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.

Evidence for a modulating effect of transcutaneous auricular vagus nerve stimulation (taVNS) on salivary alpha-amylase as indirect noradrenergic marker: A pooled mega-analysis.

BACKGROUND: Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has received tremendous attention as a potential neuromodulator of cognitive and affective functions, which likely exerts its effects via activation of the locus coeruleus-noradrenaline (LC-NA) system. Reliable effects of taVNS on markers of LC-NA system activity, however, have not been demonstrated yet. METHODS: The aim of the present study was to overcome previous limitations by pooling raw data from a large sample of ten taVNS studies (371 healthy participants) that collected salivary alpha-amylase (sAA) as a potential marker of central NA release. RESULTS: While a meta-analytic approach using summary statistics did not yield any significant effects, linear mixed model analyses showed that afferent stimulation of the vagus nerve via taVNS increased sAA levels compared to sham stimulation (b = 0.16, SE = 0.05, p = 0.001). When considering potential confounders of sAA, we further replicated previous findings on the diurnal trajectory of sAA activity. CONCLUSION(S): Vagal activation via taVNS increases sAA release compared to sham stimulation, which likely substantiates the assumption that taVNS triggers NA release. Moreover, our results highlight the benefits of data pooling and data sharing in order to allow stronger conclusions in research.

Learn to breathe, breathe to learn? No evidence for effects of slow deep breathing at a 0.1 Hz frequency on reversal learning.

This study sought to investigate whether slow deep breathing (SDB) facilitates reversal learning. We also explored whether SDB modulates the renewal effect. After learning a series of cue-outcome associations (early acquisition phase) in a predictive learning task, 37 participants paced their breathing according to a normal (NPB group; 0.2 Hz) or a slow (SDB group; 0.1 Hz) pattern while completing the reversal and renewal phases. Response correctness, heart rate variability (HRV, i.e., Root mean square of successive differences), and respiratory rate were assessed. Findings indicated that both groups adopted the targeted breathing pattern. As expected, the SDB (vs. NPB) group displayed a steeper rise in HRV from early acquisition to the later phases of the task during which the breathing manipulation took place. However, the performance of the NPB and SDB groups did not significantly differ in any phase of the predictive learning task. Despite the inconclusive findings on the effect of SDB on reversal and renewal, these results confirm that SDB can be performed while performing a learning task.

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 respiratory occlusion discrimination task: A new paradigm to measure respiratory interoceptive accuracy.

Interoception, or the sense of the internal state of the body, is hypothesized to be essential for a wide range of psychobiological processes and the development and perpetuation of several (mental) health problems. However, the study of interoceptive accuracy, the objectively measured capacity to detect or discriminate conscious bodily signals, has been hampered by the use of tasks with questionable construct validity and is often limited to studying interoception solely in the cardiac domain. We developed a novel task to measure interoceptive accuracy in the respiratory domain, the respiratory occlusion discrimination (ROD) task. In this task, interoceptive accuracy is defined as an individual's ability to detect small differences in lengths of short respiratory occlusions, assessed by means of an adaptive staircase procedure. This article describes a validation study (N = 97) aimed at investigating the internal consistency, test-retest reliability, and discriminant validity of the ROD task. The average just noticeable difference of lengths of respiratory occlusion was 74.22 ms, with large inter-individual variability (SD = 37.1 ms). The results of the validation study indicate acceptable internal consistency (Cronbach's alpha = 0.70), 1-week test-retest reliability (r = 0.53), and discriminant validity, as indicated by a lack of correlation between the ROD task and an auditory discrimination task with identical design (r = 0.18), and a weak correlation with breathing behavior (r = -0.27). The ROD task is a promising novel paradigm to study interoceptive accuracy and its role in various psychobiological processes and disorders.

Investigating Pain-Related Avoidance Behavior using a Robotic Arm-Reaching Paradigm.

Avoidance behavior is a key contributor to the transition from acute pain to chronic pain disability. Yet, there has been a lack of ecologically valid paradigms to experimentally investigate pain-related avoidance. To fill this gap, we developed a paradigm (the robotic arm-reaching paradigm) to investigate the mechanisms underlying the development of pain-related avoidance behavior. Existing avoidance paradigms (mostly in the context of anxiety research) have often operationalized avoidance as an experimenter-instructed, low-cost response, superimposed on stimuli associated with threat during a Pavlovian fear conditioning procedure. In contrast, the current method offers increased ecological validity in terms of instrumental learning (acquisition) of avoidance, and by adding a cost to the avoidance response. In the paradigm, participants perform arm-reaching movements from a starting point to a target using a robotic arm, and freely choose between three different movement trajectories to do so. The movement trajectories differ in probability of being paired with a painful electrocutaneous stimulus, and in required effort in terms of deviation and resistance. Specifically, the painful stimulus can be (partly) avoided at the cost of performing movements requiring increased effort. Avoidance behavior is operationalized as the maximal deviation from the shortest trajectory on each trial. In addition to explaining how the new paradigm can help understand the acquisition of avoidance, we describe adaptations of the robotic arm-reaching paradigm for (1) examining the spread of avoidance to other stimuli (generalization), (2) modeling clinical treatment in the lab (extinction of avoidance using response prevention), as well as (3) modeling relapse, and return of avoidance following extinction (spontaneous recovery). Given the increased ecological validity, and numerous possibilities for extensions and/or adaptations, the robotic arm-reaching paradigm offers a promising tool to facilitate the investigation of avoidance behavior and to further our understanding of its underlying processes.

Avoiding Based on Shades of Gray: Generalization of Pain-Related Avoidance Behavior to Novel Contexts.

Avoidance behavior is protective, yet in the absence of genuine bodily threat, it may become disabling. Therefore, we investigated whether avoidance generalizes to novel safe contexts based on the similarity with the acquisition context. Healthy participants performed arm movements using a robotic arm to reach a target. Three trajectories (T1-3) led to the target. During acquisition, a painful stimulus could be partly/completely prevented by performing more effortful trajectories (ie, longer and more force needed), T2/T3, in the pain-avoidance context (eg, black background); in the yoked context (eg, white background), the same reinforcement schedule was applied irrespective of the chosen trajectories. Generalization of avoidance was tested in 2 novel contexts (eg, shades of gray backgrounds). We assessed self-reported pain-expectancy and pain-related fear for all trajectories, and avoidance behavior (ie, maximal deviation from T1). Results confirm that fear and expectancy ratings reflect the response-outcome contingencies and differential learning selectively generalized to the novel context resembling the original pain-avoidance context. Furthermore, a linear trend in avoidance behavior across contexts emerged, which is indicative of a generalization gradient. Participants avoided more in the context resembling the original pain-avoidance context than in the one resembling the yoked context, but this effect was not statistically significant. PERSPECTIVE: Perspective: We demonstrated acquisition of pain-related avoidance behavior in a within-subjects design, showing modulation of pain-related fear and pain-expectancy by context and providing limited evidence that avoidance selectively generalizes to novel, similar contexts. These results provide insight regarding the underlying mechanisms of the spreading of protective behavior in chronic pain patients.

Can Slow Deep Breathing Reduce Pain? An Experimental Study Exploring Mechanisms.

Slow deep breathing (SDB) is commonly employed in the management of pain, but the underlying mechanisms remain equivocal. This study sought to investigate effects of instructed breathing patterns on experimental heat pain and to explore possible mechanisms of action. In a within-subject experimental design, healthy volunteers (n = 48) performed 4 breathing patterns: 1) unpaced breathing, 2) paced breathing (PB) at the participant's spontaneous breathing frequency, 3) SDB at 6 breaths per minute with a high inspiration/expiration ratio (SDB-H), and 4) SDB at 6 breaths per minute with a low inspiration/expiration ratio (SDB-L). During presentation of each breathing pattern, participants received painful heat stimuli of 3 different temperatures and rated each stimulus on pain intensity. Respiration, heart rate, and blood pressure were recorded. Compared to unpaced breathing, participants reported less intense pain during each of the 3 instructed breathing patterns. Among the instructed breathing patterns, pain did not differ between PB and SDB-H, and SDB-L attenuated pain more than the PB and SDB-H patterns. The latter effect was paralleled by greater blood pressure variability and baroreflex effectiveness index during SDB-L. Cardiovascular changes did not mediate the observed effects of breathing patterns on pain. PERSPECTIVES: SDB is more efficacious to attenuate pain when breathing is paced at a slow rhythm with an expiration that is long relative to inspiration, but the underlying mechanisms remain to be elucidated.

Reinstatement after human feature-positive discrimination learning.

In two experiments, using an online conditioned suppression task, we investigated the possibility of reinstatement of extinguished feature-target compound presentations after sequential feature-positive discrimination training in humans. Furthermore, given a hierarchical account of Pavlovian modulation (e.g., Bonardi, 1998; Bonardi and Jennings, 2009), we predicted A-US reinstatement to be stronger than US-only reinstatement. In Experiment 1, participants learned a sequential feature-positive discrimination (X→A+|A-), which was subsequently extinguished (X→A-). During the following reinstatement phase, group US-only received US-only presentations (not signalled), group A-US received A-US presentations, and the Control group received exposure to the context, but no CSs or USs, for an equal amount of time. Reinstatement of differential X→A/A responding was observed in the US-only group but not in the Control or A-US groups. Although differential X→A/A responding was not significant in group A-US, responding to the X→A compound was significantly stronger compared to that in group US-only. Hence, it could be the case the group A-US showed stronger reinstatement, but that differential responding was abolished due to excitation gained by A. Experiment 2 was set up to circumvent the acquired excitation of A by testing transfer of the feature after A-US reinstatement to a different target, B. Participants acquired two discriminations, X→A/A and Y→B/B, of which X→A was then extinguished. Subsequently, group A-US received reinforced presentations of A during a reinstatement phase while group Control received exposure to the context. Final testing of the novel X→B compound was hypothesized to show higher responding in group A-US than in group Control, but findings of this approach were limited due to acquired equivalence and/or perceptual factors causing a secondary extinction effect. We conclude to have obtained clear evidence in favour of reinstatement of differential responding after human Feature-Positive discrimination training and subsequent compound extinction, but no evidence in favour of A-US presentations being a stronger trigger for reinstatement than are US-only presentations.

Acquisition and extinction of operant pain-related avoidance behavior using a 3 degrees-of-freedom robotic arm.

Ample empirical evidence endorses the role of associative learning in pain-related fear acquisition. Nevertheless, research typically focused on self-reported and psychophysiological measures of fear. Avoidance, which is overt behavior preventing the occurrence of an aversive (painful) stimulus, has been largely neglected so far. Therefore, we aimed to fill this gap and developed an operant conditioning procedure for pain-related avoidance behavior. Participants moved their arm to a target location using the HapticMaster (FCS Robotics; Moog Inc, East Aurora, New York), a 3 degrees-of-freedom, force-controlled robotic arm. Three movement trajectories led to the target location. If participants in the Experimental Group took the shortest/easiest trajectory, they always received a painful stimulus (T1 = 100% reinforcement; no resistance). If they deviated from this trajectory, the painful stimulus could be partly or totally prevented (T2 = 50% reinforcement; T3 = 0% reinforcement), but more effort was needed (T2 = moderate resistance and deviation; T3 = strongest resistance and largest deviation). The Yoked Group received the same reinforcement schedule irrespective of their own behavior. During the subsequent extinction phase, no painful stimuli were delivered. Self-reported pain-expectancy and pain-related fear were assessed, and avoidance behavior was operationalized as the maximal distance from the shortest trajectory. During acquisition, the Experimental Group reported more pain-related fear and pain-expectancy to T1 vs T2 vs T3 and deviated more from the shortest trajectory than the Yoked Group. During subsequent extinction, avoidance behavior, self-reported fear, and pain-expectancy decreased significantly, but conditioned differences persisted despite the absence of painful stimuli. To conclude, this operant learning task might provide a valid paradigm to study pain-related avoidance behavior in future studies.

The effect of stimulus distribution form on the acquisition and rate of conditioned responding: implications for theory.

In four experiments rats were conditioned to an auditory conditioned stimulus (conditioned stimulus; CS) that was paired with food, and learning about the CS was compared across two conditions in which the mean duration of the CS was equated. In one, the CS was of a single, fixed duration on every trial, and in the other the CS duration was drawn from an exponential distribution, and hence changed from trial to trial. Higher rates of conditioned responding to the fixed than to the variable stimulus were observed, in both between- (Experiment 1) and within-subject designs (Experiments 2 and 3). Moreover, this difference was maintained when stimuli trained with fixed or variable durations were tested under identical conditions (i.e., with equal numbers of fixed and variable duration trials)-suggesting that the difference could not be attributed to performance effects (Experiment 3). In order to estimate the speed of acquisition of conditioned responding, the scaled cumulative distribution of a Weibull function was fitted to the trial-by-trial response rates for each rat. In the within-subject experiments specific differences in the pattern of acquisition to fixed and variable CS were shown; a somewhat different pattern was found when intertrial interval (ITI) was manipulated (Experiment 4). The implications of these findings for theories of conditioning and timing are discussed.

Narrowing down the conditions for extinction of Pavlovian feature-positive discriminations in humans.

The aim of this study was to delineate the minimal conditions for extinction of Pavlovian modulation in humans. Previous experiments at our lab showed that, after X-- A+/A- acquisition training, X- trials did not extinguish differential X-- A+/A- responding, while X-- A- trials did. Additionally, X-- A- extinction training seemed only to extinguish differential X-- A+/A- responding, while leaving differential responding on a concurrently trained Y [Symbol: see text] B+/B- discrimination intact. It thus seemed that the X-- A+/A- discrimination can only be extinguished by X-- A- extinction trials. (Rescorla, Journal of Experimental Psychology: Animal Behavior Processes 12, 16-24, 1986), on the other hand, found that the minimal conditions for extinction were broader in pigeons: Namely, he found that an acquired X-- A+/A- discrimination could be extinguished by presenting the original feature X in combination with a different target (B) that was minimally trained as an exciter. We thus wanted to examine whether this was also the case in humans. We found that nonreinforced X-- B- presentations did not abolish discriminative X-- A/A responding when target B was a nonreinforced stimulus. Nonreinforced X-- B- trials did extinguish the X-- A+/A- discrimination when target B had previously been trained as a target for modulation (X-- B+/B- or Y [Symbol: see text] B+/B- training) or as a reinforced exciter (B+). Our results thusf parallel and extend those in nonhuman animals (Rescorla, Journal of Experimental Psychology: Animal Behavior Processes 12, 16-24, 1986).

A free software package for a human online-conditioned suppression preparation.

MartiansV2 is both a language syntax in which experiments can be written and an implementation of this syntax in a runtime application that, when fed a valid experiment text file, will execute the given experiment. It is based on the original Martians preparation, which has proven a valuable tool for assessing human online-conditioned suppression performance through research on a wide array of learning phenomena. This article can be read as a manual, both for using the Martians paradigm in general and for getting started with MartiansV2.