Learned symptom-specific fear towards a visceral sensation and its impact on perceptual habituation.

OBJECTIVE: Impaired habituation of bodily sensations has been suggested as a contributing factor to chronic pain. We examined in healthy volunteers the influence of fear learning towards a non-painful sensation in the esophagus on the perceptual habituation of this sensation. METHODS: In a homoreflexive fear learning paradigm, non-painful electrical sensations in the esophagus were used as a conditioned stimulus (CS). This sensation was presented 42 times before, during, and after fear learning. In the fear learning group (n = 41), the CS was paired with a painful electrical sensation in the esophagus (unconditioned stimulus; US). In the control group (n = 41), the CS was not paired with the US. Ratings for CS intensity, US expectancy, startle electromyogram (EMG), skin conductance responses (SCR) and event-related potentials (ERPs) to the CS were assessed. RESULTS: Compared to the control group, fear learning was observed in the fear learning group as evidenced by potentiated startle responses after the CS relative to ITI (t(1327) = 3.231, p = .001) and higher US expectancy ratings (t(196) = 3.17, p = .002). SCRs did not differ between groups (F1, 817 = 1.241, p = .33). Despite successful fear learning, the fear learning group did not show a distinct pattern of habituation to the visceral CS relative to the control group (intensity ratings: F1, 77.731 = 0.532 p = .47; ERPs: F1, 520.78 = 0.059, p = .94). CONCLUSION: Acquired fear to non-painful esophageal sensations does not affect their perceptual habituation patterns.

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.

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.

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.

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.

The breathing brain: The potential of neural oscillations for the understanding of respiratory perception in health and disease.

Dyspnea or breathlessness is a symptom occurring in multiple acute and chronic illnesses, however, the understanding of the neural mechanisms underlying its subjective experience is limited. In this topical review, we propose neural oscillatory dynamics and cross-frequency coupling as viable candidates for a neural mechanism underlying respiratory perception, and a technique warranting more attention in respiration research. With the evidence for the potential of neural oscillations in the study of normal and disordered breathing coming from disparate research fields with a limited history of interdisciplinary collaboration, the main objective of the review was to converge the existing research and suggest future directions. The existing findings show that distinct limbic and cortical activations, as measured by hemodynamic responses, underlie dyspnea, however, the time-scale of these activations is not well understood. The recent findings of oscillatory neural activity coupled with the respiratory rhythm could provide the solution to this problem, however, more research with a focus on dyspnea is needed. We also touch on the findings of distinct spectral patterns underlying the changes in breathing due to experimental manipulations, meditation and disease. Subsequently, we suggest general research directions and specific research designs to supplement the current knowledge using neural oscillation techniques. We argue for the benefits of interdisciplinary collaboration and the converging of neuroimaging and behavioral methods to best explain the emergence of the subjective and aversive individual experience of dyspnea.

To breathe or not to breathe: Interoceptive predictions in an anxious brain.

Respiration is gaining traction as an important and consciously accessible interoceptive domain with strong relationships to anxiety. In this issue of Neuron, Harrison et al. (2021) report a tour de force investigation into this relationship at multiple levels of interoception, featuring a novel respiratory learning task.

Is it a painful error? The effect of unpredictability and intensity of punishment on the error-related negativity, and somatosensory evoked potentials.

We examined how predictable and unpredictable punishment intensity contingent on error commission modulated ERN amplitudes. We recorded the ERN in 35 healthy volunteers performing the Eriksen flanker task. Errors were punished with predictable nonpainful, painful or unpredictable electrical stimulation. Furthermore, we investigated trait anxiety. We observed that ERN amplitudes did not differ across conditions, nor were there significant effects of anxiety. In contrast, we found that predictable painful punishments led to smaller Error Positivity (Pe). The effects of predictability and intensity were present in Somatosensory Evoked Potentials elicited by the punishments. N1 amplitudes were increased for painful compared to nonpainful stimulation, and P2/P3 amplitudes for painful compared to nonpainful, and for unpredictable compared to predictable stimulation. We suggest that unpredictability and increased painfulness of punishments enhance the potential motivational significance of the errors, but do not potentiate ERN amplitudes beyond the ones elicited by errors punished with predictable nonpainful stimulation.

The test-retest reliability of the respiratory-related evoked potential.

The respiratory-related evoked potential (RREP) is an established technique to study the neural processing of respiratory sensations. We examined the test-retest reliability of the RREP during an unloaded baseline condition (no dyspnea) and an inspiratory resistive loaded breathing condition (dyspnea) over a one-week period. RREPs were evoked by short inspiratory occlusions (150 ms) while EEG was continuously measured. The mean amplitudes of the RREP components Nf, P1, N1, P2, and P3 were studied. For the no dyspnea condition, moderate test-retest reliability for Nf (intraclass correlation coefficient ICC: 0.73) and P1 (ICC: 0.74), good test-retest reliability for N1 (ICC: 0.89) and P3 (ICC: 0.76), and excellent test-retest reliability for P2 (ICC: 0.92) was demonstrated. For the dyspnea condition, moderate test-retest reliability was found for Nf (ICC: 0.69) and P1 (ICC: 0.57) and good test-retest reliability for N1 (ICC: 0.77), P2 (ICC: 0.84), and P3 (ICC: 0.77). This indicates that the RREP components Nf, P1, N1, P2, and P3, elicited by inspiratory occlusions, show adequate reliability in a test-retest study design with or without parallel sustained resistive load-induced dyspnea.

The impact of unpredictability of dyspnea offset on dyspnea perception, fear, and respiratory neural gating.

Dyspnea is a debilitating and threatening symptom in various diseases. Affected patients often report the unpredictability of dyspnea episodes being particularly anxiety-provoking and amplifying the perception of dyspnea. Experimental studies testing dyspnea unpredictability together with related neural processes, physiological fear responses, and dyspnea-related personality traits are sparse. Therefore, we investigated the impact of unpredictability of dyspnea offset on dyspnea perception and fear ratings, respiratory neural gating and physiological fear indices, as well as the influence of interindividual differences in fear of suffocation (FoS). Forty healthy participants underwent a task manipulating the offset predictability of resistive load-induced dyspnea including one unloaded safety condition. Respiratory variables, self-reports of dyspnea intensity, dyspnea unpleasantness, and fear were recorded. Moreover, respiratory neural gating was measured in a paired inspiratory occlusion paradigm using electroencephalography, while electrodermal activity, startle eyeblink, and startle probe N100 were assessed as physiological fear indices. Participants reported higher dyspnea unpleasantness and fear when dyspnea offset was unpredictable compared to being predictable. Individuals with high levels of FoS showed the greatest increase in fear and overall higher levels of fear and physiological arousal across all conditions. Respiratory neural gating, startle eyeblink, and startle probe N100 showed general reductions during dyspnea conditions but no difference between unpredictable and predictable dyspnea conditions. Together, the current results suggest that the unpredictable offset of dyspnea amplifies dyspnea perception and fear, especially in individuals with high levels of FoS. These effects were unrelated to respiratory neural gating or physiological fear responses, requiring future studies on underlying mechanisms.

Cross-modal relationships of neural gating with the subjective perception of respiratory and somatosensory sensations.

Neural gating is a phenomenon whereby the response to a stimulus in the electroencephalogram (EEG) is attenuated when preceded by an identical stimulus. Attenuation of paired auditory clicks has repeatedly been shown to be affected in mental disorders, for example, schizophrenia. Neural gating has also been measured for respiratory and somatosensory sensations, however the attenuation of bodily relevant stimuli has not yet been systematically related to the subjective perception of bodily sensations. This research direction is potentially relevant to explaining disease trajectories in psychosomatic conditions characterized by chronic breathlessness and/or pain. In the present study, we recorded high-density EEG from 85 healthy young adults while they experienced brief paired respiratory occlusions and brief paired electrocutaneous stimulation of the wrist. The event-related potential N1 was measured centro-laterally in response to the second relative to the first stimulus to quantify neural gating in both sensory domains. Participants experienced resistive loaded breaths and electrocutaneous stimuli of various intensities, rated their perceived intensity and unpleasantness, and performed magnitude estimation. Relationships of respiratory and somatosensory neural gating to the subjective intensity and unpleasantness of sensations, as well as the ability to discriminate sensations of varying intensities, were investigated intra-modally and cross-modally. We report significant relationships of the somatosensory neural gating to perceived intensity and unpleasantness of respiratory and somatosensory sensations, with the stronger neural gating relating to a stronger subjective intensity and unpleasantness. We discuss these unexpected findings through the lens of individual differences and different theoretical accounts on the origins of cortical attenuation of repetitive stimuli.

Error-related negativity relates to the neural processing of brief aversive bodily sensations.

The error-related negativity (ERN) is an event-related potential occurring in the electroencephalogram (EEG) within 100 ms after the commission of an error. The ERN is thought to partially reflect emotionally aversive aspects of error commission, however, it has thus far not been related to the neural processing of other aversive events, such as brief aversive bodily sensations. Therefore, the present study investigated the links between the ERN and the N1 amplitudes of respiratory-related evoked potentials (RREP) and somatosensory evoked potentials (SEP). During the acquisition of high-density EEG, 41 healthy participants performed a Flanker task to evoke the ERN, while RREP and SEP were separately elicited, using inspiratory occlusions and electrocutaneous stimulation of the wrist. Significant positive correlations were observed between the amplitudes of the ERN and the N1 of RREP and SEP, suggesting relationships between the neural processing of different emotionally aversive events, namely errors and bodily sensations.

The role of mid-insula in the relationship between cardiac interoceptive attention and anxiety: evidence from an fMRI study.

Interoception refers to the perception of the internal bodily states. Recent accounts highlight the role of the insula in both interoception and the subjective experience of anxiety. The current study aimed to delve deeper into the neural correlates of cardiac interoception; more specifically, the relationship between interoception-related insular activity, interoceptive accuracy, and anxiety. This was done using functional magnetic resonance imaging (fMRI) in an experimental design in which 40 healthy volunteers focused on their heartbeat and anxious events. Interoceptive accuracy and anxiety levels were measured using the Heartbeat Perception Task and State Trait Anxiety Inventory, respectively. The results showed posterior, mid and anterior insular activity during cardiac interoception, whereas anxiety-related activation showed only anterior insular activity. Activation of the anterior insula when focused on cardiac interoception was positively correlated to state and trait anxiety levels, respectively. Moreover, the mid-insular activity during the cardiac attention condition not only related to individuals' interoceptive accuracy but also to their levels of state and trait anxiety, respectively. These findings confirm that there are distinct neural representations of heartbeat attention and anxious experience across the insular regions, and suggest the mid-insula as a crucial link between cardiac interoception and anxiety.

Exteroceptive expectations modulate interoceptive processing: repetition-suppression effects for visual and heartbeat evoked potentials.

Interoception refers to the signaling of internal bodily commands. Here, we explore repetition suppression of intero- and exteroceptive neural markers to test whether the perception and predictability of exteroceptive stimulus material affects their expression. Participants completed a repetition suppression paradigm in which angry or neutral facial expressions repeated or alternated. Participants received either an implicit (experiment 1) or explicit (experiment 2) cue enabling the formation of expectations regarding the upcoming facial expression. We measured the heartbeat-evoked potential (HEP) indexing cardiac processing and visual evoked potentials (VEP) in response to viewing the second (repeated or alternated) face. Repeating angry facial expressions produced repetition suppression of both HEP and VEP amplitude while repeating neutral expressions led to repetition enhancement of HEP amplitude. This effect was magnified when participants were explicitly aware of predictive cues. Furthermore, repetition suppression of HEP amplitude correlated with neural attenuation of VEP activity. Results highlight repetition effects for interoceptive as well as exteroceptive neural markers and support top-down, expectation-based accounts of the phenomenon. Furthermore, results demonstrate that the perception of exteroceptive stimulus information has an effect on the processing of interoceptive signals and suggest a direct neural connection between the processing of external and internal sensory information.

Meta-regression analysis to indirectly compare prophylaxis with dalteparin or enoxaparin in patients at high risk for venous thromboembolic events.

BACKGROUND: Dalteparin and enoxaparin are recommended as thromboprophylaxis for at least 10 days in patients undergoing abdominal surgery (AS) or hospitalized patients with acute medical illnesses. Even though both agents have proven clinical effectiveness through randomized trials, there have been no head-to-head studies. In this evaluation, indirect statistical techniques were used to compare safety and efficacy between dalteparin and enoxaparin in these 2 high-risk patient populations. METHODS: A literature search was conducted from January 1980 to November 2010 for randomized trials evaluating dalteparin or enoxaparin prophylaxis following AS or in hospitalized patients. Binary outcomes for safety and efficacy were statistically pooled using fixed or random effects models in cases of significant heterogeneity. In trials where a common control was used (eg, unfractionated heparin [UH]), indirect statistical comparisons between dalteparin and enoxaparin were performed using meta-regression analysis with active drug as the primary independent variable. RESULTS: The meta-analysis in AS patients showed that enoxaparin or dalteparin had comparable efficacy to UH in terms of venous thromboembolic events (VTEs; relative risk reduction [RR] = 0.87, P = .46). The indirect statistical comparison was unable to find significant differences between enoxaparin and dalteparin in terms of risk for VTE (P = .84), major bleeding (P = .38), heparin-induced thrombocytopenia ([HIT]; P = .084), or death (P = .97). In acutely ill medical patients, treatment with enoxaparin or dalteparin had a 52% VTE risk reduction compared to placebo (RR = 0.48, P < .001). The indirect comparison was also unable to find significant differences between enoxaparin and dalteparin in terms of VTEs (P = .15), major bleeds (P = .39), HIT (P = .48), and death (P = .41). CONCLUSIONS: The findings suggest comparable safety and efficacy between dalteparin and enoxaparin in AS and in acutely ill medical patients.

Meta regression analysis to indirectly compare dalteparin to enoxaparin for the prevention of venous thromboembolic events following total hip replacement.

BACKGROUND: Patients undergoing elective total hip replacement (THR) surgery are at an increased risk for venous thromboembolic events (VTEs). Dalteparin and enoxaparin are recommended as thromboprophylaxis for at least 10 days in these patients. Even though both agents have proven clinical effectiveness through placebo controlled studies, there have been no head to head trials to assess comparative effectiveness. Indirect statistical techniques were used to compare safety and efficacy between dalteparin and enoxaparin following THR surgery. METHODS: A literature search was conducted from January 1980 to November 2009 for randomized trials evaluating dalteparin or enoxaparin prophylaxis in THR patients. In trials where a common control was used (e.g. placebo), indirect statistical comparisons between dalteparin and enoxaparin were performed using meta regression analysis with active drug as the primary independent variable. RESULTS: A total of nine placebo controlled enoxaparin (n = 5) and dalteparin (n = 4) trials met the inclusion criteria. THR patients treated with enoxaparin or dalteparin had a 50% VTE risk reduction compared to the placebo control (RR = 0.50, p < 0.001). This benefit was achieved without a significant increase in the risk for major bleeds (RR = 1.19, p = 0.76), heparin induced thrombocytopenia (HIT) (RR = 1.13, p = 0.83) or death (RR = 0.72, p = 0.59). The indirect comparison was not able to find significant differences between enoxaparin and dalteparin in terms of VTEs (p = 0.36), major bleeds (p = 0.45), HIT (p = 0.48) and death (p = 0.86). CONCLUSIONS: The findings suggested comparable safety and efficacy between dalteparin and enoxaparin in TKR patients. Therefore, treatment decisions should be based on other considerations, such as patient or physician preference, ease of administration and cost.

Neuromuscular blocking agents: enhancing safety by reducing the risk of accidental administration.

Neuromuscular blocking agents (NMBAs) are often found as ward stock in critical care units to ensure their availability in case of urgent need. The unintentional administration of an NMBA to a non-intubated and non-ventilated patient can result in severe permanent injury or death. Incidents involving mix-ups with NMBAs have occurred within and outside of critical care units. Case reports are highlighted with the intent to increase practitioner awareness of situations that could lead to similar errors and to promote changes in the critical care environment in order to enhance medication safety with NMBAs.

To err is human, to share is divine.

Front-line health care practitioners are often safety nets preventing errors from reaching patients. Nurses in critical care environments commonly deal with high-risk patients, high-alert medications and extreme conditions, placing themselves and medication systems under greater pressures. Human error cannot be eradicated. However, the systems in which practitioners work and interact can be made safer and more fault-tolerant. When errors occur, nurses are in a unique position to provide valuable insights. Practitioner reporting and sharing of incident information internally and externally can enhance patient safety by helping to prevent recurrence of similar events.

Communication of medication orders by telephone--"writing it right".

Communication is commonly cited as a contributing factor to adverse events causing patient harm (Baker et al., 2004). There are numerous ways and reasons that communication failures can occur, such as poor handwriting, transcription errors, lack of verification, lack of integration of information, and ineffective team functioning. Errors that can occur in critical care with the verbal communication and receipt of a telephone order will be highlighted. These examples, together with proposed strategies for improving telephone order safety, are intended to promote awareness and potential practice changes in the critical care environment.

Secondary lines require "primary" attention.

An incident report received from an intensive care unit involving the administration of a secondary infusion is reprinted, with permission, and includes material from an ISMP Canada Safety Bulletin (ISMP Canada, 2005). The incident highlights a general shortcoming of many infusion pumps: lack of the capability to recognize primary versus secondary infusions. Reliance on practitioner vigilance to ensure appropriate administration adds to their already demanding practice. Secondary lines require "primary" attention from manufacturers to enhance infusion pump design and, in the interim, by all practitioners using infusion pumps with such limitations.