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![| Localization of correlations between intensity (A) and unpleasantness (B,C) ratings and changes in fMRI activation over time for dyspnea anticipation [(cue dyspnea late−cue baseline late)−(cue dyspnea early−cue baseline early)]. (A) and (B) show negative correlations, while (C) shows positive correlations. Correlations displayed at p uncorr < 0.005 are superimposed on a representative single subjects T1-weighted MR image. Color-bars indicate T-values. OFC, orbitofrontal cortex; PAG, periaqueductal gray; R, right.](profile/Matthias-Gamer/publication/278793006/figure/fig3/AS:392017805889536@1470475736166/Localization-of-correlations-between-intensity-A-and-unpleasantness-B-C-ratings-and.png)
| Localization of correlations between intensity (A) and unpleasantness (B,C) ratings and changes in fMRI activation over time for dyspnea anticipation [(cue dyspnea late−cue baseline late)−(cue dyspnea early−cue baseline early)]. (A) and (B) show negative correlations, while (C) shows positive correlations. Correlations displayed at p uncorr < 0.005 are superimposed on a representative single subjects T1-weighted MR image. Color-bars indicate T-values. OFC, orbitofrontal cortex; PAG, periaqueductal gray; R, right.
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Dyspnea is a prevalent and threatening cardinal symptom in many diseases including asthma. Whether patients suffering from dyspnea show habituation or sensitization toward repeated experiences of dyspnea is relevant for both quality of life and treatment success. Understanding the mechanisms, including the underlying brain activation patterns, that...
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Context 1
... visual cortex as a control area showed no significant correlations with either intensity or unpleasantness during either dyspnea anticipation or dyspnea perception at a liberal threshold of p uncorr < 0.001. For dyspnea anticipation, the ROI-based analysis showed a significant negative correlation of intensity with the of brain activation ( cue dyspnea vs. cue baseline) within the right OFC, extending into the ACC (Figure 3A, Supplementary Figure S3A). This indicated that sensitization toward dyspnea intensity was associated with decreased OFC activation, while habituation was associated with increasing OFC activation. ...
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... indicated that sensitization toward dyspnea intensity was associated with decreased OFC activation, while habituation was associated with increasing OFC activation. For unpleasantness a significant negative correlation was found within the midbrain/PAG (Figure 3B, Supplementary Figure S3B) while positive correlations were found for the anterior insular cortex bilaterally ( Figure 3C, Supplementary Figures S3C-E). Sensitization toward dyspnea unpleasantness was, thus, associated with decreasing activation in the midbrain/PAG and increasing activation in the anterior insula. ...
Context 3
... indicated that sensitization toward dyspnea intensity was associated with decreased OFC activation, while habituation was associated with increasing OFC activation. For unpleasantness a significant negative correlation was found within the midbrain/PAG (Figure 3B, Supplementary Figure S3B) while positive correlations were found for the anterior insular cortex bilaterally ( Figure 3C, Supplementary Figures S3C-E). Sensitization toward dyspnea unpleasantness was, thus, associated with decreasing activation in the midbrain/PAG and increasing activation in the anterior insula. ...
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... dyspnea perception ( dyspnea vs. baseline), we found a significant negative correlation within the right OFC for both intensity and unpleasantness, which extended into the ACC (Figures 4A,B, Supplementary Figures S3F,G). Thus, as during dyspnea anticipation, increasing OFC activation was associated with habituation, while decreasing OFC activation was associated with sensitization toward dyspnea, for both, intensity and unpleasantness. ...
Context 5
... as during dyspnea anticipation, increasing OFC activation was associated with habituation, while decreasing OFC activation was associated with sensitization toward dyspnea, for both, intensity and unpleasantness. The of brain activation ( dyspnea vs. baseline) within the right anterior insular cortex showed a significant positive correlation with unpleasantness ( Figure 4C, Supplementary Figure S3H), indicating that increasing activation of the anterior insular cortex during dyspnea perception was associated with sensitization and decreasing activation with habituation. Coordinates, Z-, r-, and p-values are summarized in Table 3. ...
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We report a functional magnetic resonance imaging (fMRI) study which investigated whether brain areas involved in updating task rules within the frontal lobe of the cerebral cortex show activity related to the modality of motor response used in the task. Participants performed a rule switching task using different effector modalities. In some block...
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... Indeed, OSA patients have an increased drive to breathe (Mezzanotte et al., 1992;Saboisky et al., 2007;Steier et al., 2010) and exhibit a respiratory-related activation of the cerebral cortex visible under the form of slow preinspiratory potentials (PIPs) (Launois et al., 2015), two circumstances generally associated with dyspnea. Respiratory habituation has been described experimentally (Subhan et al., 2003;Von Leupoldt et al., 2011;Wan et al., 2009) and hypothesized to proceed from downregulation of the insular cortex (Stoeckel et al., 2015;Von Leupoldt et al., 2011) or impaired somatosensory processing (Davenport et al., 2000;Fauroux et al., 2007) as it exists in OSA patients (Donzel-Raynaud et al., 2009;Grippo et al., 2011). Demonstrating respiratory habituation in OSA patients would require showing first that a neurophysiological phenomenon usually associated with dyspnea can be evidenced in the absence of dyspnea and second that this phenomenon disappears in response to an intervention associated with "pseudo-relief". ...
Patients with obstructive sleep apneas (OSA) do not complain from dyspnea during resting breathing. Placement of a mandibular advancement device (MAD) can lead to a sense of improved respiratory comfort (“pseudo‐relief”) ascribed to a habituation phenomenon. To substantiate this conjecture, we hypothesized that, in non‐dyspneic awake OSA patients, respiratory‐related electroencephalographic figures, abnormally present during awake resting breathing, would disappear or change in parallel with MAD‐associated pseudo‐relief. In 20 patients, we compared natural breathing and breathing with MAD on: breathing discomfort (transitional visual analog scale, VAS‐2); upper airway mechanics, assessed in terms of pressure peak/time to peak (TTP) ratio respiratory‐related electroencephalography (EEG) signatures, including slow event‐related preinspiratory potentials; and a between‐state discrimination based on continuous connectivity evaluation. MAD improved breathing and upper airway mechanics. The 8 patients in whom the EEG between‐state discrimination was considered effective exhibited higher Peak/TTP improvement and transitional VAS ratings while wearing MAD than the 12 patients where it was not. These results support the notion of habituation to abnormal respiratory‐related afferents in OSA patients and fuel the causative nature of the relationship between dyspnea, respiratory‐related motor cortical activity and impaired upper airway mechanics in this setting.
... Detection is done by voice analysis, so evaluation can be standardized, resulting in reduced variability or bias between different physicians who administer the test in the form of questionnaires. Moreover, the responses given in a questionnaire can be influenced by the patient's mood or habituation to the disease [15]- [17] . ...
... The amygdala is responsible for generating fear associated with threat signals such as pain (Phan et al., 2002;Veinante et al., 2013), and as part of the interoceptive pathway likely performs the same role in response to air hunger. The amygdala also responds to anticipation of air hunger (Stoeckel et al., 2015a(Stoeckel et al., , 2016, and its response can be modulated by changing affective state (without change in air hunger intensity) (Stoeckel et al., 2018). Responses to anticipation and susceptibility to influence by affective states suggest the amygdala's role is specific to the affective, rather than sensory, dimension of air hunger. ...
... Two studies using mild resistive loads (30 and 24 cm H 2 O) that were insufficient to induce any reported respiratory discomfort (consistent with neither showing somatosensory cortical activations) provide pseudo-controls to account for respiratory motor responses, rather than sensory or affective components (Gozal et al., 1995;Isaev et al., 2002). Insular Cortex: All studies imposing sufficient load to generate "discomfort" cause activation of the IC (Peiffer et al., 2001(Peiffer et al., , 2008von Leupoldt et al., 2008von Leupoldt et al., , 2009aStoeckel et al., 2015aStoeckel et al., , 2016Esser et al., 2017;Faull et al., 2018). The IC is not activated by mild resistive loads that do not induce discomfort (Gozal et al., 1995;Isaev et al., 2002). ...
... The PAG influences the control of breathing and may have a role in respiratory interoception (reviewed in (Faull et al., 2019)). PAG activity increases during tracheal occlusion in rats (Zhang et al., 2009;Pate and Davenport, 2012) and loaded breathing and hypercapnia in humans von Leupoldt et al., 2009b;Stoeckel et al., 2015a), but not during volume restriction. In their review, Faull et al. propose that the PAG is the site of integration of frontal lobe and sensory inputs so respiratory responses can be compared to, and modified by, prior experience (Faull et al., 2019). ...
The clinical term dyspnea (a.k.a. breathlessness or shortness of breath) encompasses at least three qualitatively distinct sensations that warn of threats to breathing: air hunger, effort to breathe, and chest tightness. Air hunger is a primal homeostatic warning signal of insufficient alveolar ventilation that can produce fear and anxiety and severely impacts the lives of patients with cardiopulmonary, neuromuscular, psychological, and end-stage disease. The sense of effort to breathe informs of increased respiratory muscle activity and warns of potential impediments to breathing. Most frequently associated with bronchoconstriction, chest tightness may warn of airway inflammation and constriction through activation of airway sensory nerves. This chapter reviews human and functional brain imaging studies with comparison to pertinent neurorespiratory studies in animals to propose the interoceptive networks underlying each sensation. The neural origins of their distinct sensory and affective dimensions are discussed, and areas for future research are proposed. Despite dyspnea's clinical prevalence and impact, management of dyspnea languishes decades behind the treatment of pain. The neurophysiological bases of current therapeutic approaches are reviewed; however, a better understanding of the neural mechanisms of dyspnea may lead to development of novel therapies and improved patient care.
... Individuals who have both asthma and elevated anxiety levels have been observed to have trouble distinguishing between them, because the symptoms overlap (Boudreau et al., 2015). Other experimental studies have shown that respiratory symptoms can be triggered due to conditional learning, and that individuals with elevated anxiety levels may have a particular tendency for this type of associative learning (Stoeckel et al., 2015(Stoeckel et al., , 2016. Hence, associative learning may cause anxious individuals with asthma to overreact to harmless stimuli. ...
There is an established relationship between anxiety and asthma, which is associated with poor health outcomes. Most previous cognitive behavior therapies (CBT) have focused on comorbid panic disorder whereas anxiety related to asthma may rather be illness-specific. The feasibility of an online CBT targeting avoidance behavior in anxiety related to asthma was evaluated, using a pretest-posttest design. Thirty participants with self-reported anxiety related to asthma were offered an eight-week treatment with therapist support. Mean adherence was good (80% of content), and most participants (89%) reported adequate relief after treatment. Catastrophizing about asthma (CAS), assessed at 2 months after treatment, improved significantly with a large effect size (Cohen's d = 1.52). All secondary outcomes, including asthma control, avoidance behavior, fear of asthma symptoms and quality of life, improved significantly with moderate to large effect sizes (d: 0.40–1.44). All improvements were stable at 4 months follow up. Weekly ratings showed that a decrease in avoidance behavior predicted a decrease in CAS the following week throughout the treatment period. We conclude that CBT targeting avoidance behavior is a feasible treatment for anxiety related to asthma. The results justify investigation of efficacy and mechanisms of change in a randomized controlled trial.
ClinicalTrials.gov, ID: NCT03486756.
... Bu reseptörlerden gelen giriş sinyalleri daha sonra duyusal ileticiler tarafından beyin sapına iletilir ve giriş uyarıları ayrıca esas olarak limbik sistem ve sensorimotor kortekste işlenir. Sonucunda hastada nefes darlığı algısı oluşur (23)(24)(25). COVID-19'da dispne algısındaki azalma iki mekanizma ile açıklanabilir; SARS-CoV-2'nin limbik sistemde (özellikle insular bölgede) beyin hücrelerini ifade eden ACE2'ye doğrudan invazyonu veya dispne algısını ifade etmede ana rolü olan kortikolimbik ağdaki sitokin fırtınasının dolaylı toksik etkisi ile oluşabilir (25,26). Santral sinir sistemi SARS-CoV-2 tarafından iki mekanizma ile tutulur. ...
... Sonucunda hastada nefes darlığı algısı oluşur (23)(24)(25). COVID-19'da dispne algısındaki azalma iki mekanizma ile açıklanabilir; SARS-CoV-2'nin limbik sistemde (özellikle insular bölgede) beyin hücrelerini ifade eden ACE2'ye doğrudan invazyonu veya dispne algısını ifade etmede ana rolü olan kortikolimbik ağdaki sitokin fırtınasının dolaylı toksik etkisi ile oluşabilir (25,26). Santral sinir sistemi SARS-CoV-2 tarafından iki mekanizma ile tutulur. ...
Aralık 2019'da Wuhan şehrinde ortaya çıkan ve tüm dünyaya yayılan koronavirüs hastalığı (COVID-19) akciğerde oluşturduğu hasar sonucu hastalar, en sık nefes darlığı (dispne) şikayeti ile başvurmakta ve hipoksemi varlığında hastaneye yatırılarak tedavi edilmektedirler. Hastalığın prognozunu da etkileyen ve mortal seyretmesine yol açan hipokseminin oluşum mekanizması ile oksijen tedavisinin kime, ne zaman ve nasıl verilmesi bu makalede açıklanmaya çalışılmıştır.
... Control of ventilation and responses to environmental and physiological drivers of dyspnea are complex (62). Neural signaling to the brain regarding breathing includes 1) chemoreception by the peripheral and central chemoreceptors of arterial PO 2 , pH, and PCO 2 and 2) afferent signaling from the lungs, respiratory muscles, and chest wall regarding muscle effort, depth of breathing, lung stretching, and inflammation to the brain stem respiratory control center and its "corollary projection" to higher cortical centers such as the amygdala and anterior insular cortex, in which the conscious sensation of breathing resides (63). In addition, factors such as fever, anxiety, sympathetic nervous system activation, and increased metabolism contribute to ventilation and dyspnea perception. ...
The ongoing COVID-19 pandemic has been unprecedented on many levels, not least of which are the challenges in understanding the pathophysiology of these new critically ill patients. One widely-reported phenomenon is that of a profoundly hypoxemic patient with minimal to no dyspnea out of proportion to the extent of radiographic abnormalities and changes in lung compliance. This apparently unique presentation, sometimes called "happy hypoxemia or hypoxia" but better described as "silent hypoxemia", has led to the speculation of underlying pathophysiologic differences between COVID-19 lung injury and ARDS from other causes. We explore three proposed distinctive features of COVID-19 that likely bear on the genesis of silent hypoxemia, including differences in lung compliance, pulmonary vascular responses to hypoxia, and nervous system sensing and response to hypoxemia. In the context of known principles of respiratory physiology and neurobiology, we discuss whether these particular findings are due to direct viral effects or, equally plausible, are within the spectrum of typical ARDS pathophysiology and the wide range of hypoxic ventilatory and pulmonary vascular responses, and dyspnea perception in healthy people. Comparisons between lung injury patterns in COVID-19 and other causes of ARDS are clouded by the extent and severity of this pandemic, which may underlie the description of "new" phenotypes while limiting our ability to confirm these phenotypes by more invasive and longitudinal studies. However, given the uncertainty about anything unique in the pathophysiology of COVID-19 lung injury, there are no compelling pathophysiologic reasons at present to support a different therapeutic approach for these patients to the proven standards of care in ARDS.
... The amygdala plays an important role in fear generation in response to a wide variety of stimuli (193), including pain and in particular visceral pain (236) that has a stronger affective component than somatic pain (230). As the amygdala is activated by fearful anticipation of dyspnea [i.e., while no dyspnea is present (227,228)], it is likely that the amygdala is part of the emotional response, rather than sensory perception of air hunger itself. Similarly, the amygdala's response to loaded breathing can be manipulated by modifying the subject's affective state, but the same is not true for the insula or anterior cingulate cortex (229); again suggesting that the insula and anterior cingulate cortex are involved with air hunger perception, while the amygdala mediates the fear component of the emotional response. ...
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.
... Input signals from these receptors are then transmitted to the brainstem by sensory afferents, and input impulses are further processed mainly in the limbic system and sensorimotor cortex [31,32]. This issue has been considered to be closely associated with dyspnea perception [33]. ...
... Afferent signals are transmitted via the vagal nerve to the central nervous system (CNS) and are then sent to the amygdala and medial dorsal regions of the thalamus and finally ascend specific parts of the limbic system, including the insular and cingulate cortices [40,33]. These structures are thought to process the unpleasant aspect of dyspnea and it seems that COVID-19 infection modifies the function of these areas of the brain [41,42]. ...
... The thalamus and hippocampus are critical neural areas for receiving respiratory sensory input [33]. After effective integration and processing of afferent inputs in the CNS, these structures subsequently produce efferent outputs and send impulses via the phrenic and thoracic spinal nerves to the diaphragm and intercostal muscles, respectively (Fig. 1). ...
SARS-CoV-2 mainly invades respiratory epithelial cells by adhesion to angiotensin-converting enzyme 2 (ACE-2) and thus, infected patients may develop mild to severe inflammatory responses and acute lung injury. Afferent impulses that result from the stimulation of pulmonary mechano-chemoreceptors, peripheral and central chemoreceptors by inflammatory cytokines are conducted to the brainstem. Integration and processing of these input signals occur within the central nervous system, especially in the limbic system and sensorimotor cortex, and importantly feedback regulation exists between O2, CO2, and blood pH. Despite the intensity of hypoxemia in COVID-19, the intensity of dyspnea sensation is inappropriate to the degree of hypoxemia in some patients (silent hypoxemia). We hypothesize that SARS-CoV-2 may cause neuronal damage in the corticolimbic network and subsequently alter the perception of dyspnea and the control of respiration. SARS-CoV-2 may enter the CNS via direct (neuronal and hematologic route) and indirect routes. We theorize that SARS-CoV-2 infection-induced neuronal cell damage may change the balance of endogenous neuropeptides or neurotransmitters that distribute through large areas of the nervous system to produce cellular and perceptual effects. Thus, SARS-CoV-2-associated neuronal damage may influence the control of respiration by interacting in neuromodulation. This would open up possible lines of study for the progress in the central mechanism of COVID-19-induced hypoxia. Future research is desirable to confirm or disprove such a hypothesis.
... These studies found that not only sensorimotor areas such as the sensorimotor cortex, supplementary motor area, SII and thalamus, but also emotion-related areas such as insular cortex, amygdala, anterior cingulate cortex (ACC), hippocampus, and periaqueductal gray (PAG) were activated with inspiratory resistive loads. Partly, these activations in emotion-related areas such as insula, ACC, hippocampus and amygdala were associated with elevated levels of negative affect such as anxiety or increased unpleasantness of breathlessness 14,15,19,21,25,[28][29][30][31] . In addition, a few researchers have used transient inspiratory occlusion in a single breath to measure brain activation associated with breathlessness 16,18 . ...
... Our results also demonstrated that the high-anxious group had a trend of increased neural activation in some ROIs including the insula, middle cingulate cortex, and hippocampus during respiratory occlusion events, which were not observed in the lower anxious group. These findings are consistent with some previous studies examining the effects of anxiety and negative affect, or diseased states 14,15,19,21,25,[29][30][31] . For example, Stoeckel et al. (2016) used resistive loading to elicit dyspnea sensation in healthy subjects. ...
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.
... This has been demonstrated experimentally (Subhan et al., 2003;von Leupoldt et al., 2011;Wan et al., 2009) and suspected clinically (Kikuchi et al., 1994;Reilly et al., 2016). Habituation could proceed, at least in part, from downregulation of the insular cortex (Stoeckel et al., 2015;von Leupoldt et al., 2009). It could also proceed from altered somatosensory processing of respiratory stimuli (Davenport et al., 2000;Fauroux et al., 2007), a phenomenon that can be present in OSAS patients (Donzel-Raynaud et al., 2009;Grippo et al., 2011). ...
