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Breathing Control, Brain, and Bodily Self-consciousness: Toward Immersive Digiceuticals to Alleviate Respiratory Suffering
Abstract
Breathing is peculiar among autonomic functions through several characteristics. It generates a very rich afferent traffic from an array of structures belonging to the respiratory system to various areas of the brain. It is intimately associated with bodily movements. It bears particular relationships with consciousness as its efferent motor control can be automatic or voluntary. In this review within the scope of "respiratory neurophysiology" or "respiratory neuroscience", we describe the physiological organisation of breathing control. We then review findings linking breathing and bodily self-consciousness through respiratory manipulations using virtual reality (VR). After discussing the currently admitted neurophysiological model for dyspnea, as well as a new Bayesian model applied to breathing control, we propose that visuo-respiratory paradigms -as developed in cognitive neuroscience- will foster insights into some of the basic mechanisms of the human respiratory system and will also lead to the development of immersive VR-based digital health tools (i.e. digiceuticals).
... Interestingly, however, breathing can also be voluntarily controlled. Volitional behaviors can alter or compromise (if temporary) breathing rhythms [6][7][8][9][10][11] , suggesting top-down neural mechanisms that modulate brainstem breathing networks 7 . ...
... Interestingly, however, breathing can also be voluntarily controlled. Volitional behaviors can alter or compromise (if temporary) breathing rhythms [6][7][8][9][10][11] , suggesting top-down neural mechanisms that modulate brainstem breathing networks 7 . ...
... By contrast, slow breathing or mindfulness skills are practiced across various cultures to regulate emotions [19][20][21] . Thus, while breathing is primarily an automatic process, it may be modulated by behavioral, voluntary and emotional inputs from suprapontine structures 2,6,22 , including the cerebral cortex 7,11,23 . However, precise neural circuits for top-down coordination of breathing and those capable of slowing breathing rates during stressful conditions to relieve negative affect remain unidentified. ...
Although breathing is primarily automatic, its modulation by behavior and emotions suggests cortical inputs to brainstem respiratory networks, which hitherto have received little characterization. Here we identify in mice a top-down breathing pathway from dorsal anterior cingulate cortex (dACC) neurons to pontine reticular nucleus GABAergic inhibitory neurons (PnCGABA), which then project to the ventrolateral medulla (VLM). dACC→PnC activity correlates with slow breathing cycles and volitional orofacial behaviors and is influenced by anxiogenic conditions. Optogenetic stimulation of the dACC→PnCGABA→VLM circuit simultaneously slows breathing and suppresses anxiety-like behaviors, whereas optogenetic inhibition increases both breathing rate and anxiety-like behaviors. These findings suggest that the dACC→PnCGABA→VLM circuit has a crucial role in coordinating slow breathing and reducing negative affect. Our study elucidates a circuit basis for top-down control of breathing, which can influence emotional states.
... Similarly to the current study using DBS, parallel changes in ventilation were absent, making significant changes in dyspnoea-related brain activity the likely underlying mechanism of action of these techniques [57,76,77], however their implementation in current clinical routine is widely lacking. More recently, several immersive virtual reality-based interventions (digital therapeutics/digiceuticals) have been suggested to relieve dyspnoea [78,79]. For example, synchronous flashing of the online respiratory signal onto a three-dimensional avatar silhouette synchronous to patient's respiratory movements has been demonstrated to improve dyspnoea, presumably via increased perception of breathing control (breathing agency) and/or ventilatory adaptations [78,80]. ...
... More recently, several immersive virtual reality-based interventions (digital therapeutics/digiceuticals) have been suggested to relieve dyspnoea [78,79]. For example, synchronous flashing of the online respiratory signal onto a three-dimensional avatar silhouette synchronous to patient's respiratory movements has been demonstrated to improve dyspnoea, presumably via increased perception of breathing control (breathing agency) and/or ventilatory adaptations [78,80]. Moreover, patient education and psychotherapeutic interventions such as cognitive behavioural therapy or mindfulness-based interventions, which target specific cognitions, emotions, expectations, health knowledge and behaviours, have been shown to not only improve mental health (e.g. ...
... Cependant, si la respiration répond à des besoins métaboliques ou structurels comme discuté précédemment, elle peut aussi répondre à des besoins cognitifs ou sociaux. En effet, comme mis en revue par Betka et ses collègues en 2022 (Betka et al., 2022), des connexions existent entre les régions motrices primaires et supplémentaires impliquant le contrôle conscient de la musculature respiratoire. Notons également l'existence de projections limbiques (amygdale notamment) sur les centres de contrôles de la respiration impliquant naturellement la respiration dans la panoplie d'acte moteurs permettant la communication émotionnelle (Boiten et al., 1994). ...
... Les vocalisations nécessitent en effet un effort respiratoire (expiratoire notamment) particulier, synchronisant à la fois les muscles respiratoires thoraciques (diaphragme notamment) qui poussent de l'air, avec les muscles laryngés qui resserrent les plis vocaux (muscles cricothyroïdiens principalement). Ces actes moteurs nécessitent un contrôle fin des motoneurones spinaux, ce qui se traduit par le fait que les neurones du cortex moteur primaire impliqués dans le contrôle respiratoire sont déjà prémoteurs (Betka et al., 2022). Une telle évolution pourrait aller de pair avec l'apparition chez le primate du cortex préfrontal dorso-latéral. ...
In its quest for the well-being of the body and mind, human beings have long sought to control 1) their olfactory environment and 2) their breathing in order to modify their emotional states. However, the neural, physiological, and psychological substrates of the relationship between odors, respiration, and relaxation have not yet been explored in a unified manner. The olfactory system plays a central role in these relationships, as it shares phylogenetic, anatomical, and functional connections with the limbic system, a neural network involved in the control of our autonomic functions and emotions. Furthermore, if respiratory rhythm significantly influences the activities of the olfactory system, the team in which I conducted my thesis research has shown in rodent models that not all respiratory patterns are equal: the slow and deep nasal respiratory pattern, characteristic of the calm awake state in rats, is the one that promotes the synchronization of oscillatory activities in the olfactory system, and consequently, in the brain, with the respiratory rhythm. Thus, the slow and deep nasal respiratory pattern could, in humans, be associated with a similar calm awake state that corresponds to a state of relaxation. Pleasant odors, on the other hand, are capable of slowing down respiration while inducing a state of relaxation. Therefore, my doctoral research aims to decipher the links between the hedonic valence of odors, respiratory patterns, and the sensation of relaxation. It is structured into two axes. In the first axis, I test the hypothesis that deep nasal breathing facilitates the brain synchronization of large brain networks, promoting relaxation. To address this, I had the privilege of obtaining intracerebral electroencephalographic data from humans, in addition to physiological and psychometric data. The second axis aims to decipher the neural and physiological mechanisms underlying the effect of pleasant odors on the sensation of relaxation. This axis was divided into two questions. The first sought to understand the impact of odors with different hedonic valences on respiration, brain activity, and physiological and psychological relaxation. Assuming that pleasant odors slow down respiration, synchronizing large brain networks and leading to psychological and physiological relaxation, I recorded scalp electroencephalographic activity in healthy participants, as well as psycho-physiological data. In the second question, I compared the olfactory sensory modality to another sensory modality in their ability to modify respiration, brain activity, and physiological and psychological relaxation. To do this, I recorded similar data in healthy participants exposed to pleasant olfactory stimuli compared to pleasant auditory stimuli, with the hypothesis that pleasant odors have a particular capacity to induce a state of relaxation. Overall, this work allowed me to highlight that 1) slow respiratory patterns have a major effect on brain rhythms and the calming of physiological rhythms but are not specifically associated with psychological relaxation, and 2) the effects of odors on brain activity and physiology are mainly related to respiration, of which the olfactory-motor act is an integral part. Therefore, considering the respiratory state variations they induce, I strongly recommend interpreting the results of any experiment using olfactory stimuli through the lens of respiratory changes. Through the prism of respiratory action, the olfactory system could have privileged access to the well-being of the body and, to a lesser extent, the mind.
... HEP has been linked with cardiac function (32,33), but also with various cognitive and affective processes (7,(34)(35)(36)(37)(38)(39)(40)(41). Although less investigated than cardiac signals, respiratory signals have also been shown to modulate brain oscillations at rest in widespread brain networks (42,43). Similarly to cardiac signals, respiration has also been shown to influence a range of cognitive and motor processes (44)(45)(46)(47)(48)(49)(50)(51). ...
... Alternatively, some of the observed modulations could also be linked to lung movement relayed by the vagus nerve, to mechanoreceptors in the chest wall whose projections appear to play a role in shaping respiratory sensations (106,107), or to chest expansions-contractions relayed by somatosensory pathways. Finally, basal ganglia and thalamus activity have also been common findings in neuroimaging studies of volitional breathing as well as investigating complex behavioral breathing acts, such as breathing during speech, while singing or exercising (12,42,61,108,109). ...
Visceral signals are constantly processed by our central nervous system, enable homeostatic regulation, and influence perception, emotion, and cognition. While visceral processes at the cortical level have been extensively studied using non-invasive imaging techniques, very few studies have investigated how this information is processed at the single neuron level, both in humans and animals. Subcortical regions, relaying signals from peripheral interoceptors to cortical structures, are particularly understudied and how visceral information is processed in thalamic and subthalamic structures remains largely unknown. Here, we took advantage of intraoperative microelectrode recordings in patients undergoing surgery for deep brain stimulation (DBS) to investigate the activity of single neurons related to cardiac and respiratory functions in three subcortical regions: ventral intermedius nucleus (Vim) and ventral caudalis nucleus (Vc) of the thalamus, and subthalamic nucleus (STN). We report that the activity of a large portion of the recorded neurons (about 70%) was modulated by either the heartbeat, the cardiac inter-beat interval, or the respiration. These cardiac and respiratory response patterns varied largely across neurons both in terms of timing and their kind of modulation. A substantial proportion of these visceral neurons (30%) was responsive to more than one of the tested signals, underlining specialization and integration of cardiac and respiratory signals in STN and thalamic neurons. By extensively describing single unit activity related to cardiorespiratory function in thalamic and subthalamic neurons, our results highlight the major role of these subcortical regions in the processing of visceral signals.
... Awareness of the respiratory rhythm and its somato-afferent consequences have long been seen as a central gateway to insight and altered states of consciousness in meditation techniques, in particular mindfulness meditation (Grossman, 2010;Brown & Gerbarg, 2009). More recently, the sensations emanating from the act of breathing have been found to be central to a sense of body agency or body self-consciousness (Monti et al., 2020;Betka et al., 2022). What more might be expected of such a formidable neuroviscerally integrating force? ...
... The voluntary recruitment of breathing supports the advanced human capacity of speech and vocalization, which is a skill at the center of planning and purposeful behavior. Breathing maneuvers can serve as "probes" that produce somato-afferent feedback and thereby contribute to body selfconsciousness (Betka et al., 2022). On the other hand, during wakeful and sleep states, there is an automaticity of respiration that protects us by maintaining breathing within certain biological limits. ...
... Not described before, we observed that the removal of visual afferents triggered an increase of the PRC. Vision and breathing are centrally connected, as illustrated by the ability of visuorespiratory manipulations to interfere with bodily self-consciousness [29]. We hypothesize that, in our experiment, removing visual feedback could have modified the baseline visuo-respiratory interaction, thereby modifying bodily self-consciousness [29] with possible consequences on balance and PRC. ...
... Vision and breathing are centrally connected, as illustrated by the ability of visuorespiratory manipulations to interfere with bodily self-consciousness [29]. We hypothesize that, in our experiment, removing visual feedback could have modified the baseline visuo-respiratory interaction, thereby modifying bodily self-consciousness [29] with possible consequences on balance and PRC. This hypothesis is supported by the occurrence of breathing pattern changes when visual afferent are removed (increase in Ti). ...
Alteration of posturo-respiratory coupling (PRC) may precede postural imbalance in patients with chronic respiratory disease. PRC assessment would be appropriate for early detection of respiratory-related postural dysfunction. PRC may be evaluated by respiratory emergence (REm), the proportion of postural oscillations attributed to breathing activity; assessed by motion analysis) as measured from the displacement of the center of pressure (CoP) (measured with a force platform). To propose a simplified method of PRC assessment (using motion capture only), we hypothesized that the REm can appropriately be measured derived from single body segment the postural oscillations of a single body segment rather than whole body postural oscillations. An optoelectronic system recorded the breathing pattern and the postural oscillations of six body segments in 50 healthy participants (22 women), 34 years [26; 48]. The CoP displacements were assessed using a force platform. One-minute recordings were made in standing position in four conditions by varying vision (eyes opened/closed) and jaw position (rest position/dental contact). The Sway Path and Mean Velocity of the CoP and of the representative point of each body segment were recorded. The REm was measured along the major and the minor axis of the 95% confidence ellipse of the CoP position (REm_MajorAxis
CoP
; REm_MinorAxis
CoP
) and of that of each body segment. SwayPath
CoP
and MV
CoP
varied widely across the four conditions (par<0.000001). These changes were related to the visual condition (p<0.000001) while the jaw position had no effect. The REm_MajorAxis
CoP
and the REm_MinorAxis
CoP
changed across conditions (p<0.05); this was related to vision while jaw induced changes only for the REm_MinorAxis
CoP
. The SwayPath, the Mean Velocity and the REm of all body segments were significantly correlated to the CoP, but the highest correlations were observed for the thorax, the pelvis and the shoulder. PRC may be assessed from the postural oscillations of thorax, pelvis and shoulder. This should simplify the evaluation of respiratory-related postural interactions in the clinical environment, by using a single device to simultaneously assess postural oscillations on body segments, and breathing pattern. In addition, this study provides reference data for PRC and its sensory-related modulations on body segments along the postural chain.
... HEP has been linked with cardiac function (MacKinnon et al., 2013;Schandry & Montoya, 1996), but also with various cognitive and affective processes (Gray et al., 2007;Montoya et al., 1993;Park et al., 2014Park et al., , 2016Park et al., , 2018Pollatos & Schandry, 2004;Schandry et al., 1986;Shao et al., 2011;Solcà et al., 2020). Although less investigated than cardiac signals, respiratory signals have also been shown to modulate brain oscillations at rest in widespread brain networks (Betka et al., 2022;Kluger & Gross, 2021). Similarly to cardiac signals, respiration has also been shown to influence a range of cognitive and motor processes (Adler et al., 2014;Allard et al., 2017;Kluger et al., 2021;Park et al., 2020;Perl et al., 2019;Rassler & Raabe, 2003;Schulz et al., 2016;Zelano et al., 2016). ...
... Alternatively, some of the observed modulations could also be linked to mechanoreceptors in the chest wall whose projections appear to play a role in shaping respiratory sensations (Homma et al., 1988). Finally, basal ganglia and thalamus activity have also been common findings in neuroimaging studies of volitional breathing as well as investigating complex behavioral breathing acts, such as breathing during speech, while singing or exercising (Betka et al., 2022;McKay et al., 2003;Murphy et al., 2017;K. T. S. Pattinson et al., 2009). ...
Visceral signals are constantly processed by our central nervous system, enable homeostatic regulation, and influence perception, emotion, and cognition. While visceral processes at cortical level have been extensively studied using non-invasive imaging techniques, very few studies have investigated how this information is processed at the single neuron level, both in humans and animals. Subcortical regions, relaying signals from peripheral interoceptors to cortical structures, are particularly understudied and how visceral information is processed in thalamic and subthalamic structures remains largely unknown. Here, we took advantage of intraoperative microelectrode recordings in patients undergoing surgery for deep brain stimulation (DBS) to investigate the activity of single neurons related to cardiac and respiratory functions in three subcortical regions: Ventral Intermedius nucleus (Vim) and Ventral caudalis nucleus (Vc) of the thalamus, and subthalamic nucleus (STN). We report that the activity of a large portion of the recorded neurons (about 70%) was modulated by either the heartbeat, the cardiac inter-beat interval, or the respiration. These cardiac and respiratory response patterns varied largely across neurons both in terms of timing and their kind of modulation. We observed neurons with increases or decreases in firing rate in response to either the heartbeat or the inter-beat interval. Peaks of neural activity were found at different phases of the cardiac and respiratory cycles. Whereas most neurons only responded to one of the tested signals, a substantial proportion of these visceral neurons (30%) was responsive to more than one of the tested signals, underlining specialization and integration of cardiac and respiratory signals in STN and thalamic neurons. By extensively describing for the first time single unit activity related to cardiorespiratory function in thalamic and subthalamic neurons, our results highlight the major role of these subcortical regions in the processing of visceral signals.
... Both previous examples illustrate complex interplay between volitional control and automatic commands of respiration, the former being able to temporarily bypass the later, an unique case for a life-sustaining physiological requirement in animals (Trevizan-Baú et al., 2024). Research in animals, further supported by one human neuroimaging investigation of volitional respiratory control (McKay et al., 2003) and a model of dyspnea (Betka et al., 2022), suggests a complex interplay between respiration-related cortical networks and the involvement of brainstem automatic respiration generation. ...
Discussion is a fundamental social activity requiring coordination of speech between interlocutors. Speech production is a complex human behaviour that involves several anatomo-physiological processes, including inspiration and expiration. The aim of the present study is to investigate the neurophysiological underpinnings of speech-related respiration events in conversational turn-taking. We made use of an existing corpus of natural conversations between a participant and its interlocutor (Human or Robot) focusing on synchronised (1) behavioural (conversation turn-taking), (2) respiratory (maxima of inspiration) and (3) neurophysiological (fMRI) data. Precisely timed conversation transcripts from 25 participants were used to categorise breathing maxima based on their timing relative to the participant’s speech onset. In agreement with the literature, the closest respiration time maximum to each speech turn occurred on average 200 ms prior to speech onset. The fMRI second-level contrast ( p FWE < 0.05, extend k > 5 cm ³ ) Resp+ (maximum respiration associated with speech) versus Resp-, exclusively masked to exclude speech related areas, revealed bilateral activations in the central sulcus, the brainstem and the cerebellum. The brainstem cluster comprises respiratory pattern generators, possibly the preBötzinger complex, that need to be inhibited to enslave breathing to speech production and not physiological needs, while the central sulcus cluster is likely to be located in the postcentral primary sensory cortex receiving upper torso inputs indicating that lungs are filled, and the cerebellum clusters could play a role in the timing of speech onset, 200 ms after a respiration maximum. These results show how cortical, cerebellar and brainstem coordinated control of breathing during conversational turn-taking is part of the intricate physiological mechanisms that contribute to natural communication dynamics.
... The pneumotaxic and apneustic centres function to prevent lung overdistension. Automatic breathing can be interrupted or overridden by voluntary control mechanisms, and while there are separate anatomical pathways for automatic and voluntary breathing, these pathways demonstrate significant functional overlap [1,20]. Automatic breathing, controlled by reticular formation respiratory networks, chemoreceptors, and respiratory mechanoreceptors, can be influenced by descending inputs from emotional and cognitive neural networks. ...
Breathing is a complex, vital function that can be modulated to influence physical and mental well-being. However, the role of cortical and subcortical brain regions in voluntary control of human respiration is underexplored. Here we investigated the influence of damage to human frontal, temporal or limbic regions on the sensation and regulation of breathing patterns. Participants performed a respiratory regulation task across regular and irregular frequencies ranging from 6 to 60 breaths per minute (bpm), with a counterbalanced hand motor control task. Interoceptive and affective states induced by each condition were assessed via questionnaire, and autonomic signals were indexed via skin conductance. Participants with focal lesions to the bilateral frontal lobe, right insula/basal ganglia and left medial temporal lobe showed reduced performance relative to individually matched healthy comparisons during the breathing and motor tasks. They also reported significantly higher anxiety during the 60 bpm regular and irregular breathing trials, with anxiety correlating with difficulty in rapid breathing specifically within this group. This study demonstrates that damage to frontal, temporal or limbic regions is associated with abnormal voluntary respiratory and motor regulation and tachypnoea-related anxiety, highlighting the role of the forebrain in affective and motor responses during breathing.
This article is part of the theme issue ‘Sensing and feeling: an integrative approach to sensory processing and emotional experience’.
... Breathing control involves brain's motor, sensory and limbic areas, as well as midbrain structures, underlying the multidimensional aspects of such a system. (Betka, Adler, Similowski & Blanke, 2022) The definition obtained within the PM database gives clear instructions which describe the actions that should be taken for "breathing control". On the other hand, the definition within the SD database provides a more detailed description of the processes that are involved during "breathing control". ...
Respiration is an indispensable aspect of life that significantly influences both the physical and mental well-being of individuals, depending on such factors as depth and rhythm. Exploring the distinctions between chest and abdominal breathing is crucial for understanding their profound impacts, and embracing appropriate breathing exercises has proven to be advantageous for short-term relief and long-term holistic health. While acknowledged for diverse therapeutic applications, such as mitigating vocal cord fatigue, a comprehensive exploration of breathing exercises remains essential. Sport scientists and coaches are encouraged to acquire a set of breathing exercises for future implementation in the training routines. This study strives to conduct an interdisciplinary literature review to shed light on the aims, meaning, and classification of breathing exercises. Employing a literature review methodology, were analysed peer-reviewed articles from PubMed and ScienceDirect published during the years from 2000 to 2023, focusing on such keywords as breathing exercises, deep breathing, nasal breathing, abdominal breathing, thoracic breathing, pursed-lip breathing, breathing control, and respiratory muscle training. The research findings illustrate the multifaceted definitions, components, aims, and classifications of breathing exercises. This study establishes a foundation for identifying distinct subtypes, contributing to a more nuanced understanding of the significance and purpose of breathing exercises in enhancing overall well-being.
... Congruent breathing also enhanced participants' sense of agency, leading to a greater perception of controlling the avatar's movements when the avatar 'breathed' in phase with the participants. The sense of controlling the avatar through breathing signals was discussed in two recent reviews 75,76 . Crucially, it appears that different forms of voluntary control over one's breath may differentially impact the sense of agency 77 . ...
We capitalized on the respiratory bodily illusion that we discovered in a previous study and called ‘Embreathment’ where we showed that breathing modulates corporeal awareness in men. Despite the relevance of the issue, no such studies are available in women. To bridge this gap, we tested whether the synchronization of avatar-participant respiration patterns influenced females’ bodily awareness. We collected cardiac and respiratory interoceptive measures, administered body (dis)satisfaction questionnaires, and tracked participants’ menstrual cycles via a mobile app. Our approach allowed us to characterize the ‘Embreathment’ illusion in women, and explore the relationships between menstrual cycle, interoception and body image. We found that breathing was as crucial as visual appearance in eliciting feelings of ownership and held greater significance than any other cue with respect to body agency in both women and men. Moreover, a positive correlation between menstrual cycle days and body image concerns, and a negative correlation between interoceptive sensibility and body dissatisfaction were found, confirming that women’s body dissatisfaction arises during the last days of menstrual cycle and is associated with interoception. These findings have potential implications for corporeal awareness alterations in clinical conditions like eating disorders and schizophrenia.
... In general, there is only a moderately strong relationship between peripheral organ dysfunction and patients' breathlessness, and a considerable number of patients lack any measurable organic symptom correlate [1]. Recently, concepts based on the processing of respiratory information in the brain have been developed that describe how persistent breathlessness that is not sufficiently explained by organ dysfunction could manifest [6][7][8][9][10]. These concepts highlight that perception of symptoms occurs in the brain, even if the initial cause resides in body periphery, and that symptoms can be just as authentic and disabling when peripheral organs are intact, but information relayed from sensors to the brain is misprocessed. ...
Breathlessness is among the most common post-COVID symptoms. In a considerable number of patients, severe breathlessness cannot be explained by peripheral organ impairment. Recent concepts have described how such persistent breathlessness could arise from dysfunctional processing of respiratory information in the brain. In this paper, we present a first quantitative and testable mathematical model of how processing of respiratory-related signals could lead to breathlessness perception. The model is based on recent theories that the brain holds an adaptive and dynamic internal representation of a respiratory state that is based on previous experiences and comprises gas exchange between environment, lung and tissue cells. Perceived breathlessness reflects the brain’s estimate of this respiratory state signaling a potentially hazardous disequilibrium in gas exchange. The internal respiratory state evolves from the respiratory state of the last breath, is updated by a sensory measurement of CO2 concentration, and is dependent on the current activity context. To evaluate our model and thus test the assumed mechanism, we used data from an ongoing rebreathing experiment investigating breathlessness in patients with post-COVID without peripheral organ dysfunction (N = 5) and healthy control participants without complaints after COVID-19 (N = 5). Although the observed breathlessness patterns varied extensively between individual participants in the rebreathing experiment, our model shows good performance in replicating these individual, heterogeneous time courses. The model assumes the same underlying processes in the central nervous system in all individuals, i.e., also between patients and healthy control participants, and we hypothesize that differences in breathlessness are explained by different weighting and thus influence of these processes on the final percept. Our model could thus be applied in future studies to provide insight into where in the processing cascade of respiratory signals a deficit is located that leads to (post-COVID) breathlessness. A potential clinical application could be, e.g., the monitoring of effects of pulmonary rehabilitation on respiratory processing in the brain to improve the therapeutic strategies.
... The pneumotaxic and apneustic centers function to prevent lung over-distension. Automatic breathing can be interrupted or overridden by voluntary control mechanisms, and while there are separate anatomic pathways for automatic and voluntary breathing, these pathways demonstrate significant functional overlap (Prasad, Pal & Chen, 2021;Betka et al., 2022). Automatic breathing, controlled by FR's respiratory networks, chemoreceptors, and respiratory mechanoreceptors, can be influenced by descending inputs from emotional and cognitive neural networks. ...
Breathing is a complex, vital function that can be modulated to influence physical and mental well-being. However, the role of cortical and subcortical brain regions in voluntary control of human respiration is underexplored. Here we investigated the influence of damage to human frontal, temporal, or limbic regions on the sensation and regulation of breathing patterns. Participants performed a respiratory regulation task across regular and irregular frequencies ranging from 6 to 60 breaths per minute (bpm), with a counterbalanced hand motor control task. Interoceptive and affective states induced by each condition were assessed via questionnaire and autonomic signals were indexed via skin conductance. Participants with focal lesions to the bilateral frontal lobe, right insula/basal ganglia, and left medial temporal lobe demonstrated significantly lower performance than individually matched healthy comparisons during the breathing and motor tasks. They also reported significantly higher anxiety during the 60-bpm regular and irregular breathing trials than healthy participants. Correlations between task performance, anxiety, and difficulty varied across experimental conditions and groups. This study demonstrates that damage to frontal, temporal, or limbic regions is associated with abnormal voluntary respiratory and motor regulation and tachypnea-related anxiety, highlighting the role of the forebrain in affective and motor responses during breathing.
Highlights
Impaired human respiratory regulation is associated with cortical/subcortical brain lesions
Frontolimbic/temporal regions contribute to rhythmic breathing and hand motor control
Frontolimbic/temporal damage is associated with anxiety during tachypnea/irregular breathing
The human forebrain is vital for affective and interoceptive experiences during breathing
... In this regard, prior interventions using immersive VR-based Digital Therapeutics, also referred to as digiceuticals 11 , have demonstrated alleviation of chronic pain in patients with complex regional pain syndrome or spinal cord injury 12,13 . In the respiratory domain, visuo-respiratory stimulation has been associated with an increased feeling of breathing control (breathin g agency) 14 , a reduced negative emotional state related to experimental dyspnea 15 , as well as changes in physiological measures of breathin g 8,16 . ...
Background
Immersive virtual reality (iVR)-based digital therapeutics (DTx) are gaining clinical attention in the field of pain management. Based on known analogies between pain and dyspnea, we investigated the effects of visual-respiratory feedback, on persistent dyspnea in patients recovering from COVID-19 pneumonia.
Methods
We performed a controlled, randomized, single-blind, cross-over proof-of-concept study (feasibility and initial clinical-efficacy) to evaluate an iVR-based intervention to alleviate dyspnea in patients recovering from COVID-19 pneumonia. Included patients reported persistent dyspnea (≥5 on a 10-point scale) and preserved cognitive function (MoCA>24). Assignment was random and concealed. Patients received synchronous (intervention) or asynchronous (control) feedback of their breathing, embodied via a gender-matched virtual body. The virtual body flashed in a waxing and waning visual effect which could be synchronous or asynchronous to the patient's respiratory movements. Outcomes were assessed using questionnaires and breathing recordings.
Results
Study enrollment was open between November 2020 and April 2021. Twenty-six patients were enrolled (27% women; age: median=55, interquartile range (IQR)=18). Data were available for 24 of 26 patients. The median (IQR) rating on a 7-point Likert-scale of breathing comfort improved from 1(2) at baseline, to 2(1) for synchronous feedback, but remained unchanged at 1(1.5) for asynchronous feedback (p<0.05) between iVR conditions). Moreover, 91.2% of all patients were satisfied with the intervention (p<0.0001) and 66.7% perceived it as beneficial for their breathing (p<0.05).
Conclusion
Our iVR-based DTx presents a feasible and safe respiratory rehabilitation tool that improves breathing comfort in patients recovering from COVID-19 infection presenting with persistent dyspnea. Future research should investigate the intervention's generalizability to persistent dyspnea with other etiologies and its potential for preventing chronification.
... Pernapasan merupakan saluran yang sangat penting yang sejauh ini menghasilkan lalu lintas aferen yang intens dari berbagai sumber. Setiap napas melibatkan otot-otot yang berkontraksi, artikulasi bergerak, perubahan tekanan intratoraks dan abdomen, mengembang dan mengempisnya saluran bronkus dan parenkim paru sehingga terjadi pertukaran gas O 2 dan CO 2 (Betka et al., 2022). Latihan pernapasan adalah terapi fisik yang murah dan mudah dilakukan untuk pasien PPOK, yang dianggap sebagai komponen penting terapi non farmakologi dari rehabilitasi paru (Yang et al., 2022). ...
This study aims to determine breathing techniques that can be used to reduce dyspnea in COPD patients. The method used is to search articles on several electronic databases, namely Proquest, ScienceDirect, PubMed, Embase, and EBSCOHost, using the keywords Breathing Technique, Dyspnea, and COPD. Inclusion criteria were COPD patients, articles with RCT or clinical trial research designs published in the last ten years, and interventions that included breathing techniques. The results showed that several breathing techniques could reduce dyspnea in COPD patients, including pursed lip breathing, active cycle breathing, breathing control, deep breathing, and yoga. In conclusion, these breathing techniques can be used in COPD patients. Breathing techniques can reduce dyspnea and improve quality of life, sputum discharge, lung capacity, and anxiety. Keywords: Breathing Technique, COPD, Dyspnea
... New conceptual frameworks suggest that paced breathing, for example through LRC, may change predictive coding and sensory integration to reduce dyspnea (Betka et al., 2022). A systematic review and meta-analysis proposed that slow-paced breathing can indeed improve interoception and self-regulation according to the neurovisceral integration model . ...
Breathing sustains life from birth until death via the simple movement of air. The recent 2020 SARS-Covid-19 epidemic has reminded many of the significance of breathing and the consequence of it being taken away. Recent work suggests that breathing pattern (BP) metrics are under-utilized and under-reported in the literature; for example, breathing rate (BR) has tremendous diagnostic value in sport and health and is simple to measure, but is still hotly debated for its regulation and individuality. This work (chapter 2) presents a suitable method for BP measurement in the field together with a custom-developed breath detection algorithm. Results show high accuracy (>99%) and enhanced capabilities including locomotor-respiratory coupling (LRC) analysis. LRC was measured in various contexts (chapters 3 and 4), revealing possible influence upon other aspects of BP. Not only is breathing measurement valuable in sports science, but also the potential to influence it. Like other physiological processes such as heart rate and skin temperature, breathing automatically maintains critical regulatory functions; however, unlike these examples, it is unique because it can be volitionally controlled. Some experts believe that since breathing is a tightly regulated system, disturbing its natural pattern could be ineffective or even harmful. On the contrary, breathing techniques commonly used in yoga, meditation, and breathwork have shown immense promise for their positive effects on HRV, airway limitations, and cognitive performance. Chapter 5 summarizes such breathing strategies with respect to exercise, specifically describing why, how, and when they can be used during running. It concludes with the recommendation of LRC as a comprehensive, beneficial breathing technique to use for improving performance and/or the subjective experience of running. Chapter 6 showcases a custom-built smartphone app for LRC audio guidance, demonstrating that it can support beginner runners in performing LRC with high adherence during field and laboratory running. This work ends with a discussion of its main findings, practical applications, and possible future directions. Breathing is at once one of the most well-studied and also untapped biological processes in sports science to be understood and advanced. This writing aims to progress and contribute to its importance.
... There is an urgent need to offer new non-invasive tools to alleviate persistent dyspnoea in COVID-19 [116,117]. In this context, BETKA et al. [118] (Geneva, Switzerland) developed an immersive virtual reality-based digital therapeutic, based on known analogies between pain and dyspnoea [119]. ...
It is a challenge to keep abreast of all the clinical and scientific advances in the field of respiratory medicine. This article contains an overview of laboratory-based science, clinical trials and qualitative research that were presented during the 2022 European Respiratory Society International Congress within the sessions from the five groups of the Assembly 1 – Respiratory clinical care and physiology. Selected presentations are summarised from a wide range of topics: clinical problems, rehabilitation and chronic care, general practice and primary care, electronic/mobile health (e-health/m-health), clinical respiratory physiology, exercise and functional imaging.
... Brièvement, la dyspnée est la plainte qui résulte de ce que l'on peut proposer d'appeler la souffrance « neuro-respiratoire », c'est-à-dire d'un ensemble d'activations cérébrales correspondant à la perception d'un stimulus périphérique (respiratoire ou autre) et au traitement cognitif et émotionnel de ce stimulus (128). ...
« Manquer d'air », « suffoquer », « étouffer », c’est là l'une des pires épreuves auxquelles peut être soumis un être humain. Ainsi, la dyspnée, définie comme "la perception consciente de la respiration assortie d'un affect négatif tels que la peur ou l’anxiété", modifie profondément la vie des patients qui en souffrent, en particulier lorsqu'elle ne peut pas être soulagée adéquatement par un traitement. On parle alors de dyspnée persistante. Il s'agit d'une situation particulièrement désespérante pour les patients, les proches et les soignants. Elle concerne de nombreux patients atteints de maladies respiratoires, cardiaques et neuromusculaires ou cancéreuses, notamment aux stades avancés. Elle est pourtant notoirement sous-évaluée autant collectivement, comme problème de santé public, qu'individuellement, comme souffrance physique et psychologique. Les professionnels de santé sous-estiment l'intensité et l'impact de la dyspnée. Ces constats, à l’origine du concept d’invisibilité de la dyspnée, sont une injustice. Cette injustice existe sur le plan épistémique, en ceci que les patients ne peuvent faire reconnaitre leur expérience dans toute sa significativité et que l'invisibilité de la dyspnée empêche de facto les patients concernés de bénéficier, de la part des soignants, de la "considération" qui leur donnerait accès à des approches thérapeutiques adaptées. Cela se traduit, in fine, par une injustice dans la prise en charge médicale. L'objectif de cette thèse est de contribuer à corriger cette situation, au travers d'une triple approche, phénoménologique, expérientielle et expérimentale. L’approche phénoménologique s'adresse à l'injustice épistémique telle que décrite ci-dessus. Ainsi, elle a pour objectif de donner la parole aux patients, et à travers cela de décrire la façon ils perçoivent leur maladie ainsi que l'appréhension qu'ont les autres (famille, environnement social, soignants). Elle a permis de conceptualiser différentes formes d'invisibilité (sur le plan temporel et catégoriel), de mettre en lumière certaines particularités de la souffrance respiratoire (symbolique du souffle par exemple) et d’identifier différents déterminants de l’invisibilité de la dyspnée. L’approche expérientielle nous a permis d’explorer certaines de nos hypothèses élaborées à partir de ces déterminants de l’invisibilité de la dyspnée. Ainsi, dans le contexte de pandémie de Covid 19 qui a généralisé le port du masque, nous avons pu démontrer que le port du masque génère une expérience de dyspnée et que cette expérience de masse d’une dyspnée induite sensibilise la population générale au concept de santé respiratoire et aux vécus des malades souffrant de dyspnée). L’approche expérientielle permet également de tester la portée correctrice d’actions, notamment pédagogiques à destination des soignants, intégrant à un enseignement spécifique à la dyspnée une composante expérientielle. L’étude menée dans cette perspective a montré que l’aspect expérientiel de l’enseignement améliore la compréhension par les étudiants du vécu des patients dyspnéiques. Enfin, l’approche expérimentale vise à objectiver et quantifier l’impact de l’invisibilité de la dyspnée sur le vécu (notamment affectif) de celle-ci. Des volontaires sains, exposés à deux épisodes successifs de dyspnée expérimentale, sont randomisés dans un bras qualifié de « neutre » et un qualifié de « sollicitude empathique ». La sollicitude empathique étant ici conceptualisée comme un levier de correction de l’invisibilité de la dyspnée. Les différences de vécu des volontaires sains peuvent donc être considérés comme une première estimation, bien qu’indirecte, de l’impact de l’invisibilité de la dyspnée dans le cadre de la relation soignant-soigné. Les travaux de ce travail de thèse sont les premières, mais indispensables, étapes pour repenser la dyspnée et sa prise en considération dans notre société et dans le soin.
... Interoception research has also profited much from the rise of the neurosciences, which finally elevates this area of inquiry to the full study of brain -periphery interactions related to processing of internal sensations. The review of Betka et al. (2022) extends the study of respiration to an integrative perspective encompassing autonomic and voluntary control, peripheral and CNS regulatory aspects, and afferent and efferent functions. Studying novel virtual reality paradigms, they show that body-self-consciousness can arise from this integration, suggesting a centrality of respiration to global interoception as an aspect of self-awareness, and proposing the application of a predictive coding model of respiratory sensation. ...
Interoception research can substantially contribute to treatment modalities that improve organic disease management and mental health. Studies in asthma have demonstrated that feedback of added resistive loads can improve accuracy of detecting airway obstruction and that diaries of symptoms and spirometry self-measurement can improve estimations of lung function and asthma control. Multifaceted blood glucose perception training that combines accuracy training by self-measurement diaries with education about determinants of blood glucose can improve blood glucose control in individuals suffering from diabetes. In panic disorders, interoceptive exposure training with systematic elicitation of bodily sensations by exercises, including dyspnea by hyper- or hypoventilation, has aimed to reduce patients’ catastrophic interpretations of feared sensations. In addition, a range of relaxation and meditation techniques have been devised to enhance aspects of interoception, such as the detection of muscle tension by progressive muscle relaxation or attention to breathing via meditation techniques inspired by Buddhist practices, with the ultimate goal of improving general well-being. Although many approaches have yielded promising results, more attention to ecologically or physiologically valid selection of targets and personalization of treatment is warranted. This includes consideration of possible adverse effects of training on clinical outcomes through heightened attention to symptoms of illness.
Exploring a novel approach to mental health technology, this study illuminates the intricate interplay between exteroception (the perception of the external world), and interoception (the perception of the internal world). Drawing on principles of sensory substitution, we investigated how interoceptive signals, particularly respiration, could be conveyed through exteroceptive modalities, namely vision and hearing. To this end, we developed a unique, immersive multisensory environment that translates respiratory signals in real-time into dynamic visual and auditory stimuli. The system was evaluated by employing a battery of various psychological assessments, with the findings indicating a significant increase in participants' interoceptive sensibility and an enhancement of the state of flow, signifying immersive and positive engagement with the experience. Furthermore, a correlation between these two variables emerged, revealing a bidirectional enhancement between the state of flow and interoceptive sensibility. Our research is the first to present a sensory substitution approach for substituting between interoceptive and exteroceptive senses, and specifically as a transformative method for mental health interventions, paving the way for future research.
Die Atmung wirkt sich auf die motorische Kontrolle und die Haltungsstabilität aus. Erklärt werden im folgenden Artikel der Begriff des Atemmusters und die Auswirkung des dysfunktionalen Atemmusters Mundatmungssyndrom auf die Haltung. Diese Haltungsanpassung wird mit ihren Auswirkungen auf die Atemmuskeln beschrieben. Um dieses Krankheitsbild besser zu verstehen, wird auf ihre pathologische Emotionsregulierung eingegangen. Zuletzt wird ein osteopathischer Therapieansatz vorgestellt.
Respiratory difficulties and mortality following severe cervical spinal cord injury (CSCI) result primarily from malfunctions of respiratory pathways and the paralyzed diaphragm. Nonetheless, individuals with CSCI can experience partial recovery of respiratory function through respiratory neuroplasticity. For decades, researchers have revealed the potential mechanism of respiratory nerve plasticity after CSCI, and have made progress in tissue healing and functional recovery. While most existing studies on respiratory plasticity after spinal cord injuries have focused on the cervical spinal cord, there is a paucity of research on respiratory-related brain structures following such injuries. Given the interconnectedness of the spinal cord and the brain, traumatic changes to the former can also impact the latter. Consequently, are there other potential therapeutic targets to consider? This review introduces the anatomy and physiology of typical respiratory centers, explores alterations in respiratory function following spinal cord injuries, and delves into the structural foundations of modified respiratory function in patients with CSCI. Additionally, we propose that magnetic resonance neuroimaging holds promise in the study of respiratory function post-CSCI. By studying respiratory plasticity in the brain and spinal cord after CSCI, we hope to guide future clinical work.
Highlights
What are the main findings? The constrained disorder principle (CDP) defines systems by their inherent disorder bounded by variable boundaries.
What is the implication of the main finding? The present paper describes the mechanisms of breathing and cellular respiration, focusing on their inherent variability and how the CDP accounts for the variability in breathing and respiration.
The article describes using CDP-based artificial intelligence platforms to augment the respiratory process’s efficiency and treat respiratory diseases.
Abstract
Variability characterizes breathing, cellular respiration, and the underlying quantum effects. Variability serves as a mechanism for coping with changing environments; however, this hypothesis does not explain why many of the variable phenomena of respiration manifest randomness. According to the constrained disorder principle (CDP), living organisms are defined by their inherent disorder bounded by variable boundaries. The present paper describes the mechanisms of breathing and cellular respiration, focusing on their inherent variability. It defines how the CDP accounts for the variability and randomness in breathing and respiration. It also provides a scheme for the potential role of respiration variability in the energy balance in biological systems. The paper describes the option of using CDP-based artificial intelligence platforms to augment the respiratory process’s efficiency, correct malfunctions, and treat disorders associated with the respiratory system.
Objective:
Suicide risk in bipolar disorder (BD) is estimated to be up to 20 times higher than in the general population. While there is a large body of evidence suggesting that increased sympathetic activation is associated with disease and death, there is a paucity of research on the role of autonomic nervous system (ANS) dysfunction in patients with BD who have attempted suicide.
Methods:
Fifty-three participants with BD used a wearable device to assess the association between history of suicide attempt, current suicidal ideation, and ANS dysfunction, including measures of heart rate variability (HRV) and respiratory rate. Data were analyzed in a series of unadjusted and adjusted bivariate models of association controlling for relevant variables.
Results:
A history of suicide attempts was significantly associated with an increase in respiratory rate (p < 0.01). These results remained significant after adjusting for age, BMI, and current mood state. There was no association between current suicidal ideation and heart rate or respiratory rate. In the frequency domain, HRV parameters suggest reduced parasympathetic (i.e., vagal) activity in participants with a history of suicide attempts and in those with current suicidality, suggesting changes in sympathicovagal balance in BD.
Conclusions:
Our results suggest that changes in the ANS in patients with BD and a history of suicide attempt are not restricted to pure vagally mediated HRV parameters, but rather signal a general ANS dysregulation. This ANS imbalance may be contributing to illness burden and cardiovascular disease. Further research on the relationship between ANS and suicidality in BD is needed.
Grid cells in entorhinal cortex (EC) encode an individual’s location in space and rely on environmental cues and self-motion cues derived from the individual’s body. Body-derived signals are also primary signals for the sense of self and based on integrated sensorimotor signals (proprioceptive, tactile, visual, motor) that have been shown to enhance self-centered processing. However, it is currently unknown whether such sensorimotor signals that modulate self-centered processing impact grid cells and spatial navigation. Integrating the online manipulation of bodily signals, to modulate self-centered processing, with a spatial navigation task and an fMRI measure to detect grid cell-like representation (GCLR) in humans, we report improved performance in spatial navigation and decreased GCLR in EC. This decrease in entorhinal GCLR was associated with an increase in retrosplenial cortex activity, which was correlated with participants’ navigation performance. These data link self-centered processes during spatial navigation to entorhinal and retrosplenial activity and highlight the role of different bodily factors at play when navigating in VR. fMRI recordings from human participants manipulating a virtual avatar in a spatial navigation task show higher performance, but lower grid cell-like activity, compared to the navigation where no avatar is visible.
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.
Many interoceptive tasks (i.e. measuring the sensitivity to bodily signals) are based upon heartbeats perception. However, the temporal perception of heartbeats— when heartbeats are felt—varies among individuals. Moreover, the spatial perception of heartbeats— where on the body heartbeats are felt—has not been characterized in relation to temporal. This study used a multi-interval heartbeat discrimination task in which participants judged the timing of their own heartbeats in relation to external tones. The perception of heartbeats in both time and spatial domains, and relationship between these domains was investigated. Heartbeat perception occurred on average ~ 250 ms after the ECG R-wave, most frequently sampled from the left part of the chest. Participants’ confidence in discriminating the timing of heartbeats from external tones was maximal at 0 ms (tone played at R-wave). Higher confidence was related to reduced dispersion of sampling locations, but Bayesian statistics indicated the absence of relationship between temporal and spatial heartbeats perception. Finally, the spatial precision of heartbeat perception was related to state-anxiety scores, yet largely independent of cardiovascular parameters. This investigation of heartbeat perception provides fresh insights concerning interoceptive signals that contribute to emotion, cognition and behaviour.
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 utilized two datasets to test the Neurologic Pain Signature (the NPS), an established pain neuromarker. In Study 1, brain activity was measured using high-field functional magnetic resonance imaging (7T fMRI, N=40) during 5-25 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, though no direct comparisons with painful events were possible. Local NPS patterns in anterior/mid-insula, 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.
Rationale
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 to the high symptom load 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 multi-modal models of breathlessness in identifying behavioural phenotypes, and for advancing understanding of differences in breathlessness burden.
Interoception, the perception of bodily states, is thought to be inextricably linked to affective qualities such as anxiety. While 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 modelling and high-field (7 Tesla) fMRI to assess brain activity relating to dynamic changes in respiratory resistance of varying predictability. Notably, the anterior insula was associated with both interoceptive prediction certainty and prediction errors, suggesting an important role in representing and updating models of the body. Individuals with low vs. moderate anxiety traits showed differential anterior insula activity for prediction certainty. Multimodal analyses of data from fMRI, computational assessments of metacognition, and questionnaires demonstrated that anxiety-interoception links span all levels, from perceptual sensitivity to metacognition, with the largest effects seen at higher levels of interoceptive processes.
Surgical treatment of tumors, epileptic foci or of vascular origin, requires a detailed individual pre-surgical workup and intra-operative surveillance of brain functions to minimize the risk of post-surgical neurological deficits and decline of quality of life. Most attention is attributed to language, motor functions, and perception. However, higher cognitive functions such as social cognition, personality, and the sense of self may be affected by brain surgery. To date, the precise localization and the network patterns of brain regions involved in such functions are not yet fully understood, making the assessment of risks of related post-surgical deficits difficult. It is in the interest of neurosurgeons to understand with which neural systems related to selfhood and personality they are interfering during surgery. Recent neuroscience research using virtual reality and clinical observations suggest that the insular cortex, medial prefrontal cortex, and temporo-parietal junction are important components of a neural system dedicated to self-consciousness based on multisensory bodily processing, including exteroceptive and interoceptive cues (bodily self-consciousness (BSC)). Here, we argue that combined extra- and intra-operative approaches using targeted cognitive testing, functional imaging and EEG, virtual reality, combined with multisensory stimulations, may contribute to the assessment of the BSC and related cognitive aspects. Although the usefulness of particular biomarkers, such as cardiac and respiratory signals linked to virtual reality, and of heartbeat evoked potentials as a surrogate marker for intactness of multisensory integration for intra-operative monitoring has to be proved, systemic and automatized testing of BSC in neurosurgical patients will improve future surgical outcome.
The sensation that develops as a long breath hold continues is what this article is about. We term this sensation of an urge to breathe "air hunger." Air hunger, a primal sensation, alerts us to a failure to meet an urgent homeostatic need maintaining gas exchange. Anxiety, frustration, and fear evoked by air hunger motivate behavioral actions to address the failure. The unpleasantness and emotional consequences of air hunger make it the most debilitating component of clinical dyspnea, a symptom associated with respiratory, cardiovascular, and metabolic diseases. In most clinical populations studied, air hunger is the predominant form of dyspnea (colloquially, shortness of breath). Most experimental subjects can reliably quantify air hunger using rating scales, that is, there is a consistent relationship between stimulus and rating. Stimuli that increase air hunger include hypercapnia, hypoxia, exercise, and acidosis; tidal expansion of the lungs reduces air hunger. Thus, the defining experimental paradigm to evoke air hunger is to elevate the drive to breathe while mechanically restricting ventilation. Functional brain imaging studies have shown that air hunger activates the insular cortex (an integration center for perceptions related to homeostasis, including pain, food hunger, and thirst), as well as limbic structures involved with anxiety and fear. Although much has been learned about air hunger in the past few decades, much remains to be discovered, such as an accepted method to quantify air hunger in nonhuman animals, fundamental questions about neural mechanisms, and adequate and safe methods to mitigate air hunger in clinical situations. © 2021 American Physiological Society. Compr Physiol 11:1449-1483, 2021.
In this paper, we propose a new interface to control VR(Virtual reality) contents, games, and animations in real-time using the user’s breath and the acceleration sensor of a mobile device. Although interaction techniques are very important in VR and physically-based animations, UI(User interface) methods using different types of devices or controllers have not been covered. Most of the proposed interaction techniques have focused on screen touch and motion recognition. The direction of the breath is calculated using the position and angle between the user and the mobile device, and the control position to handle the contents is determined using the acceleration sensor built into the mobile device. Finally, to remove the noise contained in the input breath, the magnitude of the wind is filtered using a kernel modeling a pattern similar to the actual breath. To demonstrate the superiority of this study, we produced real-time interaction results by applying the breath as an external force of VR contents, games, and animations.
Grid cells in entorhinal cortex (EC) encode an individual’s location in space and rely on environmental cues and self-motion cues derived from the individual’s body. Body-derived signals are also primary signals for the sense of self as located in space (i.e. bodily self-consciousness, BSC). However, it is currently unknown whether BSC impacts grid cell activity and how such changes relate to experimental modulations of BSC. Integrating BSC with a spatial navigation task and an fMRI measure to detect grid cell-like representation (GCLR) in humans, we report a robust GCLR modulation in EC when participants navigated during an enhanced BSC state. These changes were further associated with improved spatial navigation performance and increased activity in posterior parietal and retrosplenial cortex. These data link entorhinal grid cell activity with BSC and show that BSC modulates ego-versus allocentric spatial processes about an individual’s location in space in a distributed spatial navigation system.
Background
Patients with chronic obstructive pulmonary disease (COPD) are prone to dyspnea, increased respiratory rate and other anxiety-inducing symptoms. Hypnosis constitutes a complementary procedure capable of improving subjective feelings of anxiety.
Objective
Assessing the efficacy of a 15-minute hypnosis intervention for immediate improvement of anxiety in severe COPD patients.
Methods
Twenty-one participants, COPD patients (mean FEV1 < 32.3%), were randomly assigned to two individual sessions in crossover (sham and hypnosis, 24-h washout period, arms: hypnosis-sham [n=11]/sham-hypnosis [n=10]). We tracked pre- and post-intervention anxiety (STAI-6 score) as primary endpoint.
Results
Nineteen (90.5%) participants completed the study. Anxiety diminished significantly after hypnosis (STAI-6 scores −23.8% [SD = 18.4%] hypnosis vs −3.1% [32.8%] sham; χ²=8, P<0.01, Bayes Factor 5.5). Respiratory rate also decreased after hypnosis. Improvements in SpO2 and Borg exertion scores were registered after both conditions.
Conclusion
A 15-minute hypnosis session improved participants’ anxiety and lowered respiratory rate (as opposed to sham). Improvements in anxiety were correlated with an alleviation in respiratory strain. Results imply that hypnosis can contribute to the improvement of anxiety levels and breathing mechanics in severe COPD patients.
Registration Id
ISRCTN10029862.
Immersive virtual reality is transforming medical and psychological research and treatment, including the treatment of clinical pain. In this short perspective paper, we present some of the methodological difficulties that are rarely discussed in the literature of pain research when using virtual reality. These often-unmentioned problems can confound research investigations or interfere with the therapeutic efficacy in clinical trials. We propose practical solutions based on our research experience. We first outline the mechanisms of, and challenges to, the sensations of embodiment and presence, which are critical to creating effective virtual reality illusions, before discussing the particular considerations that need to be contemplated when working with patients with clinical pain. Finally, we discuss some upcoming technological advances that may influence significantly this rapidly expanding field in the near future.
Following the interoceptive inference framework, we set out to replicate our previously reported association of self-control and interoceptive prediction and strived to investigate the neural underpinnings subserving the relationship between self-control and aversive interoceptive predictive models. To this end, we used fMRI and a within-subject design including an inspiratory breathing-load task to examine the prediction of aversive interoceptive perturbation and a craving-regulation for palatable foods task to measure self-control. In this current study, we could successfully replicate previous effects with an independent sample (n=39) and observed that individuals who ‘over-estimated’ their upcoming interoceptive state with respect to experienced dyspnea (i.e., anticipated versus experienced) were more effective in the down-regulation of craving using negative future-thinking strategies. These individuals, again, obtained higher scores on a measure of trait self-control, i.e. self-regulation to achieve long-term goals. On a neural level, we found evidence that the anterior insula (AI) and the presupplementary motor area (preSMA), which were recruited in both tasks, partly accounted for these effects. Specifically, levels of AI activation during the anticipation of the aversive interoceptive state (breathing restriction) were associated with self-controlled behavior in the craving task, whereas levels of interoceptive prediction during the breathing task were conversely associated with activation in preSMA during the down-regulation of craving, whose anticipatory activity was correlated with self-control success. Moreover, during the self-control task, levels of interoceptive prediction were associated with connectivity in a spatially distributed network including among other areas the insula and regions of cognitive control, while during the interoceptive prediction task, levels of self-control were associated with connectivity in a spatially distributed network including among other regions the insula and preSMA. In sum, these findings consolidate the notion that self-control is directly linked to interoceptive inference and highlight the contribution of AI and preSMA as candidate regions underlying this relationship possibly creating processing advantages in self-control situations referring to the prediction of future internal states.
Previous studies investigated bodily self-consciousness (BSC) by experimentally exposing subjects to multisensory conflicts (i.e., visuo-tactile, audio-tactile, visuo-cardiac) in virtual reality (VR) that involve the participant's torso in a paradigm known as the full-body illusion (FBI). Using a modified FBI paradigm, we found that synchrony of visuo-respiratory stimulation (i.e., a flashing outline surrounding an avatar in VR; the flash intensity depending on breathing), is also able to modulate BSC by increasing self-location and breathing agency toward the virtual body. Our aim was to investigate such visuo-respiratory effects and determine whether respiratory motor commands contributes to BSC, using non-invasive mechanical ventilation (i.e., machine-delivered breathing). Seventeen healthy participants took part in a visuo-respiratory FBI paradigm and performed the FBI during two breathing conditions: (a) "active breathing" (i.e., participants actively initiate machine-delivered breaths) and (b) "passive breathing" (i.e., breaths' timing was determined by the machine). Respiration rate, tidal volume, and their variability were recorded. In line with previous results, participants experienced subjective changes in self-location, breathing agency, and self-identification toward the avatar's body, when presented with synchronous visuo-respiratory stimulation. Moreover, drift in self-location was reduced and tidal volume variability were increased by asynchronous visuo-respiratory stimulations. Such effects were not modulated by breathing control manipulations. Our results extend previous FBI findings showing that visuo-respiratory stimulation affects BSC, independently from breathing motor command initiation. Also, variability of respiratory parameters was influenced by visuo-respiratory feedback and might reduce breathing discomfort. Further exploration of such findings might inform the development of respiratory therapeutic tools using VR in patients.
Voluntary action is a fundamental element of self-consciousness. The readiness potential (RP), a slow drift of neural activity preceding self-initiated movement, has been suggested to reflect neural processes underlying the preparation of voluntary action; yet more than fifty years after its introduction, interpretation of the RP remains controversial. Based on previous research showing that internal bodily signals affect sensory processing and ongoing neural activity, we here investigated the potential role of interoceptive signals in voluntary action and the RP. We report that (1) participants initiate voluntary actions more frequently during expiration, (2) this respiration-action coupling is absent during externally triggered actions, and (3) the RP amplitude is modulated depending on the respiratory phase. Our findings demonstrate that voluntary action is coupled with the respiratory system and further suggest that the RP is associated with fluctuations of ongoing neural activity that are driven by the involuntary and cyclic motor act of breathing. Voluntary action and free will have been associated with cortical activity, referred to as “the readiness potential” that precedes self-initiated actions by about 1 s. Here, the authors show that the involuntary and cyclic motor act of breathing is coupled with voluntary action and the readiness potential.
We compared the perception and neural processing of respiratory sensations between 20 COPD patients and 20 healthy controls by means of respiratory-related evoked potentials (RREP) in the electroencephalogram (EEG). RREPs were induced by short inspiratory occlusions while 129-channel EEG was measured. COPD patients rated the occlusions as more intense and unpleasant (p’s < 0.001) and showed higher mean amplitudes for the RREP components P1 (p = 0.0004), N1 (p = 0.024), P2 (p = 0.019), and P3 (p = 0.018). Our results indicate that COPD patients demonstrate greater perception and neural processing of respiratory sensations, which presumably reflects the highly aversive and attention-demanding character of these sensations for COPD patients.
Recent theories posit that physiological signals contribute to corporeal awareness, the basic feeling that one has a body (body ownership) that acts according to one’s will (body agency) and occupies a specific position (body location). Combining physiological recordings with immersive virtual reality, we found that an ecological mapping of real respiratory patterns onto a virtual body illusorily changes corporeal awareness. This new way of inducing a respiratory bodily illusion, called “embreathment,” revealed that breathing is almost as important as visual appearance for inducing body ownership and more important than any other cue for body agency. These effects were moderated by individual levels of interoception, as assessed through a standard heartbeat-counting task and a new “pneumoception” task. By showing that respiratory, visual, and spatial signals exert a specific and weighted influence on the fundamental feeling that one is an embodied agent, we pave the way for a comprehensive hierarchical model of corporeal awareness.
NEW & NOTEWORTHY Our body is the only object we sense from the inside; however, it is unclear how much inner physiology contributes to the global sensation of having a body and controlling it. We combine respiration recordings with immersive virtual reality and find that making a virtual body breathe like the real body gives an illusory sense of ownership and agency over the avatar, elucidating the role of a key physiological process like breathing in corporeal awareness.
Respiratory sensations such as breathlessness are prevalent in many diseases and are amplified by increased levels of anxiety. Cortical activation in response to inspiratory occlusions in high- and low-anxious individuals was found different in previous studies using the respiratory-related evoked potential method. However, specific brain areas showed different activation patterns remained unknown in these studies. Therefore, the purpose of this study was to compare cortical and subcortical neural substrates of respiratory sensation in response to inspiratory mechanical occlusion stimuli between high- and low-anxious individuals using functional magnetic resonance imaging (fMRI). In addition, associations between brain activation patterns and levels of anxiety, and breathlessness were examined. Thirty-four (17 high- and 17 low-anxious) healthy non-smoking adults with normal lung function completed questionnaires on anxiety (State Trait Anxiety Inventory - State), and participated in a transient inspiratory occlusion fMRI experiment. The participants breathed with a customized face-mask while respiration was repeatedly interrupted by a transient inspiratory occlusion of 150-msec, delivered every 2 to 4 breaths. Breathlessness was assessed by self-report. At least 32 occluded breaths were collected for data analysis. The results showed that compared to the low-anxious group, the high-anxious individuals demonstrated significantly greater neural activations in the hippocampus, insula, and middle cingulate gyrus in response to inspiratory occlusions. Moreover, a significant relationship was found between anxiety levels and activations of the right inferior parietal gyrus, and the right precuneus. Additionally, breathlessness levels were significantly associated with activations of the bilateral thalamus, bilateral insula and bilateral cingulate gyrus. The above evidences support stronger recruitment of emotion-related cortical and subcortical brain areas in higher anxious individuals, and thus these areas play an important role in respiratory mechanosensation mediated by anxiety.
A significant body of experimental evidence has demonstrated that it is possible to induce the illusion of ownership of a fake limb or even an entire fake body using multisensory correlations. Recently, immersive virtual reality has allowed users to experience the same sensations of ownership over a virtual body inside an immersive virtual environment, which in turn allows virtual reality users to have the feeling of being “embodied” in a virtual body. Using such virtual embodiment to manipulate body perception is starting to be extensively investigated and may have clinical implications for conditions that involve altered body image such as chronic pain. Here, we review experimental and clinical studies that have explored the manipulation of an embodied virtual body in immersive virtual reality for both experimental and clinical pain relief. We discuss the current state of the art, as well as the challenges faced by, and ideas for, future research. Finally, we explore the potentialities of using an embodied virtual body in immersive virtual reality in the field of neurorehabilitation, specifically in the field of pain.
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.
Increasing evidence points to the role of interoception in body perception and in constructing the bodily self. Body ownership illusion (BOI) in virtual reality (VR) is a widely used paradigm to study body perception. However, existing research has focused mainly on exteroceptive sensory modalities, and studies on interoception and BOI remain scarce. The postulated mechanism of BOI is related to the multisensory integration of information and visuo-tactile or visuo-kinesthetic sensory conflict resolution. In this within-subjects experimental study, we introduced systematic visuo-interoceptive (visuo-respiratory) conflicts and tested if participants would resolve them by adjusting their respiration rate (RR). Participants observed a virtual breathing avatar body from the first-person perspective while their own RR was recorded. The VR system was connected to a respiration monitor. The avatar was first breathing for 60 seconds in accordance with the participant's RR; then, it was either slowing down or speeding up, each condition lasting for 180 seconds. The dependent variable was changed in participants' RR, expressed as a linear regression slope coefficient. Forty participants were included in each experimental condition, in a counterbalanced order. There was a change in RR in the predicted direction in both conditions. Participants' RR decreased on average by 0.48 breaths/minute and increased by 0.64 breaths/minute, leading to a change of 1.45 and 1.93 breaths/minute, respectively, over the entire timespan of the experiment. The difference between conditions was statistically significant (V = 192, p < 0.01). Because a change in RR of even 1 breath/minute is considered clinically significant, the results of this study-apart from demonstrating visuo-respiratory conflict resolution-may have an applied significance.
The maintenance of upright balance in healthy humans requires the preservation of a horizontal gaze, best achieved through dynamical adjustments of spinal curvatures and a pelvic tilt that keeps the head-to-pelvis alignment close to vertical. It is currently unknown whether the spinal and pelvic compensations of respiratory-related postural perturbations are associated with preservation of the head-to-pelvis vertical alignment. We tested this hypothesis by comparing postural alignment variables at extreme lung volume (total lung capacity, TLC; residual volume, RV) with their reference value at functional residual capacity (FRC). Forty-eight healthy subjects [22 women; median age of 34 (26; 48) years] were studied using low dose biplanar X-rays (BPXR; EOS®system). Personalized three-dimensional models of the spine and pelvis were reconstructed at the three lung volumes. Extreme lung volumes were associated with changes of thoracic curvature bringing it outside the normal range. Maximal inspiration reduced thoracic kyphosis [T1–T12 angle = 47° (37; 56), -4° variation (-9; 1), p = 0.0007] while maximal expiration induced hyperkyphosis [T1–T12 angle = 63° (55; 68); +10° variation (5; 12), p = 9 × 10-12]. Statistically significant (all p < 0.01) cervical and pelvic compensatory changes occurred [C3–C7 angle: +4° (-2; 11) and pelvic tilt +1° (0; 3) during maximal inspiration; C3–C7 angle: -7° (-18; -1) and pelvic tilt +5° (1; 8) during maximal expiration], resulting in preserved head-to-pelvis alignment (no change in the angle between the vertical plane and the line connecting the odontoid process and the midpoint of the line connecting the center of the two femoral heads ODHA). Lung volume related postural perturbations were more marked as a function of age, but age did not affect the head-to-pelvis alignment. These findings should help understand balance alterations in patients with chronic respiratory diseases that modify lung volume and rib cage geometry.
Significance
Breathing is a vital rhythmic behavior that originates from neural networks within the brainstem. It is hypothesized that the breathing rhythm is generated by spatially distinct networks localized to discrete kernels or compartments. Here, we provide evidence that the functional boundaries of these compartments expand and contract dynamically based on behavioral or physiological demands. The ability of these rhythmic networks to change in size may allow the breathing rhythm to be very reliable, yet flexible enough to accommodate the large repertoire of mammalian behaviors that must be integrated with breathing.
Context:
Dyspnea is a common and distressing symptom in respiratory diseases. Despite advances in the treatment of various lung diseases, the treatment modalities for dyspnea remain limited.
Objectives:
This study aims to examine the effect of 20-minute mindful breathing on the rapid reduction of dyspnea at rest in patients with lung cancer, chronic obstructive pulmonary disease, and asthma.
Methods:
We conducted a parallel-group, nonblinded, randomized controlled trial of standard care plus 20-minute mindful breathing vs. standard care alone for patients with moderate to severe dyspnea due to lung disease, named previously, at the respiratory unit of University Malaya Medical Centre in Malaysia, from August 1, 2017, to March 31, 2018.
Results:
Sixty-three participants were randomly assigned to standard care plus a 20-minute mindful breathing session (n = 32) or standard care alone (n = 31), with no difference in their demographic and clinical characteristics. There was statistically significant reduction in dyspnea in the mindful breathing group compared with the control group at minute 5 (U = 233.5, n1 = 32, n2 = 31, mean rank1 = 23.28, mean rank2 = 37.72, z = -3.574, P < 0.001) and minute 20 (U = 232.0, n1 = 32, n2 = 31, mean rank1 = 23.00, mean rank2 = 36.77, z = -3.285, P = 0.001).
Conclusion:
Our results provide evidence that a single session of 20-minute mindful breathing is effective in reducing dyspnea rapidly for patients with lung cancer, chronic obstructive pulmonary disease, and asthma.
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 and subcortical mechanosensation of breathing can be measured by short respiratory occlusions. However, the corresponding neural substrates involved in the respiratory sensation elicited by a respiratory mechanical stimulus remained unclear. Therefore, we applied the functional magnetic resonance imaging (fMRI) technique to study cortical activations of respiratory mechanosensation. We hypothesized that thalamus, frontal cortex, somatosensory cortex, and inferior parietal cortex would be significantly activated in response to respiratory mechanical stimuli. We recruited 23 healthy adults to participate in our event-designed fMRI experiment. During the 12-min scan, participants breathed with a specialized face-mask. Single respiratory occlusions of 150 ms were delivered every 2–4 breaths. At least 32 successful occlusions were collected for data analysis. The results showed significant neural activations in the thalamus, supramarginal gyrus, middle frontal gyrus, inferior frontal triangularis, and caudate (AlphaSim corrected p < 0.05). In addition, subjective ratings of breathlessness were significantly correlated with the levels of neural activations in bilateral thalamus, right caudate, right supramarginal gyrus, left middle frontal gyrus, left inferior triangularis. Our results demonstrated cortical sources of respiratory sensations elicited by the inspiratory occlusion paradigm in healthy adults were located in the thalamus, supramarginal gyrus, and the middle frontal cortex, inferior frontal triangularis, suggesting subcortical, and cortical neural sources of the respiratory mechanosensation are thalamo-cortical based, especially the connections to the premotor area, middle and ventro-lateral prefrontal cortex, as well as the somatosensory association cortex. Finally, level of neural activation in thalamus is associated with the subjective rating of breathlessness, suggesting respiratory sensory information is gated at the thalamic level.
To our knowledge, this is the first study exploring the interferences between inspiratory loading and cognition in healthy subjects with the concomitant use of neuropsychological tests and electroencephalographic recordings. Inspiratory loading was associated with dyspnea, respiratory-related changes in brain activation, and a pattern of deterioration of neuropsychological tests suggestive of attentional disruption. Inspiratory loading is therefore likely to impact cognitive performances through both motor-cognitive interference (engagement of cortical networks) and sensory-cognitive interference (dyspnea-related shift in attentional focus).
Background
Immersive virtual reality (iVR)-based digital therapeutics (DTx) are gaining clinical attention in the field of pain management. Based on known analogy between chronic pain and dyspnea, we investigated the effects of visual respiratory feedback in iVR, on refractory breathlessness in patients recovering from severe COVID-19 pneumonia.
Methods
We performed a controlled, randomized, single-blind, cross-over clinical study to evaluate an iVR-based intervention to alleviate refractory breathlessness in patients recovering from COVID-19 pneumonia. The single-site study was conducted at the university hospital of Geneva, Switzerland. Patients reported refractory breathlessness (≥5 on a 10-point dyspnea scale) and had a MoCA score of ≥24. Cross-over groups were randomly assigned, concealed from the referring clinician. Participants received synchronous (intervention) or asynchronous (control) feedback of their breathing, embodied via a gender-matched avatar in iVR. Prior to the first exposure and following both experimental conditions, patients completed questionnaires. Breathing patterns were captured continuously. The COVVR clinical study is registered with ClinicalTrials.gov ( NCT04844567 ) and is now closed.
Findings
Study enrollment was open between November 2020 and April 2021. A total of 26 patients (27% women; age: mean=57, SD±12) were enrolled; 14 patients were randomly assigned to the “synchronous/asynchronous” sequence, 12 to the “asynchronous/synchronous” sequence. Data was available for all except two (7.7%) of 26 patients. The mean rating of breathing comfort was 0.1 at baseline, 0.8±1.8 for asynchronous, and 1.3±1.4 synchronous feedback (estimated difference of 0.5 (95%CI 0.05 to 1.04; p<0.05) between iVR conditions). Of all patients, 91.2% were satisfied with the intervention (1.8±1.6, t=5.201, p<0.0001, 95%CI 1.173 to inf) and 66.7% perceived it as beneficial for their breathing (0.7±1.9, t=1.806, p<0.05, 95%CI 0.036 to inf). No adverse events were reported.
Interpretation
Based on these findings, we propose that our iVR-based DTx is a feasible and safe neuro-rehabilitation tool that improves breathing comfort in patients recovering from severe COVID-19 infection. More research is needed to generalize this tool in other groups of patients suffering from refractory breathlessness.
Funding
Marie Skłodowska-Curie Individual Fellowship (H2020-MSCA-IF-2019 894111/ RESPVR), Bertarelli Foundation
Dyspnea or breathlessness is a symptom occurring in multiple acute and chronic illnesses, however, the understanding of the neural mechanisms underlying its subjective experience is limited. In this topical review, we propose neural oscillatory dynamics and cross-frequency coupling as viable candidates for a neural mechanism underlying respiratory perception, and a technique warranting more attention in respiration research. With the evidence for the potential of neural oscillations in the study of normal and disordered breathing coming from disparate research fields with a limited history of interdisciplinary collaboration, the main objective of the review was to converge the existing research and suggest future directions. The existing findings show that distinct limbic and cortical activations, as measured by hemodynamic responses, underlie dyspnea, however, the time-scale of these activations is not well understood. The recent findings of oscillatory neural activity coupled with the respiratory rhythm could provide the solution to this problem, however, more research with a focus on dyspnea is needed. We also touch on the findings of distinct spectral patterns underlying the changes in breathing due to experimental manipulations, meditation and disease. Subsequently, we suggest general research directions and specific research designs to supplement the current knowledge using neural oscillation techniques. We argue for the benefits of interdisciplinary collaboration and the converging of neuroimaging and behavioral methods to best explain the emergence of the subjective and aversive individual experience of dyspnea.
Nasal breathing generates a rhythmic signal which entrains cortical network oscillations in widespread brain regions on a cycle-to-cycle time scale. It is unknown, however, how respiration and neuronal network activity interact on a larger time scale: are breathing frequency and typical neuronal oscillation patterns correlated? Is there any directionality or temporal relationship? To address these questions, we recorded field potentials from the posterior parietal cortex of mice together with respiration during REM sleep. In this state, the parietal cortex exhibits prominent θ and γ oscillations while behavioral activity is minimal, reducing confounding signals. We found that the instantaneous breathing frequency strongly correlates with the instantaneous frequency and amplitude of both θ and γ oscillations. Cross-correlograms and Granger causality revealed specific directionalities for different rhythms: changes in θ activity precede and Granger-cause changes in breathing frequency, suggesting control by the functional state of the brain. On the other hand, the instantaneous breathing frequency Granger causes changes in γ frequency, suggesting that γ is influenced by a peripheral reafference signal. These findings show that changes in breathing frequency temporally relate to changes in different patterns of rhythmic brain activity. We hypothesize that such temporal relations are mediated by a common central drive likely to be located in the brainstem.
Introduction
. The ventral premotor area (VPM) plays a crucial role in executing various aspects of motor control. These include hand reaching, joint coordination, and direction of movement in space. While many studies discuss the VPM and its relationship to the rest of the motor network, there is minimal literature examining the connectivity of the VPM outside of the motor network. Using region-based fMRI studies, we built a neuroanatomical model to account for these extra-motor connections.
Methods.
Thirty region-based fMRI studies were used to generate an activation likelihood estimation (ALE) using BrainMap software. Cortical parcellations overlapping the ALE were used to construct a preliminary model of the VPM connections outside the motor network. Diffusion spectrum imaging (DSI)-based fiber tractography was performed to determine the connectivity between cortical parcellations in both hemispheres, and a laterality index (LI) was calculated with resultant tract volumes. The resulting connections were described using the cortical parcellation scheme developed by the Human Connectome Project (HCP).
Results.
Four cortical regions were found to comprise the VPM. These four regions included 6v, 4, 3b, and 3a. Across mapped brains, these areas showed consistent interconnections between each other. Additionally, ipsilateral connections to the primary motor cortex, supplementary motor area, and dorsal premotor cortex were demonstrated. Inter-hemispheric asymmetries were identified, especially with areas 1, 55b, and MI connecting to the ipsilateral VPM regions.
Conclusion.
We describe a preliminary cortical model for the underlying connectivity of the ventral premotor area. Future studies should further characterize the neuroanatomic underpinnings of this network for neurosurgical applications.
Cues such as odours that do not per se evoke bronchoconstriction can become triggers of asthma exacerbations. Despite its clinical significance, the neural basis of this respiratory nocebo effect is unknown.
We investigated this effect in a functional magnetic resonance imaging (fMRI) study involving 36 healthy volunteers. The experiment consisted of an experience phase in which volunteers experienced dyspnoea while being exposed to an odorous gas (“Histarinol”). Volunteers were told that Histarinol induces dyspnoea by bronchoconstriction. This was compared with another odorous gas which did not evoke dyspnoea. Dyspnoea was actually induced by a concealed, resistive load inserted into the breathing system. In a second, expectation phase, Histarinol and the control gas were both followed by an identical, very mild load. Respiration parameters were continuously recorded and participants rated dyspnoea intensity after each trial.
Dyspnoea ratings were significantly higher in Histarinol compared with control conditions, both in the experience and in the expectation phase, despite identical physical resistance in the expectation phase. Insula fMRI signal matched the actual load, i.e. a significant difference between Histarinol and control in the experience phase, but no difference in the expectation phase. The periaqueductal gray showed a significantly higher fMRI signal during the expectation of dyspnoea. Finally, Histarinol-related deactivations during the expectation phase in the rostral anterior cingulate cortex mirrored similar responses for nocebo effects in pain.
These findings highlight the neural basis of expectation effects associated with dyspnoea, which has important consequences for our understanding of the perception of respiratory symptoms.
Spinal cord stimulation (SCS) is an approved treatment for truncal and limb neuropathic pain. However, pain relief is often suboptimal and SCS efficacy may reduce over time, requiring sometimes the addition of other pain therapies, stimulator revision, or even explantation. We designed and tested a new procedure by combining SCS with immersive virtual reality (VR) to enable analgesia in patients with chronic leg pain. We coupled SCS and VR by linking SCS-induced paresthesia with personalized visual bodily feedback that was provided by VR and matched to the spatiotemporal patterns of SCS-induced paresthesia. In this cross-sectional prospective interventional study, 15 patients with severe chronic pain and an SCS implant underwent congruent SCS-VR (personalized visual feedback of the perceived SCS-induced paresthesia displayed on the patient's virtual body) and 2 control conditions (incongruent SCS-VR and VR alone). We demonstrate the efficacy of neuromodulation-enhanced VR for the treatment of chronic pain by showing that congruent SCS-VR reduced pain ratings on average by 44%. Spinal cord stimulation–VR analgesia was stronger than that in both control conditions (enabling stronger analgesic effects than incongruent SCS-VR analgesia or VR alone) and kept increasing over successive stimulations, revealing the selectivity and consistency of the observed effects. We also show that analgesia persists after congruent SCS-VR had stopped, indicating carry over effects and underlining its therapeutic potential. Linking latest VR technology with recent insights from the neuroscience of body perception and SCS neuromodulation, our personalized new SCS-VR platform highlights the impact of immersive digiceutical therapies for chronic pain.
Registration: clinicaltrials.gov, Identifier: NCT02970006.
Neural gating is a phenomenon whereby the response to a stimulus in the electroencephalogram (EEG) is attenuated when preceded by an identical stimulus. Attenuation of paired auditory clicks has repeatedly been shown to be affected in mental disorders, e.g. schizophrenia. Neural gating has also been measured for respiratory and somatosensory sensations, however the attenuation of bodily-relevant stimuli has not yet been systematically related to the subjective perception of bodily sensations. This research direction is potentially relevant to explaining disease trajectories in psychosomatic conditions characterized by chronic breathlessness and/or pain. In the present study, we recorded high-density EEG from 85 healthy young adults while they experienced brief paired respiratory occlusions and brief paired electrocutaneous stimulation of the wrist. The event-related potential N1 was measured centro-laterally in response to the second relative to the first stimulus to quantify neural gating in both sensory domains. Participants experienced resistive loaded breaths and electrocutaneous stimuli of various intensities, rated their perceived intensity and unpleasantness, and performed magnitude estimation. Relationships of respiratory and somatosensory neural gating to the subjective intensity and unpleasantness of sensations, as well as the ability to discriminate sensations of varying intensities, were investigated intra-modally and cross-modally. We report significant relationships of the somatosensory neural gating to perceived intensity and unpleasantness of respiratory and somatosensory sensations, with the stronger neural gating relating to a stronger subjective intensity and unpleasantness. We discuss these unexpected findings through the lens of individual differences and different theoretical accounts on the origins of cortical attenuation of repetitive stimuli.
This brief review provides a summary of existing research on virtual reality (VR) applications to pain. We distinguish three categories of studies - VR applications to clinical acute pain, chronic pain, and acute experimental pain, which are currently equally represented in the literature. The review highlights specific advancements in VR pain research as well as areas in need of more development in scrutiny. In particular, we note the pressing need for theoretical scaffolding to facilitate replicable, theoretically-driven methodology, communication, and advancements across the field. To that end, we provide a preliminary heuristic model of VR application to pain experience. The model distinguishes three categories of factors inherent in VR application to pain: VR Configuration Factors, User Experiential Factors, and Pain Targets and Outcomes. VR Configuration Factors comprise technical input devices, system processes, and output devices, which present a virtual world to the user and enable User Experiential Factors of presence, interactivity, immersion, and embodiment. These interdependent experiential factors serve as potential mediators and moderators for subsequent changes in cognitive, emotional, social, behavioral, and physiological outcomes that serve as Targets of pain-related therapy. Given that rapid technological progress can both facilitate and frustrate research progress within the field, systematic, theoretically-informed inquiry into factors comprising and driving the effects of VR pain applications, combined with more rigorous theoretically-informed methodology, is a critical challenge.
Importance
Morphine is used as palliative treatment of chronic breathlessness in patients with advanced chronic obstructive pulmonary disease (COPD). Evidence on respiratory adverse effects and health status is scarce and conflicting.
Objective
To assess the effects of regular, low-dose, oral sustained-release morphine on disease-specific health status (COPD Assessment Test; CAT), respiratory outcomes, and breathlessness in patients with COPD.
Interventions
Participants were randomly assigned to 10 mg of regular, oral sustained-release morphine or placebo twice daily for 4 weeks, with the possibility to increase to 3 times daily after 1 or 2 weeks.
Design, Setting, and Participants
The Morphine for Treatment of Dyspnea in Patients With COPD (MORDYC) study was a randomized, double-blind, and placebo-controlled study of a 4-week intervention. Patients were enrolled between November 1, 2016, and January 24, 2019. Participants were recruited in a pulmonary rehabilitation center and 2 general hospitals after completion of a pulmonary rehabilitation program. Outpatients with COPD and moderate to very severe chronic breathlessness (modified Medical Research Council [mMRC] breathlessness grades 2-4) despite optimal pharmacological and nonpharmacological treatment were included. A total of 1380 patients were screened, 916 were ineligible, and 340 declined to participate.
Main Outcomes and Measures
Primary outcomes were CAT score (higher scores represent worse health status) and arterial partial pressure of carbon dioxide (Paco2). Secondary outcome was breathlessness in the previous 24 hours (numeric rating scale). Data were analyzed by intention to treat. Subgroup analyses in participants with mMRC grades 3 to 4 were performed.
Results
A total of 111 of 124 included participants were analyzed (mean [SD] age, 65.4 [8.0] years; 60 men [54%]). Difference in CAT score was 2.18 points lower in the morphine group (95% CI, –4.14 to –0.22 points; P = .03). Difference in Paco2 was 1.19 mm Hg higher in the morphine group (95% CI, –2.70 to 5.07 mm Hg; P = .55). Breathlessness remained unchanged. Worst breathlessness improved in participants with mMRC grades 3 to 4 (1.33 points lower in the morphine group; 95% CI, –2.50 to –0.16 points; P = .03). Five participants of 54 in the morphine group (9%) and 1 participant of 57 in the placebo group (2%) withdrew because of adverse effects. No morphine-related hospital admissions or deaths occurred.
Conclusions and Relevance
In this randomized clinical trial, regular, low-dose, oral sustained-release morphine for 4 weeks improved disease-specific health status in patients with COPD without affecting Paco2 or causing serious adverse effects. The worst breathlessness improved in participants with mMRC grades 3 to 4. A larger randomized clinical trial with longer follow-up in patients with mMRC grades 3 to 4 is warranted.
Trial Registration
ClinicalTrials.gov Identifier: NCT02429050
Telemedicine could be a key to control the world-wide disruptive and spreading novel coronavirus disease (COVID-19) pandemic. The COVID-19 virus directly targets the lungs, leading to pneumonia-like symptoms and shortness of breath with life-threatening consequences. Despite the fact that self-quarantine and social distancing are indispensable during the pandemic, the procedure for testing COVID-19 contraction is conventionally available through nasal swabs, saliva test kits, and blood work at healthcare settings. Therefore, devising personalized self-testing kits for COVID-19 virus and other similar viruses is heavily admired. Many e-health initiatives have been made possible by the advent of smartphones with embedded software, hardware, high-performance computing, and connectivity capabilities. A careful review of breathing sounds and their implications in identifying breathing complications suggests that the breathing sounds of COVID-19 contracted users may reveal certain acoustic signal patterns, which is worth investigating. To this end, acquiring respiratory data solely from breathing sounds fed to the smartphone's microphone strikes as a very appealing resolution. The acquired breathing sounds can be analyzed using advanced signal processing and analysis in tandem with new deep/machine learning and pattern recognition techniques to separate the breathing phases, estimate the lung volume, oxygenation, and to further classify the breathing data input into healthy or unhealthy cases. The ideas presented have the potential to be deployed as self-test breathing monitoring apps for the ongoing global COVID-19 pandemic, where users can check their breathing sound pattern frequently through the app.
The neuroanatomy that supports the act of normal breathing consists of a central neural network of inspiratory and expiratory neurons that project to spinal and brainstem motor nuclei that ultimately innervate the respiratory muscles (diaphragm, intercostals, abdominal, and upper airway). This central neural network receives afferent feedback from sensors that monitor the mechanical effectiveness of lung expansion (mechanoreceptors) and the adequacy of arterial oxygen and carbon dioxide levels (chemoreceptors). The integrated respiratory neural drive is adjusted to accomplish a wide range of reflex activities, from sleep to exercise, as well as voluntary maneuvers such as vocalization or breath holding. The optimization of respiration to meet these various demands is accomplished by the respiratory neural control system, which initiates a respiratory rhythm (central pattern generator located within the brainstem) that is modulated by afferent information from the sensors and other higher brain centers into an integrated neural output to respiratory muscles. A number of clinical disorders produce abnormal breathing patterns. The causes of the neuropathology can be disease linked or genetic. The abnormal pattern that is produced depends on the location of the defect within the respiratory network and can result in failure to breathe or altered breathing patterns.
Background
The dorsal premotor area (DPM) plays an important role in hand coordination and muscle recruitment for lifting activities. Lesions in the area have demonstrated that the DPM is critical in the integration of movements that require combinations of reaching, grasping, and lifting. While many have looked at its functional connectivity, few studies have shown the full anatomical connectivity of DPM including its connections beyond the motor network. Using region-based fMRI studies, we built a neuroanatomical model to account for these extra-motor connections.
Objective
In this study, we performed meta-analysis and tractography with the goal of creating a map of the dorsal premotor network using the Human Connectome Project parcellation scheme nomenclature (i.e. the Glasser Atlas). While there are other possible ways to map this, we feel that it is critical that neuroimaging begin to move towards all of its data expressed in a single nomenclature which can be compared across studies, and a potential framework that we can build upon in future studies.
Methods
Thirty region-based fMRI studies were used to generate an activation likelihood estimation (ALE) using BrainMap software (Research Imaging Institute of Texas Health Science Center San Antonio). Cortical parcellations overlapping the ALE were used to construct a preliminary model of the Dorsal Premotor Area. Diffusion spectrum imaging (DSI) based tractography was performed to determine the connectivity between cortical parcellations and connections throughout cortex. The resulting connectivities were described using the cortical parcellation scheme developed by the Human Connectome Project (HCP).
Results
Three left hemisphere regions were found to comprise the Dorsal Premotor Area. These included areas 6a, 6d. and 6v, Across mapped brains, these areas showed consistent interconnections between each other. Additionally, ipsilateral connections to the premotor cortex, sensorimotor cortex, superior and inferior parietal lobule, middle and inferior frontal gyrus, and insula were demonstrated. Connections to the contralateral supplementary motor area and premotor cortex were also identified.
Conclusions
We describe a preliminary cortical model for the underlying structural connectivity of the Dorsal Premotor Area. Future studies should further characterize the neuroanatomic underpinnings of this network.
Background
Chronic respiratory diseases are associated with cognitive dysfunction, but whether dyspnea by itself negatively impacts on cognition has not been demonstrated. Cortical networks engaged in subjects experiencing dyspnea are also activated during other tasks that require cognitive input and may provoke a negative impact through interference with each other.
Methods
This crossover randomised trial investigated whether experimentally-induced dyspnea would negatively impact on locomotion and cognitive function among 40 healthy adults. Crossover conditions were unloaded breathing or loaded breathing using an inspiratory threshold load. To evaluate locomotion, participants were assessed by the Timed Up and Go test. Cognitive function was assessed by categorical and phonemic verbal fluency tests, the Trail Making Test A and B (executive function), the CODE test from the WAIS-IV (processing speed), and by direct and indirect digit span (working memory).
Results
The mean time difference to perform the Timed Up and Go test between unloaded and loaded breathing was −0.752 s (−1.012 to −0.492; p<0.001). Executive function, processing speed and working memory performed better during unloaded breathing, particularly for subjects starting first with the loaded breathing condition.
Conclusion
Our data suggest that respiratory threshold loading to elicit dyspnea had a major impact on locomotion and cognitive function in healthy adults.
Background:
Seizure-induced inhibition of respiration plays a critical role in sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying seizure-induced central apnea in pediatric epilepsy are unknown.
Methods:
We studied eight pediatric patients with intractable epilepsy undergoing intracranial electroencephalography (iEEG). We recorded respiration during seizures and during electrical stimulation mapping of 174 forebrain sites. A machine learning algorithm was used to delineate brain regions that inhibit respiration.
Results:
In two patients, apnea coincided with seizure spread to the amygdala. Supporting a role for the amygdala in breathing inhibition in children, electrically stimulating the amygdala produced apnea in all eight subjects (3- to 17-years-old). These effects did not depend on epilepsy type and were relatively specific to the amygdala as no other site affected breathing. Remarkably, patients were unaware that they had stopped breathing, and none reported dyspnea or arousal, findings critical for SUDEP. Finally, a machine learning algorithm based on 45 stimulation sites and 210 stimulation trials identified a focal subregion in the human amygdala that consistently produced apnea. This site, which we refer to as the Amygdala Inhibition of Respiration (AIR) site includes the medial subregion of the basal nuclei, cortical and medial nuclei, amygdala transition areas, and intercalated neurons.
Conclusions:
A focal site in the amygdala inhibits respiration and induces apnea (AIR site) when electrically stimulated and during seizures in children with epilepsy. This site may prove valuable for determining those at greatest risk for SUDEP and as a therapeutic target.
Trial registration:
This study was not affiliated with any formal clinical trial.
Funding:
NIH, CNS, Roy J. Carver Charitable Trust.
Context:
Chronic breathlessness is a clinical syndrome that results in significant distress and disability. Morphine can reduce chronic breathlessness when the contributing aetiologies are optimally treated.
Objective:
Does oxycodone reduce chronic breathlessness compared with placebo?
Methods:
A multi-site, randomised, placebo-controlled, double-blind, parallel-arm, fixed-dose trial of oral controlled-release oxycodone 15mg (5 mg 8 hourly) or placebo (ACTRN12609000806268 at www.anzctr.org.au). 'As needed' immediate-release morphine (2.5mg per dose; ≤6 doses/day) was available for both arms as required by one ethics committee overseeing the trial.Recruitment occurred from 2010 to 2014 in 14 inpatient and outpatient respiratory, cardiology and palliative care services across Australia. Participants were adults, with chronic breathlessness (modified Medical Research Council Scale 3 or 4), who were opioid naïve. The primary endpoint was the proportion of people with >15% reduction from baseline in the intensity of breathlessness now (0-100 mm visual analogue scale) comparing arms days 5-7. Secondary endpoints were 'average' and 'worst' breathlessness; quality of life; function; and harms.
Results:
Of 157 participants randomised, 155 were included (74 oxycodone, 81 placebo), but the study did not reach target recruitment. There was no difference between groups for the primary outcome (p=0.489) nor any of the pre-specified secondary outcomes. Placebo participants used more 'as needed' morphine (mean 7.0 versus 4.2 doses; p≤0.001). Oxycodone participants reported more nausea (p<0.001).
Conclusions:
There was no signal of benefit from oxycodone over placebo. Future research should focus on investigating the existence of an opioid class effect on the reduction of chronic breathlessness.
The ventral surface of the rostral medulla oblongata has been suspected since the 1960s to harbor central respiratory chemoreceptors [i.e., acid-activated neurons that regulate breathing to maintain a constant arterial PCO2 (PaCO2)]. The key neurons, a.k.a. the retrotrapezoid nucleus (RTN), have now been identified. In this review we describe their transcriptome, developmental lineage, and anatomical projections. We also review their contribution to CO2 homeostasis and to the regulation of breathing automaticity during sleep and wake. Finally, we discuss several mechanisms that contribute to the activation of RTN neurons by CO2in vivo: cell-autonomous effects of protons; paracrine effects of pH mediated by surrounding astrocytes and blood vessels; and excitatory inputs from other CO2-responsive CNS neurons.
Introduction
Morphine may decrease the intensity of chronic breathlessness but data from a large randomised controlled trial (RCT) are lacking. This first, large, parallel-group trial aimed to test the efficacy and safety of regular, low-dose, sustained-release (SR) morphine compared with placebo for chronic breathlessness.
Methods
Multisite (14 inpatient and outpatient cardiorespiratory and palliative care services in Australia), parallel-arm, double-blind RCT. Adults with chronic breathlessness (modified Medical Research Council≥2) were randomised to 20 mg daily oral SR morphine and laxative (intervention) or placebo and placebo laxative (control) for 7 days. Both groups could take ≤6 doses of 2.5 mg, ‘ as needed ’, immediate-release morphine (≤15 mg/24 hours) as required by the ethics review board. The primary endpoint was change from baseline in intensity of breathlessness now (0–100 mm visual analogue scale; two times per day diary) between groups. Secondary endpoints included: worst , best and average breathlessness ; unpleasantness of breathlessness now , fatigue; quality of life; function; and harms.
Results
Analysed by intention-to-treat, 284 participants were randomised to morphine (n=145) or placebo (n=139). There was no difference between arms for the primary endpoint (mean difference −0.15 mm (95% CI −4.59 to 4.29; p=0.95)), nor secondary endpoints. The placebo group used more doses of oral morphine solution during the treatment period (mean 8.7 vs 5.8 doses; p=0.001). The morphine group had more constipation and nausea/vomiting. There were no cases of respiratory depression nor obtundation.
Conclusion
No differences were observed between arms for breathlessness, but the intervention arm used less rescue immediate-release morphine.
Trial registration number
ACTRN12609000806268.
Although recent studies on self-consciousness emphasized the importance of bodily processing and multisensory integration, such research has focused solely on bodily signals originating from the outside of the body (i.e., exteroceptive bodily signals) or internal bodily signals from visceral organs (i.e., interoceptive bodily signals) and how each system contributes to self-consciousness, without much interaction between the two approaches. Reviewing the latest evidence on interoceptive bodily processing and the combination of exteroceptive and interoceptive bodily signals for self-consciousness, we propose an integrated neural system reconciling these two largely separated views and delineate how it accounts for fundamental aspects of self-consciousness such as self-identification and self-location, as well as its experienced global unity and temporal continuity.
Glutamate is the predominant excitatory neurotransmitter in the ventral respiratory column; however, the contribution of glutamatergic excitation in the individual subregions to respiratory rhythm generation has not been fully delineated. In an adult, in vivo, decerebrate rabbit model during conditions of mild hyperoxic hypercapnia we blocked glutamatergic excitation using the receptor antagonists 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX) and d(–)-2-amino-5-phosphonopentanoic acid (AP5). Disfacilitation of the preBötzinger Complex caused a decrease in inspiratory and expiratory duration as well as peak phrenic amplitude and ultimately apnea. Disfacilitation of the Bötzinger Complex caused a decrease in inspiratory and expiratory duration; subsequent disfacilitation of the preBötzinger Complex resulted in complete loss of the respiratory pattern but maintained tonic inspiratory activity. We conclude that glutamatergic drive to the preBötzinger Complex is essential for respiratory rhythm generation. Glutamatergic drive to the Bötzinger Complex significantly affects inspiratory and expiratory phase duration. Bötzinger Complex neurons are responsible for maintaining the silent expiratory phase of the phrenic neurogram.