Self-regulating arousal via pupil-based biofeedback.

The brain's arousal state is controlled by several neuromodulatory nuclei known to substantially influence cognition and mental well-being. Here we investigate whether human participants can gain volitional control of their arousal state using a pupil-based biofeedback approach. Our approach inverts a mechanism suggested by previous literature that links activity of the locus coeruleus, one of the key regulators of central arousal and pupil dynamics. We show that pupil-based biofeedback enables participants to acquire volitional control of pupil size. Applying pupil self-regulation systematically modulates activity of the locus coeruleus and other brainstem structures involved in arousal control. Furthermore, it modulates cardiovascular measures such as heart rate, and behavioural and psychophysiological responses during an oddball task. We provide evidence that pupil-based biofeedback makes the brain's arousal system accessible to volitional control, a finding that has tremendous potential for translation to behavioural and clinical applications across various domains, including stress-related and anxiety disorders.

Pupil dilation response elicited by violations of auditory regularities is a promising but challenging approach to probe consciousness at the bedside.

Pupil dilation response (PDR) has been proposed as a physiological marker of conscious access to a stimulus or its attributes, such as novelty. In a previous study on healthy volunteers, we adapted the auditory "local global" paradigm and showed that violations of global regularity elicited a PDR. Notably without instructions, this global effect was present only in participants who could consciously report violations of global regularities. In the present study, we used a similar approach in 24 non-communicating patients affected with a Disorder of Consciousness (DoC) and compared PDR to ERPs regarding diagnostic and prognostic performance. At the group level, global effect could not be detected in DoC patients. At the individual level, the only patient with a PDR global effect was in a MCS and recovered consciousness at 6 months. Contrasting the most regular trials to the most irregular ones improved PDR's diagnostic and prognostic power in DoC patients. Pupillometry is a promising tool but requires several methodological improvements to enhance the signal-to-noise ratio and make it more robust for probing consciousness and cognition in DoC patients.

Pupil dilation scales with movement distance of real but not of imagined reaching movements.

Pupillary responses have been reliably identified for cognitive and motor tasks, but less is known about their relation to mentally simulated movements (known as motor imagery). Previous work found pupil dilations during the execution of simple finger movements, where peak pupillary dilation scaled with the complexity of the finger movement and force required. Recently, pupillary dilations were reported during imagery of grasping and piano playing. Here, we examined whether pupillary responses are sensitive to the dynamics of the underlying motor task for both executed and imagined reach movements. Participants reached or imagined reaching to one of three targets placed at different distances from a start position. Both executed and imagined movement times scaled with target distance, and they were highly correlated, confirming previous work and suggesting that participants did imagine the respective movement. Increased pupillary dilation was evident during motor execution compared with rest, with stronger dilations for larger movements. Pupil dilations also occurred during motor imagery, however, they were generally weaker than those during motor execution and they were not influenced by imagined movement distance. Instead, dilations during motor imagery resembled pupil responses obtained during a nonmotor imagery task (imagining a previously viewed painting). Our results demonstrate that pupillary responses can reliably capture the dynamics of an executed goal-directed reaching movement, but suggest that pupillary responses during imagined reaching movements reflect general cognitive processes, rather than motor-specific components related to the simulated dynamics of the sensorimotor system.NEW & NOTEWORTHY Pupil size is influenced by the performance of cognitive and motor tasks. Here, we demonstrate that pupil size increases not only during execution but also during mental simulation of goal-directed reaching movements. However, pupil dilations scale with movement amplitude of executed but not of imagined movement, whereas they are similar during motor imagery and a nonmotor imagery task.

Short-term transcutaneous vagus nerve stimulation increases pupil size but does not affect EEG alpha power: A replication of Sharon et al. (2021, Journal of Neuroscience).

BACKGROUND: Transcutaneous auricular vagus nerve stimulation (taVNS) has been tested as a potential treatment for pharmaco-resistant epilepsy and depression. Its clinical efficacy is thought to depend on taVNS-induced activation of the locus coeruleus and other neuromodulator systems. However, unlike for invasive VNS in rodents, there is little evidence for an effect of taVNS on noradrenergic activity. OBJECTIVE: We attempted to replicate recently published findings by Sharon et al. (2021), showing that short bursts of taVNS transiently increased pupil size and decreased EEG alpha power, two correlates of central noradrenergic activity. METHODS: Following the original study, we used a single-blind, sham-controlled, randomized cross-over design. Human volunteers (n = 29) received short-term (3.4 s) taVNS at the maximum level below the pain threshold, while we collected resting-state pupil-size and EEG data. To analyze the data, we used scripts provided by Sharon and colleagues. RESULTS: Consistent with Sharon et al. (2021), pupil dilation was significantly larger during taVNS than during sham stimulation (p = .009; Bayes factor supporting the difference = 7.45). However, we failed to replicate the effect of taVNS on EEG alpha power (p = .37); the data were four times more likely under the null hypothesis (BF10 = 0.28). CONCLUSION: Our findings support the effectiveness of short-term taVNS in inducing transient pupil dilation, a correlate of phasic noradrenergic activity. However, we failed to replicate the recent finding by Sharon et al. (2021) that taVNS attenuates EEG alpha activity. Overall, this study highlights the need for continued research on the neural mechanisms underlying taVNS efficacy and its potential as a treatment option for pharmaco-resistant conditions. It also highlights the need for direct replications of influential taVNS studies.

Short bursts of transcutaneous auricular vagus nerve stimulation enhance evoked pupil dilation as a function of stimulation parameters.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a neurostimulatory technique hypothesised to enhance central noradrenaline. Currently, there is scarce evidence in support of a noradrenergic mechanism of taVNS and limited knowledge on its stimulation parameters (i.e., intensity and pulse width). Therefore, the present study aimed to test whether taVNS enhances pupil dilation, a noradrenergic biomarker, as a function of stimulation parameters. Forty-nine participants received sham (i.e., left ear earlobe) and taVNS (i.e., left ear cymba concha) stimulation in two separate sessions, in a counterbalanced order. We administered short bursts (5s) of seven stimulation settings varying as a function of pulse width and intensity and measured pupil size in parallel. Each stimulation setting was administered sixteen times in separate blocks. We expected short bursts of stimulation to elicit phasic noradrenergic activity as indexed by event-related pupil dilation and event-related temporal derivative. We hypothesised higher stimulation settings, quantified as the total charge per pulse (pulse width x intensity), to drive greater event-related pupil dilation and temporal derivative in the taVNS compared to sham condition. Specifically, we expected stimulation settings in the taVNS condition to be associated with a linear increase in event-related pupil dilation and temporal derivative. We found stimulation settings to linearly increase both pupil measures. In line with our hypothesis, the observed dose-dependent effect was stronger in the taVNS condition. We also found taVNS to elicit more intense and unpleasant sensations than sham stimulation. These results support the hypothesis of a noradrenergic mechanism of taVNS. However, future studies should disentangle whether stimulation elicited sensations mediate the effect of taVNS on evoked pupil dilation.

The catecholamine precursor Tyrosine reduces autonomic arousal and decreases decision thresholds in reinforcement learning and temporal discounting.

Supplementation with the catecholamine precursor L-Tyrosine might enhance cognitive performance, but overall findings are mixed. Here, we investigate the effect of a single dose of tyrosine (2g) vs. placebo on two catecholamine-dependent trans-diagnostic traits: model-based control during reinforcement learning (2-step task) and temporal discounting, using a double-blind, placebo-controlled, within-subject design (n = 28 healthy male participants). We leveraged drift diffusion models in a hierarchical Bayesian framework to jointly model participants' choices and response times (RTS) in both tasks. Furthermore, comprehensive autonomic monitoring (heart rate, heart rate variability, pupillometry, spontaneous eye blink rate) was performed both pre- and post-supplementation, to explore potential physiological effects of supplementation. Across tasks, tyrosine consistently reduced participants' RTs without deteriorating task-performance. Diffusion modeling linked this effect to attenuated decision-thresholds in both tasks and further revealed increased model-based control (2-step task) and (if anything) attenuated temporal discounting. On the physiological level, participants' pupil dilation was predictive of the individual degree of temporal discounting. Tyrosine supplementation reduced physiological arousal as revealed by increases in pupil dilation variability and reductions in heart rate. Supplementation-related changes in physiological arousal predicted individual changes in temporal discounting. Our findings provide first evidence that tyrosine supplementation might impact psychophysiological parameters, and suggest that modeling approaches based on sequential sampling models can yield novel insights into latent cognitive processes modulated by amino-acid supplementation.

Arousal-based pupil modulation is dictated by luminance.

Pupillometry has become a standard measure for assessing arousal state. However, environmental factors such as luminance, a primary dictator of pupillary responses, often vary across studies. To what degree does luminance interact with arousal-driven pupillary changes? Here, we parametrically assessed luminance-driven pupillary responses across a wide-range of luminances, while concurrently manipulating cognitive arousal using auditory math problems of varying difficulty. At the group-level, our results revealed that the modulatory effect of cognitive arousal on pupil size interacts multiplicatively with luminance, with the largest effects occurring at low and mid-luminances. However, at the level of individuals, there were qualitatively distinct individual differences in the modulatory effect of cognitive arousal on luminance-driven pupillary responses. Our findings suggest that pupillometry as a measure for assessing arousal requires more careful consideration: there are ranges of luminance levels that are more ideal in observing pupillary differences between arousal conditions than others.

Effects of transcutaneous auricular vagus nerve stimulation on reversal learning, tonic pupil size, salivary alpha-amylase, and cortisol.

This study investigated whether transcutaneous auricular vagus nerve stimulation (taVNS) enhances reversal learning and augments noradrenergic biomarkers (i.e., pupil size, cortisol, and salivary alpha-amylase [sAA]). We also explored the effect of taVNS on respiratory rate and cardiac vagal activity (CVA). Seventy-one participants received stimulation of either the cymba concha (taVNS) or the earlobe (sham) of the left ear. After learning a series of cue-outcome associations, the stimulation was applied before and throughout a reversal phase in which cue-outcome associations were changed for some (reversal), but not for other (distractor) cues. Tonic pupil size, salivary cortisol, sAA, respiratory rate, and CVA were assessed at different time points. Contrary to our hypothesis, taVNS was not associated with an overall improvement in performance on the reversal task. Compared to sham, the taVNS group performed worse for distractor than reversal cues. taVNS did not increase tonic pupil size and sAA. Only post hoc analyses indicated that the cortisol decline was steeper in the sham compared to the taVNS group. Exploratory analyses showed that taVNS decreased respiratory rate but did not affect CVA. The weak and unexpected effects found in this study might relate to the lack of parameters optimization for taVNS and invite to further investigate the effect of taVNS on cortisol and respiratory rate.

The effects of transcutaneous auricular vagal nerve stimulation on pupil size.

OBJECTIVE: Mechanisms of action and optimal stimulation parameters of transcutaneous auricular vagus nerve stimulation (taVNS) are currently unknown. Pupil size has gained attention as a promising biomarker of vagal activation in different studies on animal models. The aim of this study is to investigate the effects of taVNS on pupil diameter in healthy subjects. METHODS: All subjects received taVNS at the left external acoustic meatus and control stimulation at the left earlobe during the same experimental session. Different intensities (0.5 mA; 1.0 mA; 2.0 mA; 3.0 mA) for both conditions were tested. Tonic pupil size was recorded in both eyes at baseline and during each stimulation using an infrared-automated pupillometer in three different illuminance conditions (scotopic, mesopic, photopic). RESULTS: In scotopic illuminance condition, a significant interaction between intensity and condition (real vs control) was found for the left eye. Post-Hoc analysis showed that during real taVNS at 2 mA, pupil size was significantly larger in comparison to baseline and 2 mA control stimulation. CONCLUSIONS: Our study demonstrates that taVNS induces pupil dilation under specific illuminance conditions and at specific stimulation intensity. SIGNIFICANCE: The effects of taVNS are strictly dependent on technical aspects, such as stimulation parameters and experimental set-up.

The influence of sham feedback on physiological processing during fear-driven stimulation.

Biofeedback constitutes a well-established, non-invasive method to voluntary interfere in emotional processing by means of cognitive strategies. However, treatment durations exhibit strong inter-individual variations and first successes can often be achieved only after a large number of sessions. Sham feedback constitutes a rather untapped approach by providing feedback that does not correspond to the participant's actual state. The current study aims to gain insights into mechanisms of sham feedback processing in order to support new techniques in biofeedback therapy. We carried out two experiments and applied different types of sham feedback on skin conductance responses and pupil size changes during affective processing. Results indicate that standardized but context-sensitive sham signals based on skin conductance responses exert a stronger influence on emotional regulation compared to individual sham feedback from ongoing pupil dynamics. Also, sham feedback should forego unnatural signal behavior to avoid irritation and skepticism among participants. Altogether, a reasonable combination of stimulus features and sham feedback characteristics enables to considerably reduce the actual bodily responsiveness already within a single session.

Linear and non linear measures of pupil size as a function of hypnotizability.

Higher arousal and cortical excitability have been observed in high hypnotizable individuals (highs) with respect to low hypnotizables (lows), which may be due to differences in the activation of ascending activating systems. The present study investigated the possible hypnotizability-related difference in the cortical noradrenergic tone sustained by the activity of the Locus Coeruleus which is strongly related to pupil size. This was measured during relaxation in three groups of participants-highs (N = 15), lows (N = 15) and medium hypnotizable individuals (mediums, N = 11)-in the time and frequency domains and through the Recurrence Quantification Analysis. ECG and Skin Conductace (SC) were monitored to extract autonomic indices of relaxation (heart interbeats intervals, parasympathetic component of heart rate variability (RMSSD) and tonic SC (MeanTonicSC). Most variables indicated that participants relaxed throughout the session. Pupil features did not show significant differences between highs, mediums and lows, except for the spectral Band Median Frequency which was higher in mediums than in lows and highs at the beginning, but not at the end of the session.Thus, the present findings of pupil size cannot account for the differences in arousal and motor cortex excitability observed between highs and lows in resting conditions.

Pupillometry as a reliable metric of auditory detection and discrimination across diverse stimulus paradigms in animal models.

Estimates of detection and discrimination thresholds are often used to explore broad perceptual similarities between human subjects and animal models. Pupillometry shows great promise as a non-invasive, easily-deployable method of comparing human and animal thresholds. Using pupillometry, previous studies in animal models have obtained threshold estimates to simple stimuli such as pure tones, but have not explored whether similar pupil responses can be evoked by complex stimuli, what other stimulus contingencies might affect stimulus-evoked pupil responses, and if pupil responses can be modulated by experience or short-term training. In this study, we used an auditory oddball paradigm to estimate detection and discrimination thresholds across a wide range of stimuli in guinea pigs. We demonstrate that pupillometry yields reliable detection and discrimination thresholds across a range of simple (tones) and complex (conspecific vocalizations) stimuli; that pupil responses can be robustly evoked using different stimulus contingencies (low-level acoustic changes, or higher level categorical changes); and that pupil responses are modulated by short-term training. These results lay the foundation for using pupillometry as a reliable method of estimating thresholds in large experimental cohorts, and unveil the full potential of using pupillometry to explore broad similarities between humans and animal models.

Time effect for in-situ dry needling on the autonomic nervous system, a pilot study.

Study design: Pilot study.Background: Dry needling has been an emerging treatment option for physical therapists over the last decade. Despite the fact that studies have demonstrated the overall benefit of dry needling, there is no clear understanding how long needles should be left in place (situ). This pilot study investigated the effects of needles remaining in situ based on autonomic responses over time.Methods: A convenience sample of 21 subjects were recruited for this study. Automated pupillometry was utilized to obtain a direct measure of autonomic nervous system activity. Directly following a baseline measurement, 8 type J Seirin Acupuncture needles were inserted paravertebral at the C7-T3 segments. A total of 8 post-needling 60 seconds pupil measurements were taken at 3 minutes intervals for 24 minutes post needling.Outcomes: A statistical significant difference in mean pupil diameter was found following the needle intervention (p < .01), which implies an increased sympathetic activity. This subject sample had a statistically significantly larger mean pupil diameter immediately after the needling, which lasted until measure point 7, at 18 minutes (P < .05). At measure point 8 there was no longer a statistical significant difference compared to the premeasurement measure.Discussion: The results of this study provide evidence that dry needling results in a significant increased activity of the sympathetic nervous system for up to 18 minutes. Between 18 and 21 minutes autonomic activity returned to a non-significant difference compared to baseline. The results of this study could assist clinicians in clinical decision making to determine needle placement time.

Background luminance effects on pupil size associated with emotion and saccade preparation.

Pupil dilation is consistently evoked by affective and cognitive processing, and this dilation can result from sympathetic activation or parasympathetic inhibition. The relative contributions of the sympathetic and parasympathetic systems on the pupillary response induced by emotion and cognition may be different. Sympathetic and parasympathetic activity is regulated by global luminance level. Higher luminance levels lead to greater activation of the parasympathetic system while lower luminance levels lead to greater activation of the sympathetic system. To understand the contributions of the sympathetic and parasympathetic nervous systems to pupillary responses associated with emotion and saccade preparation, emotional auditory stimuli were presented following the fixation cue whose color indicated instruction to perform a pro- or anti-saccade while varying the background luminance level. Pupil dilation was evoked by emotional auditory stimuli and modulated by arousal level. More importantly, greater pupil dilation was observed with a dark background, compared to a bright background. In contrast, pupil dilation responses associated with saccade preparation were larger with the bright background than the dark background. Together, these results suggest that arousal-induced pupil dilation was mainly mediated by sympathetic activation, but pupil dilation related to saccade preparation was primarily mediated by parasympathetic inhibition.

Spontaneous pupillary oscillations increase during mindfulness meditation.

A significant body of literature has shown that pupil size varies with cognitive and perceptual states [1,2]. Furthermore, the pupil diameter oscillates spontaneously at low frequencies, sometimes referred to as pupillary hippus [3,4]. Oscillation amplitude varies with many neural factors, including arousal and cortical excitability. Here we show that pupillary oscillations are modulated by mindfulness meditation, increasing by 53% compared to pre- and post-meditation baselines. The effect occurs only in trained meditators and is specific for low frequencies (below 1 Hz), with delta frequencies (1-5 Hz) unchanged. The study suggests that pupil size may be a useful marker of the altered cortical state during meditation.

Effects of singing bowl exposure on Karolinska sleepiness scale and pupillographic sleepiness test: A randomised crossover study.

BACKGROUND: The aim of this study was to investigate the effects on subjective and objective sleepiness of a stay above a large struck singing bowl compared to a relaxation period in a silent singing bowl. METHODS: Fifty-eight healthy subjects were recruited for the study, 48 participated on two days, one week apart, during the same timeslot. The Karolinska sleepiness scale was used to evaluate current subjective sleepiness, and the relative pupillary unrest index to assess objective sleepiness. In this randomized cross-over study, the intervention consisted of a 20-minute stay in a hammock while the singing bowl, positioned beneath, was struck seven times. The controlled comparator was a 20-minute stay in the same hammock above the singing bowl, but without being struck. After these two interventions subjective and objective sleepiness were re-evaluated. RESULTS: The mean relative pupillary unrest index values after relaxation in the struck and silent singing bowl groups were 0.74 and respectively 0.71 (p = 0.460). The median Karolinska sleepiness scale value after relaxation with the struck singing bowl was 3 compared with 4 (p = 0.041) for the silent singing bowl. DISCUSSION: This study evaluated the influence of a struck singing bowl on sleepiness during daytime. Subjective sleepiness was significantly lower after relaxation above a struck singing bowl. After gender stratification, the difference was still significant in women. Objective sleepiness was not different in both groups. Finally, we can only speculate if women may be more susceptible to subjective improvements in case of sleepiness and show another perception of relaxation in a struck singing bowl compared to men.

Moving beyond belief: A narrative review of potential biomarkers for transcutaneous vagus nerve stimulation.

Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive neurostimulation technique that is currently being tested as a potential treatment for a myriad of neurological and psychiatric disorders. However, the working mechanisms underlying tVNS are poorly understood and it remains unclear whether stimulation activates the vagus nerve for every participant. Finding a biological marker of tVNS is imperative, as it can help guide research on clinical applications and can inform researchers on optimal stimulation sites and parameters to further optimize treatment efficacy. In this narrative review, we discuss five potential biomarkers for tVNS and review currently available evidence for these markers for both invasive and tVNS. While some of these biomarkers hold promise from a theoretical perspective, none of the potential biomarkers provide clear and definitive indications that tVNS increases the vagal activity or augments activity in the locus coeruleus-noradrenaline network. We conclude the review by providing several recommendations for how to tackle the challenges and opportunities when researching potential biomarkers for the effects of tVNS.

From ear to eye? No effect of transcutaneous vagus nerve stimulation on human pupil dilation: A report of three studies.

Transcutaneous stimulation of the auricular branch of the vagus nerve (tVNS) has been proposed as a treatment for a spectrum of physical and psychological disorders. One of the proposed working mechanisms of tVNS is a modulatory effect on the locus coeruleus - noradrenaline (LC-NA) network. We tested this hypothesis in humans in a series of three studies: one focusing on high trait worriers, and two in healthy populations. In all three studies, we tested whether tVNS increases resting pupil diameter - as an index of LC-NA network activity. Additionally, we tested whether tVNS affects task performance and task-related pupil dilation during an Attentional Blink task. We found no evidence that tVNS increases pupil diameter or task-related pupil dilation in any of the tasks. No consistent effects of tVNS on performance on the attentional blink task were found. Overall, the results of these studies indicate that tVNS does not affect these behavioral and physiological indices of noradrenergic activity.

Effective combination of pupil light reflex and heart rate variability to assess foot bath effects on autonomic function in healthy adults.

OBJECTIVES: To evaluate the effects of a foot bath on autonomic nervous system (ANS) activities as measured by pupil light reflex (PLR) and heart rate variability (HRV) in healthy adults. METHODS: PLR and HRV were assessed before and during a foot bath in healthy subjects (n = 110). The subjects dipped their feet in 40 °C water at a level below their knees for 15 min The light reflex in PLR was elicited at four ascending stimulus intensities. Linear-mixed effect models were fit with PLR parameters, and a Wilcoxon signed-rank test with HRV parameters. In PLR analysis, an interaction term between the foot bath intervention and the stimulus intensity was included as a fixed effect. RESULTS: The PLR analysis showed significant interactions in five out of seven parameters. The altered patterns indicated enhanced activity of the parasympathetic nervous system (PNS) due to the intervention. In contrast, the HRV analysis showed few alterations of PNS activities due to the intervention. CONCLUSIONS: The study results demonstrated differences in altered PNS activity during a foot bath, when assessed by PLR and HRV. In PLR, the stimulus intensity was a crucial factor for the evaluation of foot bath effects. Taken together, the combination of PLR and HRV effectively evaluates ANS activities during a foot bath.

Pupillometric decoding of high-level musical imagery.

Humans report imagining sound where no physical sound is present: we replay conversations, practice speeches, and "hear" music all within the confines of our minds. Research has identified neural substrates underlying auditory imagery; yet deciphering its explicit contents has been elusive. Here we present a novel pupillometric method for decoding what individuals hear "inside their heads". Independent of light, pupils dilate and constrict in response to noradrenergic activity. Hence, stimuli evoking unique and reliable patterns of attention and arousal even when imagined should concurrently produce identifiable patterns of pupil-size dynamics (PSDs). Participants listened to and then silently imagined music while eye-tracked. Using machine learning algorithms, we decoded the imagined songs within- and across-participants following classifier-training on PSDs collected during both imagination and perception. Echoing findings in vision, cross-domain decoding accuracy increased with imagery strength. These data suggest that light-independent PSDs are a neural signature sensitive enough to decode imagination.