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.

Beyond RPE: The Perception of Exercise Under Normal and Ketotic Conditions.

AIM: Subjective perceptions of exercising exertion are integral to maintaining homeostasis. Traditional methods have utilized scores of 'rating of perceived exertion' (RPE) to quantify these subjective perceptions, and here we aimed to test whether RPE may encompass identifiable localized perceptions from the lungs (breathlessness) and legs (leg discomfort), as well as their corresponding measures of anxiety. We utilized the intervention of ketoacidosis (via consumption of an exogenous ketone ester drink) to independently perturb exercise-related metabolites and humoral signals, thus allowing us to additionally identify the possible contributing physiological signals to each of these perceptions. METHODS: Twelve trained volunteers underwent two incremental bicycle ergometer tests to exhaustion, following ingestion of either an exogenous ketone ester or a taste-matched placebo drink. Cardiorespiratory measures, blood samples and perceived exertion scales were taken throughout. Firstly, two-way repeated-measures ANOVAs were employed to identify the overall effects of ketoacidosis, followed by generalized linear mixed model regression to isolate physiological predictors contributing to each perception. RESULTS: Rating of perceived exertion was found to contain contributions from localized perceptions of breathlessness and leg discomfort, with no measurable effect of ketoacidosis on overall exertion. Leg discomfort, anxiety of breathing and anxiety of leg discomfort were increased during ketoacidosis, and correspondingly contained pH within their prediction models. Anxiety of leg discomfort also encompassed additional humoral signals of blood glucose and ketone concentrations. CONCLUSION: These results indicate the presence of localized components of RPE in the form of breathlessness and leg discomfort. Furthermore, subjective perceptions of anxiety appear to result from a complex interplay of humoral signals, which may be evolutionarily important when monitoring exertion under times of metabolic stress, such as during starvation.

Nutritional Ketoacidosis During Incremental Exercise in Healthy Athletes.

Purpose: Ketosis, achieved through ingestion of ketone esters, may influence endurance exercise capacity by altering substrate metabolism. However, the effects of ketone consumption on acid-base status and subsequent metabolic and respiratory compensations are poorly described. Methods: Twelve athletically trained individuals completed an incremental bicycle ergometer exercise test to exhaustion following the consumption of either a ketone ester [(R)-3-hydroxybutyrate-(R)-1,3-butanediol] or a taste-matched control drink (bitter flavoured water) in a blinded, cross-over study. Respiratory gases and arterialised blood gas samples were taken at rest and at regular intervals during exercise. Results: Ketone ester consumption increased blood D-ß-hydroxybutyrate concentration from 0.2 to 3.7 mM/L (p < 0.01), causing significant falls versus control in blood pH to 7.37 and bicarbonate to 18.5 mM/L before exercise. To compensate for ketoacidosis, minute ventilation was modestly increased (p < 0.05) with non-linearity in the ventilatory response to exercise (ventilatory threshold) occurring at a 22 W lower workload (p < 0.05). Blood pH and bicarbonate concentrations were the same at maximal exercise intensities. There was no difference in exercise performance having consumed the ketone ester or control drink. Conclusion: Athletes compensated for the greater acid load caused by ketone ester ingestion by elevating minute ventilation and earlier hyperventilation during incremental exercise.

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.

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.

On the Metabolism of Exogenous Ketones in Humans.

Background and aims: Currently there is considerable interest in ketone metabolism owing to recently reported benefits of ketosis for human health. Traditionally, ketosis has been achieved by following a high-fat, low-carbohydrate "ketogenic" diet, but adherence to such diets can be difficult. An alternative way to increase blood D-ß-hydroxybutyrate (D-ßHB) concentrations is ketone drinks, but the metabolic effects of exogenous ketones are relatively unknown. Here, healthy human volunteers took part in three randomized metabolic studies of drinks containing a ketone ester (KE); (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, or ketone salts (KS); sodium plus potassium ßHB. Methods and Results: In the first study, 15 participants consumed KE or KS drinks that delivered ~12 or ~24 g of ßHB. Both drinks elevated blood D-ßHB concentrations (D-ßHB Cmax: KE 2.8 mM, KS 1.0 mM, P < 0.001), which returned to baseline within 3-4 h. KS drinks were found to contain 50% of the L-ßHB isoform, which remained elevated in blood for over 8 h, but was not detectable after 24 h. Urinary excretion of both D-ßHB and L-ßHB was <1.5% of the total ßHB ingested and was in proportion to the blood AUC. D-ßHB, but not L-ßHB, was slowly converted to breath acetone. The KE drink decreased blood pH by 0.10 and the KS drink increased urinary pH from 5.7 to 8.5. In the second study, the effect of a meal before a KE drink on blood D-ßHB concentrations was determined in 16 participants. Food lowered blood D-ßHB Cmax by 33% (Fed 2.2 mM, Fasted 3.3 mM, P < 0.001), but did not alter acetoacetate or breath acetone concentrations. All ketone drinks lowered blood glucose, free fatty acid and triglyceride concentrations, and had similar effects on blood electrolytes, which remained normal. In the final study, participants were given KE over 9 h as three drinks (n = 12) or a continuous nasogastric infusion (n = 4) to maintain blood D-ßHB concentrations greater than 1 mM. Both drinks and infusions gave identical D-ßHB AUC of 1.3-1.4 moles.min. Conclusion: We conclude that exogenous ketone drinks are a practical, efficacious way to achieve ketosis.

Breathlessness and the body: Neuroimaging clues 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 learnt from past experiences (priors), which are then checked against incoming afferent signals. In this model, psychological factors may act as moderators. They may alter priors, change the relative attention towards incoming sensory information, or alter comparisons between priors and sensations, leading to more variable interpretation of an equivalent afferent input. In the present study we conducted a supplementary analysis of previously published data (Hayen et al., 2017). We hypothesised that individual differences in psychological traits (anxiety, depression, anxiety sensitivity) would correlate with the variability of subjective perceptions of equivalent breathlessness challenges. To better understand the resulting inferential leap in the brain, we explored where these behavioural measures correlated with functional brain activity across subjects. Behaviourally, anxiety sensitivity was found to positively correlate with each subject's variability of intensity and unpleasantness during mild breathlessness, and with variability of unpleasantness during strong breathlessness. In the brain, anxiety sensitivity was found to negatively correlate with precuneus activity during anticipation, positively correlate with anterior insula activity 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.

Treating breathlessness via the brain: changes in brain activity over a course of pulmonary rehabilitation.

Breathlessness in chronic obstructive pulmonary disease (COPD) is often discordant with airway pathophysiology ("over-perception"). Pulmonary rehabilitation profoundly affects breathlessness, without influencing lung function. Learned associations influence brain mechanisms of sensory perception. We hypothesised that improvements in breathlessness with pulmonary rehabilitation may be explained by changing neural representations of learned associations.In 31 patients with COPD, we tested how pulmonary rehabilitation altered the relationship between brain activity during a breathlessness-related word-cue task (using functional magnetic resonance imaging), and clinical and psychological measures of breathlessness.Changes in ratings of breathlessness word cues positively correlated with changes in activity in the insula and anterior cingulate cortex. Changes in ratings of breathlessness-anxiety negatively correlated with activations in attention regulation and motor networks. Baseline activity in the insula, anterior cingulate cortex and prefrontal cortex correlated with improvements in breathlessness and breathlessness-anxiety.Pulmonary rehabilitation is associated with altered neural responses related to learned breathlessness associations, which can ultimately influence breathlessness perception. These findings highlight the importance of targeting learned associations within treatments for COPD, demonstrating how neuroimaging may contribute to patient stratification and more successful personalised therapy.

The cortical connectivity of the periaqueductal gray and the conditioned response to the threat of breathlessness.

Previously we observed differential activation in individual columns of the periaqueductal grey (PAG) during breathlessness and its conditioned anticipation (Faull et al., 2016b). Here, we have extended this work by determining how the individual columns of the PAG interact with higher cortical centres, both at rest and in the context of breathlessness threat. Activation was observed in ventrolateral PAG (vlPAG) and lateral PAG (lPAG), where activity scaled with breathlessness intensity ratings, revealing a potential interface between sensation and cognition during breathlessness. At rest the lPAG was functionally correlated with cortical sensorimotor areas, conducive to facilitating fight/flight responses, and demonstrated increased synchronicity with the amygdala during breathlessness. The vlPAG showed fronto-limbic correlations at rest, whereas during breathlessness anticipation, reduced functional synchronicity was seen to both lPAG and motor structures, conducive to freezing behaviours. These results move us towards understanding how the PAG might be intricately involved in human responses to threat.

Opioid suppression of conditioned anticipatory brain responses to breathlessness.

Opioid painkillers are a promising treatment for chronic breathlessness, but are associated with potentially fatal side effects. In the treatment of breathlessness, their mechanisms of action are unclear. A better understanding might help to identify safer alternatives. Learned associations between previously neutral stimuli (e.g. stairs) and repeated breathlessness induce an anticipatory threat response that may worsen breathlessness, contributing to the downward spiral of decline seen in clinical populations. As opioids are known to influence associative learning, we hypothesized that they may interfere with the brain processes underlying a conditioned anticipatory response to breathlessness in relevant brain areas, including the amygdala and the hippocampus. Healthy volunteers viewed visual cues (neutral stimuli) immediately before induction of experimental breathlessness with inspiratory resistive loading. Thus, an association was formed between the cue and breathlessness. Subsequently, this paradigm was repeated in two identical neuroimaging sessions with intravenous infusions of either low-dose remifentanil (0.7ng/ml target-controlled infusion) or saline (randomised). During saline infusion, breathlessness anticipation activated the right anterior insula and the adjacent operculum. Breathlessness was associated with activity in a network including the insula, operculum, dorsolateral prefrontal cortex, anterior cingulate cortex and the primary sensory and motor cortices. Remifentanil reduced breathlessness unpleasantness but not breathlessness intensity. Remifentanil depressed anticipatory activity in the amygdala and the hippocampus that correlated with reductions in breathlessness unpleasantness. During breathlessness, remifentanil decreased activity in the anterior insula, anterior cingulate cortex and sensory motor cortices. Remifentanil-induced reduction in breathlessness unpleasantness was associated with increased activity in the rostral anterior cingulate cortex and nucleus accumbens, components of the endogenous opioid system known to decrease the perception of aversive stimuli. These findings suggest that in addition to effects on brainstem respiratory control, opioids palliate breathlessness through an interplay of altered associative learning mechanisms. These mechanisms provide potential targets for novel ways to develop and assess treatments for chronic breathlessness.

Psychophysical Differences in Ventilatory Awareness and Breathlessness between Athletes and Sedentary Individuals.

PURPOSE: Breathlessness is a complex set of symptoms that are comprised of both sensory and affective (emotional) dimensions. While ventilation is now understood to be a potential limiter to performance in highly-trained individuals, the contribution of breathlessness-anxiety in those nearing maximal ventilation during intense exercise has not yet been considered as a limiter to performance. METHODS: In this study, we compared the physiology and psychology of breathlessness in 20 endurance athletes with 20 untrained age- and sex-matched sedentary controls. Subjects completed baseline spirometry and anxiety questionnaires, an incremental exercise test to exhaustion and a steady-state hypercapnic ventilatory response test, with concurrent measures of breathlessness intensity and breathlessness-anxiety. RESULTS: Compared with sedentary subjects, athletes reported equivalent breathlessness intensity but greater breathlessness-anxiety at maximal exercise (athletes vs. sedentary (mean ± SD): breathlessness intensity (0-100%) 80.7 (22.7) vs. 72.5 (17.2), p = 0.21; breathlessness-anxiety (0-100%), 45.3 (36.3) vs. 22.3 (20.0), p = 0.02). Athletes operated at higher proportions of their maximal ventilatory capacity (MVV) (athletes vs. sedentary (mean ventilation ± SD; % MVV): 101.6 (27.2) vs. 73.7 (30.1), p = 0.003). In the athletes there was a positive linear correlation between ventilation and breathlessness score during the hypercapnic challenge that was not observed in the sedentary controls. CONCLUSION: The results of this study indicate that whilst operating at high proportions of maximal ventilation, breathlessness-anxiety becomes increasingly prominent in athletes. Our results suggest that ventilatory perception pathways may be a target for improved athletic performance in some individuals.

Conditioned respiratory threat in the subdivisions of the human periaqueductal gray.

The sensation of breathlessness is the most threatening symptom of respiratory disease. The different subdivisions of the midbrain periaqueductal gray (PAG) are intricately (and differentially) involved in integrating behavioural responses to threat in animals, while the PAG has previously only been considered as a single entity in human research. Here we investigate how these individual PAG columns are differently involved with respiratory threat. Eighteen healthy subjects were conditioned to associate shapes with certain or uncertain impending respiratory load, and scanned the following day during anticipation and application of inspiratory loading using 7 T functional MRI. We showed activity in the ventrolateral PAG (vlPAG) during anticipation of resistive loading, with activity in the lateral PAG (lPAG) during resistive loading, revealing spatially and temporally distinct functions within this structure. We propose that lPAG is involved with sensorimotor responses to breathlessness, while the vlPAG operates within the threat perception network for impending breathlessness.

Functional subdivision of the human periaqueductal grey in respiratory control using 7 tesla fMRI.

The periaqueductal grey (PAG) is a nucleus within the midbrain, and evidence from animal models has identified its role in many homeostatic systems including respiration. Animal models have also demonstrated a columnar structure that subdivides the PAG into four columns on each side, and these subdivisions have different functions with regard to respiration. In this study we used ultra-high field functional MRI (7 T) to image the brainstem and superior cortical areas at high resolution (1mm(3)voxels), aiming to identify activation within the columns of the PAG associated with respiratory control. Our results showed deactivation in the lateral and dorsomedial columns of the PAG corresponding with short (~10s) breath holds, along with cortical activations consistent with previous respiratory imaging studies. These results demonstrate the involvement of the lateral and dorsomedial PAG in the network of conscious respiratory control for the first time in humans. This study also reveals the opportunities of 7 T functional MRI for non-invasively investigating human brainstem nuclei at high-resolutions.

The effect of acetazolamide on saccadic latency at 3459 meters.

OBJECTIVE: The effect of altitude on brain function is not yet well understood, nor is the influence of height and speed of ascent. Additionally, the relationship between acute mountain sickness (AMS) symptoms and brain function at altitude is unclear. We hypothesized that a deterioration from baseline measures of brain function occurs after rapid, mechanical ascent to 3459 m and would be less pronounced in persons taking acetazolamide. METHODS: In this double blind, randomized, placebo-controlled study, 20 healthy volunteers (14 men, 6 women; mean age [±SD] 43 ± 16 years) were alternately allocated to acetazolamide 250 mg or to placebo, taken every 12 hours commencing 3 days before ascent. Prosaccadic and antisaccadic eye movements, heart rate, arterial saturation, and Lake Louise AMS scores were assessed at sea level and 15 to 22 hours after ascent to 3459 m. RESULTS: Arterial oxygen saturation was significantly lower in the placebo group compared to the acetazolamide group at altitude (Wilcoxon signed-rank test, median [interquartile range]: acetazolamide vs placebo: 92% [5] vs 85% [5]; P = .007), with no differences in prosaccadic latency, heart rate, or Lake Louise score. No differences in saccadic latencies from baseline to altitude were observed in the placebo group, whereas prosaccadic latencies were significantly longer at altitude with acetazolamide (altitude vs baseline: 153 ms [41] vs 176 ms [52], P = .008). CONCLUSIONS: Brain function, measured by saccadic eye movements, appears to be unimpaired after rapid ascent to 3459 m. Although acetazolamide improves oxygen saturations, it may worsen prosaccades, possibly indicating adverse effects of acetazolamide on brain function at moderate altitude.

Physiological noise in brainstem FMRI.

The brainstem is directly involved in controlling blood pressure, respiration, sleep/wake cycles, pain modulation, motor, and cardiac output. As such it is of significant basic science and clinical interest. However, the brainstem's location close to major arteries and adjacent pulsatile cerebrospinal fluid filled spaces, means that it is difficult to reliably record functional magnetic resonance imaging (fMRI) data from. These physiological sources of noise generate time varying signals in fMRI data, which if left uncorrected can obscure signals of interest. In this Methods Article we will provide a practical introduction to the techniques used to correct for the presence of physiological noise in time series fMRI data. Techniques based on independent measurement of the cardiac and respiratory cycles, such as retrospective image correction (RETROICOR, Glover et al., 2000), will be described and their application and limitations discussed. The impact of a physiological noise model, implemented in the framework of the general linear model, on resting fMRI data acquired at 3 and 7 T is presented. Data driven approaches based such as independent component analysis (ICA) are described. MR acquisition strategies that attempt to either minimize the influence of physiological fluctuations on recorded fMRI data, or provide additional information to correct for their presence, will be mentioned. General advice on modeling noise sources, and its effect on statistical inference via loss of degrees of freedom, and non-orthogonality of regressors, is given. Lastly, different strategies for assessing the benefit of different approaches to physiological noise modeling are presented.