Pharmacological Elevation of Catecholamine Levels Improves Perceptual Decisions, But Not Metacognitive Insight.

Perceptual decisions are often accompanied by a feeling of decision confidence. Where the parietal cortex is known for its crucial role in shaping such perceptual decisions, metacognitive evaluations are thought to additionally rely on the (pre)frontal cortex. Because of this supposed neural differentiation between these processes, perceptual and metacognitive decisions may be divergently affected by changes in internal (e.g., attention, arousal) and external (e.g., task and environmental demands) factors. Although intriguing, causal evidence for this hypothesis remains scarce. Here, we investigated the causal effect of two neuromodulatory systems on behavioral and neural measures of perceptual and metacognitive decision-making. Specifically, we pharmacologically elevated levels of catecholamines (with atomoxetine) and acetylcholine (with donepezil) in healthy adult human participants performing a visual discrimination task in which we gauged decision confidence, while electroencephalography was measured. Where cholinergic effects were not robust, catecholaminergic enhancement improved perceptual sensitivity, while at the same time leaving metacognitive sensitivity unaffected. Neurally, catecholaminergic elevation did not affect sensory representations of task-relevant visual stimuli but instead enhanced well-known decision signals measured over the centroparietal cortex, reflecting the accumulation of sensory evidence over time. Crucially, catecholaminergic enhancement concurrently impoverished neural markers measured over the frontal cortex linked to the formation of metacognitive evaluations. Enhanced catecholaminergic neuromodulation thus improves perceptual but not metacognitive decision-making.

A disinhibitory circuit mechanism explains a general principle of peak performance during mid-level arousal.

Perceptual decision-making is highly dependent on the momentary arousal state of the brain, which fluctuates over time on a scale of hours, minutes, and even seconds. The textbook relationship between momentary arousal and task performance is captured by an inverted U-shape, as put forward in the Yerkes-Dodson law. This law suggests optimal performance at moderate levels of arousal and impaired performance at low or high arousal levels. However, despite its popularity, the evidence for this relationship in humans is mixed at best. Here, we use pupil-indexed arousal and performance data from various perceptual decision-making tasks to provide converging evidence for the inverted U-shaped relationship between spontaneous arousal fluctuations and performance across different decision types (discrimination, detection) and sensory modalities (visual, auditory). To further understand this relationship, we built a neurobiologically plausible mechanistic model and show that it is possible to reproduce our findings by incorporating two types of interneurons that are both modulated by an arousal signal. The model architecture produces two dynamical regimes under the influence of arousal: one regime in which performance increases with arousal and another regime in which performance decreases with arousal, together forming an inverted U-shaped arousal-performance relationship. We conclude that the inverted U-shaped arousal-performance relationship is a general and robust property of sensory processing. It might be brought about by the influence of arousal on two types of interneurons that together act as a disinhibitory pathway for the neural populations that encode the available sensory evidence used for the decision.

Catecholaminergic neuromodulation and selective attention jointly shape perceptual decision-making.

Perceptual decisions about sensory input are influenced by fluctuations in ongoing neural activity, most prominently driven by attention and neuromodulator systems. It is currently unknown if neuromodulator activity and attention differentially modulate perceptual decision-making and/or whether neuromodulatory systems in fact control attentional processes. To investigate the effects of two distinct neuromodulatory systems and spatial attention on perceptual decisions, we pharmacologically elevated cholinergic (through donepezil) and catecholaminergic (through atomoxetine) levels in humans performing a visuo-spatial attention task, while we measured electroencephalography (EEG). Both attention and catecholaminergic enhancement improved decision-making at the behavioral and algorithmic level, as reflected in increased perceptual sensitivity and the modulation of the drift rate parameter derived from drift diffusion modeling. Univariate analyses of EEG data time-locked to the attentional cue, the target stimulus, and the motor response further revealed that attention and catecholaminergic enhancement both modulated pre-stimulus cortical excitability, cue- and stimulus-evoked sensory activity, as well as parietal evidence accumulation signals. Interestingly, we observed both similar, unique, and interactive effects of attention and catecholaminergic neuromodulation on these behavioral, algorithmic, and neural markers of the decision-making process. Thereby, this study reveals an intricate relationship between attentional and catecholaminergic systems and advances our understanding about how these systems jointly shape various stages of perceptual decision-making.

Functional magnetic resonance imaging responses during perceptual decision-making at 3 and 7 T in human cortex, striatum, and brainstem.

While functional magnetic resonance imaging (fMRI) at ultra-high field (7 T) promises a general increase in sensitivity compared to lower field strengths, the benefits may be most pronounced for specific applications. The current study aimed to evaluate the relative benefit of 7 over 3 T fMRI for the assessment of responses evoked in different brain regions by a well-controlled cognitive task. At 3 and 7 T, the same participants made challenging perceptual decisions about visual motion combined with monetary rewards for correct choices. Previous work on this task has extensively characterized the underlying cognitive computations and single-cell responses in cortical and subcortical structures. We quantified the evoked fMRI responses in extrastriate visual cortical areas, the striatum, and the brainstem during the decision interval and the post-feedback interval of the task. The dependence of response amplitudes on field strength during the decision interval differed between cortical, striatal, and brainstem regions, with a generally bigger 7 versus 3 T benefit in subcortical structures. We also found stronger responses during relatively easier than harder decisions at 7 T for dopaminergic midbrain nuclei, in line with reward expectation. Our results demonstrate the potential of 7 T fMRI for illuminating the contribution of small brainstem nuclei to the orchestration of cognitive computations in the human brain.

Pupil Dilation and the Slow Wave ERP Reflect Surprise about Choice Outcome Resulting from Intrinsic Variability in Decision Confidence.

Central to human and animal cognition is the ability to learn from feedback in order to optimize future rewards. Such a learning signal might be encoded and broadcasted by the brain's arousal systems, including the noradrenergic locus coeruleus. Pupil responses and the positive slow wave component of event-related potentials reflect rapid changes in the arousal level of the brain. Here, we ask whether and how these variables may reflect surprise: the mismatch between one's expectation about being correct and the outcome of a decision, when expectations fluctuate due to internal factors (e.g., engagement). We show that during an elementary decision task in the face of uncertainty both physiological markers of phasic arousal reflect surprise. We further show that pupil responses and slow wave event-related potential are unrelated to each other and that prediction error computations depend on feedback awareness. These results further advance our understanding of the role of central arousal systems in decision-making under uncertainty.

Graded recruitment of pupil-linked neuromodulation by parametric stimulation of the vagus nerve.

Vagus nerve stimulation (VNS) is thought to affect neural activity by recruiting brain-wide release of neuromodulators. VNS is used in treatment-resistant epilepsy, and is increasingly being explored for other disorders, such as depression, and as a cognitive enhancer. However, the promise of VNS is only partially fulfilled due to a lack of mechanistic understanding of the transfer function between stimulation parameters and neuromodulatory response, together with a lack of biosensors for assaying stimulation efficacy in real time. We here develop an approach to VNS in head-fixed mice on a treadmill and show that pupil dilation is a reliable and convenient biosensor for VNS-evoked cortical neuromodulation. In an 'optimal' zone of stimulation parameters, current leakage and off-target effects are minimized and the extent of pupil dilation tracks VNS-evoked basal-forebrain cholinergic axon activity in neocortex. Thus, pupil dilation is a sensitive readout of the moment-by-moment, titratable effects of VNS on brain state.

Pupil-linked phasic arousal predicts a reduction of choice bias across species and decision domains.

Decisions are often made by accumulating ambiguous evidence over time. The brain's arousal systems are activated during such decisions. In previous work in humans, we found that evoked responses of arousal systems during decisions are reported by rapid dilations of the pupil and track a suppression of biases in the accumulation of decision-relevant evidence (de Gee et al., 2017). Here, we show that this arousal-related suppression in decision bias acts on both conservative and liberal biases, and generalizes from humans to mice, and from perceptual to memory-based decisions. In challenging sound-detection tasks, the impact of spontaneous or experimentally induced choice biases was reduced under high phasic arousal. Similar bias suppression occurred when evidence was drawn from memory. All of these behavioral effects were explained by reduced evidence accumulation biases. Our results point to a general principle of interplay between phasic arousal and decision-making.

Choice history biases subsequent evidence accumulation.

Perceptual choices depend not only on the current sensory input but also on the behavioral context, such as the history of one's own choices. Yet, it remains unknown how such history signals shape the dynamics of later decision formation. In models of decision formation, it is commonly assumed that choice history shifts the starting point of accumulation toward the bound reflecting the previous choice. We here present results that challenge this idea. We fit bounded-accumulation decision models to human perceptual choice data, and estimated bias parameters that depended on observers' previous choices. Across multiple task protocols and sensory modalities, individual history biases in overt behavior were consistently explained by a history-dependent change in the evidence accumulation, rather than in its starting point. Choice history signals thus seem to bias the interpretation of current sensory input, akin to shifting endogenous attention toward (or away from) the previously selected interpretation.

Humans strategically shift decision bias by flexibly adjusting sensory evidence accumulation.

Decision bias is traditionally conceptualized as an internal reference against which sensory evidence is compared. Instead, we show that individuals implement decision bias by shifting the rate of sensory evidence accumulation toward a decision bound. Participants performed a target detection task while we recorded EEG. We experimentally manipulated participants' decision criterion for reporting targets using different stimulus-response reward contingencies, inducing either a liberal or a conservative bias. Drift diffusion modeling revealed that a liberal strategy biased sensory evidence accumulation toward target-present choices. Moreover, a liberal bias resulted in stronger midfrontal pre-stimulus 2-6 Hz (theta) power and suppression of pre-stimulus 8-12 Hz (alpha) power in posterior cortex. Alpha suppression in turn was linked to the output activity in visual cortex, as expressed through 59-100 Hz (gamma) power. These findings show that observers can intentionally control cortical excitability to strategically bias evidence accumulation toward the decision bound that maximizes reward.

Author Correction: Task-evoked pupil responses reflect internal belief states.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Task-evoked pupil responses reflect internal belief states.

Perceptual decisions about the state of the environment are often made in the face of uncertain evidence. Internal uncertainty signals are considered important regulators of learning and decision-making. A growing body of work has implicated the brain's arousal systems in uncertainty signaling. Here, we found that two specific computational variables, postulated by recent theoretical work, evoke boosts of arousal at different times during a perceptual decision: decision confidence (the observer's internally estimated probability that a choice was correct given the evidence) before feedback, and prediction errors (deviations from expected reward) after feedback. We monitored pupil diameter, a peripheral marker of central arousal state, while subjects performed a challenging perceptual choice task with a delayed monetary reward. We quantified evoked pupil responses during decision formation and after reward-linked feedback. During both intervals, decision difficulty and accuracy had interacting effects on pupil responses. Pupil responses negatively scaled with decision confidence prior to feedback and scaled with uncertainty-dependent prediction errors after feedback. This pattern of pupil responses during both intervals was in line with a model using the observer's graded belief about choice accuracy to anticipate rewards and compute prediction errors. We conclude that pupil-linked arousal systems are modulated by internal belief states.

Dynamic modulation of decision biases by brainstem arousal systems.

Decision-makers often arrive at different choices when faced with repeated presentations of the same evidence. Variability of behavior is commonly attributed to noise in the brain's decision-making machinery. We hypothesized that phasic responses of brainstem arousal systems are a significant source of this variability. We tracked pupil responses (a proxy of phasic arousal) during sensory-motor decisions in humans, across different sensory modalities and task protocols. Large pupil responses generally predicted a reduction in decision bias. Using fMRI, we showed that the pupil-linked bias reduction was (i) accompanied by a modulation of choice-encoding pattern signals in parietal and prefrontal cortex and (ii) predicted by phasic, pupil-linked responses of a number of neuromodulatory brainstem centers involved in the control of cortical arousal state, including the noradrenergic locus coeruleus. We conclude that phasic arousal suppresses decision bias on a trial-by-trial basis, thus accounting for a significant component of the variability of choice behavior.

Cognitive and Ocular Factors Jointly Determine Pupil Responses under Equiluminance.

Changes in pupil diameter can reflect high-level cognitive signals that depend on central neuromodulatory mechanisms. However, brain mechanisms that adjust pupil size are also exquisitely sensitive to changes in luminance and other events that would be considered a nuisance in cognitive experiments recording pupil size. We implemented a simple auditory experiment involving no changes in visual stimulation. Using finite impulse-response fitting we found pupil responses triggered by different types of events. Among these are pupil responses to auditory events and associated surprise: cognitive effects. However, these cognitive responses were overshadowed by pupil responses associated with blinks and eye movements, both inevitable nuisance factors that lead to changes in effective luminance. Of note, these latter pupil responses were not recording artifacts caused by blinks and eye movements, but endogenous pupil responses that occurred in the wake of these events. Furthermore, we identified slow (tonic) changes in pupil size that differentially influenced faster (phasic) pupil responses. Fitting all pupil responses using gamma functions, we provide accurate characterisations of cognitive and non-cognitive response shapes, and quantify each response's dependence on tonic pupil size. These results allow us to create a set of recommendations for pupil size analysis in cognitive neuroscience, which we have implemented in freely available software.

Decision-related pupil dilation reflects upcoming choice and individual bias.

A number of studies have shown that pupil size increases transiently during effortful decisions. These decision-related changes in pupil size are mediated by central neuromodulatory systems, which also influence the internal state of brain regions engaged in decision making. It has been proposed that pupil-linked neuromodulatory systems are activated by the termination of decision processes, and, consequently, that these systems primarily affect the postdecisional brain state. Here, we present pupil results that run contrary to this proposal, suggesting an important intradecisional role. We measured pupil size while subjects formed protracted decisions about the presence or absence ("yes" vs. "no") of a visual contrast signal embedded in dynamic noise. Linear systems analysis revealed that the pupil was significantly driven by a sustained input throughout the course of the decision formation. This sustained component was larger than the transient component during the final choice (indicated by button press). The overall amplitude of pupil dilation during decision formation was bigger before yes than no choices, irrespective of the physical presence of the target signal. Remarkably, the magnitude of this pupil choice effect (yes > no) reflected the individual criterion: it was strongest in conservative subjects choosing yes against their bias. We conclude that the central neuromodulatory systems controlling pupil size are continuously engaged during decision formation in a way that reveals how the upcoming choice relates to the decision maker's attitude. Changes in brain state seem to interact with biased decision making in the face of uncertainty.