State-dependent pupil dilation rapidly shifts visual feature selectivity.

To increase computational flexibility, the processing of sensory inputs changes with behavioural context. In the visual system, active behavioural states characterized by motor activity and pupil dilation1,2 enhance sensory responses, but typically leave the preferred stimuli of neurons unchanged2-9. Here we find that behavioural state also modulates stimulus selectivity in the mouse visual cortex in the context of coloured natural scenes. Using population imaging in behaving mice, pharmacology and deep neural network modelling, we identified a rapid shift in colour selectivity towards ultraviolet stimuli during an active behavioural state. This was exclusively caused by state-dependent pupil dilation, which resulted in a dynamic switch from rod to cone photoreceptors, thereby extending their role beyond night and day vision. The change in tuning facilitated the decoding of ethological stimuli, such as aerial predators against the twilight sky10. For decades, studies in neuroscience and cognitive science have used pupil dilation as an indirect measure of brain state. Our data suggest that, in addition, state-dependent pupil dilation itself tunes visual representations to behavioural demands by differentially recruiting rods and cones on fast timescales.

Spiking activity in the visual thalamus is coupled to pupil dynamics across temporal scales.

The processing of sensory information, even at early stages, is influenced by the internal state of the animal. Internal states, such as arousal, are often characterized by relating neural activity to a single "level" of arousal, defined by a behavioral indicator such as pupil size. In this study, we expand the understanding of arousal-related modulations in sensory systems by uncovering multiple timescales of pupil dynamics and their relationship to neural activity. Specifically, we observed a robust coupling between spiking activity in the mouse dorsolateral geniculate nucleus (dLGN) of the thalamus and pupil dynamics across timescales spanning a few seconds to several minutes. Throughout all these timescales, 2 distinct spiking modes-individual tonic spikes and tightly clustered bursts of spikes-preferred opposite phases of pupil dynamics. This multi-scale coupling reveals modulations distinct from those captured by pupil size per se, locomotion, and eye movements. Furthermore, coupling persisted even during viewing of a naturalistic movie, where it contributed to differences in the encoding of visual information. We conclude that dLGN spiking activity is under the simultaneous influence of multiple arousal-related processes associated with pupil dynamics occurring over a broad range of timescales.

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.

Pupillary Responses Reflect Dynamic Changes in Multiple Cognitive Factors During Associative Learning in Primates.

Associative learning involves complex interactions of multiple cognitive factors. While adult subjects can articulate these factors verbally, for model animals such as macaques, we rely on behavioral outputs. In our study, we used pupillary responses as an alternative measure to capture these underlying cognitive changes. We recorded the dynamic changes in the pupils of three male macaques when they learned the associations between visual stimuli and reward sizes under the classical Pavlovian experimental paradigm. We found that during the long-term learning process, the gradual changes in the pupillary response reflect the changes in the cognitive state of the animals. The pupillary response can be explained by a linear combination of components corresponding to multiple cognitive factors. These components reflect the impact of visual stimuli on the pupils, the prediction of reward values associated with the visual stimuli, and the macaques' understanding of the current experimental reward rules. The changing patterns of these factors during interday and intraday learning clearly demonstrate the enhancement of current reward-stimulus association and the weakening of previous reward-stimulus association. Our study shows that the dynamic response of pupils can serve as an objective indicator to characterize the psychological changes of animals, understand their learning process, and provide important tools for exploring animal behavior during the learning process.

Double Dissociation of Spontaneous Alpha-Band Activity and Pupil-Linked Arousal on Additive and Multiplicative Perceptual Gain.

Perception is a probabilistic process dependent on external stimulus properties and one's internal state. However, which internal states influence perception and via what mechanisms remain debated. We studied how spontaneous alpha-band activity (8-13 Hz) and pupil fluctuations impact visual detection and confidence across stimulus contrast levels (i.e., the contrast response function, CRF). In human subjects of both sexes, we found that low prestimulus alpha power induced an "additive" shift in the CRF, whereby stimuli were reported present more frequently at all contrast levels, including contrast of zero (i.e., false alarms). Conversely, prestimulus pupil size had a "multiplicative" effect on detection such that stimuli occurring during large pupil states (putatively corresponding to higher arousal) were perceived more frequently as contrast increased. Signal detection modeling reveals that alpha power changes detection criteria equally across the CRF but not detection sensitivity (d'), whereas pupil-linked arousal modulated sensitivity, particularly for higher contrasts. Interestingly, pupil size and alpha power were positively correlated, meaning that some of the effect of alpha on detection may be mediated by pupil fluctuations. However, pupil-independent alpha still induced an additive shift in the CRF corresponding to a criterion effect. Our data imply that low alpha boosts detection and confidence by an additive factor, rather than by a multiplicative scaling of contrast responses, a profile which captures the effect of pupil-linked arousal. We suggest that alpha power and arousal fluctuations have dissociable effects on behavior. Alpha reflects the baseline level of visual excitability, which can vary independent of arousal.

Neural Representation of Valenced and Generic Probability and Uncertainty.

Representing the probability and uncertainty of outcomes facilitates adaptive behavior by allowing organisms to prepare in advance and devote attention to relevant events. Probability and uncertainty are often studied only for valenced (appetitive or aversive) outcomes, raising the question of whether the identified neural machinery also processes the probability and uncertainty of motivationally neutral outcomes. Here, we aimed to dissociate valenced from valence-independent (i.e., generic) probability (p; maximum at p = 1) and uncertainty (maximum at p = 0.5) signals using human neuroimaging. In a Pavlovian task (n = 41; 19 females), different cues predicted appetitive, aversive, or neutral liquids with different probabilities (p = 0, p = 0.5, p = 1). Cue-elicited motor responses accelerated, and pupil sizes increased primarily for cues that predicted valenced liquids with higher probability. For neutral liquids, uncertainty rather than probability tended to accelerate cue-induced responding and decrease pupil size. At the neural level, generic uncertainty signals were limited to the occipital cortex, while generic probability also activated the anterior ventromedial prefrontal cortex. These generic probability and uncertainty signals contrasted with cue-induced responses that only encoded the probability and uncertainty of valenced liquids in medial prefrontal, insular, and occipital cortices. Our findings show a behavioral and neural dissociation of generic and valenced signals. Thus, some parts of the brain keep track of motivational charge while others do not, highlighting the need and usefulness of characterizing the exact nature of learned representations.

Pupil-Linked Arousal Modulates Precision of Stimulus Representation in Cortex.

Neural responses are naturally variable from one moment to the next, even when the stimulus is held constant. What factors might underlie this variability in neural population activity? We hypothesized that spontaneous fluctuations in cortical stimulus representations are created by changes in arousal state. We tested the hypothesis using a combination of fMRI, probabilistic decoding methods, and pupillometry. Human participants (20 female, 12 male) were presented with gratings of random orientation. Shortly after viewing the grating, participants reported its orientation and gave their level of confidence in this judgment. Using a probabilistic fMRI decoding technique, we quantified the precision of the stimulus representation in the visual cortex on a trial-by-trial basis. Pupil size was recorded and analyzed to index the observer's arousal state. We found that the precision of the cortical stimulus representation, reported confidence, and variability in the behavioral orientation judgments varied from trial to trial. Interestingly, these trial-by-trial changes in cortical and behavioral precision and confidence were linked to pupil size and its temporal rate of change. Specifically, when the cortical stimulus representation was more precise, the pupil dilated more strongly prior to stimulus onset and remained larger during stimulus presentation. Similarly, stronger pupil dilation during stimulus presentation was associated with higher levels of subjective confidence, a secondary measure of sensory precision, as well as improved behavioral performance. Taken together, our findings support the hypothesis that spontaneous fluctuations in arousal state modulate the fidelity of the stimulus representation in the human visual cortex, with clear consequences for behavior.

Neural α Oscillations and Pupil Size Differentially Index Cognitive Demand under Competing Audiovisual Task Conditions.

Cognitive demand is thought to modulate two often used, but rarely combined, measures: pupil size and neural α (8-12 Hz) oscillatory power. However, it is unclear whether these two measures capture cognitive demand in a similar way under complex audiovisual-task conditions. Here we recorded pupil size and neural α power (using electroencephalography), while human participants of both sexes concurrently performed a visual multiple object-tracking task and an auditory gap detection task. Difficulties of the two tasks were manipulated independent of each other. Participants' performance decreased in accuracy and speed with increasing cognitive demand. Pupil size increased with increasing difficulty for both the auditory and the visual task. In contrast, α power showed diverging neural dynamics: parietal α power decreased with increasing difficulty in the visual task, but not with increasing difficulty in the auditory task. Furthermore, independent of task difficulty, within-participant trial-by-trial fluctuations in pupil size were negatively correlated with α power. Difficulty-induced changes in pupil size and α power, however, did not correlate, which is consistent with their different cognitive-demand sensitivities. Overall, the current study demonstrates that the dynamics of the neurophysiological indices of cognitive demand and associated effort are multifaceted and potentially modality-dependent under complex audiovisual-task conditions.SIGNIFICANCE STATEMENT Pupil size and oscillatory α power are associated with cognitive demand and effort, but their relative sensitivity under complex audiovisual-task conditions is unclear, as is the extent to which they share underlying mechanisms. Using an audiovisual dual-task paradigm, we show that pupil size increases with increasing cognitive demands for both audition and vision. In contrast, changes in oscillatory α power depend on the respective task demands: parietal α power decreases with visual demand but not with auditory task demand. Hence, pupil size and α power show different sensitivity to cognitive demands, perhaps suggesting partly different underlying neural mechanisms.

Relating Pupil Diameter and Blinking to Cortical Activity and Hemodynamics across Arousal States.

Arousal state affects neural activity and vascular dynamics in the cortex, with sleep associated with large changes in the local field potential and increases in cortical blood flow. We investigated the relationship between pupil diameter and blink rate with neural activity and blood volume in the somatosensory cortex in male and female unanesthetized, head-fixed mice. We monitored these variables while the mice were awake, during periods of rapid eye movement (REM), and non-rapid eye movement (NREM) sleep. Pupil diameter was smaller during sleep than in the awake state. Changes in pupil diameter were coherent with both gamma-band power and blood volume in the somatosensory cortex, but the strength and sign of this relationship varied with arousal state. We observed a strong negative correlation between pupil diameter and both gamma-band power and blood volume during periods of awake rest and NREM sleep, although the correlations between pupil diameter and these signals became positive during periods of alertness, active whisking, and REM. Blinking was associated with increases in arousal and decreases in blood volume when the mouse was asleep. Bilateral coherence in gamma-band power and in blood volume dropped following awake blinking, indicating a reset of neural and vascular activity. Using only eye metrics (pupil diameter and eye motion), we could determine the arousal state of the mouse ('Awake,' 'NREM,' 'REM') with >90% accuracy with a 5 s resolution. There is a strong relationship between pupil diameter and hemodynamics signals in mice, reflecting the pronounced effects of arousal on cerebrovascular dynamics.SIGNIFICANCE STATEMENT Determining arousal state is a critical component of any neuroscience experiment. Pupil diameter and blinking are influenced by arousal state, as are hemodynamics signals in the cortex. We investigated the relationship between cortical hemodynamics and pupil diameter and found that pupil diameter was strongly related to the blood volume in the cortex. Mice were more likely to be awake after blinking than before, and blinking resets neural activity. Pupil diameter and eye motion can be used as a reliable, noninvasive indicator of arousal state. As mice transition from wake to sleep and back again over a timescale of seconds, monitoring pupil diameter and eye motion permits the noninvasive detection of sleep events during behavioral or resting-state experiments.

Pupil Size and Eye Movements Differently Index Effort in Both Younger and Older Adults.

The assessment of mental effort is increasingly relevant in neurocognitive and life span domains. Pupillometry, the measure of the pupil size, is often used to assess effort but has disadvantages. Analysis of eye movements may provide an alternative, but research has been limited to easy and difficult task demands in younger adults. An effort measure must be sensitive to the whole effort profile, including "giving up" effort investment, and capture effort in different age groups. The current study comprised three experiments in which younger (n = 66) and older (n = 44) adults listened to speech masked by background babble at different signal-to-noise ratios associated with easy, difficult, and impossible speech comprehension. We expected individuals to invest little effort for easy and impossible speech (giving up) but to exert effort for difficult speech. Indeed, pupil size was largest for difficult but lower for easy and impossible speech. In contrast, gaze dispersion decreased with increasing speech masking in both age groups. Critically, gaze dispersion during difficult speech returned to levels similar to easy speech after sentence offset, when acoustic stimulation was similar across conditions, whereas gaze dispersion during impossible speech continued to be reduced. These findings show that a reduction in eye movements is not a byproduct of acoustic factors, but instead suggest that neurocognitive processes, different from arousal-related systems regulating the pupil size, drive reduced eye movements during high task demands. The current data thus show that effort in one sensory domain (audition) differentially impacts distinct functional properties in another sensory domain (vision).

The Costs (and Benefits?) of Effortful Listening for Older Adults: Insights from Simultaneous Electrophysiology, Pupillometry, and Memory.

Although the impact of acoustic challenge on speech processing and memory increases as a person ages, older adults may engage in strategies that help them compensate for these demands. In the current preregistered study, older adults (n = 48) listened to sentences-presented in quiet or in noise-that were high constraint with either expected or unexpected endings or were low constraint with unexpected endings. Pupillometry and EEG were simultaneously recorded, and subsequent sentence recognition and word recall were measured. Like young adults in prior work, we found that noise led to increases in pupil size, delayed and reduced ERP responses, and decreased recall for unexpected words. However, in contrast to prior work in young adults where a larger pupillary response predicted a recovery of the N400 at the cost of poorer memory performance in noise, older adults did not show an associated recovery of the N400 despite decreased memory performance. Instead, we found that in quiet, increases in pupil size were associated with delays in N400 onset latencies and increased recognition memory performance. In conclusion, we found that transient variation in pupil-linked arousal predicted trade-offs between real-time lexical processing and memory that emerged at lower levels of task demand in aging. Moreover, with increased acoustic challenge, older adults still exhibited costs associated with transient increases in arousal without the corresponding benefits.

Violation of identity-specific action-effect prediction increases pupil size and attenuates auditory event-related potentials at P2 latencies when action-effects are behaviorally relevant.

Self-initiated sensory action effects are widely assumed to lead to less intense perception and reduced neural responses compared to externally triggered stimuli (sensory attenuation). However, it is unclear if sensory attenuation occurs in all cases of action-effect prediction. Specifically, when predicted action-effects are relevant to determine follow-up actions attenuation could be detrimental. We quantified auditory event-related potentials (ERP) in electroencephalography (EEG) when human participants created two-sound sequences by pressing two keys on a keyboard associated with different pitch, giving rise to identity-specific action-effect prediction after the first keypress. The first sound corresponded to (congruent) or violated (incongruent) the predicted pitch and was either relevant for the selection of the second keypress to correctly complete the sequence (Relevance) or irrelevant (Control Movement), or there was only one keypress and sound (Baseline). We found a diminished P2-timed ERP component in incongruent compared to congruent trials when the sound was relevant for the subsequent action. This effect of action-effect prediction was due to an ERP reduction for incongruent relevant sounds compared to incongruent irrelevant sounds at P2 latencies and correlated negatively with modulations of pupil dilation. Contrary to our expectation, we did not observe an N1 modulation by congruency in any condition. Attenuation of the N1 component seems absent for predicted identity-specific auditory action effects, while P2-timed ERPs as well as pupil size are sensitive to predictability, at least when action effects are relevant for the selection of the next action. Incongruent relevant stimuli thereby take a special place and seem to be subject to attentional modulations and error processing.

Olfaction modulates cortical arousal independent of perceived odor intensity and pleasantness.

Throughout history, various odors have been harnessed to invigorate or relax the mind. The mechanisms underlying odors' diverse arousal effects remain poorly understood. We conducted five experiments (184 participants) to investigate this issue, using pupillometry, electroencephalography, and the attentional blink paradigm, which exemplifies the limit in attentional capacity. Results demonstrated that exposure to citral, compared to vanillin, enlarged pupil size, reduced resting-state alpha oscillations and alpha network efficiency, augmented beta-gamma oscillations, and enhanced the coordination between parietal alpha and frontal beta-gamma activities. In parallel, it attenuated the attentional blink effect. These effects were observed despite citral and vanillin being comparable in perceived odor intensity, pleasantness, and nasal pungency, and were unlikely driven by semantic biases. Our findings reveal that odors differentially alter the small-worldness of brain network architecture, and thereby brain state and arousal. Furthermore, they establish arousal as a unique dimension in olfactory space, distinct from intensity and pleasantness.

Ocular working memory signals are flexible to behavioral priority and subjective imagery strength.

The pupillary light response was long considered a brainstem reflex, outside of cognitive influence. However, newer findings indicate that pupil dilation (and eye movements) can reflect content held "in mind" with working memory (WM). These findings may reshape understanding of ocular and WM mechanisms, but it is unclear whether the signals are artifactual or functional to WM. Here, we ask whether peripheral and oculomotor WM signals are sensitive to the task-relevance or "attentional state" of WM content. During eye-tracking, human participants saw both dark and bright WM stimuli, then were retroactively cued to the item that would most likely be tested. Critically, we manipulated the attentional priority among items by varying the cue reliability across blocks. We confirmed previous findings that remembering darker items is associated with larger pupils (vs. brighter), and that gaze is biased toward cued item locations. Moreover, we discovered that pupil and eye movement responses were influenced differently by WM item relevance. Feature-specific pupillary effects emerged only for highly prioritized WM items but were eliminated when cues were less reliable, and pupil effects also increased with self-reported visual imagery strength. Conversely, gaze position consistently veered toward the cued item location, regardless of cue reliability. However, biased microsaccades occurred at a higher frequency when cues were more reliable, though only during a limited post-cue time window. Therefore, peripheral sensorimotor processing is sensitive to the task-relevance or functional state of internal WM content, but pupillary and eye movement WM signals show distinct profiles. These results highlight a potential role for early visual processing in maintaining multiple WM content dimensions.NEW & NOTEWORTHY Here, we found that working memory (WM)-driven ocular inflections-feature-specific pupillary and saccadic biases-were muted for memory items that were less behaviorally relevant. This work illustrates that functionally informative goal signals may extend as early as the sensorimotor periphery, that pupil size may be under more fine-grained control than originally thought, and that ocular signals carry multiple dimensions of cognitively relevant information.

The pupil dilation response as an indicator of visual cue uncertainty and auditory outcome surprise.

In everyday perception, we combine incoming sensory information with prior expectations. Expectations can be induced by cues that indicate the probability of following sensory events. The information provided by cues may differ and hence lead to different levels of uncertainty about which event will follow. In this experiment, we employed pupillometry to investigate whether the pupil dilation response to visual cues varies depending on the level of cue-associated uncertainty about a following auditory outcome. Also, we tested whether the pupil dilation response reflects the amount of surprise about the subsequently presented auditory stimulus. In each trial, participants were presented with a visual cue (face image) which was followed by an auditory outcome (spoken vowel). After the face cue, participants had to indicate by keypress which of three auditory vowels they expected to hear next. We manipulated the cue-associated uncertainty by varying the probabilistic cue-outcome contingencies: One face was most likely followed by one specific vowel (low cue uncertainty), another face was equally likely followed by either of two vowels (intermediate cue uncertainty) and the third face was followed by all three vowels (high cue uncertainty). Our results suggest that pupil dilation in response to task-relevant cues depends on the associated uncertainty, but only for large differences in the cue-associated uncertainty. Additionally, in response to the auditory outcomes, the pupil dilation scaled negatively with the cue-dependent probabilities, likely signalling the amount of surprise.

The influence of transcranial direct current stimulation to the trigeminal nerve on attention and arousal.

One mechanism by which transcranial direct current stimulation (tDCS) has been proposed to improve attention is by transcutaneous stimulation of cranial nerves, thereby activating the locus coeruleus (LC). Specifically, placement of the electrodes over the frontal bone and mastoid is thought to facilitate current flow across the face as a path of least resistance. The face is innervated by the trigeminal nerve, and the trigeminal nerve is interconnected with the LC. In this study, we tested whether stimulating the trigeminal nerve impacts indices of LC activity and performance on a sustained attention task. We replicated previous research that shows deterioration in task performance, increases in the rate of task-unrelated thoughts, and reduced pupil responses due to time on task irrespective of tDCS condition (sham, anodal, and cathodal stimulation). Importantly, tDCS did not influence pupil dynamics (pretrial or stimulus-evoked), self-reported attention state, nor task performance in active versus sham stimulation conditions. The findings reported here are consistent with theories about arousal centered on a hypothesized link between LC activity indexed by pupil size, task performance, and self-reported attention state but fail to support hypotheses that tDCS over the trigeminal nerve influences indices of LC function.

Pupil dilation reflects effortful action invigoration in overcoming aversive Pavlovian biases.

"Pavlovian" or "motivational" biases describe the phenomenon that the valence of prospective outcomes modulates action invigoration: Reward prospect invigorates action, whereas punishment prospect suppresses it. The adaptive role of these biases in decision-making is still unclear. One idea is that they constitute a fast-and-frugal decision strategy in situations characterized by high arousal, e.g., in presence of a predator, which demand a quick response. In this pre-registered study (N = 35), we tested whether such a situation-induced via subliminally presented angry versus neutral faces-leads to increased reliance on Pavlovian biases. We measured trial-by-trial arousal by tracking pupil diameter while participants performed an orthogonalized Motivational Go/NoGo Task. Pavlovian biases were present in responses, reaction times, and even gaze, with lower gaze dispersion under aversive cues reflecting "freezing of gaze." The subliminally presented faces did not affect responses, reaction times, or pupil diameter, suggesting that the arousal manipulation was ineffective. However, pupil dilations reflected facets of bias suppression, specifically the physical (but not cognitive) effort needed to overcome aversive inhibition: Particularly strong and sustained dilations occurred when participants managed to perform Go responses to aversive cues. Conversely, no such dilations occurred when they managed to inhibit responses to Win cues. These results suggest that pupil diameter does not reflect response conflict per se nor the inhibition of prepotent responses, but specifically effortful action invigoration as needed to overcome aversive inhibition. We discuss our results in the context of the "value of work" theory of striatal dopamine.

Altered pupil responses to social and non-social stimuli in Shank3 mutant dogs.

Pupillary response, an important process in visual perception and social and emotional cognition, has been widely studied for understanding the neural mechanisms of neuropsychiatric disorders. However, there have been few studies on pupil response to social and non-social stimuli in animal models of neurodevelopmental disorders including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder. Here, we developed a pupilometer using a robust eye feature-detection algorithm for real-time pupillometry in dogs. In a pilot study, we found that a brief light flash induced a less-pronounced and slower pupil dilation response in gene-edited dogs carrying mutations in Shank3; mutations of its ortholog in humans were repeatedly identified in ASD patients. We further found that obnoxious, loud firecracker sound of 120 dB induced a stronger and longer pupil dilation response in Shank3 mutant dogs, whereas a high reward food induced a weaker pupillary response in Shank3 mutants than in wild-type control dogs. In addition, we found that Shank3 mutants showed compromised pupillary synchrony during dog-human interaction. These findings of altered pupil response in Shank3 mutant dogs recapitulate the altered sensory responses in ASD patients. Thus, this study demonstrates the validity and value of the pupilometer for dogs, and provides an effective paradigm for studying the underlying neural mechanisms of ASD and potentially other psychiatric disorders.

Effects of caffeine intake on pupillary parameters in humans: a systematic review and meta-analysis.

Caffeine is a widely used drug that broadly affects human cognition and brain function. Caffeine acts as an antagonist to the adenosine receptors in the brain. Previous anecdotal reports have also linked caffeine intake with changes in pupil diameter. By modifying the retinal irradiance, pupil diameter modulates all ocular light exposure relevant for visual (i.e., perception, detection and discrimination of visual stimuli) and non-visual (i.e., circadian) functions. To date, the extent of the influence of caffeine on pupillary outcomes, including pupil diameter, has not been examined in a systematic review. We implemented a systematic review laid out in a pre-registered protocol following PRISMA-P guidelines. We only included original research articles written in English reporting studies with human participants, in which caffeine was administered, and pupil diameter was measured using objective methods. Using broad search strategies, we consulted various databases (PsycINFO, Medline, Embase, Cochrane Library, bioRxiv and medRxiv) and used the Covidence platform to screen, review and extract data from studies. After importing studies identified through database search (n = 517 imported, n = 46 duplicates), we screened the title and abstracts (n = 471), finding 14 studies meeting our eligibility criteria. After full-text review, we excluded seven studies, leaving only a very modest number of included studies (n = 7). Extraction of information revealed that the existing literature on the effect of caffeine on pupil parameters is very heterogeneous, differing in pupil assessment methods, time of day of caffeine administration, dose, and protocol timing and design. The evidence available in the literature does not provide consistent results but studies rated as valid by quality assessment suggest a small effect of caffeine on pupil parameters. We summarize the numeric results as both differences in absolute pupil diameter and in terms of effect sizes. More studies are needed using modern pupil assessment methods, robust study design, and caffeine dose-response methodology.

Pupillary response is associated with the reset and switching of functional brain networks during salience processing.

The interface between processing internal goals and salient events in the environment involves various top-down processes. Previous studies have identified multiple brain areas for salience processing, including the salience network (SN), dorsal attention network, and the locus coeruleus-norepinephrine (LC-NE) system. However, interactions among these systems in salience processing remain unclear. Here, we simultaneously recorded pupillometry, EEG, and fMRI during an auditory oddball paradigm. The analyses of EEG and fMRI data uncovered spatiotemporally organized target-associated neural correlates. By modeling the target-modulated effective connectivity, we found that the target-evoked pupillary response is associated with the network directional couplings from late to early subsystems in the trial, as well as the network switching initiated by the SN. These findings indicate that the SN might cooperate with the pupil-indexed LC-NE system in the reset and switching of cortical networks, and shed light on their implications in various cognitive processes and neurological diseases.