Structural and resting state functional connectivity beyond the cortex.

Mapping the structural and functional connectivity of the central nervous system has become a key area within neuroimaging research. While detailed network structures across the entire brain have been probed using animal models, non-invasive neuroimaging in humans has thus far been dominated by cortical investigations. Beyond the cortex, subcortical nuclei have traditionally been less accessible due to their smaller size and greater distance from radio frequency coils. However, major neuroimaging developments now provide improved signal and the resolution required to study these structures. Here, we present an overview of the connectivity between the amygdala, brainstem, cerebellum, spinal cord and the rest of the brain. While limitations to their imaging and analyses remain, we also provide some recommendations and considerations for mapping brain connectivity beyond the cortex.

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.

Incorporating uncertainty within dynamic interoceptive learning.

Introduction: Interoception, the perception of the internal state of the body, has been shown to be closely linked to emotions and mental health. Of particular interest are interoceptive learning processes that capture associations between environmental cues and body signals as a basis for making homeostatically relevant predictions about the future. One method of measuring respiratory interoceptive learning that has shown promising results is the Breathing Learning Task (BLT). While the original BLT required binary predictions regarding the presence or absence of an upcoming inspiratory resistance, here we extended this paradigm to capture continuous measures of prediction (un)certainty. Methods: Sixteen healthy participants completed the continuous version of the BLT, where they were asked to predict the likelihood of breathing resistances on a continuous scale from 0.0 to 10.0. In order to explain participants' responses, a Rescorla-Wagner model of associative learning was combined with suitable observation models for continuous or binary predictions, respectively. For validation, we compared both models against corresponding null models and examined the correlation between observed and modeled predictions. The model was additionally extended to test whether learning rates differed according to stimuli valence. Finally, summary measures of prediction certainty as well as model estimates for learning rates were considered against interoceptive and mental health questionnaire measures. Results: Our results demonstrated that the continuous model fits closely captured participant behavior using empirical data, and the binarised predictions showed excellent replicability compared to previously collected data. However, the model extension indicated that there were no significant differences between learning rates for negative (i.e. breathing resistance) and positive (i.e. no breathing resistance) stimuli. Finally, significant correlations were found between fatigue severity and both prediction certainty and learning rate, as well as between anxiety sensitivity and prediction certainty. Discussion: These results demonstrate the utility of gathering enriched continuous prediction data in interoceptive learning tasks, and suggest that the updated BLT is a promising paradigm for future investigations into interoceptive learning and potential links to mental health.

A systematic review of brief respiratory, embodiment, cognitive, and mindfulness interventions to reduce state anxiety.

Introduction: Anxiety is one of the most prevalent mental health conditions worldwide, and psychotherapeutic techniques can be employed to help manage and mitigate symptoms. While the available therapies are numerous, key strategies often involve cognitive and/or embodiment techniques. Within body-centered methods, breathing-oriented approaches are particularly prevalent, using either attention towards or active control of breathing. As the perception of body states (i.e., interoception) is thought to be an integral component of emotion generation, these embodiment and breathing techniques may be key in addressing the miscommunication between the brain and body that is thought to exist with anxiety. Therefore, we conducted a systematic review and meta-analysis to assess the effects of acute administration of psychological interventions for state anxiety. Results: This systematic review was conducted in accordance with the PRISMA statement and registered prospectively in PROSPERO. A literature search for randomized controlled trials was conducted in PubMed, PsycINFO, and Scopus. We considered interventions that focused on cognitive, embodiment or breathing strategies, or a combination of these techniques. Twelve studies met our inclusion criteria, and study characteristics, quality and effect sizes were assessed. A single cognitive study was found to produce a moderate reduction in state anxiety, while moderate to large effects were found across studies assessing embodiment practices. In contrast, studies which utilized breathing-based interventions alone produced inconsistent results, with both attention towards and active control of breathing producing large to no effects depending on the technique employed. Finally, consistent moderate effects were found with combination techniques that involved passive attention (e.g., towards cognitions, body and/or breathing), with active combination techniques producing inconsistent results. Discussion: While study numbers are limited regarding brief interventions, cognitive and embodiment techniques are consistently helpful for reducing state anxiety, while breathing-based exercises need to consider the specific technique employed, and how successful this may be for each individual. Furthermore, combined practices such as mindfulness can also be successful, although care must be taken when introducing an active change to one or more elements. PROSPERO Systematic Review Registration Number: CRD42024507585 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024507585.

The Effect of Acute Exercise on State Anxiety: A Systematic Review.

Acute exercise has been shown to induce a small reduction in state anxiety, yet the most beneficial exercise stimulus is not clear. This review provides an update on the papers published since the last comprehensive review in 2015, with specific emphasis on whether study quality has improved. Randomised control trials, conducted in samples of healthy adults with non-clinical anxiety, were sourced from PubMed, PsycInfo, and Scopus. Study characteristics and study quality were assessed in nine studies comprising thirteen exercise conditions. Acute exercise significantly reduced anxiety in 53% (N = 7/13) of the exercise conditions. In comparison to a control condition, four showed exercising to be more effective, and one was as effective as the control. Two of the effective studies did not contain a control group. Six conditions were ineffective in reducing anxiety. There was no clear pattern of what combination of exercise mode, duration, and intensity was most effective, suggesting a variety may be effective in reducing anxiety. Methodological limitations still exist within the research, e.g., participant recruitment not considering baseline anxiety; variations in the control condition content. Future research should include participant samples exhibiting moderate-to-high levels of anxiety and examine self-selected exercise intensities.

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.

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.

The Effect of Blood Ketone Concentration and Exercise Intensity on Exogenous Ketone Oxidation Rates in Athletes.

INTRODUCTION: Exogenous ketones potentially provide an alternative, energetically advantageous fuel to power exercising skeletal muscle. However, there is limited evidence regarding their relative contribution to energy expenditure during exercise. Furthermore, the effect of blood ketone concentration and exercise intensity on exogenous ketone oxidation rates is unknown. METHODS: Six athletes completed cycling ergometer exercise on three occasions within a single-blind, random-order controlled, crossover design study. Exercise duration was 60 min, consisting of 20-min intervals at 25%, 50%, and 75% maximal power output (WMax). Participants consumed (i) bitter flavored water (control), (ii) a low-dose ß-hydroxybutyrate (ßHB) ketone monoester (KME; 252 mg·kg BW-1, "low ketosis"), or (iii) a high-dose ßHB KME (752 mg·kg BW-1, "high ketosis"). The KME contained a 13C isotope label, allowing for the determination of whole-body exogenous ßHB oxidation rates through sampled respiratory gases. RESULTS: Despite an approximate doubling of blood ßHB concentrations between low- and high-ketosis conditions (~2 mM vs ~4.4 mM), exogenous ßHB oxidation rates were similar at rest and throughout exercise. The contribution of exogenous ßHB oxidation to energy expenditure peaked during the 25% WMax exercise intensity but was relatively low (4.46% ± 2.71%). Delta efficiency during cycling exercise was significantly greater in the low-ketosis (25.9% ± 2.1%) versus control condition (24.1% ± 1.9%; P = 0.027). CONCLUSIONS: Regardless of exercise intensity, exogenous ßHB oxidation contributes minimally to energy expenditure and is not increased by elevating circulating concentrations greater than ~2 mM. Despite low exogenous ßHB oxidation rates, exercise efficiency was significantly improved when blood ßHB concentration was raised to ~2 mM.

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.

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.

Interoception of breathing and its relationship with anxiety.

Interoception, the perception of internal bodily states, is thought to be inextricably linked to affective qualities such as anxiety. Although interoception spans sensory to metacognitive processing, it is not clear whether anxiety is differentially related to these processing levels. Here we investigated this question in the domain of breathing, using computational modeling and high-field (7 T) fMRI to assess brain activity relating to dynamic changes in inspiratory resistance of varying predictability. Notably, the anterior insula was associated with both breathing-related prediction certainty and prediction errors, suggesting an important role in representing and updating models of the body. Individuals with low versus moderate anxiety traits showed differential anterior insula activity for prediction certainty. Multi-modal analyses of data from fMRI, computational assessments of breathing-related metacognition, and questionnaires demonstrated that anxiety-interoception links span all levels from perceptual sensitivity to metacognition, with strong effects seen at higher levels of interoceptive processes.

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.

TAPAS: An Open-Source Software Package for Translational Neuromodeling and Computational Psychiatry.

Psychiatry faces fundamental challenges with regard to mechanistically guided differential diagnosis, as well as prediction of clinical trajectories and treatment response of individual patients. This has motivated the genesis of two closely intertwined fields: (i) Translational Neuromodeling (TN), which develops "computational assays" for inferring patient-specific disease processes from neuroimaging, electrophysiological, and behavioral data; and (ii) Computational Psychiatry (CP), with the goal of incorporating computational assays into clinical decision making in everyday practice. In order to serve as objective and reliable tools for clinical routine, computational assays require end-to-end pipelines from raw data (input) to clinically useful information (output). While these are yet to be established in clinical practice, individual components of this general end-to-end pipeline are being developed and made openly available for community use. In this paper, we present the Translational Algorithms for Psychiatry-Advancing Science (TAPAS) software package, an open-source collection of building blocks for computational assays in psychiatry. Collectively, the tools in TAPAS presently cover several important aspects of the desired end-to-end pipeline, including: (i) tailored experimental designs and optimization of measurement strategy prior to data acquisition, (ii) quality control during data acquisition, and (iii) artifact correction, statistical inference, and clinical application after data acquisition. Here, we review the different tools within TAPAS and illustrate how these may help provide a deeper understanding of neural and cognitive mechanisms of disease, with the ultimate goal of establishing automatized pipelines for predictions about individual patients. We hope that the openly available tools in TAPAS will contribute to the further development of TN/CP and facilitate the translation of advances in computational neuroscience into clinically relevant computational assays.

Remote, Automated, and MRI-Compatible Administration of Interoceptive Inspiratory Resistive Loading.

Research on how humans perceive sensory inputs from their bodies ("interoception") has been rapidly gaining momentum, with interest across a host of disciplines from physiology through to psychiatry. However, studying interoceptive processes is not without significant challenges, and many methods utilized to access internal states have been largely devoted to capturing and relating naturally occurring variations in interoceptive signals (such as heartbeats) to measures of how the brain processes these signals. An alternative procedure involves the controlled perturbation of specific interoceptive axes. This is challenging because it requires non-invasive interventions that can be repeated many times within a subject and that are potent but safe. Here we present an effective methodology for instigating these perturbations within the breathing domain. We describe a custom-built circuitry that is capable of delivering inspiratory resistive loads automatically and precisely. Importantly, our approach is compatible with magnetic resonance imaging (MRI) environments, allowing for the administration of complicated experimental designs in neuroimaging as increasingly required within developing fields such as computational psychiatry/psychosomatics. We describe the experimental setup for both the control and monitoring of the inspiratory resistive loads, and demonstrate its possible utilities within different study designs. This methodology represents an important step forward from the previously utilized, manually controlled resistive loading setups, which present significant experimental burdens with prolonged and/or complicated sequences of breathing stimuli.