Pain by mistake:investigating a link between error-related negativity and pain avoidance behavior

ABSTRACT: Pain can be considered as a signal of "bodily error": Errors put organisms at danger and activate behavioral defensive systems. If the error is of physical nature, pain is the warning signal that motivates protective action such as avoidance behavior to safeguard our body's integrity. Interestingly, an important component of neural error processing, the error-related negativity (ERN), has been found to be related to avoidance in anxiety disorders. The present study is the first to extend these findings to pain and investigate the relationship between ERN and pain-related avoidance behavior. It was hypothesized that individuals with larger ERN amplitudes would show more pain-related avoidance behavior and would be more persistent in their avoidance despite changes in the environment. Fifty-three healthy individuals performed the Eriksen Flanker task during which their brain activity upon correct and erroneous motor responses was recorded by means of high-density electroencephalography. Avoidance behavior was assessed with an arm-reaching task using the HapticMaster robot arm. Results showed that, in contrast to our hypothesis, avoidance was not related to ERN amplitudes. Surprisingly, persons with elevated ERN amplitudes showed low levels of avoidance specifically during early acquisition trials. In contrast to earlier findings in anxiety disorders, individuals with elevated ERN amplitudes did not engage in more pain-related avoidance behavior. In fact, the opposite pattern was found at the start of acquisition: individuals with higher compared to lower ERN amplitudes were slower in learning to avoid pain. Replications and future studies on the relationship between ERN and avoidance behavior are needed

Breathlessness and inflammation: relationship and implications

Purpose of Review: Breathlessness and chronic inflammation both span a wide range of disease contexts and hold prognostic significance. The possibility of a causal relationship between the two has been hypothesised. The aims of this article are 1) to review the intersections between breathlessness and inflammation in the literature, 2) to describe potential mechanisms connecting the two phenomena, and 3) to discuss the potential clinical implications of a causal relationship. Recent findings: There is a very limited literature exploring the relationship between systemic inflammation and breathlessness in COPD, heart failure and cancer. One large study in cancer patients is suggestive of a weak association between self-reported breathlessness and inflammation. Studies exploring the relationship between inflammation and MRC Dyspnoea grade have produced inconsistent findings. Though a causal relationship has not yet been demonstrated, this relationship might be mediated through the effects of both inflammation and breathlessness on the skeletal muscle and stress hormone systems. Summary: There is much progress to be made in this area. Interventional studies, evaluating the impact of anti-inflammatory interventions on breathlessness, are needed to help determine whether a causal relationship exists. If proven, this relationship might have important implications for both the treatment and impact of breathlessness

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

Structural Brain Changes Related to Disease Duration in Patients with Asthma

Dyspnea is the impairing, cardinal symptom patients with asthma repeatedly experience over the course of the disease. However, its accurate perception is also crucial for timely initiation of treatment. Reduced perception of dyspnea is associated with negative treatment outcome, but the underlying brain mechanisms of perceived dyspnea in patients with asthma remain poorly understood. We examined whether increasing disease duration in fourteen patients with mild-to-moderate asthma is related to structural brain changes in the insular cortex and brainstem periaqueductal grey (PAG). In addition, the association between structural brain changes and perceived dyspnea were studied. By using magnetic resonance imaging in combination with voxel-based morphometry, gray matter volumes of the insular cortex and the PAG were analysed and correlated with asthma duration and perceived affective unpleasantness of resistive load induced dyspnea. Whereas no associations were observed for the insular cortex, longer duration of asthma was associated with increased gray matter volume in the PAG. Moreover, increased PAG gray matter volume was related to reduced ratings of dyspnea unpleasantness. Our results demonstrate that increasing disease duration is associated with increased gray matter volume in the brainstem PAG in patients with mild-to-moderate asthma. This structural brain change might contribute to the reduced perception of dyspnea in some patients with asthma and negatively impact the treatment outcome

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

Background: Neural gating of respiratory sensations (NGRS) characterises the brain\u27s 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

Subjective evaluation of experimental dyspnoea: effects of isocapnia and repeated exposure

Resistive respiratory loading is an established stimulus for the induction of experimental dyspnoea. In comparison to unloaded breathing, resistive loaded breathing alters end-tidal CO2 (PETCO2), which has independent physiological effects (e.g. upon cerebral blood flow). We investigated the subjective effects of resistive loaded breathing with stabilized PETCO2 (isocapnia) during manual control of inspired gases on varying baseline levels of mild hypercapnia increased PETCO2). Furthermore, to investigate whether perceptual habituation to dyspnoea stimuli occurs, the study was repeated over four experimental sessions. Isocapnic hypercapnia did not affect dyspnoea unpleasantness during resistive loading. A post hoc analysis revealed a small increase of respiratory unpleasantness during unloaded breathing at +0.6 kPa, the level that reliably induced isocapnia. We didnot observe perceptual habituation over the four sessions. We conclude that isocapnic respiratory loading allows stable induction of respiratory unpleasantness, making it a good stimulus for multi-session studies of dyspnoea

Prenatal stress exposure is associated with increased dyspnoea perception in adulthood

Prenatal exposure to maternal stress is associated with increased perception of dyspnea in adulthood 28 years later

Brain Responses during the Anticipation of Dyspnea

Dyspnea is common in many cardiorespiratory diseases. Already the anticipation of this aversive symptom elicits fear in many patients resulting in unfavorable health behaviors such as activity avoidance and sedentary lifestyle. This study investigated brain mechanisms underlying these anticipatory processes. We induced dyspnea using resistive-load breathing in healthy subjects during functional magnetic resonance imaging. Blocks of severe and mild dyspnea alternated, each preceded by anticipation periods. Severe dyspnea activated a network of sensorimotor, cerebellar, and limbic areas. The left insular, parietal opercular, and cerebellar cortices showed increased activation already during dyspnea anticipation. Left insular and parietal opercular cortex showed increased connectivity with right insular and anterior cingulate cortex when severe dyspnea was anticipated, while the cerebellum showed increased connectivity with the amygdala. Notably, insular activation during dyspnea perception was positively correlated with midbrain activation during anticipation. Moreover, anticipatory fear was positively correlated with anticipatory activation in right insular and anterior cingulate cortex. The results demonstrate that dyspnea anticipation activates brain areas involved in dyspnea perception. The involvement of emotion-related areas such as insula, anterior cingulate cortex, and amygdala during dyspnea anticipation most likely reflects anticipatory fear and might underlie the development of unfavorable health behaviors in patients suffering from dyspnea

Impact of Disease-Specific Fears on Pulmonary Rehabilitation Trajectories in Patients with COPD

Disease-specific fears predict health status in chronic obstructive pulmonary disease (COPD), but their role in pulmonary rehabilitation (PR) remains poorly understood and especially longer-term evaluations are lacking. We therefore investigated changes in disease-specific fears over the course of PR and six months after PR, and investigated associations with PR outcomes (COPD assessment test (CAT) and St. Georges respiratory questionnaire (SGRQ)) in a subset of patients with COPD (n = 146) undergoing a 3-week inpatient PR program as part of the STAR study (Clinicaltrials.gov, ID: NCT02966561). Disease-specific fears as measured with the COPD anxiety questionnaire improved after PR. For fear of dyspnea, fear of physical activity and fear of disease progression, improvements remained significant at six-month follow-up. Patients with higher disease-specific fears at baseline showed elevated symptom burden (CAT and SGRQ Symptom scores), which persisted after PR and at follow-up. Elevated disease-specific fears also resulted in reduced improvements in Quality of Life (SGRQ activity and impact scales) after PR and at follow-up. Finally, improvement in disease-specific fears was associated with improvement in symptom burden and quality of life. Adjustment for potential confounding variables (sex, smoking status, age, lung function, and depressive symptoms) resulted in comparable effects. These findings show the role of disease-specific fears in patients with COPD during PR and highlight the need to target disease-specific fears to further improve the effects of PR