Breathlessness in a virtual world: An experimental paradigm testing how discrepancy between VR visual gradients and pedal resistance during stationary cycling affects breathlessness perception.

INTRODUCTION: The sensation of breathlessness is often attributed to perturbations in cardio-pulmonary physiology, leading to changes in afferent signals. New evidence suggests that these signals are interpreted in the light of prior "expectations". A misalignment between afferent signals and expectations may underly unexplained breathlessness. Using a novel immersive virtual reality (VR) exercise paradigm, we investigated whether manipulating an individual's expectation of effort (determined by a virtual hill gradient) may alter their perception of breathlessness, independent from actual effort (the physical effort of cycling). METHODS: Nineteen healthy volunteers completed a single experimental session where they exercised on a cycle ergometer while wearing a VR headset. We created an immersive virtual cycle ride where participants climbed up 100 m hills with virtual gradients of 4%, 6%, 8%, 10% and 12%. Each virtual hill gradient was completed twice: once with a 4% cycling ergometer resistance and once with a 6% resistance, allowing us to dissociate expected effort (virtual hill gradient) from actual effort (power). At the end of each hill, participants reported their perceived breathlessness. Linear mixed effects models were used to examine the independent contribution of actual effort and expected effort to ratings of breathlessness (0-10 scale). RESULTS: Expectation of effort (effect estimate ± std. error, 0.63 ± 0.11, P < 0.001) and actual effort (0.81 ± 0.21, P < 0.001) independently explained subjective ratings of breathlessness, with comparable contributions of 19% and 18%, respectively. Additionally, we found that effort expectation accounted for 6% of participants' power and was a significant, independent predictor (0.09 ± 0.03; P = 0.001). CONCLUSIONS: An individuals' expectation of effort is equally important for forming perceptions of breathlessness as the actual effort required to cycle. A new VR paradigm enables this to be experimentally studied and could be used to re-align breathlessness and enhance training programmes.

The effect of d-cycloserine on brain processing of breathlessness over pulmonary rehabilitation: an experimental medicine study.

Research question: Pulmonary rehabilitation is the best treatment for chronic breathlessness in COPD but there remains an unmet need to improve efficacy. Pulmonary rehabilitation has strong parallels with exposure-based cognitive behavioural therapies (CBT), both clinically and in terms of brain activity patterns. The partial N-methyl-d-aspartate (NMDA)-receptor agonist d-cycloserine has shown promising results in enhancing efficacy of CBT, thus we hypothesised that it would similarly augment the effects of pulmonary rehabilitation in the brain. Positive findings would support further development in phase 3 clinical trials. Methods: 72 participants with mild-to-moderate COPD were recruited to a double-blind pre-registered (ClinicalTrials.gov identifier: NCT01985750) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250 mg d-cycloserine or placebo, administered immediately prior to the first four sessions of pulmonary rehabilitation. Primary outcome measures were differences between d-cycloserine and placebo in brain activity in the anterior insula, posterior insula, anterior cingulate cortices, amygdala and hippocampus following completion of pulmonary rehabilitation. Secondary outcomes included the same measures at an intermediate time point and voxel-wise difference across wider brain regions. An exploratory analysis determined the interaction with breathlessness anxiety. Results: No difference between d-cycloserine and placebo groups was observed across the primary or secondary outcome measures. d-cycloserine was shown instead to interact with changes in breathlessness anxiety to dampen reactivity to breathlessness cues. Questionnaire and measures of respiratory function showed no group difference. This is the first study testing brain-active drugs in pulmonary rehabilitation. Rigorous trial methodology and validated surrogate end-points maximised statistical power. Conclusion: Although increasing evidence supports therapeutic modulation of NMDA pathways to treat symptoms, we conclude that a phase 3 clinical trial of d-cycloserine would not be worthwhile.

Functional connectivity between interoceptive brain regions is associated with distinct health-related domains: A population-based neuroimaging study.

Interoception is the sensation, perception, and integration of signals from within the body. It has been associated with a broad range of physiological and psychological processes. Further, interoceptive variables are related to specific regions and networks in the human brain. However, it is not clear whether or how these networks relate empirically to different domains of physiological and psychological health at the population level. We analysed a data set of 19,020 individuals (10,055 females, 8965 males; mean age: 63 years, age range: 45-81 years), who have participated in the UK Biobank Study, a very large-scale prospective epidemiological health study. Using canonical correlation analysis (CCA), allowing for the examination of associations between two sets of variables, we related the functional connectome of brain regions implicated in interoception to a selection of nonimaging health and lifestyle related phenotypes, exploring their relationship within modes of population co-variation. In one integrated and data driven analysis, we obtained four statistically significant modes. Modes could be categorised into domains of arousal and affect and cardiovascular health, respiratory health, body mass, and subjective health (all p < .0001) and were meaningfully associated with distinct neural circuits. Circuits represent specific neural "fingerprints" of functional domains and set the scope for future studies on the neurobiology of interoceptive involvement in different lifestyle and health-related phenotypes. Therefore, our research contributes to the conceptualisation of interoception and may lead to a better understanding of co-morbid conditions in the light of shared interoceptive structures.

Brain activity measured by functional brain imaging predicts breathlessness improvement during pulmonary rehabilitation.

BACKGROUND: Chronic breathlessness in chronic obstructive pulmonary disease (COPD) is effectively treated with pulmonary rehabilitation. However, baseline patient characteristics predicting improvements in breathlessness are unknown. This knowledge may provide better understanding of the mechanisms engaged in treating breathlessness and help to individualise therapy. Increasing evidence supports the role of expectation (ie, placebo and nocebo effects) in breathlessness perception. In this study, we tested functional brain imaging markers of breathlessness expectation as predictors of therapeutic response to pulmonary rehabilitation, and asked whether D-cycloserine, a brain-active drug known to influence expectation mechanisms, modulated any predictive model. METHODS: Data from 71 participants with mild-to-moderate COPD recruited to a randomised double-blind controlled experimental medicine study of D-cycloserine given during pulmonary rehabilitation were analysed (ID: NCT01985750). Baseline variables, including brain-activity, self-report questionnaires responses, clinical measures of respiratory function and drug allocation were used to train machine-learning models to predict the outcome, a minimally clinically relevant change in the Dyspnoea-12 score. RESULTS: Only models that included brain imaging markers of breathlessness-expectation successfully predicted improvements in Dyspnoea-12 score (sensitivity 0.88, specificity 0.77). D-cycloserine was independently associated with breathlessness improvement. Models that included only questionnaires and clinical measures did not predict outcome (sensitivity 0.68, specificity 0.2). CONCLUSIONS: Brain activity to breathlessness related cues is a strong predictor of clinical improvement in breathlessness over pulmonary rehabilitation. This implies that expectation is key in breathlessness perception. Manipulation of the brain's expectation pathways (either pharmacological or non-pharmacological) therefore merits further testing in the treatment of chronic breathlessness.

Perceptual and Ventilatory Responses to Hypercapnia in Athletes and Sedentary Individuals.

Purpose: Hypercapnic chemosensitivity traditionally captures the ventilatory response to elevated pressures of carbon dioxide in the blood. However, hypercapnia also contributes to subjective breathing perceptions, and previously we demonstrated a closer matching of perception to changes in ventilation in athletes compared to controls. Here we investigated any potential underlying hypercapnic chemosensitivity differences between groups, and explored whether these measures relate to ventilatory and perceptual responses during exercise as well as trait levels of affect. Methods: A hypercapnic challenge, incremental maximal exercise test and affective questionnaires were completed by 20 endurance athletes and 20 age-/sex-matched sedentary controls. The hypercapnic challenge involved elevating end-tidal PCO2 by 0.8% (6.1 mmHg) and 1.5% (11.2 mmHg) for 3 min each (randomised), with constant end-tidal oxygen. Ventilatory and perceptual responses to hypercapnia were compared between groups, and within each group the relationships between hypercapnic chemosensitivity (slope analyses) and exercising ventilation and perceptions were calculated using Spearman's non-parametric correlations. Results: While absolute ventilation differences during hypercapnia and exercise were observed, no group differences were found across hypercapnic chemosensitivity (slope) measures. Correlation analyses revealed the anxiety hypercapnic response was related to maximal exercise anxiety, but only in sedentary individuals. Conclusion: Ventilatory and perceptual hypercapnic chemosensitivity do not differ between athletes and sedentary individuals. However, ventilatory and anxiety hypercapnic chemosensitivities were related to ventilatory and anxiety responses during exercise in untrained individuals only. Athletes may employ additional strategies during exercise to reduce the influence of chemosensitivity on ventilatory and perceptual responses.

Baseline Psychological Traits Contribute to Lake Louise Acute Mountain Sickness Score at High Altitude.

Talks, Benjamin James, Catherine Campbell, Stephanie J. Larcombe, Lucy Marlow, Sarah L. Finnegan, Christopher T. Lewis, Samuel J.E. Lucas, Olivia K. Harrison, and Kyle T.S. Pattinson. Baseline psychological traits contribute to Lake Louise Acute Mountain Sickness score at high altitude. High Alt Med Biol. 23:69-77, 2022. Background: Interoception refers to an individual's ability to sense their internal bodily sensations. Acute mountain sickness (AMS) is a common feature of ascent to high altitude that is only partially explained by measures of peripheral physiology. We hypothesized that interoceptive ability may explain the disconnect between measures of physiology and symptom experience in AMS. Methods: Two groups of 18 participants were recruited to complete a respiratory interoceptive task three times at 2-week intervals. The control group remained in Birmingham (140 m altitude) for all three tests. The altitude group completed test 1 in Birmingham, test 2 the day after arrival at 2,624 m, and test 3 at 2,728 m after an 11-day trek at high altitude (up to 4,800 m). Results: By measuring changes to metacognitive performance, we showed that acute ascent to altitude neither presented an interoceptive challenge, nor acted as interoceptive training. However, AMS symptom burden throughout the trek was found to relate to sea level measures of anxiety, agoraphobia, and neuroticism. Conclusions: This suggests that the Lake Louise AMS score is not solely a reflection of physiological changes on ascent to high altitude, despite often being used as such by researchers and commercial trekking companies alike.

Beneficial Effect of Sodium Nitrite on EEG Ischaemic Markers in Patients with Subarachnoid Haemorrhage.

Subarachnoid haemorrhage (SAH) is associated with long-term disability, serious reduction in quality of life and significant mortality. Early brain injury (EBI) refers to the pathological changes in cerebral metabolism and blood flow that happen in the first few days after ictus and may lead on to delayed cerebral ischaemia (DCI). A disruption of the nitric oxide (NO) pathway is hypothesised as a key mechanism underlying EBI. A decrease in the alpha-delta power ratio (ADR) of the electroencephalogram has been related to cerebral ischaemia. In an experimental medicine study, we tested the hypothesis that intravenous sodium nitrite, an NO donor, would lead to increases in ADR. We studied 33 patients with acute aneurysmal SAH in the EBI phase. Participants were randomised to either sodium nitrite or saline infusion for 1 h. EEG measurements were taken before the start of and during the infusion. Twenty-eight patients did not develop DCI and five patients developed DCI. In the patients who did not develop DCI, we found an increase in ADR during sodium nitrite versus saline infusion. In the five patients who developed DCI, we did not observe a consistent pattern of ADR changes. We suggest that ADR power changes in response to nitrite infusion reflect a NO-mediated reduction in cerebral ischaemia and increase in perfusion, adding further evidence to the role of the NO pathway in EBI after SAH. Our findings provide the basis for future clinical trials employing NO donors after SAH.

Early brain injury and cognitive impairment after aneurysmal subarachnoid haemorrhage.

The first 72 h following aneurysm rupture play a key role in determining clinical and cognitive outcomes after subarachnoid haemorrhage (SAH). Yet, very little is known about the impact of so called "early brain injury" on patents with clinically good grade SAH (as defined as World Federation of Neurosurgeons Grade 1 and 2). 27 patients with good grade SAH underwent MRI scanning were prospectively recruited at three time-points after SAH: within the first 72 h (acute phase), at 5-10 days and at 3 months. Patients underwent additional, comprehensive cognitive assessment 3 months post-SAH. 27 paired healthy controls were also recruited for comparison. In the first 72 h post-SAH, patients had significantly higher global and regional brain volume than controls. This change was accompanied by restricted water diffusion in patients. Persisting abnormalities in the volume of the posterior cerebellum at 3 months post-SAH were present to those patients with worse cognitive outcome. When using this residual abnormal brain area as a region of interest in the acute-phase scans, we could predict with an accuracy of 84% (sensitivity 82%, specificity 86%) which patients would develop cognitive impairment 3 months later, despite initially appearing clinically indistinguishable from those making full recovery. In an exploratory sample of good clinical grade SAH patients compared to healthy controls, we identified a region of the posterior cerebellum for which acute changes on MRI were associated with cognitive impairment. Whilst further investigation will be required to confirm causality, use of this finding as a risk stratification biomarker is promising.

The Filter Detection Task for measurement of breathing-related interoception and metacognition.

The study of the brain's processing of sensory inputs from within the body ('interoception') has been gaining rapid popularity in neuroscience, where interoceptive disturbances are thought to exist across a wide range of chronic physiological and psychological conditions. Here we present a task and analysis procedure to quantify specific dimensions of breathing-related interoception, including interoceptive sensitivity, decision bias, metacognitive bias, and metacognitive performance. Two major developments address some of the challenges presented by low trial numbers in interoceptive experiments: (i) a novel adaptive algorithm to maintain task performance at 70-75% accuracy; (ii) an extended hierarchical metacognitive model to estimate regression parameters linking metacognitive performance to relevant (e.g. clinical) variables. We demonstrate the utility of the task and analysis developments, using both simulated data and three empirical datasets. This methodology represents an important step towards accurately quantifying interoceptive dimensions from a simple experimental procedure that is compatible with clinical settings.

Dissociating breathlessness symptoms from mood in asthma.

It is poorly understood why asthma symptoms are often discordant with objective medical tests. Differences in interoception (perception of internal bodily processes) may help explain symptom discordance, which may be further influenced by mood and attention. We explored inter-relationships between interoception, mood and attention in 63 individuals with asthma and 30 controls. Questionnaires, a breathing-related interoception task, two attention tasks, and standard clinical assessments were performed. Questionnaires were analysed using exploratory factor analysis, and linear regression examined relationships between measures. K-means clustering also defined asthma subgroups. Two concordant asthma subgroups (symptoms related appropriately to pathophysiology, normal mood) and one discordant subgroup (moderate symptoms, minor pathophysiology, low mood) were found. In all participants, negative mood correlated with decreased interoceptive ability and faster reaction times in an attention task. Our findings suggest that interpreting bodily sensations relates to mood, and this effect may be heightened in subgroups of individuals with asthma.

A common model for the breathlessness experience across cardiorespiratory disease.

Chronic breathlessness occurs across many different conditions, often independently of disease severity. Yet, despite being strongly linked to adverse outcomes, the consideration of chronic breathlessness as a stand-alone therapeutic target remains limited. Here we use data-driven techniques to identify and confirm the stability of underlying features (factors) driving breathlessness across different cardiorespiratory diseases. Questionnaire data on 182 participants with main diagnoses of asthma (21.4%), COPD (24.7%), heart failure (19.2%), idiopathic pulmonary fibrosis (18.7%), other interstitial lung disease (2.7%), and "other diagnoses" (13.2%) were entered into an exploratory factor analysis (EFA). Participants were stratified based on their EFA factor scores. We then examined model stability using 6-month follow-up data and established the most compact set of measures describing the breathlessness experience. In this dataset, we have identified four stable factors that underlie the experience of breathlessness. These factors were assigned the following descriptive labels: 1) body burden, 2) affect/mood, 3) breathing burden and 4) anger/frustration. Stratifying patients by their scores across the four factors revealed two groups corresponding to high and low burden. These two groups were not related to the primary disease diagnosis and remained stable after 6 months. In this work, we identified and confirmed the stability of underlying features of breathlessness. Previous work in this domain has been largely limited to single-diagnosis patient groups without subsequent re-testing of model stability. This work provides further evidence supporting disease independent approaches to assess breathlessness.

Investigating the specificity of the neurologic pain signature against breathlessness and finger opposition.

ABSTRACT: Brain biomarkers of pain, including pain-predictive "signatures" based on brain activity, can provide measures of neurophysiological processes and potential targets for interventions. A central issue relates to the specificity of such measures, and understanding their current limits will both advance their development and explore potentially generalizable properties of pain to other states. Here, we used 2 data sets to test the neurologic pain signature (NPS), an established pain neuromarker. In study 1, brain activity was measured using high-field functional magnetic resonance imaging (7T fMRI, N = 40) during 5 to 25 seconds of experimental breathlessness (induced by inspiratory resistive loading), conditioned breathlessness anticipation, and finger opposition. In study 2, we assessed anticipation and breathlessness perception (3T, N = 19) under blinded saline (placebo) and remifentanil administration. The NPS responded to breathlessness, anticipation, and finger opposition, although no direct comparisons with painful events were possible. Local NPS patterns in anterior or midinsula, S2, and dorsal anterior cingulate responded to breathlessness and finger opposition and were reduced by remifentanil. Local NPS responses in the dorsal posterior insula did not respond to any manipulations. Therefore, significant global NPS activity alone is not specific for pain, and we offer insight into the overlap between NPS responses, breathlessness, and somatomotor demand.

Breathlessness in COPD: linking symptom clusters with brain activity.

BACKGROUND: Current models of breathlessness often fail to explain disparities between patients' experiences of breathlessness and objective measures of lung function. While a mechanistic understanding of this discordance has thus far remained elusive, factors such as mood, attention and expectation have all been implicated as important modulators of breathlessness. Therefore, we have developed a model to better understand the relationships between these factors using unsupervised machine learning techniques. Subsequently we examined how expectation-related brain activity differed between these symptom-defined clusters of participants. METHODS: A cohort of 91 participants with mild-to-moderate chronic obstructive pulmonary disease (COPD) underwent functional brain imaging, self-report questionnaires and clinical measures of respiratory function. Unsupervised machine learning techniques of exploratory factor analysis and hierarchical cluster modelling were used to model brain-behaviour-breathlessness links. RESULTS: We successfully stratified participants across four key factors corresponding to mood, symptom burden and two capability measures. Two key groups resulted from this stratification, corresponding to high and low symptom burden. Compared with the high symptom burden group, the low symptom burden group demonstrated significantly greater brain activity within the anterior insula, a key region thought to be involved in monitoring internal bodily sensations (interoception). CONCLUSIONS: This is the largest functional neuroimaging study of COPD to date, and is the first to provide a clear model linking brain, behaviour and breathlessness expectation. Furthermore, it was possible to stratify participants into groups, which then revealed differences in brain activity patterns. Together, these findings highlight the value of multimodal models of breathlessness in identifying behavioural phenotypes and for advancing understanding of differences in breathlessness burden.

Findings of a feasibility study of pre-operative pulmonary rehabilitation to reduce post-operative pulmonary complications in people with chronic obstructive pulmonary disease scheduled for major abdominal surgery.

Background: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of complications and death following surgery. Pulmonary complications are particularly prominent.  Pulmonary rehabilitation is a course of physical exercise and education that helps people with COPD manage their condition.  Although proven to improve health outcomes in patients with stable COPD, it has never been formally tested as a pre-surgical intervention in patients scheduled for non-cardiothoracic surgery.  If a beneficial effect were to be demonstrated, pulmonary rehabilitation for pre-surgical patients with COPD might be rapidly implemented across the National Health Service, as pulmonary rehabilitation courses are already well established across much of the United Kingdom (UK). Methods: We performed a feasibility study to test study procedures and barriers to identification and recruitment to a randomised controlled trial testing whether pulmonary rehabilitation, delivered before major abdominal surgery in a population of people with COPD, would reduce the incidence of post-operative pulmonary complications.  This study was run in two UK centres (Oxford and Newcastle upon Tyne). Results:  We determined that a full randomised controlled trial would not be feasible, due to failure to identify and recruit participants.  We identified an unmet need to identify more effectively patients with COPD earlier in the surgical pathway.  Service evaluations suggested that barriers to identification and recruitment would likely be the same across other UK hospitals. Conclusions:  Although pulmonary rehabilitation is a potentially beneficial intervention to prevent post-operative pulmonary complications, a randomised controlled trial is unlikely to recruit sufficient participants to answer our study question conclusively at the present time, when spirometry is not automatically conducted in all patients planned for surgery.  As pulmonary rehabilitation is a recommended treatment for all people with COPD, alternative study methods combined with earlier identification of candidate patients in the surgical pathway should be considered. Trial registration: ISRCTN29696295, 31/08/2017.

Breathlessness and the brain: the role of expectation.

PURPOSE OF REVIEW: Breathlessness debilitates countless people with a wide range of common diseases. For some people, the experience of breathlessness is poorly explained by the findings of medical tests. This disparity complicates diagnostic and treatment options and means that disease-modifying treatments do not always have the expected effect upon symptoms. These observations suggest that brain processing of respiratory perceptions may be somewhat independent of disease processes. This may help to explain the dissonance observed in some patients between physical disease markers and the lived experience of breathlessness. RECENT FINDINGS: A body of breathlessness research using functional neuroimaging has identified a relatively consistent set of brain areas that are associated with breathlessness. These areas include the insula, cingulate and sensory cortices, the amygdala and the periaqueductal gray matter. We interpret these findings in the context of new theories of perception that emphasize the importance of distributed brain networks. Within this framework, these perceptual networks function by checking an internal model (a set of expectations) against peripheral sensory inputs, instead of the brain acting as a passive signal transducer. Furthermore, other factors beyond the physiology of breathlessness can influence the system. SUMMARY: A person's expectations and mood are major contributors to the function of the brain networks that generate perceptions of breathlessness. Breathlessness, therefore, arises from inferences made by the brain's integration of both expectations and sensory inputs. By better understanding individual differences across these contributing perceptual factors, we will be better poised to develop targeted and individualized treatments for breathlessness that could complement disease-modifying therapies.

The midbrain periaqueductal gray as an integrative and interoceptive neural structure for breathing.

The periaqueductal gray (PAG) plays a critical role in autonomic function and behavioural responses to threatening stimuli. Recent evidence has revealed the PAG's potential involvement in the perception of breathlessness, a highly threatening respiratory symptom. In this review, we outline the current evidence in animals and humans on the role of the PAG in respiratory control and in the perception of breathlessness. While recent work has unveiled dissociable brain activity within the lateral PAG during perception of breathlessness and ventrolateral PAG during conditioned anticipation in healthy humans, this is yet to be translated into diseases dominated by breathlessness symptomology, such as chronic obstructive pulmonary disease. Understanding how the sub-structures of the PAG differentially interact with interoceptive brain networks involved in the perception of breathlessness will help towards understanding discordant symptomology, and may reveal treatment targets for those debilitated by chronic and pervasive breathlessness.

Modeling of dynamic cerebrovascular reactivity to spontaneous and externally induced CO2 fluctuations in the human brain using BOLD-fMRI.

In this work, we investigate the regional characteristics of the dynamic interactions between arterial CO2 and BOLD (dynamic cerebrovascular reactivity - dCVR) during normal breathing and hypercapnic, externally induced step CO2 challenges. To obtain dCVR curves at each voxel, we use a custom set of basis functions based on the Laguerre and gamma basis sets. This allows us to obtain robust dCVR estimates both in larger regions of interest (ROIs), as well as in individual voxels. We also implement classification schemes to identify brain regions with similar dCVR characteristics. Our results reveal considerable variability of dCVR across different brain regions, as well as during different experimental conditions (normal breathing and hypercapnic challenges), suggesting a differential response of cerebral vasculature to spontaneous CO2 fluctuations and larger, externally induced CO2 changes that are possibly associated with the underlying differences in mean arterial CO2 levels. The clustering results suggest that anatomically distinct brain regions are characterized by different dCVR curves that in some cases do not exhibit the standard, positive valued curves that have been previously reported. They also reveal a consistent set of dCVR cluster shapes for resting and forcing conditions, which exhibit different distribution patterns across brain voxels.

Cortical processing of breathing perceptions in the athletic brain.

Athletes regularly endure large increases in ventilation and accompanying perceptions of breathlessness. Whilst breathing perceptions often correlate poorly with objective measures of lung function in both healthy and clinical populations, we have previously demonstrated closer matching between subjective breathlessness and changes in ventilation in endurance athletes, suggesting that athletes may be more accurate during respiratory interoception. To better understand the link between exercise and breathlessness, we sought to identify the mechanisms by which the brain processing of respiratory perception might be optimised in athletes. Twenty endurance athletes and twenty sedentary controls underwent 7 T functional magnetic resonance imaging. Inspiratory resistive loading induced conscious breathing perceptions (breathlessness), and a delay-conditioning paradigm was employed to evoke preceding periods of breathlessness-anticipation. Athletes demonstrated anticipatory brain activity that positively correlated with resulting breathing perceptions within key interoceptive areas, such as the thalamus, insula and primary sensorimotor cortices, which was negatively correlated in sedentary controls. Athletes also exhibited altered connectivity between interoceptive attention networks and primary sensorimotor cortex. These functional differences in athletic brains suggest that exercise may alter anticipatory representations of respiratory sensations. Future work may probe whether these brain mechanisms are harnessed when exercise is employed to treat breathlessness within chronic respiratory disease.