A ubiquitous effect of dynamic priors on perceptual decisions under uncertainty is choice history bias: the tendency to systematically repeat, or alternate, previous choices, even when stimulus categories are presented in a random sequence. Here, we directly test for a causal impact of catecholamines on these priors. We pharmacologically elevated catecholamine levels in human participants through the application of the noradrenaline reuptake inhibitor atomoxetine. We quantified the resulting changes in observers history biases in a visual perceptual decision task. Choice history biases in this task were highly idiosyncratic, tending toward choice repetition or alternation in different individuals. Atomoxetine decreased these biases (toward either repetition or alternation) compared to placebo. Behavioral modeling indicates that this bias reduction was due to a reduced bias in the accumulation of sensory evidence, rather than of the starting point of the accumulation process. Atomoxetine had no significant effect on other behavioral measures tested, including response time and choice accuracy. Atomoxetine and variations of pupil-linked arousal at slower and faster timescales had analogous effects on choice history bias. We conclude that catecholamines reduce the impact of a specific form of prior on perceptual decisions.

neuroscience↗

Large-scale Dynamical Fingerprints of Distributed Synaptic Alterations in Early-Stage Psychosis

Psychotic disorders, such as schizophrenia, present a major challenge for research and clinical practice: its pathogenesis is complex, the individual symptomatology is heterogenous, and there is a lack of biomarkers for the early detection, diagnosis, and individualized treatment. Mounting evidence indicates that the synaptic and microcircuitry alterations underlying psychosis are widely distributed in the brain. Here, we developed a magnetoencephalography approach to map the resulting alterations of local cortical population dynamics across the human cerebral cortex. We identified large-scale patterns of changes in neural dynamics that were remarkably similar between first-episode psychosis patients and individuals at clinical high risk for psychosis. These spatial patterns also resembled those induced by pharmacological manipulations of excitatory NMDA glutamate receptors and inhibitory GABA-A receptors in healthy participants. Differences in those spatial patterns of cortical dynamics between psychosis patients related to individual symptomatology. Our study opens a new window on the distributed pathophysiology of psychosis. TeaserCortex-wide changes in neural mass dynamics due to psychosis resemble changes due to GABA-A or NMDA receptor manipulation and relate to clinical symptoms.

neuroscience↗

Confirmation Bias through Selective Use of Evidence in Human Cortex

Decision-makers often process new evidence selectively, depending on their current beliefs about the world. We asked whether such confirmation biases result from biases in the encoding of sensory evidence in the brain, or alternatively in the utilization of encoded evidence for behavior. Human participants estimated the source of a sequence of visual-spatial evidence samples while we measured cortical population activity with magnetoencephalography. Halfway through the sequence, participants were prompted to judge the more likely source category. We find that processing of subsequent evidence depends on its consistency with the previously chosen category. Evidence encoded in parietal cortex contributes more to the estimation report when that evidence is consistent with the previous choice compared to when it contradicts that choice. Our results indicate that information contradicting pre-existing beliefs has little impact on subsequent behavior, despite being precisely encoded in the brain. This provides room for deliberative control to counteract confirmation biases.

neuroscience↗

Task-irrelevant stimuli reliably boost phasic pupil-linked arousal but do not affect decision formation

The arousal systems of the brainstem, specifically the locus coeruleus-noradrenaline system, respond "phasically" during decisions. These central arousal transients are accompanied by dilations of the pupil. Mechanistic attempts to understand the impact of phasic arousal on cognition would benefit from the ability to experimentally manipulate arousal in a temporally precise manner. Here, we evaluated a non-invasive candidate approach for such a manipulation in humans: presenting task-irrelevant auditory stimuli at different latencies during the execution of a challenging task. Task-irrelevant auditory stimuli drive responses of brainstem nuclei involved in the control of pupil size. But it is unknown whether such sound-evoked responses mimic the central arousal transients evoked during cognitive computations. A large body of evidence has implicated central arousal transients in a bias reduction during challenging perceptual decisions. We thus used challenging visual decisions as a testbed, combining them with task-irrelevant sounds of varying onset latency or duration. Across three experiments, the sounds consistently elicited well-controlled pupil responses that superimposed onto task-evoked responses. While we replicated a negative correlation between task-evoked pupil responses and bias established in previous work, the task-irrelevant sounds had no behavioral effect. This dissociation suggests that cognitive task engagement and task-irrelevant sounds may recruit distinct neural systems contributing to the control of pupil size.

neuroscience↗

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↗

Rhythmic sampling of multiple decision alternatives in the human brain

Humans and other animals navigate decisions by sequentially attending to (sampling) subsets of the available information. The internal dynamics of the selective sampling of decision-relevant information remain unknown. Here we use magnetoencephalography recordings and neural decoding to track the spontaneous dynamics of the locus and strength of covert attention as human participants performed a three-alternative perceptual choice task. The strength of covert attention fluctuated rhythmically around 11 Hz. A shift of attention from one alternative to another tends to occur at the trough of this oscillation, presumably enabling comparisons. These shifts further reset the attentional oscillation. By contrast, at the peak of the oscillation, attention tends to increase the focus on the currently sampled alternative, presumably deepening processing of that alternative. We propose intrinsic attentional oscillations as a core mechanism governing the flexible sampling of decision alternatives.

neuroscience↗

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↗

40 Hz Steady-State Responses in Human Auditory Cortex Depend on GABAergic Neuronal Inhibition

The 40 Hz auditory steady-state response (ASSR), an oscillatory brain response to periodically modulated auditory stimuli, is a promising, non-invasive physiological biomarker for schizophrenia and related neuropsychiatric disorders. The 40 Hz ASSR might be amplified by synaptic interactions in cortical circuits, which are, in turn, disturbed in neuropsychiatric disorders. Here, we tested whether the 40 Hz ASSR in human auditory cortex depends on two key synaptic components of neuronal interactions within cortical circuits: excitation via N-methyl-aspartate glutamate (NMDA) receptors and inhibition via gamma-amino-butyric acid (GABA) receptors. We combined magnetoencephalography (MEG) recordings with placebo-controlled, low-dose pharmacological interventions in the same healthy human participants. All participants exhibited a robust 40 Hz ASSR in auditory cortices, especially in the right hemisphere, under placebo. The GABAA receptor-agonist lorazepam increased the amplitude of the 40 Hz ASSR, while no effect was detectable under the NMDA-blocker memantine. Our findings indicate that the 40 Hz ASSR in auditory cortex involves synaptic (and likely intracortical) inhibition via the GABA-A receptor, thus highlighting its utility as a mechanistic signature of cortical circuit dysfunctions involving GABAergic inhibition. Significance statementThe 40 Hz auditory steady-state response is a candidate non-invasive biomarker for schizophrenia and related neuropsychiatric disorders. Yet, the understanding of the synaptic basis of this neurophysiological signature in humans has remained incomplete. We combined magnetoencephalography (MEG) recordings with placebo-controlled pharmacological interventions in healthy human subjects to test the modulation of the 40 Hz ASSR in auditory cortex by two synaptic components that have been implicated in the generation of neuronal oscillations in cortical microcircuits: glutamate N-methyl-aspartate glutamate (NMDA) receptors and gamma-amino-butyric acid (GABA) -A receptors. Boosting GABAergic transmission, but not blocking NMDA-receptors, increased the amplitude of this ASSR. Thus, GABAergic inhibition modulates 40 Hz steady-state responses in auditory cortex.

neuroscience↗

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↗