Breathlessness and the body: Neuroimaging evidence for the inferential leap

Breathlessness debilitates millions of people with chronic illness. Mismatch between breathlessness severity and objective disease markers is common and poorly understood. Traditionally, sensory perception was conceptualised as a stimulus-response relationship, although this cannot explain how conditioned symptoms may occur in the absence of physiological signals from the lungs or airways. A Bayesian model is now proposed in which the brain generates sensations based on expectations learned from past experiences (priors), which are then checked against incoming afferent signals. In this model, psychological factors may act as moderators. They may either alter priors, or change the relative attention towards incoming sensory information, leading to more variable interpretation of an equivalent afferent input. In the present study we conducted a preliminary test of this model in a supplementary analysis of previously published data (Hayen 2017). We hypothesised that individual differences in psychological traits (anxiety, depression, anxiety sensitivity) would correlate with the variability of subjective evaluation of equivalent breathlessness challenges. To better understand the resulting inferential leap in the brain, we explored whether these behavioural measures correlated with activity in areas governing either prior generation or sensory afferent input. Behaviorally, anxiety sensitivity was found to positively correlate with each subject’s variability of intensity and unpleasantness during mild breathlessness, and with unpleasantness during strong breathlessness. In the brain, anxiety sensitivity was found to positively correlate with activity in the anterior insula during mild breathlessness, and negatively correlate with parietal sensorimotor areas during strong breathlessness. Our findings suggest that anxiety sensitivity may reduce the robustness of this Bayesian sensory perception system, increasing the variability of breathlessness perception and possibly susceptibility to symptom misinterpretation. These preliminary findings in healthy individuals demonstrate how differences in psychological function influence the way we experience bodily sensations, which might direct us towards better understanding of symptom mismatch in clinical populations.


Introduction
conditioned mild and strong breathlessness stimuli in 19 healthy participants (10 114 females, mean age ± SD, 24 ± 7 years). An account of conditioned responses to strong 115 breathlessness has been published previously 31 , while the mild breathlessness stimulus 116 was not considered due to its large between-subject variability. In the current report we  Behavioural and fMRI analysis 150 In this short report we will only consider the fMRI session with the saline infusion. Full 151 details on analysis procedures have been previously reported 31 , and involved robust 152 physiological noise correction of fMRI images. Whilst former analyses examined mean 153 brain responses to anticipation and breathlessness (and the changes induced by 154 remifentanil), the focus of this analysis was to explore how behavioural measures relate 155 to the mean and variability of breathlessness perceptions in each subject, and to any 156 corresponding changes in brain activity.

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Mean and variability (standard deviation) of mouth pressure, subjective intensity 158 and unpleasantness during scanning for both mild and strong loading were calculated 159 for each subject. A full correlation matrix was then created on all behavioural and 160 physiological variables, including questionnaires, mouth pressure and subjective 161 breathlessness scores for each level of loading. As the behavioural variable of ASI 162 score was shown to significantly correlate with trial-by-trial variation (standard deviation) 163 of subjective scores, the group fMRI analysis previously reported 31 was adjusted to 164 include a group mean and ASI score regressor. This analysis aimed to identify where 165 functional brain activity correlates with differences in ASI score and thus extent of 166 perceptual variability across subjects during saline administration, using whole-brain 167 correction for multiple comparisons in FSL (FMRIB's Software Library, 168 www.fmrib.ox.ac.uk/fsl). Trait anxiety and depression were highly correlated across subjects, but neither 175 correlated with ASI score (Figure 1). No behavioural scores (depression, trait anxiety or 176 anxiety sensitivity) were found to significantly correlate with mean inspiratory pressure 177 or subjective breathlessness VAS scores of intensity or unpleasantness for either mild 178 or strong breathlessness conditions ( Figure 1). When behavioural scores were 179 compared to variability (standard deviation) in physiology and subjective scores, ASI 180 was found to significantly correlate with variation in unpleasantness during both mild 181 and strong breathlessness, and intensity with mild breathlessness (Figures 1 and 3).

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Both trait anxiety and depression were strongly correlated with the variation in pressure 183 trace during strong (but not mild) breathlessness, but not subjective scores.

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When mean subjective breathlessness scores and physiology were compared, 185 average pressure, subjective intensity and unpleasantness were all strongly correlated   During mild breathlessness, the extent of perceptual variation in subjective scores of 201 both breathlessness intensity (r = 0.406, p = 0.048) and unpleasantness (r = 0.547, p = 202 0.010) were correlated with ASI score. When ASI score was subsequently investigated 203 as a modulator of brain activity during mild breathlessness, it was found to correlate with 204 brain activity in the left anterior insula only ( Figure 3). No significant activity was found to 205 correlate with ASI score during anticipation of mild breathlessness. In this study we have shown that the greater an individual's anxiety sensitivity index 219 (ASI) score, the greater the variability in breathlessness scores to a set of standardised 220 breathlessness challenges. Furthermore, during mild breathlessness, ASI score was 221 found to correlate with brain activity in the anterior insula. Conversely, during strong 222 breathlessness, ASI score was inversely correlated with activity in parietal primary 223 sensorimotor cortices.

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The extent of negative emotions such as anxiety and depression have long been 225 considered potential modulators of perception 18,19,21,23,25,35 . However, in healthy 226 populations these scores may not be sensitive enough to identify a potential role in the