Context is key: exogenous ketosis and athletic performance

Ketone bodies are energetically efficient metabolic substrates, which are synthesised from lipids during prolonged caloric deprivation. Once considered a simple metabolite to fuel the brain during starvation, ketone bodies are now recognised as having pleiotropic effects on metabolism, including modulating the availability and catabolism of other substrates. The combination of improved energetics and fuel sparing observed during ketosis is pivotal to maintaining energy homeostasis during starvation or fasting. Harnessing these actions may also offer a method to enhance human endurance. Owing to the necessity of depleting carbohydrate stores to induce ketogenesis, exercising during an endogenous ketosis is unlikely to be advantageous. In contrast, the delivery of exogenous ketones creates a novel physiological state, where high circulating ketone concentrations and replete carbohydrate stores are present. Here, we discuss the current understanding of how exogenous ketosis may mimic advantageous aspects of starvation physiology and in doing so, be used to enhance human exercise endurance performance

Context is key: exogenous ketosis and athletic performance

Ketone bodies are energetically efficient metabolic substrates, which are synthesised from lipids during prolonged caloric deprivation. Once considered a simple metabolite to fuel the brain during starvation, ketone bodies are now recognised as having pleiotropic effects on metabolism, including modulating the availability and catabolism of other substrates. The combination of improved energetics and fuel sparing observed during ketosis is pivotal to maintaining energy homeostasis during starvation or fasting. Harnessing these actions may also offer a method to enhance human endurance. Owing to the necessity of depleting carbohydrate stores to induce ketogenesis, exercising during an endogenous ketosis is unlikely to be advantageous. In contrast, the delivery of exogenous ketones creates a novel physiological state, where high circulating ketone concentrations and replete carbohydrate stores are present. Here, we discuss the current understanding of how exogenous ketosis may mimic advantageous aspects of starvation physiology and in doing so, be used to enhance human exercise endurance performance

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 delayconditioning 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.</p

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 delayconditioning 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.</p

Chronic breathlessness: re-thinking the symptom

Is chronic breathlessness a symptom or a syndrome? Although hotly debated, we would like to suggest an alternative viewpoint. Here, we speculate that the argument over chronic breathlessness being considered as either a symptom or syndrome both holds us within a reductionist framework, and somewhat misses the point

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

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

Connectivity-based segmentation of the periaqueductal gray matter in human with brainstem optimized diffusion MRI.

The periaqueductal gray matter (PAG) is a midbrain structure, involved in key homeostatic neurobiological functions, such as pain modulation and cardiorespiratory control. Animal research has identified four subdivisional columns that differ in both connectivity and function. Until now these findings have not been replicated in humans. This study used high-resolution brainstem optimized diffusion magnetic resonance imaging and probabilistic tractography to segment the human PAG into four subdivisions, based on voxel connectivity profiles. We identified four distinct subdivisions demonstrating high spatial concordance with the columns of the animal model. The resolution of these subdivisions for individual subjects permitted detailed examination of their structural connectivity without the requirement of an a priori starting location. Interestingly patterns of forebrain connectivity appear to be different to those found in nonhuman studies, whereas midbrain and hindbrain connectivity appears to be maintained. Although there are similarities in the columnar structure of the PAG subdivisions between humans and nonhuman animals, there appears to be different patterns of cortical connectivity. This suggests that the functional organization of the PAG may be different between species, and as a consequence, functional studies in nonhumans may not be directly translatable to humans. This highlights the need for focused functional studies in humans

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