Locus Coeruleus-norepinephrine System Research Articles

Impairment of autonomic emotional response for executive function in children with ADHD: A multi-modal fNIRS and pupillometric study during the Wisconsin Card Sorting Test

ObjectiveChildren with attention deficit hyperactivity disorder (ADHD) often experience difficulties with emotional control and a consequent inability to perform tasks. To clarify the effects of emotional behavior on cognitive functions, we aimed to determine the association between emotional changes and executive functions in children with ADHD by measuring the pupil diameter changes associated with emotional changes. Participants and methodsThis study included 14 children with ADHD and 10 typically developing children (TDC) aged between 10 and 16 years. During the Wisconsin Card Sorting Test (WCST), which is related to context formation and task switching among executive functions, changes in pupil diameter and frontal oxygenated hemoglobin (oxy-Hb) using functional near-infrared spectroscopy (fNIRS) were recorded simultaneously. Pupil diameter changes during “cognitive shift” and “consecutive correction” were compared between both groups. ResultsDuring cognitive shift, the pupils of children with ADHD contracted, whereas those of the TDC were mydriatic. During consecutive correction, the pupils of children with ADHD were mydriatic, whereas those of the TDC tended to contract. These results correlated with WCST performance. Moreover, during cognitive shifts, changes in bilateral frontal blood flow were increased in TDC, but not in children with ADHD. ConclusionThe locus coeruleus-norepinephrine (LC-NE) system plays an important role in pupillary diameter response. These results suggest that the LC-NE system may be dysfunctional in children with ADHD, and the system’s abnormality may lead to affective abnormalities in such patients, which results in poor performance on WCST (i.e., impaired executive functions).

Event-related transcutaneous vagus nerve stimulation modulates behaviour and pupillary responses during an auditory oddball task

Transcutaneous auricular vagus nerve stimulation (taVNS) is a neuromodulatory technique that is thought to activate the Locus Coeruleus-Noradrenaline (LC-NA) system. Standard taVNS protocols consist of the administration of intermittent or continuous stimulation over long periods. However, there is currently a limited understanding of the temporal dynamics of taVNS modulation of cognitive processes, as well as its mechanisms of action. We argue that novel stimulation approaches, informed by established theories of the LC-NA system, are needed to further our understanding of the neurocognitive underpinnings of taVNS. In this pre-registered study, we tested whether an “event-related” taVNS protocol can modulate the LC-NA system. In a within-subject design (single session) we delivered brief trains of taVNS (3 s) during an auditory oddball paradigm. The taVNS was time-locked to the target stimuli presentation and randomly interleaved with sham stimulation. Response times (RT) and stimuli-driven pupillary diameter (PD) were used as indices of LC-NA activity. Results revealed that active taVNS increased RT to targets, as compared to sham trials. Notably, in line with current theories of LC-NA functioning, taVNS modulation of target-related pupil dilation depended on pre-stimulation PD, an index of baseline LC-NA activity. In particular, active (vs. sham) taVNS was associated with smaller pupil dilation in trials where the baseline PD was small. These results demonstrate, for the first time, the effectiveness of brief event-related taVNS in the modulation of cognitive processes and highlight the importance of using pupil size as an index of tonic and phasic LC-NA activity.

Noradrenergic innervations of the medial prefrontal cortex mediate empathy for pain in rats via the α1 and β receptors

Empathy involves integrated affective and cognitive processes to share the emotional state of others. This evolutionarily conserved ability has also been identified in nonhuman primates and rodents. Our previous work demonstrated that social interaction with a cagemate rat in pain induces mechanical pain hypersensitivity in cagemate observer (CO) rats. Moreover, we also demonstrated that the medial prefrontal cortex (mPFC) and the locus coeruleus-norepinephrine (LC-NE) system are involved in this process. The LC sends noradrenergic innervations throughout the brain, and its innervation of the prefrontal cortex plays important roles in working memory and attention. The present study seeks to study the roles of the LC-to-mPFC pathway in pain empathy in rats. Selective ablation of the noradrenergic innervations of the mPFC through bilateral injections of the axonally transported catecholamine immunotoxin, saporin-conjugated antiserum to dopamine-β-hydroxylase into the mPFC diminished mechanical pain hypersensitivity in CO rats. Bilateral intra-mPFC applications of the adrenergic α1 receptor antagonist prazosin and the β receptor antagonist propranolol, but not the adrenergic α2 antagonist yohimbine, eliminated mechanical pain hypersensitivity in CO rats. In contrast, intra-mPFC applications of prazosin, yohimbine or propranolol did not affect the mechanical pain sensitivity of rats per se. Our results indicate that noradrenergic innervations in the mPFC mediate empathy for pain in rats via the α1 and β receptors.

Associations between locus coeruleus integrity and diagnosis, age, and cognitive performance in older adults with and without late-life depression: An exploratory study

Late-life depression (LLD) is a risk factor for age-dependent cognitive deterioration. Norepinephrine-related degeneration in the locus coeruleus (LC) may explain this link. To examine the LC norepinephrine system in vivo, we acquired neuromelanin-sensitive MRI (NM-MRI) in a sample of 48 participants, including 25 with LLD (18 women, age 68.08 ± 5.41) and 23 never-depressed comparison participants (ND, 12 women, age 70 ± 8.02), matched on age and cognitive status. We employed a semi-automated procedure to segment the LC into three bilateral sections along its rostro-caudal extent, and calculated relative contrast as a proxy of integrity. Then, we examined associations between integrity and LLD diagnosis, age, and cognition, as measured via the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Delis-Kaplan Executive Function System (D-KEFS). We did not identify an effect of LLD diagnosis nor age on LC integrity, but exploratory canonical correlation analysis across the combined participant sample revealed a strong (Rc = 0.853) and significant multivariate relationship between integrity and cognition (Wilks’ λ = 0.03, F(84, 162.44) = 1.66, p = <.01). The first and only significant variate explained 72.83% model variance, and linked better attention and delayed memory performance, faster processing speed, and lower verbal fluency performance with higher integrity in the right rostral but lower integrity in the left caudal LC. Our results complement prior evidence of LC involvement in cognition in healthy older adults, and extend this association to individuals with LLD.

Current challenges in reliably targeting the noradrenergic locus coeruleus using transcutaneous auricular vagus nerve stimulation (taVNS).

Transcutaneous auricular vagus nerve stimulation (taVNS), as a non-invasive brain stimulation technique may influence the locus coeruleus-norepinephrine system (LC-NE system) via modulation of the Vagus Nerve (VN) which projects to the LC. Few human studies exist examining the effects of taVNS on the LC-NE system and studies to date assessing the ability of taVNS to target the LC yield heterogeneous results. The aim of this review is to present an overview of the current challenges in assessing effects of taVNS on LC function and how translational approaches spanning animal and human research can help in this regard. A particular emphasis of the review discusses how the effects of taVNS may be influenced by changes in structure and function of the LC-NE system across the human lifespan and in disease.

Fluid intelligence and the locus coeruleus–norepinephrine system

SignificanceTo understand mind and behavior we must understand the biological basis of intelligence. Despite significant progress, we lack a complete picture that integrates different levels of brain function and explains individual differences in cognitive ability. We propose that the locus coeruleus, the source of norepinephrine for the brain, plays a key role in this puzzle. It does so at all levels of brain function, regulating processes of learning, memory, and attention. We use baseline pupil size, which covaries with locus coeruleus activity, to anchor the present analyses of the role of the locus coeruleus in cognitive ability. This work provides a foundation for future research integrating different levels of brain function with individual differences in cognitive ability.

Sex Differences in Locus Coeruleus: A Heuristic Approach That May Explain the Increased Risk of Alzheimer's Disease in Females.

This article aims to reevaluate our approach to female vulnerability to Alzheimer's disease (AD) and put forth a new hypothesis considering how sex differences in the locus coeruleus-noradrenaline (LC-NA) structure and function could account for why females are more likely to develop AD. We specifically focus our attention on locus coeruleus (LC) morphology, the paucity of estrogens, neuroinflammation, blood-brain barrier permeability, apolipoprotein ɛ4 polymorphism (APOEɛ4), and cognitive reserve. The role of the LC-NA system and sex differences are two of the most rapidly emerging topics in AD research. Current literature either investigates the LC due to it being one of the first brain areas to develop AD pathology or acknowledges the neuroprotective effects of estrogens and how the loss of these female hormones have the capacity to contribute to the sex differences seen in AD; however, existing research has neglected to concurrently examine these two rationales and therefore leaving our hypothesis undetermined. Collectively, this article should assist in alleviating current challenges surrounding female AD by providing thought-provoking connections into the interrelationship between the disruption of the female LC-NA system, the decline of estrogens, and AD vulnerability. It is therefore likely that treatment for this heterogeneous disease may need to be distinctly developed for females and males separately, and may require a precision medicine approach.

Larger pupil dilation to nonsocial sounds in infants with subsequent autism diagnosis.

Studies of infants with an elevated likelihood of autism spectrum disorder can identify basic developmental processes that are associated with subsequently emerging clinical symptoms. Atypical responsiveness to sounds in infancy is such a potential early marker of autism. Here, we used pupillometry to quantify reactivity to social and nonsocial sounds in infants with a subsequent diagnosis. Previous research suggest that pupil dilation reflects attentional alerting, and link it to the locus coeruleus norepinephrine system. We measured pupil dilation responses to child-directed speech and the sound of running water; sounds infants often hear in their everyday life. The final sample consisted of 99 ten-month-old infants (52 girls), of whom 68 had an elevated likelihood of autism and 31 were typically developing low-likelihood infants. At follow-up (36 months of age), 18 children in the elevated-likelihood group were diagnosed with autism. Compared to infants without diagnosis, the infants who were subsequently diagnosed with autism had larger pupil dilation when listening to nonsocial sounds, while reactivity to speech was strikingly similar between groups. In the total sample, more pupil dilation to the nonsocial sound was associated with higher levels of autistic symptoms. We also found that on a trial-by-trial basis, across all conditions and groups, more pupil dilation was associated with making fewer gaze shifts. This study did not find evidence of atypical pupillary reactivity to child-directed speech early in life in autism. Instead, the results suggest that certain nonsocial sounds elicit atypically strong alerting responses in infants with a subsequent autism diagnosis. These findings may have important theoretical and clinical implications.

Attentional Disengagement and the Locus Coeruleus - Norepinephrine System in Children With Autism Spectrum Disorder.

BackgroundDifferences in non-social attentional functions have been identified as among the earliest features that distinguish infants later diagnosed with autism spectrum disorder (ASD), and may contribute to the emergence of core ASD symptoms. Specifically, slowed attentional disengagement and difficulty reorienting attention have been found across the lifespan in those at risk for, or diagnosed with, ASD. Additionally, the locus coeruleus-norepinephrine (LC-NE) system, which plays a critical role in arousal regulation and selective attention, has been shown to function atypically in ASD. While activity of the LC-NE system is associated with attentional disengagement and reorienting in typically developing (TD) individuals, it has not been determined whether atypical LC-NE activity relates to attentional disengagement impairments observed in ASD.ObjectiveTo examine the relationship between resting pupil diameter (an indirect measure of tonic LC-NE activation) and attentional disengagement in children with ASD.MethodsParticipants were 21 school-aged children with ASD and 20 age- and IQ-matched TD children. The study consisted of three separate experiments: a resting eye-tracking task and visual and auditory gap-overlap paradigms. For the resting eye-tracking task, pupil diameter was monitored while participants fixated a central crosshair. In the gap-overlap paradigms, participants were instructed to fixate on a central stimulus and then move their eyes to peripherally presented visual or auditory targets. Saccadic reaction times (SRT), percentage of no-shift trials, and disengagement efficiency were measured.ResultsChildren with ASD had significantly larger resting pupil size compared to their TD peers. The groups did not differ for overall SRT, nor were there differences in SRT for overlap and gap conditions between groups. However, the ASD group did evidence impairments in disengagement (larger step/gap effects, higher percentage of no-shift trials, and reduced disengagement efficiency) compared to their TD peers. Correlational analyses showed that slower, less efficient disengagement was associated with increased pupil diameter.ConclusionConsistent with prior reports, children with ASD show significantly larger resting pupil diameter, indicative of atypically elevated tonic LC-NE activity. Associations between pupil size and measures of attentional disengagement suggest that atypically increased tonic activation of the LC-NE system may be associated with poorer attentional disengagement in children with ASD.

Effort Mobilization and Lapses of Sustained Attention.

The current study examined whether effort mobilization would enhance sustained attention and reduce lapses of attention. Participants performed a sustained attention task and were randomly assigned to either an effort condition where they were instructed to "Try Hard" on a subset of trials or were assigned to a control condition with no "Try Hard" instructions. Pupillary responses were continuously recorded, and periodically during the task participants were presented with thought probes to determine whether they were on or off task. The results suggested within the effort condition there were no behavioral differences between Try Hard and "Standard" trials. Preparatory pupil responses were increased in Try Hard trials, but there were no differences for phasic pupillary responses to stimulus onset. In contrast, examining differences between the effort and control conditions suggested that participants who received the Try Hard instructions demonstrated faster overall performance, a reduction in very long reaction times, and reported fewer off-task thoughts compared with participants in the control condition. Participants in the effort condition also demonstrated a larger ramp-up in pupillary responses during the preparatory interval and a larger phasic response to stimulus onset compared with participants in the control condition. These results are consistent with attention allocation models suggesting that participants in the effort condition mobilized more attentional effort than participants in the control condition, resulting in enhanced sustained attention and a reduction in lapses of attention. These results also are consistent with recent theories, which suggest that the locus coeruleus norepinephrine system is associated with effort mobilization.

Pupillometry Reveals the Role of Arousal in a Postexercise Benefit to Executive Function.

A single bout of aerobic exercise improves executive function; however, the mechanism(s) underlying this improvement remains unclear. Here, we employed a 20-min bout of aerobic exercise, and at pre- and immediate post-exercise sessions examined executive function via pro- (i.e., saccade to veridical target location) and anti-saccade (i.e., saccade mirror symmetrical to a target) performance and pupillometry metrics. Notably, tonic and phasic pupillometry responses in oculomotor control provided a framework to determine the degree that arousal and/or executive resource recruitment influence behavior. Results demonstrated a pre- to post-exercise decrease in pro- and anti-saccade reaction times (p = 0.01) concurrent with a decrease and increase in tonic baseline pupil size and task-evoked pupil dilations, respectively (ps < 0.03). Such results demonstrate that an exercise-induced improvement in saccade performance is related to an executive-mediated “shift” in physiological and/or psychological arousal, supported by the locus coeruleus norepinephrine system to optimize task engagement.

The modulation of brain network integration and arousal during exploration

There is growing interest in how neuromodulators shape brain networks. Recent neuroimaging studies provide evidence that brainstem arousal systems, such as the locus coeruleus-norepinephrine system (LC-NE), influence functional connectivity and brain network topology, suggesting they have a role in flexibly reconfiguring brain networks in order to adapt behavior and cognition to environmental demands. To date, however, the relationship between brainstem arousal systems and functional connectivity has not been assessed within the context of a task with an established relationship between arousal and behavior, with most prior studies relying on incidental variations in arousal or pharmacological manipulation and static brain networks constructed over long periods of time. These factors have likely contributed to a heterogeneity of effects across studies. To address these issues, we took advantage of the association between LC-NE-linked arousal and exploration to probe the relationships between exploratory choice, arousal—as measured indirectly via pupil diameter—and brain network dynamics. Exploration in a bandit task was associated with a shift toward fewer, more weakly connected modules that were more segregated in terms of connectivity and topology but more integrated with respect to the diversity of cognitive systems represented in each module. Functional connectivity strength decreased, and changes in connectivity were correlated with changes in pupil diameter, in line with the hypothesis that brainstem arousal systems influence the dynamic reorganization of brain networks. More broadly, we argue that carefully aligning dynamic network analyses with task designs can increase the temporal resolution at which behaviorally- and cognitively-relevant modulations can be identified, and offer these results as a proof of concept of this approach.

Associations between phasic arousal and decisions under risk in younger and older adults

Higher arousal is linked to simple decision strategies and an increased preference for immediate rewards in younger adults, but little is known about the influence of arousal on decision making in older adults. In light of age-related locus coeruleus-norepinephrine system declines, we predicted a reduced association between arousal and decision behavior in older adults. Younger and older participants made a series of choices between smaller, higher-probability and larger, lower-probability financial gains. Each choice was preceded by the presentation of a high-arousal or low-arousal sound. Pupil dilation was continuously recorded as an index of task-evoked arousal. Both age groups showed significant modulation of pupil dilation as a function of arousal condition. Higher-arousal sounds were associated with shorter response times, particularly in younger adults. Furthermore, higher-arousal sounds were associated with greater risk aversion in younger adults and greater risk seeking in older adults, in line with an arousal-related amplification of baseline preferences in both age groups. Jointly, these findings help inform current theories of the effects of arousal on information processing in younger and older adults.

Atypical Arousal Regulation in Children With Autism but Not With Attention-Deficit/Hyperactivity Disorder as Indicated by Pupillometric Measures of Locus Coeruleus Activity

BackgroundAtypical arousal regulation may explain slower mean reaction time (MRT) in autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder compared with typical development. The locus coeruleus–norepinephrine system (LC-NE) underlies arousal regulation and adapts its activity to the utility of a task. LC-NE tonic and phasic activity are indexed by baseline pupil size (BPS) and stimulus-evoked pupillary response (SEPR). MethodsThe study assessed pupillometry in ASD (n = 31, 3 female/28 male), attention-deficit/hyperactivity disorder (n = 28, 3 female/25 male), and typically developing control subjects (n = 31, 16 female/15 male) during a visuospatial reaction-time task that manipulates arousal by conditions with low and high task utility. We estimated linear mixed models of BPS, SEPR, and MRT in a per-trial analysis to investigate arousal regulation of task performance. ResultsSlower MRT occurred in the ASD group compared with the typically developing control group during low-utility conditions while controlling for dimensional ASD and attention-deficit/hyperactivity disorder symptoms. In low-utility conditions, BPS and SEPR were inversely related and both were associated with faster MRT. Increased ASD symptoms across groups were associated with higher BPS during low-utility conditions. Changes in BPS and SEPR between task-utility conditions were smaller in the ASD group. ConclusionsSlower visuospatial task performance in ASD is specific to low task utility. Arousal was associated with task performance and showed altered activity in ASD. Increased BPS during low-utility conditions suggested increased LC-NE tonic activity as an ASD symptom marker in children. Smaller changes in BPS and SEPR in ASD indicated attenuated LC-NE activity adaptation in response to high-utility conditions. Slower performance and atypical arousal regulation are probably associated with attenuated LC-NE activity adaptation.

Locus Coeruleus - Anterior Insula Functional Connectivity Predicts Emotion-Related Impulsivity as a Function of Reward Magnitude

Emotion-related impulsivity (ERI) is the trait-like tendency to act rashly during high emotion states. ERI predicts a broad range of psychopathology, including depression, mania, anxiety, substance abuse, aggression, and suicidality. The neurobiological underpinnings of ERI are not fully understood; however, one pupillometry study implicated the locus coeruleus - norepinephrine (LC-NE) system, which influences physiological arousal. We extend investigation of the LC-NE system and ERI using functional magnetic resonance imaging (fMRI).

The Neuroscience of the Flow State: Involvement of the Locus Coeruleus Norepinephrine System.

Flow is a state of full task engagement that is accompanied with low-levels of self-referential thinking. Flow is considered highly relevant for human performance and well-being and has, therefore, been studied extensively. Yet, the neurocognitive processes of flow remain largely unclear. In the present mini-review we focus on how the brain's locus coeruleus-norepinephrine (LC-NE) system may be involved in a range of behavioral and subjective manifestations of flow. The LC-NE system regulates decisions regarding task engagement vs. disengagement. This is done via different modes of baseline and stimulus-evoked norepinephrine release. We emphasize the theoretical and empirical overlap between the LC-NE system and flow. For both, a match between a person's skill and task challenge is important in order to induce high levels task-related attention. Moreover, psychophysiological indicators of LC-NE system activity, such as eye pupil diameter and arousal are also sensitive to flow states. Flow is related to arousal in an inverted U-shape. Similarly, in theories on the LC-NE system, task engagement is highest with intermediate levels of arousal. We argue that knowledge about the role of the LC-NE system in establishing the flow experience may help to gain fundamental knowledge of flow and can contribute to unifying various empirical findings on this topic.

Formalin-induced inflammatory pain increases excitability in locus coeruleus neurons

Chronic pain is recognized as an important problem in communities. The locus coeruleus (LC) with extensive ascending and descending projections has a critical role in modulating pain. Some studies indicate how the locus coeruleus-noradrenaline system can remain more active after nociceptive stimulation. In the present study, we examined whether formalin-induced inflammatory pain may affect the electrophysiological properties of LC neurons after 24 h. Inflammatory pain was induced by a subcutaneous injection of 2% formalin (10 μL) into the hind paw of 2–3 week-old male Wistar rats. After 24 h, horizontal slices of brain stem containing the locus coeruleus were prepared and whole-cell patch-clamp recordings were carried out on LC neurons.Findings revealed that LC neurons from formalin injected rats had a significant enhancement in firing rate, half-width and instantaneous frequency of action potentials, but their resting membrane potential, input resistance and afterhyperpolarization amplitude almost remained unchanged. In addition, action potential peak amplitude, maximum rise slope, maximum decay slope, first spike latency and rheobase current significantly decreased in LC neurons obtained from formalin-treated rats. Here, for the first time, we demonstrate that inflammatory pain after 24 h induces hyperexcitability in LC neurons, which in turn may result in changes in noradrenaline release and pain processing.

Locus coeruleus integrity and the effect of atomoxetine on response inhibition in Parkinson's disease.

Cognitive decline is a common feature of Parkinson's disease, and many of these cognitive deficits fail to respond to dopaminergic therapy. Therefore, targeting other neuromodulatory systems represents an important therapeutic strategy. Among these, the locus coeruleus-noradrenaline system has been extensively implicated in response inhibition deficits. Restoring noradrenaline levels using the noradrenergic reuptake inhibitor atomoxetine can improve response inhibition in some patients with Parkinson's disease, but there is considerable heterogeneity in treatment response. Accurately predicting the patients who would benefit from therapies targeting this neurotransmitter system remains a critical goal, in order to design the necessary clinical trials with stratified patient selection to establish the therapeutic potential of atomoxetine. Here, we test the hypothesis that integrity of the noradrenergic locus coeruleus explains the variation in improvement of response inhibition following atomoxetine. In a double-blind placebo-controlled randomized crossover design, 19 patients with Parkinson's disease completed an acute psychopharmacological challenge with 40 mg of oral atomoxetine or placebo. A stop-signal task was used to measure response inhibition, with stop-signal reaction times obtained through hierarchical Bayesian estimation of an ex-Gaussian race model. Twenty-six control subjects completed the same task without undergoing the drug manipulation. In a separate session, patients and controls underwent ultra-high field 7 T imaging of the locus coeruleus using a neuromelanin-sensitive magnetization transfer sequence. The principal result was that atomoxetine improved stop-signal reaction times in those patients with lower locus coeruleus integrity. This was in the context of a general impairment in response inhibition, as patients on placebo had longer stop-signal reaction times compared to controls. We also found that the caudal portion of the locus coeruleus showed the largest neuromelanin signal decrease in the patients compared to controls. Our results highlight a link between the integrity of the noradrenergic locus coeruleus and response inhibition in patients with Parkinson's disease. Furthermore, they demonstrate the importance of baseline noradrenergic state in determining the response to atomoxetine. We suggest that locus coeruleus neuromelanin imaging offers a marker of noradrenergic capacity that could be used to stratify patients in trials of noradrenergic therapy and to ultimately inform personalized treatment approaches.

Is baseline pupil size related to cognitive ability? Yes (under proper lighting conditions)

There has been some controversy as to whether baseline pupil size is related to individual differences in cognitive ability. Previously, we had shown that a larger baseline pupil size was associated with higher cognitive ability and that the correlation to fluid intelligence was larger than that to working memory capacity (Tsukahara, Harrison, & Engle, 2016). However, other researchers have not been able to replicate our findings – though they only measured working memory capacity and not fluid intelligence. Many of the studies showing no relationship had major methodological issues, namely small baseline pupil size values – down to the physiological minimum – that resulted in reduced variability on baseline pupil size. We conducted two large-scale studies to investigate how different lighting conditions affect baseline pupil size values and the correlation with cognitive abilities. We found that fluid intelligence, working memory capacity, and attention control did correlate with baseline pupil size except in the brightest lighting conditions. We showed that a reduced variability in baseline pupil size values is due to the monitor settings being too bright. Overall, our findings demonstrated that the baseline pupil size – working memory capacity relationship was not as strong or robust as that with fluid intelligence or attention control. Our findings have strong methodological implications for researchers investigating individual differences in task-free or task-evoked pupil size. We conclude that fluid intelligence does correlate with baseline pupil size and that this is related to the functional organization of the resting-state brain through the locus coeruleus-norepinephrine system.

Phasic pupillary responses modulate object-based attentional prioritization

Visual attention studies have demonstrated that the shape of space-based selection can be governed by salient object contours: when a portion of an enclosed space is cued, the selected region extends to the full enclosure. Although this form of object-based attention (OBA) is well established, one continuing investigation focuses on whether this selection is obligatory or under voluntary control. We attempt to dissociate between these alternatives by interrogating the locus coeruleus-norepinephrine (LC-NE) system – known to fluctuate with top-down attention – during a classic two-rectangle paradigm in a sample of healthy human participants (N = 36). An endogenous spatial pre-cue directed voluntary space-based attention (SBA) to one end of a rectangular frame. We manipulated the reliability of the cue, such that targets appearing at an uncued location within the frame occurred at low or moderate frequencies. Phasic pupillary responses time-locked to the cue display served to noninvasively measure LC-NE activity, reflecting top-down processing of the spatial cue. If OBA is controlled analogously to SBA, then object selection should emerge only when it is behaviorally expedient and when LC-NE activity reflects a high degree of top-down attention to the cue display. Our results bore this out. Thus, we conclude that OBA was voluntarily controlled, and furthermore show that phasic norepinephrine may modulate attentional strategy.