Age-related changes in the neural gating of respiratory sensations in humans.

Background: Neural gating of respiratory sensations (NGRS) characterises the brain's ability to filter out repetitive respiratory sensory stimuli. This mechanism plays a crucial role in the neural processing of respiratory stimuli. However, whether ageing affects NGRS in healthy adults is still unclear. Therefore, we aimed to measure the effect of age on NGRS as well as the corresponding S1 and S2 components of the respiratory-related evoked potentials (RREPs). Methods: Three age groups of healthy adults participated in this study: a young group (YG; age 20-39 years), a middle-aged group (MG; age 40-59 years) and an old group (OG; age ≥60 years). NGRS was measured by the RREPs in the electroencephalogram in response to short-paired respiratory occlusion stimuli (S1 and S2). The S2/S1 ratio of the RREP N1 amplitude (the negative deflection of the RREP at ∼85-135 ms) was used to characterise NGRS. Results: The results showed a significantly smaller N1 S2/S1 ratio in the YG than in the MG (p=0.01) and OG (p=0.03). Further analysis showed that the S1 N1 amplitude was larger for the YG compared with the MG (p=0.03) and OG (p=0.007). Moreover, age was significantly correlated with the N1 S2/S1 ratio (r=0.43), with higher age relating to higher N1 S2/S1 ratios. Conclusions: The greater N1 S2/S1 ratios observed in older adults suggest that ageing has a negative impact on the NGRS. This might contribute to increased experiences of respiratory sensations such as dyspnoea in ageing adults.

The effect of unpredictability on the perception of pain: a systematic review and meta-analysis.

ABSTRACT: Despite being widely assumed, the worsening impact of unpredictability on pain perception remains unclear because of conflicting empirical evidence, and a lack of systematic integration of past research findings. To fill this gap, we conducted a systematic review and meta-analysis focusing on the effect of unpredictability on pain perception. We also conducted meta-regression analyses to examine the moderating effect of several moderators associated with pain and unpredictability: stimulus duration, calibrated stimulus pain intensity, pain intensity expectation, controllability, anticipation delay, state and trait negative affectivity, sex/gender and age of the participants, type of unpredictability (intensity, onset, duration, location), and method of pain induction (thermal, electrical, mechanical pressure, mechanical distention). We included 73 experimental studies with adult volunteers manipulating the (un)predictability of painful stimuli and measuring perceived pain intensity and pain unpleasantness in predictable and unpredictable contexts. Because there are insufficient studies with patients, we focused on healthy volunteers. Our results did not reveal any effect of unpredictability on pain perception. However, several significant moderators were found, ie, targeted stimulus pain intensity, expected pain intensity, and state negative affectivity. Trait negative affectivity and uncontrollability showed no significant effect, presumably because of the low number of included studies. Thus, further investigation is necessary to clearly determine their role in unpredictable pain perception.

Neural oscillations underlying the neural gating of respiratory sensations in generalized anxiety disorder.

Individuals with generalized anxiety disorder (GAD) have been shown to have altered neural gating of respiratory sensations (NGRS) using respiratory-related evoked potentials (RREP); however, corresponding neural oscillatory activities remain unexplored. The present study aimed to investigate altered NGRS in individuals with GAD using both time and time-frequency analysis. Nineteen individuals with GAD and 28 healthy controls were recruited. Paired inspiratory occlusions were delivered to elicit cortical neural activations measured from electroencephalography. The GAD group showed smaller N1 amplitudes to the first stimulus (S1), lower evoked gamma and larger evoked beta oscillations compared to controls. Both groups showed larger N1, P3, beta power and theta power in response to S1 compared to S2, suggesting a neural gating phenomenon. These findings suggest that N1, gamma and beta frequency oscillations may be indicators for altered respiratory sensation in GAD populations and that the N1, P3, beta and theta oscillations can reflect the neural gating of respiratory sensations.

Expectations underlie the effects of unpredictable pain: a behavioral and electroencephalogram study.

ABSTRACT: Previous studies on the potential effects of unpredictability on pain perception and its neural correlates yielded divergent results. This study examined whether this may be explained by differences in acquired expectations. We presented 41 healthy volunteers with laser heat stimuli of different intensities. The stimuli were preceded either by predictable low, medium, or high cues or by unpredictable low-medium, medium-high, or low-high cues. We recorded self-reports of pain intensity and unpleasantness and laser-evoked potentials (LEPs). Furthermore, we investigated whether dynamic expectations that evolved throughout the experiment based on past trials were better predictors of pain ratings than fixed (nonevolving) expectations. Our results replicate previous findings that unpredictable pain is higher than predictable pain for low-intensity stimuli but lower for high-intensity stimuli. Moreover, we observed higher ratings for the medium-high unpredictable condition than the medium-low unpredictable condition, in line with an effect of expectation. We found significant interactions (N1, N2) for the LEP components between intensity and unpredictability. However, the few significant differences in LEP peak amplitudes between cue conditions did not survive correction for multiple testing. In line with predictive coding perspectives, pain ratings were best predicted by dynamic expectations. Surprisingly, expectations of reduced precision (increased variance) were associated with lower pain ratings. Our findings provide strong evidence that (dynamic) expectations contribute to the opposing effects of unpredictability on pain perception; therefore, we highlight the importance of controlling for them in pain unpredictability manipulations. We also suggest to conceptualize pain expectations more often as dynamic constructs incorporating previous experiences.

Neural oscillatory markers of respiratory sensory gating in human cortices.

BACKGROUND: Human respiratory sensory gating is a neural process associated with inhibiting the cortical processing of repetitive respiratory mechanical stimuli. While this gating is typically examined in the time domain, the neural oscillatory dynamics, which could offer supplementary insights into respiratory sensory gating, remain unknown. The purpose of the present study was to investigate central neural gating of respiratory sensation using both time- and frequency-domain analyses. METHODS: A total of 37 healthy adults participated in this study. Two transient inspiratory occlusions were presented within one inspiration, while responses in the electroencephalogram (EEG) were recorded. N1 amplitudes and oscillatory activities to the first stimulus (S1) and the second stimulus (S2) were measured. The perceived level of breathlessness and level of unpleasantness elicited by the occlusions were measured after the experiment. RESULTS: As expected, the N1 peak amplitude to the S1 was significantly larger than to the S2. The averaged respiratory sensory gating S2/S1 ratio for the N1 peak amplitude was 0.71. For both the evoked- and induced-oscillations, time-frequency analysis showed higher theta activations in response to S1 relative to S2. A positive correlation was observed between the perceived unpleasantness and induced theta power. CONCLUSIONS: Our results suggest that theta oscillations, evoked as well as induced, reflect the "gating" of respiratory sensation. Theta oscillation, particularly theta induced power, may be indicative of emotional processing of respiratory mechanosensation. The findings of this study serve as a foundation for future investigations into the underlying mechanisms of respiratory sensory gating, particularly in patient populations.

Interaction of panic and episodic breathlessness among patients with life-limiting diseases: a cross-sectional study.

BACKGROUND: Episodic breathlessness is often accompanied by panic. A vicious cycle of breathlessness-panic-breathlessness leads to emergencies with severe breathlessness and/or fear of dying. However, the interaction between episodic breathlessness and panic is poorly understood. Thus, the aim is a better understanding of the interaction between panic and episodic breathlessness to develop appropriate support for patients suffering from this symptom. METHODS: Patients suffering from episodic breathlessness due to life-limiting diseases answered questions on the characteristics of episodic breathlessness and panic-spectrum psychopathology, including underlying mechanisms. Using the Patient Health Questionnaire and the Structured Clinical Interview for DSM-IV Diagnoses (SCID), patients were screened for panic disorder. An open-ended question captured the patients' descriptions of panic during breathlessness episodes. RESULTS: Forty-six patients [52% women, mean age =66 years; standard deviation (SD) 7.3 years] provided information: 61% suffered from panic during the entire breathlessness episode, 39% experienced panic in every episode, and 25% were diagnosed with panic disorder. Exploratory data analysis was conducted. Patients with high scores in breathlessness catastrophizing thoughts experienced more panic in a breathlessness episode (P<0.001) and considered themselves more panic than low-scorers (P=0.024). There was a significant indirect effect of episodic breathlessness intensity on the panic experienced in an episode, and this effect was mediated by catastrophizing thoughts regarding breathlessness (b=0.164; 95% CI: 0.105, 0.222). Patients described in the open-ended question experiencing only panic or breathlessness, or a combination of both. Some patients managed to differentiate panic from episodic breathlessness, and used strategies to avoid panic in an episode. CONCLUSIONS: Research on treatment options for episodic breathlessness should not only focus on panic in breathlessness episodes, but also on underlying mechanisms such as catastrophizing thoughts, as they aggravate the burden.

Effects of transcutaneous auricular vagus nerve stimulation on P300 magnitudes and salivary alpha-amylase during an auditory oddball task.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neurostimulation technique that is thought to modulate noradrenergic activity. Previous studies have demonstrated inconsistent effects of taVNS on noradrenergic activity, which is possibly due to insufficient statistical power, suboptimal stimulation parameter settings, and data collection procedures. In this preregistered within-subject experiment, 44 healthy participants received taVNS and sham (earlobe) stimulation during two separate experimental sessions. Stimulation intensity was individually calibrated to the maximum level below pain. During each session, participants received the stimulation continuously ten minutes before an auditory novelty oddball task till the end of the experimental session. The P3b component of the event-related potential served as a marker of phasic noradrenergic activity, whereas P3a magnitude was explored as an index of dopaminergic activity. Salivary alpha-amylase (sAA) was measured as an index of tonic noradrenergic activity before and at the end of the stimulation. The taVNS and sham conditions did not differ in P3a or P3b magnitudes, nor sAA secretion. These findings call into question whether taVNS, administered continuously at high, nonpainful stimulation intensities, reliably augments noradrenergic activity via the vagus nerve.

Nonpharmacological management of psychological distress in people with COPD.

Psychological distress is prevalent in people with COPD and relates to a worse course of disease. It often remains unrecognised and untreated, intensifying the burden on patients, carers and healthcare systems. Nonpharmacological management strategies have been suggested as important elements to manage psychological distress in COPD. Therefore, this review presents instruments for detecting psychological distress in COPD and provides an overview of available nonpharmacological management strategies together with available scientific evidence for their presumed benefits in COPD. Several instruments are available for detecting psychological distress in COPD, including simple questions, questionnaires and clinical diagnostic interviews, but their implementation in clinical practice is limited and heterogeneous. Moreover, various nonpharmacological management options are available for COPD, ranging from specific cognitive behavioural therapy (CBT) to multi-component pulmonary rehabilitation (PR) programmes. These interventions vary substantially in their specific content, intensity and duration across studies. Similarly, available evidence regarding their efficacy varies significantly, with the strongest evidence currently for CBT or PR. Further randomised controlled trials are needed with larger, culturally diverse samples and long-term follow-ups. Moreover, effective nonpharmacological interventions should be implemented more in the clinical routine. Respective barriers for patients, caregivers, clinicians, healthcare systems and research need to be overcome.

Impact of trigeminal nerve and/or olfactory nerve stimulation on activity of human brain regions involved in the perception of breathlessness.

Breathlessness is a centrally processed symptom, as evidenced by activation of distinct brain regions such as the insular cortex and amygdala, during the anticipation and/or perception of breathlessness. Inhaled L-menthol or blowing cool air to the face/nose, both selective trigeminal nerve (TGN) stimulants, relieve breathlessness without concurrent improvements in physiological outcomes (e.g., breathing pattern), suggesting a possible but hitherto unexplored central mechanism of action. Four databases were searched to identify published reports supporting a link between TGN stimulation and activation of brain regions involved in the anticipation and/or perception of breathlessness. The collective results of the 29 studies demonstrated that TGN stimulation activated 12 brain regions widely implicated in the anticipation and/or perception of breathlessness, including the insular cortex and amygdala. Inhaled L-menthol or cool air to the face activated 75% and 33% of these 12 brain regions, respectively. Our findings support the hypothesis that TGN stimulation contributes to breathlessness relief by altering the activity of brain regions involved in its central neural processing.

Impact of trigeminal and/or olfactory nerve stimulation on measures of inspiratory neural drive: Implications for breathlessness.

The perception of breathlessness is mechanistically linked to the awareness of increased inspiratory neural drive (IND). Stimulation of upper airway cold receptors on the trigeminal nerve (TGN) with TGN agonists such as menthol or cool air to the face/nose has been hypothesized to reduce breathlessness by decreasing IND. The aim of this systematic scoping review was to identify and summarize the results of studies in animals and humans reporting on the impact of TGN stimulation or blockade on measures of IND. Thirty-one studies were identified, including 19 in laboratory animals and 12 in human participants. Studies in laboratory animals consistently reported that as TGN activity increased, measures of IND decreased (e.g., phrenic nerve activity). In humans, stimulation of the TGN with a stream of cool air to the face/nose decreased the sensitivity of the ventilatory chemoreflex response to hypercapnia. Otherwise, TGN stimulation with menthol or cool air to the face/note had no effect on measures of IND in humans. This review provides new insight into a potential neural mechanism of breathlessness relief with selected TGN agonists.

The effect of high versus low cognitive load on the development of nociceptive hypersensitivity: The roles of sympathetic arousal, sex and pain-related fear.

BACKGROUND: According to limited-capacity theories of attention, less attentional resources remain available when engaging in a high- versus a low-demanding cognitive task. This may reduce the perceived intensity and the evoked cortical responses of concomitant nociceptive stimuli. Whether and how the competition for limited attentional resources between a cognitive task and pain impacts the development of long-lasting hypersensitivity is unclear. METHODS: Eighty-four healthy participants were randomized into a low or high cognitive load group. Low-frequency electrical stimulation (LFS) of the skin was used to induce secondary hypersensitivity. We hypothesized that performing the high-load task during LFS would reduce the development of hypersensitivity. We examined whether painfulness, nonpain-related sympathetic arousal, or sex related to hypersensitivity, by assessing intensity and unpleasantness of mechanical pinprick stimulation. During task execution, we recorded steady-state evoked potentials evoked by LFS and skin conductance level for sympathetic arousal. Afterwards, participants reported task difficulty and LFS-related fear. For the primary outcomes, we used mixed analysis of variances. RESULTS: The results confirmed the difference in cognitive load. Although LFS successfully induced hypersensitivity, the high-load task did not reduce its development. Next, the steady-state evoked potentials did not differ between groups. Hypersensitivity correlated positively with pain-related fear and negatively with skin conductance level before LFS, despite the lack of group differences in skin conductance level. We did not find any sex differences in hypersensitivity. CONCLUSIONS: These results do not confirm that high cognitive load or sex modulate hypersensitivity, but show associations with pain-related fear and non-pain-related sympathetic arousal. SIGNIFICANCE: Previous research has mainly focused on cognitive load effects on the perception of acute painful stimuli. Yet this study extends our understanding by investigating cognitive load effects on the development of long-lasting secondary hypersensitivity, a common aspect in numerous persistent pain conditions. As cognitive tasks are presented during a painful procedure inducing secondary hypersensitivity, we test the long-lasting effects of cognitive load. Additionally, we used psychophysiological measurements to explored potential underlying mechanisms involving limited attentional resources and sympathetic arousal.

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.

Respiratory psychophysiology and COVID-19: A research agenda.

After multiple waves of the COVID-19 pandemic, it has become clear that the impact of SARS-CoV-2 will carry on for years to come. Acutely infected patients show a broad range of disease severity, depending on virus variant, vaccination status, age and the presence of underlying medical and physical conditions, including obesity. Additionally, a large number of patients who have been infected with the virus present with post-COVID syndrome. In September 2020, the International Society for the Advancement of Respiratory Psychophysiology organized a virtual interest meeting on 'Respiratory research in the age of COVID-19', which aimed to discuss how research in respiratory psychophysiology could contribute to a better understanding of psychophysiological interactions in COVID-19. In the resulting current paper, we propose an interdisciplinary research agenda discussing selected research questions on acute and long-term neurobiological, physiological and psychological outcomes and mechanisms related to respiration and the airways in COVID-19, as well as research questions on comorbidity and potential treatment options, such as physical rehabilitation.

The effect of unpredictability on the perception of breathlessness: a narrative review.

Breathlessness is an aversive bodily sensation impacting millions of people worldwide. It is often highly detrimental for patients and can lead to profound distress and suffering. Notably, unpredictable breathlessness episodes are often reported as being more severe and unpleasant than predictable episodes, but the underlying reasons have not yet been firmly established in experimental studies. This review aimed to summarize the available empirical evidence about the perception of unpredictable breathlessness in the adult population. Specifically, we examined: (1) effects of unpredictable relative to predictable episodes of breathlessness on their perceived intensity and unpleasantness, (2) potentially associated neural and psychophysiological correlates, (3) potentially related factors such as state and trait negative affectivity. Nine studies were identified and integrated in this review, all of them conducted in healthy adult participants. The main finding across studies suggested that unpredictable compared to predictable, breathlessness elicits more frequently states of high fear and distress, which may contribute to amplify the perception of unpredictable breathlessness, especially its unpleasantness. Trait negative affectivity did not seem to directly affect the perception of unpredictable breathlessness. However, it seemed to reinforce state fear and anxiety, hence possible indirect modulatory pathways through these affective states. Studies investigating neural correlates of breathlessness perception and psychophysiological measures did not show clear associations with unpredictability. We discuss the implication of these results for future research and clinical applications, which necessitate further investigations, especially in clinical samples suffering from breathlessness.

The impact of emotional context on neural substrates of respiratory sensory gating.

Psychological challenges have been found to impact respiratory symptom perception in healthy individuals as well as in patients with various neurological disorders. Human respiratory sensory gating is an objective measure to examine respiratory sensory information processing of repetitive respiratory mechanical stimuli in the central nervous system. With this electrophysiological method, patients with higher anxiety levels showed reduced respiratory sensory gating function in the cortex, and increased symptom perception. In addition, positive emotional contexts were found to increase the respiratory sensory gating function using RREPs. However, neural substrates related to emotional impacts on respiratory sensory gating remain still unclear. In the present study, we examined the emotion processing of respiratory sensory gating using functional magnetic resonance imaging. We hypothesized that positive compared with neutral stimuli would result in reduced brain activations in cortical areas with the paired occlusion paradigm. Thirty-five healthy adults participated in this event-designed fMRI experiment. Paired inspiratory occlusions (two transient occlusions with a 500 ms inter-stimulus-interval are delivered during one inspiration) were provided using an external trigger outside of the scanner. At least 40 paired inspiratory occlusions were collected for each trial. The experiment contained three runs during which participants underwent 12 min for the paired inspiratory occlusion paradigm while watching a fixation cross (the control condition), neutral and positive emotional picture series. The order of emotional picture series was randomized across the participants. Our results revealed an overall trend of reduction of brain activity from the neutral (minus fixation) condition, to the pleasant (minus fixation) condition. For bilateral thalamus and primary visual cortices, there was no significant difference in neural activation between the two contrasts of pleasant (ContrastP-F) and neutral condition (ContrastN-F). The activation of the mid-cingulate and the orbitofrontal cortex was lower in ContrastP-F compared to ContrastN-F. In conclusion, our results suggest that emotional context, especially positive valence, modulates neural correlates in middle cingulate cortex and orbitofrontal cortex in terms of respiratory sensory gating. Future studies are recommended to test emotional impacts on respiratory sensations in patients with neurological disorders.

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.

Error Processing and Pain: A New Perspective.

Errors put organisms in danger. Upon error commission, error processing allows for the updating of behavior that proved ineffective in light of the current context and goals, and for the activation of behavioral defensive systems. Pain, on the other hand, signals actual or potential danger to one's physical integrity and, likewise, motivates protective behavior. These parallels suggest the existence of cross-links between pain and error processing but so far their relationship remains elusive. In this review, we tie together findings from the field of pain research with those from electroencephalography studies on error processing [specifically the Error Related Negativity (ERN) and Positivity (Pe)]. More precisely, we discuss 3 plausible associations: Firstly, pain may enhance error processing as it increases error salience. Secondly, persons fearful of pain may be particularly vigilant towards painful errors and thus show a stronger neural response to them. Thirdly, the ERN as a component of the neural response to error commission is considered an endophenotype of threat sensitivity. As high sensitivity to pain threats is known to incite avoidance behavior, this raises the intriguing possibility that neural signatures of error processing predict pain-related protective behaviors, such as avoidance. We propose an integration of these findings into a common framework to inspire future research. PERSPECTIVE: Inspired by research in anxiety disorders, we discuss the potential bi-directional relationships between error processing and pain, and identify future directions to examine the neural and psychological processes involved in acute and chronic pain and respective avoidance behavior.

No evidence for a modulating effect of continuous transcutaneous auricular vagus nerve stimulation on markers of noradrenergic activity.

Although transcutaneous auricular vagus nerve stimulation (taVNS) is thought to increase central noradrenergic activity, findings supporting such mechanism are scarce and inconsistent. This study aimed to investigate whether taVNS modulates indirect markers of phasic and tonic noradrenergic activity. Sixty-six healthy participants performed a novelty auditory oddball task twice on separate days: once while receiving taVNS (left cymba concha), once during sham (left earlobe) stimulation. To maximize potential effects, the stimulation was delivered continuously (frequency: 25 Hz; width: 250 µs) at an intensity individually calibrated to the maximal level below pain threshold. The stimulation was administered 10 min before the oddball task and maintained throughout the session. Event-related pupil dilation (ERPD) to target stimuli and pre-stimulus baseline pupil size were assessed during the oddball task as markers of phasic and tonic noradrenergic activity, respectively. Prior to and at the end of stimulation, tonic pupil size at rest, cortisol, and salivary alpha-amylase were assessed as markers of tonic noradrenergic activity. Finally, we explored the effect of taVNS on cardiac vagal activity, respiratory rate, and salivary flow rate. Results showed a greater ERPD to both target and novelty compared to standard stimuli in the oddball task. In contrast to our hypotheses, taVNS did not impact any of the tested markers. Our findings strongly suggest that continuous stimulation of the cymba concha with the tested stimulation parameters is ineffective to increase noradrenergic activity via a vagal pathway.

The effects of unpredictability and negative affect on perception and neural gating in different interoceptive modalities.

Breathlessness and pain frequently co-occur in chronic conditions, and their unpredictability is often reported to amplify perception and negative affect (NA), however any common neural mechanisms remain largely unexplored. This study examined the effects of (unpredictable) bodily threat on perception and neural gating of respiratory and somatosensory stimuli. Healthy adults (N = 51) experienced brief paired inspiratory occlusions and electrocutaneous stimuli, with their neural activity monitored via electroencephalography. Neural gating was measured as a ratio of the N1 response to the second relative to the first stimulus in a pair. In 4/6 blocks, threatening stimulation, in form of additional loaded breaths or electrocutaneous pulses, was presented predictably or unpredictably. Participants reported: perceived intensity and unpleasantness of all stimuli, fear, trait NA and intolerance of uncertainty (IU). Threatening stimulation increased perception, fear, and N1 amplitudes, without affecting neural gating. There was no group effect of unpredictability, though interactions were found with NA and IU. Cross-modal correlations revealed significant baseline relationships in neural gating and perception, though not in their modulation by threat. The present findings demonstrate that respiratory and somatosensory modalities relate in baseline perception and neural gating, and exhibit similar modulation effects by unpleasant stimulation. Further research is encouraged to elucidate the underlying mechanisms of these relationships, and the potential interactions with stimulus unpredictability.