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Air Hunger: A Primal Sensation and a Primary Element of Dyspnea

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Abstract

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.

Figure 1. Figure 1. Air hunger provokes strong emotional response compared to maximal breathing work. Healthy naïve subjects were exposed to the maximum tolerable air hunger stimulus (blue bars) and were required to do the maximal amount of inspiratory work of breathing (red bars). Data plotted are group mean ± SE. The air hunger stimulus comprised mild hypercapnia (PETCO2 6 Torr above resting) combined with progressively decreased ventilation until the tolerable limit was reached. The work stimulus comprised constant eucapnia while the subject breathed against moderate resistance and progressively higher ventilation target until task failure. Mild hyperoxia prevailed throughout; FIO2 was 30%. Data from Banzett RB, et al., 2008 20, Figures 5 and 6. Adapted with permission of the American Thoracic Society (ATS). Copyright © 2020 ATS. All rights reserved. Am J Respir Crit Care Med 177: 1384‐1390. The Am J Respir Crit Care Med is an official journal of the ATS. Readers are encouraged to read the entire article for the correct context at (doi: 10.1164/rccm.200711‐1675OC). The authors, editors, and The ATS are not responsible for errors or omissions in adaptations.
Figure 2. Figure 2. Methodology. (A) Time tracing of physiological variables during one run of a typical air hunger study in a healthy volunteer, together with resultant stimulus‐response plot (Subject AF92 in Ref. 21). Traces from top: Tidal PCO2, Visual Analog Scale rating of Breathing Discomfort (BDVAS) at 15 s intervals, pressure at the mouthpiece (PAO), volume derived from integrated flow signal (the initial transient is due to the start‐up effect of a high‐pass filter). Inspired fraction of CO2 was varied manually to achieve desired PETCO2. Five large breaths were delivered at the time of each PCO2 step to speed gas change and to give the subject momentary relief when at high discomfort. Red bars indicate times of collection of BDVAS ratings; blue horizontal bars below BDVAS tracing indicate periods for collection of physiological data. As explained more fully in the text, the air hunger response lags changes in end‐tidal PCO2 and changes in tidal volume 14; therefore, air hunger measurements are offset in time to account for the slow air hunger dynamic response. (B) The 90 s average PETCO2 plotted against the average of 3 BDVAS ratings comprise one data point. This run resulted in 5 of the data points on this plot of breathing discomfort rating versus ΔPETCO2 expressed as Torr above mean resting PETCO2 (42.5 Torr in this subject). Each data point is labeled in both panels. Mild hyperoxia prevailed throughout; FIO2 was 30%. Adapted with permission License #4834191357251.
Figure 3. Figure 3. Normative data of the air hunger response versus CO2 stimulus showing variance in air hunger stimulus‐response among 16 normal subjects. Data re‐plotted from Ref. 12, Table 2. This figure depicts a regression line for each subject, as well as the mean of all subjects (heavy black line). In this study, subjects rated air hunger on a 7‐point ordinal scale implemented with an electronic box with 7 evenly spaced buttons ranging from no air hunger to intolerable air hunger. It was later determined that subjects treated this scale in the same way as they treated a VAS with the same scale definitions 136. Ventilation was determined by a volume‐control ventilator that delivered constant frequency and tidal volume resulting in minute ventilation of at 0.16 liter/min/kg; inspired gas contained 50% O2 and a variable fraction of CO2 manually controlled to achieve desired PETCO2. Because air hunger is a very distressing sensation, subjects were told that if they rated 100% of scale (i.e., intolerable) we would immediately reduce the stimulus, reducing discomfort in two to five breaths, or they could remove the mouthpiece and experience immediate relief. The variance of this perceptual response among subjects is similar to that reported for the reflex‐driven hypercapnic ventilatory response (HCVR).
Figure 4. Figure 4. Normative data of the air hunger response versus CO2 stimulus, summarizing data from several studies in which ventilation was near resting level with background hyperoxia. The y‐axis is the subject rating expressed as percent full scale (%FS), top of the scale defined as intolerable, PETCO2 = end‐tidal PCO2. The solid line represents the mean regression line from five studies using rating scales that defined the upper end of the scale as “intolerable” as shown in Table 1. The solid red circle represents data from Ref. 203, showing the PETCO2 at which subjects could not tolerate breathing to the ventilation target of 10 liters/min (we infer that this is the same as a rating of intolerable). The open blue circle represents data from Ref. 154, including the data supplement, showing the PCO2 in the rebreathing bag at the point where subjects could no longer tolerate rebreathing, utilizing the average of hyperoxic runs with ending ventilation closest to 10 liters/min. The vertical dotted green line shows data from Ref. 44, and represents the PETCO2 at which subjects first reported that ventilatory needs were not satisfied (they did not give a rating). One of the studies in Table A, Ref. 12, used a discrete scale, the lowest point of which is comparable to the threshold—this is indicated by x. The small PETCO2 difference between the BD0 intersection and the threshold points is probably due to the subject's “decision criterion”: that is, there must be some finite sensation before a subject will decide to report the presence of sensation.
Figure 5. Figure 5. Time course of air hunger during breath hold to break point, followed by rebreathing of alveolar gas, and second breath hold. This shows the relief of air hunger from mechanoreceptors sensitive to lung inflation is sufficient to permit a second breath hold with no improvement of blood gasses. Recordings in one subject of respiratory airflow, airway PCO2, O2 saturation (SaO2), breathing “discomfort” was reported using a visual analog scale (VAS) where the top of the scale was defined as the sensation at break point of a maximal breath hold; subjects described this sensation in terms equivalent to air hunger (see text). The subject performed a maximal duration breath hold at total lung capacity (BH1), then rebreathed five breaths of 8.2% O2 and 7.5% CO2, and then performed a second breath hold (BH2). There were progressive increases in air hunger during breath hold and a rapid, but not instantaneous relief when breathing resumed. Dashed lines represent the estimated rising PaCO2 during breath hold. Note substantial relief of air hunger during rebreathing despite increased PCO2 and decreased SaO2. Reused, with permission, from Flume P, et al., 1994 91; License #4823800766466.
Figure 6. Figure 6. Effect of increased ventilation on air hunger in healthy subjects, quantifying mechanoreceptor relief. In all cases, PETCO2 was kept the same in both ventilation conditions by raising inspired PCO2 as ventilation was increased. Solid triangles show data from Ref. 105 Experiment 3 during mechanical ventilation; solid diamonds show data from Ref. 85 during mechanical ventilation; open squares show data from Ref. 162 during bag‐limited ventilation. All studies were done under mild hyperoxia. Given the somewhat different methods, starting points, and individual subjects, the responses are quite similar and show a profound inhibition (relief) of air hunger at the higher ventilation.
Figure 7. Figure 7. Effect of minute ventilation on air hunger. Composite graph of two studies using widely different methodologies in which PETCO2 and tidal volume were varied against a background of constant hyperoxia. (A) The solid line indicates the mean air hunger response of 12 subjects to alterations of PETCO2 when ventilation was restricted to mean of 10 liters/min by a bag‐limit device combined with a metronome set at 14 breaths/min; the hollow square points connected by the dashed line are from the same subjects when the ventilation limit was increased from 10 to 20 liters/min by increasing flow to the bag 162. The filled red circles are from a different study in which four subjects breathed to targets of 5, 10, and 20 liters/min and a metronome set at 14 breaths/min as PETCO2 was slowly raised until the subject reported that the sensation was intolerable 203. Tolerance limit is assumed to be 100%FS air hunger. The dotted lines are hypothetical; the right dotted line is constructed from data points from the two studies, and the left dotted line is assumed to have the same slope extending from one data point, but the region below the question mark on the 5 liters/min line cannot be explored in steady state without extraordinary methods such as extracorporeal exchange to reduce PETCO2 at low ventilation. (B) An approximate 3‐D representation of the same data.
Figure 8. Figure 8. Time course of air hunger response to onset of hypoxia shows the same biphasic response as the hypoxic ventilatory response. Solid circles represent the average air hunger response to a step reduction in PETO2 during constant mechanical ventilation at eucapnia. For comparison, the open circles depict the average response of ventilation during free breathing to a step reduction in PETO2 during constant at eucapnia during a separate session in the same subjects. Reused from Moosavi SH, et al., 2004 157 with permission RightsLink.
Figure 9. Figure 9. Time course of air hunger response to a step change in tidal volume at constant PETCO2 and PETO2. Although mechanoreceptors respond fully on the first breath, central neural processes act as a low‐pass filter, slowing the perceptual response. Step changes in tidal volume were effected during mechanical volume‐control ventilation, while PETCO2 and PETO2 were held constant by altering inspired gasses. Breath by breath mean tidal volumes (VT) and air hunger ratings were averaged from 30 steps in six healthy subjects. Breaths were aligned with respect to the step change in tidal volume. This experiment was conducted under mild hyperoxia (PETO2 ∼160 Torr). Reprinted from Evans KC, et al., 2002 85 with permission RightsLink.
Figure 10. Figure 10. Likely neural pathways for air hunger based on current information. Inputs and outputs are in italics, structures are normal font. The heavy blue arrows indicate the currently favored pathway for air hunger sensation; green arrows indicate the generally accepted pathway for reflex ventilatory response; black indicates structures and stimuli in common for air hunger and ventilatory responses; red dashed arrow indicates the pathway for relief (inhibition) of air hunger sensation by mechanoreceptor input coming from slowly adapting pulmonary stretch receptors (SAPSRs). SAPSR input projects both to brainstem neurons and to cortical neurons—the level at which air hunger relief is effected is currently unknown.
Figure 11. Figure 11. Differential effect on respiratory sensations of partial neuromuscular block with short‐acting agent (mivacurium). These data show that air hunger and work/effort sensations are distinct, driven by different neural mechanisms. Air hunger ratings, blue filled circles; work ratings, red filled circles; breathing effort ratings, open squares. (A) Subjects breathed to a 30 liter/min target while eucapnic PETCO2 was maintained by altering inspired PCO2. In panel (A), it can be seen that during volitional hyperpnea partial paralysis had a large effect on perceived work and effort of breathing, which increased as more voluntary (cortical) motor command was needed to maintain the ventilation target. In contrast, air hunger remained at zero throughout because the prevailing level of reflex (medullary) drive was low throughout. (B) Ventilation was stimulated by hypercapnia to achieve approximately 30 liters/min. In panel (B), it can be seen that during CO2‐driven hyperpnea air hunger increased in concert with work and effort because medullary motor command was elevated (implying greater medullary corollary discharge). The degree of partial paralysis was sufficient to reduce vital capacity by 40% compared to control (and reduced handgrip strength by 60%); full vital capacity had returned at the time of recovery measurements. Data re‐plotted, with permission, from Figure 2 of Moosavi SH, et al., 2000 160; License # 4826560010506.
Figure 12. Figure 12. Lack of effect of opiate on work/effort breathing discomfort (left panel) contrasts with pronounced effect of opiate on air hunger breathing discomfort (right panel). This is another demonstration that air hunger is distinct from work/effort sensations because they can be separately manipulated. The left panel shows data re‐plotted from Figure 1 of Ref. 232. Subjects breathed against large inspiratory threshold loads, but respiratory rate and tidal volume were well maintained, from which we infer that blood gasses were not compromised (there were no measures of arterial or end‐tidal gasses). Ratings of “discomfort” are expressed as percent of full scale (%FS). The minimum and maximum ends of the scale were not defined, but seven descriptors were placed along the scale. The maximum discomfort elicited by the largest threshold load (74% of maximum static inspiratory pressure) was equivalent to the verbal scale label “unpleasant”; the low ratings of discomfort in this experiment probably reflect the fact that respiratory work tasks are not very unpleasant in the absence of air hunger 20. Breathing discomfort following opiate was not different in this work/effort model. The right panel shows data re‐plotted from Ref. 15. In this experiment subjects rated “breathing discomfort” on a visual analog scale, where the scale maximum was defined as “unbearable”; these ratings are expressed as %FS. Inspired PCO2 was varied while ventilation was restricted to approximately 0.13 liter/min with a background of constant hyperoxia (FIO2 = 30%). Ratings were obtained over a range of PETCO2. Regression lines were obtained for each subject in each condition, then averaged to obtain the mean regressions shown here. The large decrease in breathing discomfort with opiate was statistically significant in this air hunger model. The drug, dosage, and route of administration differed between studies, but we assess them as roughly equivalent opiate doses. Supinski et al. confirmed effective analgesia following oral codeine using a cold pressor test. Data re‐plotted from Banzett RB, et al., 2011 15 and Supinski G, et al., 1990 232. Adapted with permission of the American Thoracic Society (ATS). Copyright © 2020 ATS. All rights reserved. Am Rev Respir Dis 141: 1516‐1521 and Am J Respir Crit Care Med 184: 920‐927. The Am J Respir Crit Care Med and Am Rev Respir Dis are official journals of the ATS. Readers are encouraged to read the entire articles for the correct context at [https://doi.org/10.1164/ajrccm/141.6.1516 & https://doi.org/10.1164/rccm.201101‐0005OC]. The authors, editors, and The ATS are not responsible for errors or omissions in adaptations.
Figure 13. Figure 13. Air hunger during complete paralysis, showing that respiratory muscle contraction is not necessary for air hunger. Because this experiment disproved a long‐held tenet, it was repeated by a completely independent laboratory. Left panel shows data extracted from Figure 3 of Ref. 95; right panel shows data extracted from Figure 3 of Ref. 16. In both cases the subject (both authors of their respective studies) was totally paralyzed with curariform neuromuscular block and mechanically ventilated at constant tidal volume and frequency (Left VT = 1.0 liter, f = 8.8, SpO2 >98%; right VT = 0.92 liter, f = 12.5, FIO2 >90%). Time ticks in both panels are at 100 s intervals. As explained more fully in the text, the air hunger response lags changes in end‐tidal PCO2 and changes in tidal volume 14,85; therefore, air hunger measurements are offset in time to account for the slow air hunger dynamic response. Subjects were told to rate “respiratory discomfort” (left panel) or “air hunger” (right panel); both subjects chose the descriptor “urge to breathe” in debriefing. Rating scale on left was marked “severe” at 50% Full Scale and “maximal” at 100%FS; Rating scale on right was marked “slight plus” at 50% Full Scale and “extreme, intolerable” at 100%FS. Reused from Banzett RB, et al., 1990 16 and Gandevia SC, et al., 1993 95 with permission; License #4823790296315 and #4826560802572.
Figure 14. Figure 14. Putative “respiratory corollary discharge” recorded in the thalamus of a decorticate, paralyzed cat. This is one example of thalamic neurons that responded to increased respiratory motor activity. Just before the beginning of the record mechanical ventilation was paused. As PCO2 rose during the “breath hold,” brainstem ventilatory motor output (reflected in phrenic nerve activity) increased. About midway through the record, a threshold appears to be reached, and there was a profound progressive increase in thalamic activity. This mirrors the rise of air hunger sensation seen during a breath hold starting at low PETCO2 in human subjects 91,173. Similar responses have been observed in midbrain neurons 46. These observations suggest a neural substrate in accord with the theory that air hunger arises from corollary discharge carrying information about medullary motor activity to cortical sensory regions (Hypothesis 3). Adapted, with permission, from Figure 1 of Chen Z, et al., 1992 47; License #4826561235292.
Figure 15. Figure 15. Effect of neural lesions on mechanoreceptor relief of air hunger (effect of ventilation on air hunger). This graph demonstrates the predominant effect of pulmonary mechanoreceptors compared to rib cage and diaphragm mechanoreceptors. In all cases moderate air hunger was evoked by elevating PETCO2 above resting level while holding ventilation constant at about 10 liters/min with a background of mild hyperoxia (FIO2 30%–50%); this is the left‐hand point on each line. Tidal volume was increased while PETCO2 was held constant by elevating inspired PCO2. The black line with filled circles shows the mean reduction of air hunger in healthy normal subjects (averaged from the three studies depicted in Figure 4) 85,105,162. The blue line with filled triangles shows the response of quadriplegics having complete spinal cord lesions at the cervical 1 to 2 level 29; Quadriplegic subjects are presumed to have no chest wall sensation, but pulmonary stretch receptor innervation via the vagus nerve is presumed intact. The green line with filled squares shows the response of heart‐lung transplant patients is less than normals and quadriplegics, suggesting that chest‐wall afferents provide less relief (Experiment 3, in Ref. 105); transplant patients have intact rib cage and diaphragm innervation but were presumed to have no pulmonary innervation [although later work showed that some pulmonary innervation returns in such patients 38].
Figure 16. Figure 16. Mechanoreceptor inhibition of putative respiratory corollary discharge by vagal pulmonary mechanoreceptor afferents in decerebrated paralyzed cats 78. In panel (A), the vagus nerves are intact, and the midbrain neuron is silent during mechanical ventilation; when the ventilator is paused (breath hold) activity appears in the midbrain neuron. Midbrain activity is once again inhibited when ventilation is resumed. In panel (B), following bilateral vagotomy, the midbrain neuron is active regardless of whether the mechanical ventilator is cycling. Vagal cooling data suggested the inhibition was mediated by slowly adapting pulmonary stretch receptors (SAPSRs). This is consistent with experiments in humans with neural lesions described in the text 92,105,145. Adapted, with permission, from Eldridge and Chen, 1992 78; License #4826561496041.
Figure 17. Figure 17. Adaptation of air hunger response to prevailing level of PETCO2 (from Ref. 28). Four ventilator‐dependent patients were adapted from a baseline “resting” 27 Torr PETCO2 to 41 Torr PETCO2 by slowly increasing inspired PCO2 over the course of 1 to 3 days. Ventilator‐delivered tidal volume and respiratory rate were held constant throughout. The acute air hunger response to a CO2 stimulus was assessed before during and after adaptation. Filled diamonds with dashed line represent the average air hunger response to acutely elevated PETCO2 before and after the adaptation period; solid circles with solid line represent the air hunger response to acutely elevated PETCO2 during chronically elevated PETCO2. Adaptation and acute testing were performed during normoxia (FIO2 21%). Modified from Bloch‐Salisbury E, et al., 1996 28 with permission RightsLink.
Figure 18. Figure 18. Word Cloud summary of brain activations during respiratory discomfort. Numerous functional imaging studies have observed regional brain activations associated with dyspnea. These studies employed either (i) mild to moderate resistive loads or (ii) mild hypercapnia combined with tidal volume restriction and so likely produced different qualitative forms dyspnea. The former stimulus evokes mainly work/effort sensation, while the latter evokes air hunger sensation. The composite results of 16 studies are represented with the regional activations associated with the distinct stimuli being differentiated by font color; activations exclusive to air hunger (3 studies) are shown in blue, those exclusive to work/effort (13 studies) are shown in red and activations common to both air hunger and work effort are shown in purple. The font size represents the number of studies in which each particular regional activation was observed. All studies observed activation of the insular cortex. BNST, Bed Nuclei of the Stria Terminalis.
Figure 19. Figure 19. Activation of the anterior insular cortex is observed in PET and fMRI studies that induce air hunger by tidal volume limitation. Panel (A) shows a transverse PET image (8 mm rostral to AC‐PC baseline) from the first published brain imaging study of air hunger. Panel (B) shows a coronal fMRI image of the same region (centered on the AC line) with red arrows indicating activations associated with the onset of air hunger and yellow arrows indicating areas associated with steady state air hunger. The insular cortex is involved in the perception of other homeostatic warning signals (e.g., pain, thirst, and food hunger) and is the most commonly observed regional activation in brain imaging studies of respiratory discomfort. The fMRI study (B) also shows activation of the dorsal anterior cingulate cortex (dACC), an area involved with integration of emotional responses to adverse stimuli. (A) Adapted, with permission, from Banzett RB, et al., 2000 18; (B) Adapted, with permission, from Binks AP, et al., 2014 26; License #4825931387868 and #4830231140126.
Figure 20. Figure 20. Functional MRI images of activation in the amygdala during respiratory discomfort. The amygdala is a component of the limbic system associated with emotional responses, particularly fear. It is activated by air hunger induced by tidal volume limitation, as observed in the fMRI study by Evans et al. (Panel A: Am, transverse view at z‐plane = 14). Von Leupoldt et al. also observed amygdala activation associated with the “unpleasantness” of uncomfortable breathing induced by resistive respiratory loads (Panel B: AM, coronal view at y = 9). (A) Adapted from Evans KC, et al., 2002 85 with permission RightsLink; (B) Adapted form von Leupoldt A, et al., 2008 237 with permission of the American Thoracic Society (ATS). Copyright © 2020 ATS. All rights reserved. Am J Respir Crit Care Med 177: 1026‐1032. The Am J Respir Crit Care Med is an official journal of the ATS. Readers are encouraged to read the entire article for the correct context at [https://doi.org/10.1164/rccm.200712‐1821OC]. The authors, editors, and The ATS are not responsible for errors or omissions in adaptations.
Figure 21. Figure 21. Proposed central network for air hunger and the emotional and behavioral responses to it. The brown lines depict the interoceptive pathway and black arrows represent known connections. BNST, bed nuclei of the stria terminals; NTS, nucleus tractus solitarius.
Figure 22. Figure 22. Rats avoid CO2—induced discomfort rather than eat. The study by Neil and Weary shows that rats given 5 min of access to a chamber that contains a food reward, avoid that chamber when CO2 in the chamber rises above 10% 171. The measurable change in behavior provides proof of concept that complex integrated processes can be included in an animal model of air hunger. Developing an animal model of air hunger presents novel issues. Because air hunger is an amalgam of integrated afferent inputs that lead to emotional and behavioral responses, a robust model cannot simply measure reflex responses but should encompass higher cortical processes. Inspired CO2 concentrations above 10% are rarely used in human studies, but the rats in this study were free breathing and afforded the mechanoreceptor relief that it brings (see section titled “30The Quantitative Relationship between Stimulus and Air Hunger. Part B—Changing Ventilation While Holding Ventilatory Drive Constant”). The rats were being encouraged to tolerate hypercapnia through the enticement of a food reward, whereas positive rewards have not been used in human studies of air hunger. There may also be important species differences in chemoreception, which is a fundamental physiological aspect that should be considered in animal model development. Reused, with permission, from Niel L and Weary DM, 2007 171; License #4825940537868.
Figure 23. Figure 23. Air hunger is the dominant sensory quality of breathing discomfort in hospitalized patients. Graph depicts the frequency with which sensory qualities are chosen by hospital inpatients as the most apt description of their dyspnea. The prominence of air hunger sensation increases as clinical dyspnea worsens. Responses are grouped by the overall level of breathing discomfort on a scale of 0 to 10 where 10 is “unbearable.” Graph summarizes 460 responses from 156 patients interviewed repeatedly during the hospital stay utilizing the Multidimensional Dyspnea Profile. Reprinted, with permission, from Stevens JP, et al., 2019 225; License #4830241184265.
Figure 24. Figure 24. Air hunger (also termed “unsatisfied inspiration”) becomes the dominant sensory quality of breathing discomfort in pulmonary patients undergoing progressive exercise. Graph depicts the frequency with which sensory qualities are chosen by patients with pulmonary hypertension (n = 26) as the most apt description of their dyspnea during symptom‐limited incremental cycle exercise. The sudden rise in selection of air hunger coincides with the point at which tidal volume becomes limited by declining inspiratory capacity. Reproduced from Boucly A, et al., 2019 32 with permission of the © ERS 2020: European Respiratory Journal 55 (2) 1802108; DOI: 10.1183/13993003.02108‐2018 Published 12 February 2020.


Figure 1. Air hunger provokes strong emotional response compared to maximal breathing work. Healthy naïve subjects were exposed to the maximum tolerable air hunger stimulus (blue bars) and were required to do the maximal amount of inspiratory work of breathing (red bars). Data plotted are group mean ± SE. The air hunger stimulus comprised mild hypercapnia (PETCO2 6 Torr above resting) combined with progressively decreased ventilation until the tolerable limit was reached. The work stimulus comprised constant eucapnia while the subject breathed against moderate resistance and progressively higher ventilation target until task failure. Mild hyperoxia prevailed throughout; FIO2 was 30%. Data from Banzett RB, et al., 2008 20, Figures 5 and 6. Adapted with permission of the American Thoracic Society (ATS). Copyright © 2020 ATS. All rights reserved. Am J Respir Crit Care Med 177: 1384‐1390. The Am J Respir Crit Care Med is an official journal of the ATS. Readers are encouraged to read the entire article for the correct context at (doi: 10.1164/rccm.200711‐1675OC). The authors, editors, and The ATS are not responsible for errors or omissions in adaptations.


Figure 2. Methodology. (A) Time tracing of physiological variables during one run of a typical air hunger study in a healthy volunteer, together with resultant stimulus‐response plot (Subject AF92 in Ref. 21). Traces from top: Tidal PCO2, Visual Analog Scale rating of Breathing Discomfort (BDVAS) at 15 s intervals, pressure at the mouthpiece (PAO), volume derived from integrated flow signal (the initial transient is due to the start‐up effect of a high‐pass filter). Inspired fraction of CO2 was varied manually to achieve desired PETCO2. Five large breaths were delivered at the time of each PCO2 step to speed gas change and to give the subject momentary relief when at high discomfort. Red bars indicate times of collection of BDVAS ratings; blue horizontal bars below BDVAS tracing indicate periods for collection of physiological data. As explained more fully in the text, the air hunger response lags changes in end‐tidal PCO2 and changes in tidal volume 14; therefore, air hunger measurements are offset in time to account for the slow air hunger dynamic response. (B) The 90 s average PETCO2 plotted against the average of 3 BDVAS ratings comprise one data point. This run resulted in 5 of the data points on this plot of breathing discomfort rating versus ΔPETCO2 expressed as Torr above mean resting PETCO2 (42.5 Torr in this subject). Each data point is labeled in both panels. Mild hyperoxia prevailed throughout; FIO2 was 30%. Adapted with permission License #4834191357251.


Figure 3. Normative data of the air hunger response versus CO2 stimulus showing variance in air hunger stimulus‐response among 16 normal subjects. Data re‐plotted from Ref. 12, Table 2. This figure depicts a regression line for each subject, as well as the mean of all subjects (heavy black line). In this study, subjects rated air hunger on a 7‐point ordinal scale implemented with an electronic box with 7 evenly spaced buttons ranging from no air hunger to intolerable air hunger. It was later determined that subjects treated this scale in the same way as they treated a VAS with the same scale definitions 136. Ventilation was determined by a volume‐control ventilator that delivered constant frequency and tidal volume resulting in minute ventilation of at 0.16 liter/min/kg; inspired gas contained 50% O2 and a variable fraction of CO2 manually controlled to achieve desired PETCO2. Because air hunger is a very distressing sensation, subjects were told that if they rated 100% of scale (i.e., intolerable) we would immediately reduce the stimulus, reducing discomfort in two to five breaths, or they could remove the mouthpiece and experience immediate relief. The variance of this perceptual response among subjects is similar to that reported for the reflex‐driven hypercapnic ventilatory response (HCVR).


Figure 4. Normative data of the air hunger response versus CO2 stimulus, summarizing data from several studies in which ventilation was near resting level with background hyperoxia. The y‐axis is the subject rating expressed as percent full scale (%FS), top of the scale defined as intolerable, PETCO2 = end‐tidal PCO2. The solid line represents the mean regression line from five studies using rating scales that defined the upper end of the scale as “intolerable” as shown in Table 1. The solid red circle represents data from Ref. 203, showing the PETCO2 at which subjects could not tolerate breathing to the ventilation target of 10 liters/min (we infer that this is the same as a rating of intolerable). The open blue circle represents data from Ref. 154, including the data supplement, showing the PCO2 in the rebreathing bag at the point where subjects could no longer tolerate rebreathing, utilizing the average of hyperoxic runs with ending ventilation closest to 10 liters/min. The vertical dotted green line shows data from Ref. 44, and represents the PETCO2 at which subjects first reported that ventilatory needs were not satisfied (they did not give a rating). One of the studies in Table A, Ref. 12, used a discrete scale, the lowest point of which is comparable to the threshold—this is indicated by x. The small PETCO2 difference between the BD0 intersection and the threshold points is probably due to the subject's “decision criterion”: that is, there must be some finite sensation before a subject will decide to report the presence of sensation.


Figure 5. Time course of air hunger during breath hold to break point, followed by rebreathing of alveolar gas, and second breath hold. This shows the relief of air hunger from mechanoreceptors sensitive to lung inflation is sufficient to permit a second breath hold with no improvement of blood gasses. Recordings in one subject of respiratory airflow, airway PCO2, O2 saturation (SaO2), breathing “discomfort” was reported using a visual analog scale (VAS) where the top of the scale was defined as the sensation at break point of a maximal breath hold; subjects described this sensation in terms equivalent to air hunger (see text). The subject performed a maximal duration breath hold at total lung capacity (BH1), then rebreathed five breaths of 8.2% O2 and 7.5% CO2, and then performed a second breath hold (BH2). There were progressive increases in air hunger during breath hold and a rapid, but not instantaneous relief when breathing resumed. Dashed lines represent the estimated rising PaCO2 during breath hold. Note substantial relief of air hunger during rebreathing despite increased PCO2 and decreased SaO2. Reused, with permission, from Flume P, et al., 1994 91; License #4823800766466.


Figure 6. Effect of increased ventilation on air hunger in healthy subjects, quantifying mechanoreceptor relief. In all cases, PETCO2 was kept the same in both ventilation conditions by raising inspired PCO2 as ventilation was increased. Solid triangles show data from Ref. 105 Experiment 3 during mechanical ventilation; solid diamonds show data from Ref. 85 during mechanical ventilation; open squares show data from Ref. 162 during bag‐limited ventilation. All studies were done under mild hyperoxia. Given the somewhat different methods, starting points, and individual subjects, the responses are quite similar and show a profound inhibition (relief) of air hunger at the higher ventilation.


Figure 7. Effect of minute ventilation on air hunger. Composite graph of two studies using widely different methodologies in which PETCO2 and tidal volume were varied against a background of constant hyperoxia. (A) The solid line indicates the mean air hunger response of 12 subjects to alterations of PETCO2 when ventilation was restricted to mean of 10 liters/min by a bag‐limit device combined with a metronome set at 14 breaths/min; the hollow square points connected by the dashed line are from the same subjects when the ventilation limit was increased from 10 to 20 liters/min by increasing flow to the bag 162. The filled red circles are from a different study in which four subjects breathed to targets of 5, 10, and 20 liters/min and a metronome set at 14 breaths/min as PETCO2 was slowly raised until the subject reported that the sensation was intolerable 203. Tolerance limit is assumed to be 100%FS air hunger. The dotted lines are hypothetical; the right dotted line is constructed from data points from the two studies, and the left dotted line is assumed to have the same slope extending from one data point, but the region below the question mark on the 5 liters/min line cannot be explored in steady state without extraordinary methods such as extracorporeal exchange to reduce PETCO2 at low ventilation. (B) An approximate 3‐D representation of the same data.


Figure 8. Time course of air hunger response to onset of hypoxia shows the same biphasic response as the hypoxic ventilatory response. Solid circles represent the average air hunger response to a step reduction in PETO2 during constant mechanical ventilation at eucapnia. For comparison, the open circles depict the average response of ventilation during free breathing to a step reduction in PETO2 during constant at eucapnia during a separate session in the same subjects. Reused from Moosavi SH, et al., 2004 157 with permission RightsLink.


Figure 9. Time course of air hunger response to a step change in tidal volume at constant PETCO2 and PETO2. Although mechanoreceptors respond fully on the first breath, central neural processes act as a low‐pass filter, slowing the perceptual response. Step changes in tidal volume were effected during mechanical volume‐control ventilation, while PETCO2 and PETO2 were held constant by altering inspired gasses. Breath by breath mean tidal volumes (VT) and air hunger ratings were averaged from 30 steps in six healthy subjects. Breaths were aligned with respect to the step change in tidal volume. This experiment was conducted under mild hyperoxia (PETO2 ∼160 Torr). Reprinted from Evans KC, et al., 2002 85 with permission RightsLink.


Figure 10. Likely neural pathways for air hunger based on current information. Inputs and outputs are in italics, structures are normal font. The heavy blue arrows indicate the currently favored pathway for air hunger sensation; green arrows indicate the generally accepted pathway for reflex ventilatory response; black indicates structures and stimuli in common for air hunger and ventilatory responses; red dashed arrow indicates the pathway for relief (inhibition) of air hunger sensation by mechanoreceptor input coming from slowly adapting pulmonary stretch receptors (SAPSRs). SAPSR input projects both to brainstem neurons and to cortical neurons—the level at which air hunger relief is effected is currently unknown.


Figure 11. Differential effect on respiratory sensations of partial neuromuscular block with short‐acting agent (mivacurium). These data show that air hunger and work/effort sensations are distinct, driven by different neural mechanisms. Air hunger ratings, blue filled circles; work ratings, red filled circles; breathing effort ratings, open squares. (A) Subjects breathed to a 30 liter/min target while eucapnic PETCO2 was maintained by altering inspired PCO2. In panel (A), it can be seen that during volitional hyperpnea partial paralysis had a large effect on perceived work and effort of breathing, which increased as more voluntary (cortical) motor command was needed to maintain the ventilation target. In contrast, air hunger remained at zero throughout because the prevailing level of reflex (medullary) drive was low throughout. (B) Ventilation was stimulated by hypercapnia to achieve approximately 30 liters/min. In panel (B), it can be seen that during CO2‐driven hyperpnea air hunger increased in concert with work and effort because medullary motor command was elevated (implying greater medullary corollary discharge). The degree of partial paralysis was sufficient to reduce vital capacity by 40% compared to control (and reduced handgrip strength by 60%); full vital capacity had returned at the time of recovery measurements. Data re‐plotted, with permission, from Figure 2 of Moosavi SH, et al., 2000 160; License # 4826560010506.


Figure 12. Lack of effect of opiate on work/effort breathing discomfort (left panel) contrasts with pronounced effect of opiate on air hunger breathing discomfort (right panel). This is another demonstration that air hunger is distinct from work/effort sensations because they can be separately manipulated. The left panel shows data re‐plotted from Figure 1 of Ref. 232. Subjects breathed against large inspiratory threshold loads, but respiratory rate and tidal volume were well maintained, from which we infer that blood gasses were not compromised (there were no measures of arterial or end‐tidal gasses). Ratings of “discomfort” are expressed as percent of full scale (%FS). The minimum and maximum ends of the scale were not defined, but seven descriptors were placed along the scale. The maximum discomfort elicited by the largest threshold load (74% of maximum static inspiratory pressure) was equivalent to the verbal scale label “unpleasant”; the low ratings of discomfort in this experiment probably reflect the fact that respiratory work tasks are not very unpleasant in the absence of air hunger 20. Breathing discomfort following opiate was not different in this work/effort model. The right panel shows data re‐plotted from Ref. 15. In this experiment subjects rated “breathing discomfort” on a visual analog scale, where the scale maximum was defined as “unbearable”; these ratings are expressed as %FS. Inspired PCO2 was varied while ventilation was restricted to approximately 0.13 liter/min with a background of constant hyperoxia (FIO2 = 30%). Ratings were obtained over a range of PETCO2. Regression lines were obtained for each subject in each condition, then averaged to obtain the mean regressions shown here. The large decrease in breathing discomfort with opiate was statistically significant in this air hunger model. The drug, dosage, and route of administration differed between studies, but we assess them as roughly equivalent opiate doses. Supinski et al. confirmed effective analgesia following oral codeine using a cold pressor test. Data re‐plotted from Banzett RB, et al., 2011 15 and Supinski G, et al., 1990 232. Adapted with permission of the American Thoracic Society (ATS). Copyright © 2020 ATS. All rights reserved. Am Rev Respir Dis 141: 1516‐1521 and Am J Respir Crit Care Med 184: 920‐927. The Am J Respir Crit Care Med and Am Rev Respir Dis are official journals of the ATS. Readers are encouraged to read the entire articles for the correct context at [https://doi.org/10.1164/ajrccm/141.6.1516 & https://doi.org/10.1164/rccm.201101‐0005OC]. The authors, editors, and The ATS are not responsible for errors or omissions in adaptations.


Figure 13. Air hunger during complete paralysis, showing that respiratory muscle contraction is not necessary for air hunger. Because this experiment disproved a long‐held tenet, it was repeated by a completely independent laboratory. Left panel shows data extracted from Figure 3 of Ref. 95; right panel shows data extracted from Figure 3 of Ref. 16. In both cases the subject (both authors of their respective studies) was totally paralyzed with curariform neuromuscular block and mechanically ventilated at constant tidal volume and frequency (Left VT = 1.0 liter, f = 8.8, SpO2 >98%; right VT = 0.92 liter, f = 12.5, FIO2 >90%). Time ticks in both panels are at 100 s intervals. As explained more fully in the text, the air hunger response lags changes in end‐tidal PCO2 and changes in tidal volume 14,85; therefore, air hunger measurements are offset in time to account for the slow air hunger dynamic response. Subjects were told to rate “respiratory discomfort” (left panel) or “air hunger” (right panel); both subjects chose the descriptor “urge to breathe” in debriefing. Rating scale on left was marked “severe” at 50% Full Scale and “maximal” at 100%FS; Rating scale on right was marked “slight plus” at 50% Full Scale and “extreme, intolerable” at 100%FS. Reused from Banzett RB, et al., 1990 16 and Gandevia SC, et al., 1993 95 with permission; License #4823790296315 and #4826560802572.


Figure 14. Putative “respiratory corollary discharge” recorded in the thalamus of a decorticate, paralyzed cat. This is one example of thalamic neurons that responded to increased respiratory motor activity. Just before the beginning of the record mechanical ventilation was paused. As PCO2 rose during the “breath hold,” brainstem ventilatory motor output (reflected in phrenic nerve activity) increased. About midway through the record, a threshold appears to be reached, and there was a profound progressive increase in thalamic activity. This mirrors the rise of air hunger sensation seen during a breath hold starting at low PETCO2 in human subjects 91,173. Similar responses have been observed in midbrain neurons 46. These observations suggest a neural substrate in accord with the theory that air hunger arises from corollary discharge carrying information about medullary motor activity to cortical sensory regions (Hypothesis 3). Adapted, with permission, from Figure 1 of Chen Z, et al., 1992 47; License #4826561235292.


Figure 15. Effect of neural lesions on mechanoreceptor relief of air hunger (effect of ventilation on air hunger). This graph demonstrates the predominant effect of pulmonary mechanoreceptors compared to rib cage and diaphragm mechanoreceptors. In all cases moderate air hunger was evoked by elevating PETCO2 above resting level while holding ventilation constant at about 10 liters/min with a background of mild hyperoxia (FIO2 30%–50%); this is the left‐hand point on each line. Tidal volume was increased while PETCO2 was held constant by elevating inspired PCO2. The black line with filled circles shows the mean reduction of air hunger in healthy normal subjects (averaged from the three studies depicted in Figure 4) 85,105,162. The blue line with filled triangles shows the response of quadriplegics having complete spinal cord lesions at the cervical 1 to 2 level 29; Quadriplegic subjects are presumed to have no chest wall sensation, but pulmonary stretch receptor innervation via the vagus nerve is presumed intact. The green line with filled squares shows the response of heart‐lung transplant patients is less than normals and quadriplegics, suggesting that chest‐wall afferents provide less relief (Experiment 3, in Ref. 105); transplant patients have intact rib cage and diaphragm innervation but were presumed to have no pulmonary innervation [although later work showed that some pulmonary innervation returns in such patients 38].


Figure 16. Mechanoreceptor inhibition of putative respiratory corollary discharge by vagal pulmonary mechanoreceptor afferents in decerebrated paralyzed cats 78. In panel (A), the vagus nerves are intact, and the midbrain neuron is silent during mechanical ventilation; when the ventilator is paused (breath hold) activity appears in the midbrain neuron. Midbrain activity is once again inhibited when ventilation is resumed. In panel (B), following bilateral vagotomy, the midbrain neuron is active regardless of whether the mechanical ventilator is cycling. Vagal cooling data suggested the inhibition was mediated by slowly adapting pulmonary stretch receptors (SAPSRs). This is consistent with experiments in humans with neural lesions described in the text 92,105,145. Adapted, with permission, from Eldridge and Chen, 1992 78; License #4826561496041.


Figure 17. Adaptation of air hunger response to prevailing level of PETCO2 (from Ref. 28). Four ventilator‐dependent patients were adapted from a baseline “resting” 27 Torr PETCO2 to 41 Torr PETCO2 by slowly increasing inspired PCO2 over the course of 1 to 3 days. Ventilator‐delivered tidal volume and respiratory rate were held constant throughout. The acute air hunger response to a CO2 stimulus was assessed before during and after adaptation. Filled diamonds with dashed line represent the average air hunger response to acutely elevated PETCO2 before and after the adaptation period; solid circles with solid line represent the air hunger response to acutely elevated PETCO2 during chronically elevated PETCO2. Adaptation and acute testing were performed during normoxia (FIO2 21%). Modified from Bloch‐Salisbury E, et al., 1996 28 with permission RightsLink.


Figure 18. Word Cloud summary of brain activations during respiratory discomfort. Numerous functional imaging studies have observed regional brain activations associated with dyspnea. These studies employed either (i) mild to moderate resistive loads or (ii) mild hypercapnia combined with tidal volume restriction and so likely produced different qualitative forms dyspnea. The former stimulus evokes mainly work/effort sensation, while the latter evokes air hunger sensation. The composite results of 16 studies are represented with the regional activations associated with the distinct stimuli being differentiated by font color; activations exclusive to air hunger (3 studies) are shown in blue, those exclusive to work/effort (13 studies) are shown in red and activations common to both air hunger and work effort are shown in purple. The font size represents the number of studies in which each particular regional activation was observed. All studies observed activation of the insular cortex. BNST, Bed Nuclei of the Stria Terminalis.


Figure 19. Activation of the anterior insular cortex is observed in PET and fMRI studies that induce air hunger by tidal volume limitation. Panel (A) shows a transverse PET image (8 mm rostral to AC‐PC baseline) from the first published brain imaging study of air hunger. Panel (B) shows a coronal fMRI image of the same region (centered on the AC line) with red arrows indicating activations associated with the onset of air hunger and yellow arrows indicating areas associated with steady state air hunger. The insular cortex is involved in the perception of other homeostatic warning signals (e.g., pain, thirst, and food hunger) and is the most commonly observed regional activation in brain imaging studies of respiratory discomfort. The fMRI study (B) also shows activation of the dorsal anterior cingulate cortex (dACC), an area involved with integration of emotional responses to adverse stimuli. (A) Adapted, with permission, from Banzett RB, et al., 2000 18; (B) Adapted, with permission, from Binks AP, et al., 2014 26; License #4825931387868 and #4830231140126.


Figure 20. Functional MRI images of activation in the amygdala during respiratory discomfort. The amygdala is a component of the limbic system associated with emotional responses, particularly fear. It is activated by air hunger induced by tidal volume limitation, as observed in the fMRI study by Evans et al. (Panel A: Am, transverse view at z‐plane = 14). Von Leupoldt et al. also observed amygdala activation associated with the “unpleasantness” of uncomfortable breathing induced by resistive respiratory loads (Panel B: AM, coronal view at y = 9). (A) Adapted from Evans KC, et al., 2002 85 with permission RightsLink; (B) Adapted form von Leupoldt A, et al., 2008 237 with permission of the American Thoracic Society (ATS). Copyright © 2020 ATS. All rights reserved. Am J Respir Crit Care Med 177: 1026‐1032. The Am J Respir Crit Care Med is an official journal of the ATS. Readers are encouraged to read the entire article for the correct context at [https://doi.org/10.1164/rccm.200712‐1821OC]. The authors, editors, and The ATS are not responsible for errors or omissions in adaptations.


Figure 21. Proposed central network for air hunger and the emotional and behavioral responses to it. The brown lines depict the interoceptive pathway and black arrows represent known connections. BNST, bed nuclei of the stria terminals; NTS, nucleus tractus solitarius.


Figure 22. Rats avoid CO2—induced discomfort rather than eat. The study by Neil and Weary shows that rats given 5 min of access to a chamber that contains a food reward, avoid that chamber when CO2 in the chamber rises above 10% 171. The measurable change in behavior provides proof of concept that complex integrated processes can be included in an animal model of air hunger. Developing an animal model of air hunger presents novel issues. Because air hunger is an amalgam of integrated afferent inputs that lead to emotional and behavioral responses, a robust model cannot simply measure reflex responses but should encompass higher cortical processes. Inspired CO2 concentrations above 10% are rarely used in human studies, but the rats in this study were free breathing and afforded the mechanoreceptor relief that it brings (see section titled “30The Quantitative Relationship between Stimulus and Air Hunger. Part B—Changing Ventilation While Holding Ventilatory Drive Constant”). The rats were being encouraged to tolerate hypercapnia through the enticement of a food reward, whereas positive rewards have not been used in human studies of air hunger. There may also be important species differences in chemoreception, which is a fundamental physiological aspect that should be considered in animal model development. Reused, with permission, from Niel L and Weary DM, 2007 171; License #4825940537868.


Figure 23. Air hunger is the dominant sensory quality of breathing discomfort in hospitalized patients. Graph depicts the frequency with which sensory qualities are chosen by hospital inpatients as the most apt description of their dyspnea. The prominence of air hunger sensation increases as clinical dyspnea worsens. Responses are grouped by the overall level of breathing discomfort on a scale of 0 to 10 where 10 is “unbearable.” Graph summarizes 460 responses from 156 patients interviewed repeatedly during the hospital stay utilizing the Multidimensional Dyspnea Profile. Reprinted, with permission, from Stevens JP, et al., 2019 225; License #4830241184265.


Figure 24. Air hunger (also termed “unsatisfied inspiration”) becomes the dominant sensory quality of breathing discomfort in pulmonary patients undergoing progressive exercise. Graph depicts the frequency with which sensory qualities are chosen by patients with pulmonary hypertension (n = 26) as the most apt description of their dyspnea during symptom‐limited incremental cycle exercise. The sudden rise in selection of air hunger coincides with the point at which tidal volume becomes limited by declining inspiratory capacity. Reproduced from Boucly A, et al., 2019 32 with permission of the © ERS 2020: European Respiratory Journal 55 (2) 1802108; DOI: 10.1183/13993003.02108‐2018 Published 12 February 2020.
References
 1.Adams L, Lane R, Shea SA, Cockcroft A, Guz A. Breathlessness during different forms of ventilatory stimulation: A study of mechanisms in normal subjects and respiratory patients. Clin Sci 69: 663‐672, 1985.
 2.Amendola L, Weary DM. Evidence for consistent individual differences in rat sensitivity to carbon dioxide. PLoS One 14: e0215808, 2019.
 3.Amour FE, Smith DL. A method for determining loss of pain sensation. J Pharmacol Exp Ther 72: 74, 1941.
 4.Anton F, Euchner I, Handwerker HO. Psychophysical examination of pain induced by defined CO2 pulses applied to the nasal mucosa. Pain 49: 53‐60, 1992.
 5.Anton F, Peppel P, Euchner I, Handwerker HO. Controlled noxious chemical stimulation: Responses of rat trigeminal brainstem neurones to CO2 pulses applied to the nasal mucosa. Neurosci Lett 123: 208‐211, 1991.
 6.Aron AR, Robbins TW, Poldrack RA. Inhibition and the right inferior frontal cortex: One decade on. Trends Cogn Sci 18: 177‐185, 2014.
 7.Augustine JR. Circuitry and functional aspects of the insular lobe in primates including humans. Brain Res Brain Res Rev 22: 229‐244, 1996.
 8.Bain AR, Drvis I, Dujic Z, MacLeod DB, Ainslie PN. Physiology of static breath holding in elite apneists. Exp Physiol 103: 635‐651, 2018.
 9.Bakers JH, Tenney SM. The perception of some sensations associated with breathing. Respir Physiol 10: 85‐92, 1970.
 10.Baliki MN, Chialvo DR, Geha PY, Levy RM, Harden RN, Parrish TB, Apkarian AV. Chronic pain and the emotional brain: Specific brain activity associated with spontaneous fluctuations of intensity of chronic back pain. J Neurosci 26: 12165‐12173, 2006.
 11.Baliki MN, Geha PY, Fields HL, Apkarian AV. Predicting value of pain and analgesia: Nucleus accumbens response to noxious stimuli changes in the presence of chronic pain. Neuron 66: 149‐160, 2010.
 12.Banzett R, Lansing R, Evans K, Shea S. Stimulus‐response characteristics of CO2‐induced air hunger in normal subjects. Respir Physiol 103: 19‐31, 1996.
 13.Banzett R, Moosavi S. Dyspnea and pain: Similarities and contrasts between two very unpleasant sensations. APS Bull 11: 1‐8, 2001.
 14.Banzett RB. Dynamic response characteristics of CO2‐induced air hunger. Respir Physiol 105: 47‐55, 1996.
 15.Banzett RB, Adams L, O'Donnell CR, Gilman SA, Lansing RW, Schwartzstein RM. Using laboratory models to test treatment: Morphine reduces dyspnea and hypercapnic ventilatory response. Am J Respir Crit Care Med 184: 920‐927, 2011.
 16.Banzett RB, Lansing RW, Brown R, Topulos GP, Yager D, Steele SM, Londoño B, Loring SH, Reid MB, Adams L, Nations CS. 'Air hunger' from increased PCO2 persists after complete neuromuscular block in humans. Respir Physiol 81: 1‐17, 1990.
 17.Banzett RB, Lansing RW, Reid MB, Adams L, Brown R. 'Air hunger' arising from increased PCO2 in mechanically ventilated quadriplegics. Respir Physiol 76: 53‐67, 1989.
 18.Banzett RB, Mulnier HE, Murphy K, Rosen SD, Wise RJ, Adams L. Breathlessness in humans activates insular cortex. Neuroreport 11: 2117‐2120, 2000.
 19.Banzett RB, O'Donnell CR, Guilfoyle TE, Parshall MB, Schwartzstein RM, Meek PM, Gracely RH, Lansing RW. Multidimensional Dyspnea Profile: An instrument for clinical and laboratory research. Eur Respir J 45: 1681‐1691, 2015.
 20.Banzett RB, Pedersen SH, Schwartzstein RM, Lansing RW. The affective dimension of laboratory dyspnea: Air hunger is more unpleasant than work/effort. Am J Respir Crit Care Med 177: 1384‐1390, 2008.
 21.Banzett RB, Schwartzstein RM, Lansing RW, O'Donnell CR. Aerosol furosemide for dyspnea: High‐dose controlled delivery does not improve effectiveness. Respir Physiol Neurobiol 247: 24‐30, 2018.
 22.Banzett RB, Sheridan AR, Baker KM, Lansing RW, Stevens JP. ‘Scared to death’ dyspnoea from the hospitalised patient's perspective. BMJ Open Respir Res 7: e000493, 2020.
 23.Basoglu M. Effective management of breathlessness: A review of potential human rights issues. Eur Respir J 49, 2017.
 24.Binks AP, Cunningham VJ, Adams L, Banzett RB. Gray matter blood flow change is unevenly distributed during moderate isocapnic hypoxia in humans. J Appl Physiol (1985) 104: 212‐217, 2008.
 25.Binks AP, Desjardin S, Riker R. ICU clinicians underestimate breathing discomfort in ventilated subjects. Respir Care 62: 150‐155, 2017.
 26.Binks AP, Evans KC, Reed JD, Moosavi SH, Banzett RB. The time‐course of cortico‐limbic neural responses to air hunger. Respir Physiol Neurobiol 204: 78‐85, 2014.
 27.Binks AP, Vovk A, Ferrigno M, Banzett RB. The air hunger response of four elite breath‐hold divers. Respir Physiol Neurobiol 159: 171‐177, 2007.
 28.Bloch‐Salisbury E, Shea SA, Brown R, Evans K, Banzett RB. Air hunger induced by acute increase in PCO2 adapts to chronic elevation of PCO2 in ventilated humans. J Appl Physiol 81: 949‐956, 1996.
 29.Bloch‐Salisbury E, Spengler CM, Brown R, Banzett RB. Self‐control and external control of mechanical ventilation give equal air hunger relief. Am J Respir Crit Care Med 157: 415‐420, 1998.
 30.Bonvallet M, Hugelin A. Sensibilité comparée du systéme réticulé activateur ascendant et du centre respiratoire aux gaz du sang et a l'adrénaline. J Physiol 47: 651‐654, 1955.
 31.Bostan AC, Dum RP, Strick PL. Cerebellar networks with the cerebral cortex and basal ganglia. Trends Cogn Sci 17: 241‐254, 2013.
 32.Boucly A, Morelot‐Panzini C, Garcia G, Weatherald J, Jais X, Savale L, Montani D, Humbert M, Similowski T, Sitbon O, Laveneziana P. Intensity and quality of exertional dyspnoea in patients with stable pulmonary hypertension. Eur Respir J 55: 1802.108, 2020.
 33.Britt DP. The humaneness of carbon dioxide as an agent of euthanasia for laboratory rodents. In: Euthanasia of Unwanted, Injured Or Diseased Animals or for Educational or Scientific Purposes. Regent's Park: Universities Federation for Animal Welfare, UK, 1986, p. 19‐31.
 34.Bruce LL, Neary TJ. The limbic system of tetrapods: A comparative analysis of cortical and amygdalar populations. Brain Behav Evol 46: 224‐234, 1995.
 35.Buckner RL. The cerebellum and cognitive function: 25 Years of insight from anatomy and neuroimaging. Neuron 80: 807‐815, 2013.
 36.Burgraff NJ, Neumueller SE, Buchholz K, Langer TM 3rd, Hodges MR, Pan L, Forster HV. Ventilatory and integrated physiological responses to chronic hypercapnia in goats. J Physiol 596: 5343‐5363, 2018.
 37.Bush G, Luu P, Posner MI. Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn Sci 4: 215‐222, 2000.
 38.Butler JE, Anand A, Crawford MR, Glanville AR, McKenzie DK, Paintal AS, Taylor JL, Gandevia SC. Changes in respiratory sensations induced by lobeline after human bilateral lung transplantation. J Physiol 534: 583‐593, 2001.
 39.Campbell EJ. A being breathing thoughtful breaths. Am J Respir Crit Care Med 162: 2027‐2028, 2000.
 40.Campbell EJ, Freedman S, Clark TJ, Robson JG, Norman J. The effect of muscular paralysis induced by tubocurarine on the duration and sensation of breath‐holding. Clin Sci 32: 425‐432, 1967.
 41.Campbell EJ, Freedman S, Smith PS, Taylor ME. The ability of man to detect added elastic loads to breathing. Clin Sci 20: 223‐231, 1961.
 42.Campbell EJ, Godfrey S, Clark TJ, Freedman S, Norman J. The effect of muscular paralysis induced by tubocurarine on the duration and sensation of breath‐holding during hypercapnia. Clin Sci 36: 323‐328, 1969.
 43.Campbell EJM, Howell JBL. The sensation of breathlessness. Br Med Bull 19: 36‐40, 1963.
 44.Castele RJ, Connors AF, Altose MD. Effects of changes in CO2 partial pressure on the sensation of respiratory drive. J Appl Physiol (1985) 59: 1747‐1751, 1985.
 45.Chen ML, Keens TG. Congenital central hypoventilation syndrome: Not just another rare disorder. Paediatr Respir Rev 5: 182‐189, 2004.
 46.Chen Z, Eldridge FL, Wagner PG. Respiratory‐associated rhythmic firing of midbrain neurones in cats: Relation to level of respiratory drive. J Physiol 437: 305‐325, 1991.
 47.Chen Z, Eldridge FL, Wagner PG. Respiratory‐associated thalamic activity is related to level of respiratory drive. Respir Physiol 90: 99‐113, 1992.
 48.Chonan T, Mulholland MB, Altose MD, Cherniack NS. Effects of changes in level and pattern of breathing on the sensation of dyspnea. J Appl Physiol (1985) 69: 1290‐1295, 1990.
 49.Chonan T, Mulholland MB, Cherniack NS, Altose MD. Effects of voluntary constraining of thoracic displacement during hypercapnia. J Appl Physiol (1985) 63: 1822‐1828, 1987.
 50.Chonan T, Okabe S, Hida W, Satoh M, Kikuchi Y, Takishima T, Shirato K. Influence of sustained hypoxia on the sensation of dyspnea. Jpn J Physiol 48: 291‐295, 1998.
 51.Claassen J, Koenen LR, Ernst TM, Labrenz F, Theysohn N, Forsting M, Bingel U, Timmann D, Elsenbruch S. Cerebellum is more concerned about visceral than somatic pain. J Neurol Neurosurg Psychiatry 91: 218‐219, 2020.
 52.Clark JM. Rate of acclimatization to chronic hypercapnia in man. In: Lambertsen CJ, editor. Underwater Physiology: Proceedings of the Fourth Symposium on Underwater Physiology. New York, NY: Academic Press, 1971, p. 399‐408.
 53.Cliffer KD, Burstein R, Giesler GJ Jr. Distributions of spinothalamic, spinohypothalamic, and spinotelencephalic fibers revealed by anterograde transport of PHA‐L in rats. J Neurosci 11: 852‐868, 1991.
 54.Coombes SA, Misra G. Pain and motor processing in the human cerebellum. Pain 157: 117‐127, 2016.
 55.Cooper J, Mason G, Raj M. Determination of the aversion of farmed mink (Mustela vison) to carbon dioxide. Vet Rec 143: 359‐361, 1998.
 56.Corfield DR, Fink GR, Ramsay SC, Murphy K, Harty HR, Watson JD, Adams L, Frackowiak RS, Guz A. Evidence for limbic system activation during CO2‐stimulated breathing in man. J Physiol 488: 77‐84, 1995.
 57.Craig AD. How do you feel? Interoception: The sense of the physiological condition of the body. Nat Rev Neurosci 3: 655‐666, 2002.
 58.Craig AD. How do you feel—now? The anterior insula and human awareness. Nat Rev Neurosci 10: 59‐70, 2009.
 59.Craig AD. Central neural substrates involved in temperature discrimination, thermal pain, thermal comfort, and thermoregulatory behavior. Handb Clin Neurol 156: 317‐338, 2018.
 60.Critchley HD, Harrison NA. Visceral influences on brain and behavior. Neuron 77: 624‐638, 2013.
 61.Crosby A, Talbot NP, Balanos GM, Donoghue S, Fatemian M, Robbins PA. Respiratory effects in humans of a 5‐day elevation of end‐tidal PCO2 by 8 Torr. J Appl Physiol (1985) 95: 1947‐1954, 2003.
 62.Cross BA, Guz A, Jain SK, Archer S, Stevens J, Reynolds F. The effect of anaesthesia of the airway in dog and man: A study of respiratory reflexes, sensations and lung mechanics. Clin Sci Mol Med 50: 439‐454, 1976.
 63.Dangers L, Laviolette L, Georges M, Gonzalez‐Bermejo J, Rivals I, Similowski T, Morelot‐Panzini C. Relieving dyspnoea by non‐invasive ventilation decreases pain thresholds in amyotrophic lateral sclerosis. Thorax 72: 230‐235, 2017.
 64.Dangers L, Laviolette L, Similowski T, Morelot‐Panzini C. Interactions between dyspnea and the brain processing of nociceptive stimuli: Experimental air hunger attenuates laser‐evoked brain potentials in humans. Front Physiol 6: 358, 2015.
 65.Davenport PW, Colrain IM, Hill PM. Scalp topography of the short‐latency components of the respiratory‐related evoked potential in children. J Appl Physiol 80: 1785‐1791, 1996.
 66.Davenport PW, Friedman WA, Thompson FJ, Franzen O. Respiratory‐related cortical potentials evoked by inspiratory occlusion in humans. J Appl Physiol 60: 1843‐1848, 1986.
 67.Davenport PW, Vovk A. Cortical and subcortical central neural pathways in respiratory sensations. Respir Physiol Neurobiol 167: 72‐86, 2009.
 68.Davis M, Walker DL, Miles L, Grillon C. Phasic vs sustained fear in rats and humans: Role of the extended amygdala in fear vs anxiety. Neuropsychopharmacology 35: 105‐135, 2010.
 69.Dell P, Bonvallet M. Direct and reflex control of the activity of the ascending activating reticular system of the cerebral trunk with oxygen and carbon dioxide of the blood. C R Seances Soc Biol Fil 148: 855‐858, 1954.
 70.Demediuk BH, Manning H, Lilly J, Fencl V, Weinberger SE, Weiss JW, Schwartzstein RM. Dissociation between dyspnea and respiratory effort. Am Rev Respir Dis 146: 1222‐1225, 1992.
 71.Denton D. The Primordial Emotions: The Dawning of Consciousness. USA: Oxford University Press, 2006, p. 296.
 72.Denton DA, McKinley MJ, Farrell M, Egan GF. The role of primordial emotions in the evolutionary origin of consciousness. Conscious Cogn 18: 500‐514, 2009.
 73.Dereli AS, Yaseen Z, Carrive P, Kumar NN. Adaptation of respiratory‐related brain regions to long‐term hypercapnia: Focus on neuropeptides in the RTN. Front Neurosci 13: 1343, 2019.
 74.Dripps RD, Comroe JH Jr. The respiratory and circulatory response of normal man to inhalation of 7.6 and 10.4 per cent CO2 with a comparison of the maximal ventilation produced by severe muscular exercise, inhalation of CO2 and maximal voluntary hyperventilation. Am J Phys 149: 43‐51, 1947.
 75.Easton PA, Slykerman LJ, Anthonisen NR. Ventilatory response to sustained hypoxia in normal adults. J Appl Physiol (1985) 61: 906‐911, 1986.
 76.Ekstrom M, Williams M, Johnson MJ, Huang C, Currow DC. Agreement between breathlessness severity and unpleasantness in people with chronic breathlessness: A longitudinal clinical study. J Pain Symptom Manag 57: 715‐723.e5, 2019.
 77.Eldridge FL. Central integration of mechanisms in exercise hyperpnea. Med Sci Sports Exerc 26: 319‐327, 1994.
 78.Eldridge FL, Chen Z. Respiratory‐associated rhythmic firing of midbrain neurons is modulated by vagal input. Respir Physiol 90: 31‐46, 1992.
 79.Eldridge FL, Gill‐Kumar P, Millhorn DE. Input‐output relationships of central neural circuits involved in respiration in cats. J Physiol 311: 81‐95, 1981.
 80.Eldridge FL, Kiley JP, Paydarfar D. Dynamics of medullary hydrogen ion and respiratory responses to square‐wave change of arterial carbon dioxide in cats. J Physiol 385: 627‐642, 1987.
 81.Elliott MW, Adams L, Cockcroft A, MacRae KD, Murphy K, Guz A. The language of breathlessness. Use of verbal descriptors by patients with cardiopulmonary disease. Am Rev Respir Dis 144: 826‐832, 1991.
 82.Esser RW, Stoeckel MC, Kirsten A, Watz H, Taube K, Lehmann K, Magnussen H, Buchel C, von Leupoldt A. Brain activation during perception and anticipation of dyspnea in chronic obstructive pulmonary disease. Front Physiol 8: 617, 2017.
 83.Evans KC. Cortico‐limbic circuitry and the airways: Insights from functional neuroimaging of respiratory afferents and efferents. Biol Psychol 84: 13‐25, 2010.
 84.Evans KC. Neuroimaging of dyspnea. In: Mahler DA, O'Donnell DE, editors. Dyspnea: Mechanisms, Measurement, and Management. Boca Raton, FL, USA: CRC Press, 2014, p. 11‐24.
 85.Evans KC, Banzett RB, Adams L, McKay L, Frackowiak RS, Corfield DR. BOLD fMRI identifies limbic, paralimbic, and cerebellar activation during air hunger. J Neurophysiol 88: 1500‐1511, 2002.
 86.Faull OK, Cox PJ, Pattinson KTS. Cortical processing of breathing perceptions in the athletic brain. NeuroImage 179: 92‐101, 2018.
 87.Faull OK, Hayen A, Pattinson KTS. Breathlessness and the body: Neuroimaging clues for the inferential leap. Cortex 95: 211‐221, 2017.
 88.Faull OK, Jenkinson M, Ezra M, Pattinson K. Conditioned respiratory threat in the subdivisions of the human periaqueductal gray. elife 5: e12047, 2016.
 89.Faull OK, Pattinson KT. The cortical connectivity of the periaqueductal gray and the conditioned response to the threat of breathlessness. elife 6: e21749, 2017.
 90.Fisher JA, Sobczyk O, Crawley A, Poublanc J, Dufort P, Venkatraghavan L, Sam K, Mikulis D, Duffin J. Assessing cerebrovascular reactivity by the pattern of response to progressive hypercapnia. Hum Brain Mapp 38: 3415‐3427, 2017.
 91.Flume P, Eldridge F, Edwards L, Houser L. The Fowler breathholding study revisited: Continuous rating of respiratory sensation. Respir Physiol 95: 53‐66, 1994.
 92.Flume PA, Eldridge FL, Edwards LJ, Mattison LE. Relief of the 'air hunger' of breathholding. A role for pulmonary stretch receptors. Respir Physiol 103: 221‐232, 1996.
 93.Forster HV, Haouzi P, Dempsey JA. Control of breathing during exercise. Compr Physiol 2: 743‐777, 2012.
 94.Fowler WS. Breaking point of breath holding. J Appl Physiol 6: 539‐545, 1954.
 95.Gandevia SC, Killian K, McKenzie DK, Crawford M, Allen GM, Gorman RB, Hales JP. Respiratory sensations, cardiovascular control, kinaesthesia and transcranial stimulation during paralysis in humans. J Physiol Lond 470: 85‐107, 1993.
 96.Garske LA, Lal R, Stewart IB, Morris NR, Cross TJ, Adams L. Exertional dyspnea associated with chest wall strapping is reduced when external dead space substitutes for part of the exercise stimulus to ventilation. J Appl Physiol (1985) 122: 1179‐1187, 2017.
 97.Gerwig M, Dimitrova A, Kolb FP, Maschke M, Brol B, Kunnel A, Boring D, Thilmann AF, Forsting M, Diener HC, Timmann D. Comparison of eyeblink conditioning in patients with superior and posterior inferior cerebellar lesions. Brain 126: 71‐94, 2003.
 98.Grogono JC, Butler C, Izadi H, Moosavi SH. Inhaled furosemide for relief of air hunger versus sense of breathing effort: A randomized controlled trial. Respir Res 19: 181, 2018.
 99.Guyenet PG. Regulation of breathing and autonomic outflows by chemoreceptors. Compr Physiol 4: 1511‐1562, 2014.
 100.Habas C, Kamdar N, Nguyen D, Prater K, Beckmann CF, Menon V, Greicius MD. Distinct cerebellar contributions to intrinsic connectivity networks. J Neurosci 29: 8586‐8594, 2009.
 101.Haldane J, Smith JL. The physiological effects of air vitiated by respiration. J Pathol Bacteriol 1: 168‐186, 1892.
 102.Haldane JS, Kellas AM, Kennaway EL. Experiments on acclimatisation to reduced atmospheric pressure. J Physiol 53: 181‐206, 1919.
 103.Harty HR, Adams L. Dose dependency of perceived breathlessness on hypoventilation during exercise in normal subjects. J Appl Physiol 77: 2666‐2674, 1994.
 104.Harty HR, Corfield DR, Schwartzstein RM, Adams L. External thoracic restriction, respiratory sensation, and ventilation during exercise in men. J Appl Physiol 86: 1142‐1150, 1999.
 105.Harty HR, Mummery CJ, Adams L, Banzett RB, Wright IG, Banner NR, Yacoub MH, Guz A. Ventilatory relief of the sensation of the urge to breathe in humans: Are pulmonary receptors important? J Physiol 490: 805‐815, 1996.
 106.Haugdahl HS, Storli SL, Meland B, Dybwik K, Romild U, Klepstad P. Underestimation of patient breathlessness by nurses and physicians during a spontaneous breathing trial. Am J Respir Crit Care Med 192: 1440‐1448, 2015.
 107.Hayashi F, Coles SK, Bach KB, Mitchell GS, McCrimmon DR. Time‐dependent phrenic nerve responses to carotid afferent activation: Intact vs. decerebellate rats. Am J Phys 265: R811‐R819, 1993.
 108.Hayen A, Wanigasekera V, Faull OK, Campbell SF, Garry PS, Raby SJM, Robertson J, Webster R, Wise RG, Herigstad M, Pattinson KTS. Opioid suppression of conditioned anticipatory brain responses to breathlessness. NeuroImage 150: 383‐394, 2017.
 109.Herigstad M, Hayen A, Evans E, Hardinge FM, Davies RJ, Wiech K, Pattinson KTS. Dyspnea‐related cues engage the prefrontal cortex: Evidence from functional brain imaging in COPD. Chest 148: 953‐961, 2015.
 110.Hill L, Flack F. The effect of excess of carbon dioxide and of want of oxygen upon the respiration and the circulation. J Physiol Lond 37: 77‐111, 1908.
 111.Hirshman CA, McCullough RE, Weil JV. Normal values for hypoxic and hypercapnic ventilatory drives in man. J Appl Physiol 38: 1095‐1098, 1975.
 112.Hoover CF. The bedside study of air hunger. JAMA 87: 813‐816, 1926.
 113.Iber C, Berssenbrugge A, Skatrud JB, Dempsey JA. Ventilatory adaptations to resistive loading during wakefulness and non‐REM sleep. J Appl Physiol Respir Environ Exerc Physiol 52: 607‐614, 1982.
 114.Janson‐Bjerklie S, Carrieri VK, Hudes M. The sensations of pulmonary dyspnea. Nurs Res 35: 154‐159, 1986.
 115.Jennings DB, Davidson JS. Acid‐base and ventilatory adaptation in conscious dogs during chronic hypercapnia. Respir Physiol 58: 377‐393, 1984.
 116.Kastrup A, Kruger G, Glover GH, Neumann‐Haefelin T, Moseley ME. Regional variability of cerebral blood oxygenation response to hypercapnia. NeuroImage 10: 675‐681, 1999.
 117.Kelvin W. Electrical Units of Measurement. In: Popular Lectures and Addresses. London: MacMillan, 1889.
 118.Killian K, Campbell E. Historical aspects of dyspnea. In: Adams L, Guz A, editors. Respiratory Sensation. New York: Marcel Dekker, 1996, p. 1‐17.
 119.Kim MJ, Loucks RA, Palmer AL, Brown AC, Solomon KM, Marchante AN, Whalen PJ. The structural and functional connectivity of the amygdala: From normal emotion to pathological anxiety. Behav Brain Res 223: 403‐410, 2011.
 120.Kirkden RD, Niel L, Lee G, Makowska IJ, Pfaffinger MJ, Weary DM. The validity of using an approach‐avoidance test to measure the strength of aversion to carbon dioxide in rats. Appl Anim Behav Sci 114: 216‐234, 2008.
 121.Klumpers F, Kroes MCW, Baas JMP, Fernández G. How human amygdala and bed nucleus of the stria terminalis may drive distinct defensive responses. J Neurosci Off J Soc Neurosci 37: 9645‐9656, 2017.
 122.Knafelc M, Davenport PW. Relationship between resistive loads and P1 peak of respiratory‐related evoked potential. J Appl Physiol (1985) 83: 918‐926, 1997.
 123.Knight LK, Depue BE. New frontiers in anxiety research: The translational potential of the bed nucleus of the stria terminalis. Front Psychiatry 10: 510, 2019.
 124.Kobayasi S, Sasaki C. Breaking point of breathholding and tolerance time in rebreathing. Jpn J Physiol 17: 43‐56, 1967.
 125.Konishi S, Nakajima K, Uchida I, Kikyo H, Kameyama M, Miyashita Y. Common inhibitory mechanism in human inferior prefrontal cortex revealed by event‐related functional MRI. Brain 122 (Pt 5): 981‐991, 1999.
 126.Koski L, Paus T. Functional connectivity of the anterior cingulate cortex within the human frontal lobe: A brain‐mapping meta‐analysis. Exp Brain Res 133: 55‐65, 2000.
 127.Kotrach HG, Bourbeau J, Jensen D. Does nebulized fentanyl relieve dyspnea during exercise in healthy man? J Appl Physiol 118: 1406‐1414, 2015.
 128.Krohn TC, Hansen AK, Dragsted N. The impact of low levels of carbon dioxide on rats. Lab Anim 37: 94‐99, 2003.
 129.Laghi F, Shaikh HS, Morales D, Sinderby C, Jubran A, Tobin MJ. Diaphragmatic neuromechanical coupling and mechanisms of hypercapnia during inspiratory loading. Respir Physiol Neurobiol 198: 32‐41, 2014.
 130.Lane R, Adams L. Metabolic acidosis and breathlessness during exercise and hypercapnia in man. J Physiol 461: 47‐61, 1993.
 131.Lane R, Adams L, Guz A. The effects of hypoxia and hypercapnia on perceived breathlessness during exercise in humans. J Physiol 428: 579‐593, 1990.
 132.Lansing R, Banzett R. Psychophysical methods in the study of respiratory sensation. In: Adams L, Guz A, editors. Respiratory Sensation. New York: Marcel Dekker, 1996, p. 69‐100.
 133.Lansing R, Banzett R, Brown R, Reid M. Airway anesthesia diminished tidal volume perception in a C1‐C2 quadriplegic. FASEB J 2: A1298, 1988.
 134.Lansing RW, Gracely RH, Banzett RB. The multiple dimensions of dyspnea: Review and hypotheses. Respir Physiol Neurobiol 167: 53‐60, 2009.
 135.Lansing RW, Im BS, Thwing JI, Legedza AT, Banzett RB. The perception of respiratory work and effort can be independent of the perception of air hunger. Am J Respir Crit Care Med 162: 1690‐1696, 2000.
 136.Lansing RW, Moosavi SH, Banzett RB. Measurement of dyspnea: Word labeled visual analog scale vs. verbal ordinal scale. Respir Physiol Neurobiol 134: 77‐83, 2003.
 137.Lebow MA, Chen A. Overshadowed by the amygdala: The bed nucleus of the stria terminalis emerges as key to psychiatric disorders. Mol Psychiatry 21: 450‐463, 2016.
 138.LeDoux JE. Emotion circuits in the brain. Annu Rev Neurosci 23: 155‐184, 2000.
 139.Levitan R. The infection that's silently killing coronavirus patients. New York Times, New York, NY, 2020.
 140.Lewis RJ, Hoy AW, Sellin M. Ciguatera and mannitol: In vivo and in vitro assessment in mice. Toxicon 31: 1039‐1050, 1993.
 141.Lindholm P, Lundgren CE. The physiology and pathophysiology of human breath‐hold diving. J Appl Physiol (1985) 106: 284‐292, 2009.
 142.Liotti M, Brannan S, Egan G, Shade R, Madden L, Abplanalp B, Robillard R, Lancaster J, Zamarripa FE, Fox PT, Denton D. Brain responses associated with consciousness of breathlessness (air hunger). Proc Natl Acad Sci U S A 98: 2035‐2040, 2001.
 143.Locher C, Raux M, Fiamma MN, Morelot‐Panzini C, Zelter M, Derenne JP, Similowski T, Straus C. Inspiratory resistances facilitate the diaphragm response to transcranial stimulation in humans. BMC Physiol 6: 7, 2006.
 144.Luft U. Aviation physiology ‐ the effects of altitude. In: Fenn W, Rahn H, editors. Handbook of Physiology, Section 3: Respiration. Washington, D.C.: American Physiological Society, 1965, p. 1099‐1145.
 145.Manning HL, Shea SA, Schwartzstein RM, Lansing RW, Brown R, Banzett RB. Reduced tidal volume increases 'air hunger' at fixed PCO2 in ventilated quadriplegics. Respir Physiol 90: 19‐30, 1992.
 146.Mansoor JK, Eldridge MW, Yoneda KY, Schelegle ES, Wood SC. Role of airway receptors in altitude‐induced dyspnea. Med Sci Sports Exerc 33: 1449‐1455, 2001.
 147.Manto M, Bower JM, Conforto AB, Delgado‐García JM, da Guarda SNF, Gerwig M, Habas C, Hagura N, Ivry RB, Mariën P, Molinari M, Naito E, Nowak DA, Oulad Ben Taib N, Pelisson D, Tesche CD, Tilikete C, Timmann D. Consensus paper: Roles of the cerebellum in motor control‐‐the diversity of ideas on cerebellar involvement in movement. Cerebellum (London, England) 11: 457‐487, 2012.
 148.Masuda A, Ohyabu Y, Kobayashi T, Yoshino C, Sakakibara Y, Komatsu T, Honda Y. Lack of positive interaction between CO2 and hypoxic stimulation for P(CO2)‐VAS response slope in humans. Respir Physiol 126: 173‐181, 2001.
 149.McDonald AJ. Is there an amygdala and how far does it extend? An anatomical perspective. Ann N Y Acad Sci 985: 1‐21, 2003.
 150.Mendonca CT, Schaeffer MR, Riley P, Jensen D. Physiological mechanisms of dyspnea during exercise with external thoracic restriction: Role of increased neural respiratory drive. J Appl Physiol 116: 570‐581, 2014.
 151.Menon V, Uddin LQ. Saliency, switching, attention and control: A network model of insula function. Brain Struct Funct 214: 655‐667, 2010.
 152.Mithoefer JC. Lung volume restriction as a ventilatory stimulus during breath holding. J Appl Physiol 14: 701‐705, 1959.
 153.Mithoefer JC. Breath holding. In: Fenn WO, Rahn H, editors. Handbook of Physiology, Section 3: Respiration. Washington, D. C.: American Physiological Society, 1965, p. 1011‐1025.
 154.Mithoefer JC, Stevens CD, Ryder HW, McGuire J. Lung volume restriction, hypoxia and hypercapnia as interrelated respiratory stimuli in normal man. J Appl Physiol 5: 797‐802, 1953.
 155.Moody CM, Chua B, Weary DM. The effect of carbon dioxide flow rate on the euthanasia of laboratory mice. Lab Anim 48: 298‐304, 2014.
 156.Moosavi S, Binks A, Lansing R, Topulos G, Banzett R, Schwartzstein R. Furosemide inhalation reduces air hunger sensitivity in healthy individuals. Am J Respir Crit Care Med 165: B20, 2002.
 157.Moosavi SH, Banzett RB, Butler JP. Time course of air hunger mirrors the biphasic ventilatory response to hypoxia. J Appl Physiol 97: 2098‐2103, 2004.
 158.Moosavi SH, Binks AP, Lansing RW, Topulos GP, Banzett RB, Schwartzstein RM. Effect of inhaled furosemide on air hunger induced in healthy humans. Respir Physiol Neurobiol 156: 1‐8, 2007.
 159.Moosavi SH, Golestanian E, Binks AP, Lansing RW, Brown R, Banzett RB. Hypoxic and hypercapnic drives to breathe generate equivalent levels of air hunger in humans. J Appl Physiol 94: 141‐154, 2003.
 160.Moosavi SH, Topulos GP, Hafer A, Lansing RW, Adams L, Brown R, Banzett RB. Acute partial paralysis alters perceptions of air hunger, work and effort at constant PCO2 and VE. Respir Physiol 122: 45‐60, 2000.
 161.Morelot‐Panzini C, Gilet H, Aguilaniu B, Devillier P, Didier A, Perez T, Pignier C, Arnould B, Similowski T. Real‐life assessment of the multidimensional nature of dyspnoea in COPD outpatients. Eur Respir J 47: 1668‐1679, 2016.
 162.Morelot‐Panzini C, O'Donnell CR, Lansing RW, Schwartzstein RM, Banzett RB. Aerosol furosemide for dyspnea: Controlled delivery does not improve effectiveness. Respir Physiol Neurobiol 247: 146‐155, 2018.
 163.Morelot‐Panzini C, Perez T, Sedkaoui K, de Bock E, Aguilaniu B, Devillier P, Pignier C, Arnould B, Bruneteau G, Similowski T. The multidimensional nature of dyspnoea in amyotrophic lateral sclerosis patients with chronic respiratory failure: Air hunger, anxiety and fear. Respir Med 145: 1‐7, 2018.
 164.Moulton EA, Elman I, Pendse G, Schmahmann J, Becerra L, Borsook D. Aversion‐related circuitry in the cerebellum: Responses to noxious heat and unpleasant images. J Neurosci 31: 3795‐3804, 2011.
 165.Moulton EA, Schmahmann JD, Becerra L, Borsook D. The cerebellum and pain: Passive integrator or active participator? Brain Res Rev 65: 14‐27, 2010.
 166.Mountcastle VB. The view from within: Pathways to the study of perception. Johns Hopkins Med J 136: 109‐131, 1975.
 167.Muza SR, Frazier DT. Response of pulmonary stretch receptors to shifts of functional residual capacity. Respir Physiol 52: 371‐386, 1983.
 168.Neuhaus C, Hinkelbein J. Cognitive responses to hypobaric hypoxia: Implications for aviation training. Psychol Res Behav Manag 7: 297‐302, 2014.
 169.Newton PJ, Davidson PM, Macdonald P, Ollerton R, Krum H. Nebulized furosemide for the management of dyspnea: Does the evidence support its use? J Pain Symptom Manag 36: 424‐441, 2008.
 170.Nicolaysen G, Ellingsen I, Owe JO, Myhre K. Arterial PCO2 and pH in man during 3 days exposure to 2.8 kpa CO2 in the inspired gas. Acta Physiol Scand 135: 399‐403, 1989.
 171.Niel L, Weary DM. Rats avoid exposure to carbon dioxide and argon. Appl Anim Behav Sci 107: 100‐109, 2007.
 172.Nishino T. Pathophysiology of dyspnea evaluated by breath‐holding test: Studies of furosemide treatment. Respir Physiol Neurobiol 167: 20‐25, 2009.
 173.Nishino T, Ide T, Sudo T, Sato J. Inhaled furosemide greatly alleviates the sensation of experimentally induced dyspnea. Am J Respir Crit Care Med 161: 1963‐1967, 2000.
 174.O'Connor S, McLoughlin P, Gallagher CG, Harty HR. Ventilatory response to incremental and constant‐workload exercise in the presence of a thoracic restriction. J Appl Physiol (1985) 89: 2179‐2186, 2000.
 175.O'Donnell CR, Lansing RW, Schwartzstein RM, Banzett R. The effect of aerosol saline on laboratory‐induced dyspnea. Lung 195: 37‐42, 2017.
 176.O'Donnell CR, Schwartzstein RM, Lansing RW, Guilfoyle T, Elkin D, Banzett RB. Dyspnea affective response: Comparing COPD patients with healthy volunteers and laboratory model with activities of daily living. BMC Pulm Med 13: 27, 2013.
 177.O'Donnell DE, Banzett RB, Carrieri‐Kohlman V, Casaburi R, Davenport PW, Gandevia SC, Gelb AF, Mahler DA, Webb KA. Pathophysiology of dyspnea in chronic obstructive pulmonary disease: A roundtable. Proc Am Thorac Soc 4: 145‐168, 2007.
 178.O'Donnell DE, Elbehairy AF, Webb KA, Neder JA. The link between reduced inspiratory capacity and exercise intolerance in chronic obstructive pulmonary disease. Ann Am Thorac Soc 14: S30‐S39, 2017.
 179.O'Donnell DE, Hong HH, Webb KA. Respiratory sensation during chest wall restriction and dead space loading in exercising men. J Appl Physiol 88: 1859‐1869, 2000.
 180.O'Donnell DE, Ora J, Webb KA, Laveneziana P, Jensen D. Mechanisms of activity‐related dyspnea in pulmonary diseases. Respir Physiol Neurobiol 167: 116‐132, 2009.
 181.O'Driscoll M, Corner J, Bailey C. The experience of breathlessness in lung cancer. Eur J Cancer Care (Engl) 8: 37‐43, 1999.
 182.Opie LH, Smith AC, Spalding JM. Conscious appreciation of the effects produced by independent changes of ventilation volume and of end‐tidal pCO2 in paralysed patients. J Physiol 149: 494‐499, 1959.
 183.O'Reilly JX, Beckmann CF, Tomassini V, Ramnani N, Johansen‐Berg H. Distinct and overlapping functional zones in the cerebellum defined by resting state functional connectivity. Cereb Cortex 20: 953‐965, 2010.
 184.Oren J, Kelly DH, Shannon DC. Long‐term follow‐up of children with congenital central hypoventilation syndrome. Pediatrics 80: 375‐380, 1987.
 185.Ottestad W, Seim M, Maehlen JO. COVID‐19 with silent hypoxemia. Tidsskr Nor Laegeforen 140, 2020. PMID: 32378842. doi: 10.4045/tidsskr.20.0299
 186.Pamenter ME, Powell FL. Time domains of the hypoxic ventilatory response and their molecular basis. Compr Physiol 6: 1345‐1385, 2016.
 187.Parshall MB, Schwartzstein RM, Adams L, Banzett RB, Manning HL, Bourbeau J, Calverley PM, Gift AG, Harver A, Lareau SC, Mahler DA, Meek PM, O'Donnell DE. An official American Thoracic Society statement: Update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med 185: 435‐452, 2012.
 188.Pate KM, Davenport PW. Tracheal occlusions evoke respiratory load compensation and neural activation in anesthetized rats. J Appl Physiol (1985) 112: 435‐442, 2012.
 189.Patterson JL Jr, Mullinax PF Jr, Bain T, Kreuger JJ, Richardson DW. Carbon dioxide‐induced dyspnea in a patient with respiratory muscle paralysis. Am J Med 32: 811‐816, 1962.
 190.Peiffer C, Costes N, Herve P, Garcia‐Larrea L. Relief of dyspnea involves a characteristic brain activation and a specific quality of sensation. Am J Respir Crit Care Med 177: 440‐449, 2008.
 191.Peiffer C, Poline JB, Thivard L, Aubier M, Samson Y. Neural substrates for the perception of acutely induced dyspnea. Am J Respir Crit Care Med 163: 951‐957, 2001.
 192.Penfield W, Faulk MEJ. The insula: Further observations on its function. Brain 78: 445‐470, 1955.
 193.Phan KL, Wager T, Taylor SF, Liberzon I. Functional neuroanatomy of emotion: A meta‐analysis of emotion activation studies in PET and fMRI. NeuroImage 16: 331‐348, 2002.
 194.Ploghaus A, Tracey I, Gati JS, Clare S, Menon RS, Matthews PM, Rawlins JN. Dissociating pain from its anticipation in the human brain. Science 284: 1979‐1981, 1999.
 195.Price DD. Psychological and neural mechanisms of the affective dimension of pain. Science 288: 1769‐1772, 2000.
 196.Pritz MB. The thalamus of reptiles and mammals: Similarities and differences. Brain Behav Evol 46: 197‐208, 1995.
 197.Raj ABM. Aversive reactions of turkeys to argon, carbon dioxide and a mixture of carbon dioxide and argon. Vet Rec 138: 592, 1996.
 198.Raj ABM. Aversion to hypercapnia or hypoxia in pigs: Behavioural responses to dyspnoea. 25th Symposium on Respiratory Psychophysiology. Newport, Rhode Island, USA: International Society for the Advancement of Respiratory Psychophysiology, 2006.
 199.Raj ABM, Gregory NG. Preferential feeding behaviour of hens in different gaseous atmospheres. Br Poult Sci 32: 57‐65, 1991.
 200.Raj ABM, Gregory NG. Welfare implications of the gas stunning of pigs 1. Determination of aversion to the initial inhalation of carbon dioxide or argon. Anim Welf 4: 273‐280, 1995.
 201.Raj ABM, Johnson SP, Wotton SB, McInstry JL. Welfare implications of gas stunning pigs: 3. The time toloss of somatosensory evoked potential and spontaneous electrocorticogram of pigs during exposure to gases. Vet J 153: 329‐339, 1997.
 202.Read DJ, Freedman S, Kafer ER. Pressures developed by loaded inspiratory muscles in conscious and anesthetized man. J Appl Physiol 37: 207‐218, 1974.
 203.Remmers JE, Brooks J, Tenney SM. Effect of controlled ventilation on the tolerable limit of hypercapnia. Respir Physiol 4: 78‐90, 1968.
 204.Roostaei T, Nazeri A, Sahraian MA, Minagar A. The human cerebellum: A review of physiologic neuroanatomy. Neurol Clin 32: 859‐869, 2014.
 205.Ruscheweyh R, Kuhnel M, Filippopulos F, Blum B, Eggert T, Straube A. Altered experimental pain perception after cerebellar infarction. Pain 155: 1303‐1312, 2014.
 206.Rushen J. The validity of behavioural measures of aversion: A review. Appl Anim Behav Sci 16: 309‐323, 1986.
 207.Santiago TV, Sinha AK, Edelman NH. Respiratory flow‐resistive load compensation during sleep. Am Rev Respir Dis 123: 382‐387, 1981.
 208.Santos M, Kitzman DW, Matsushita K, Loehr L, Sueta CA, Shah AM. Prognostic importance of dyspnea for cardiovascular outcomes and mortality in persons without prevalent cardiopulmonary disease: The Atherosclerosis Risk in Communities Study. PLoS One 11: e0165111, 2016.
 209.Schaefer KE, Nichols G Jr, Carey CR. Acid‐base balance and blood and urine electrolytes of man during acclimatization to CO2. J Appl Physiol 19: 48‐58, 1964.
 210.Schmidt M, Demoule A, Polito A, Porchet R, Aboab J, Siami S, Morelot‐Panzini C, Similowski T, Sharshar T. Dyspnea in mechanically ventilated critically ill patients. Crit Care Med 39: 2059‐2065, 2011.
 211.Schwartzstein RM, Simon PM, Weiss JW, Fencl V, Weinberger SE. Breathlessness induced by dissociation between ventilation and chemical drive. Am Rev Respir Dis 139: 1231‐1237, 1989.
 212.Shea SA, Andres LP, Shannon DC, Guz A, Banzett RB. Respiratory sensations in subjects who lack a ventilatory response to CO2. Respir Physiol 93: 203‐219, 1993.
 213.Shea SA, Harty HR, Banzett RB. Self‐control of level of mechanical ventilation to minimize CO2 induced air hunger. Respir Physiol 103: 113‐125, 1996.
 214.Simon PM, Schwartzstein RM, Weiss JW, Fencl V, Teghtsoonian M, Weinberger SE. Distinguishable types of dyspnea in patients with shortness of breath. Am Rev Respir Dis 142: 1009‐1014, 1990.
 215.Simon PM, Schwartzstein RM, Weiss JW, Lahive K, Fencl V, Teghtsoonian M, Weinberger SE. Distinguishable sensations of breathlessness induced in normal volunteers. Am Rev Respir Dis 140: 1021‐1027, 1989.
 216.Singer T, Seymour B, O'Doherty J, Kaube H, Dolan RJ, Frith CD. Empathy for pain involves the affective but not sensory components of pain. Science 303: 1157‐1162, 2004.
 217.Smith J, Albert P, Bertella E, Lester J, Jack S, Calverley P. Qualitative aspects of breathlessness in health and disease. Thorax 64: 713‐718, 2009.
 218.Smith SM, Brown HO, Toman JEP, Goodman LS. The lack of cerebral effects of d‐tubocurarine. Anesthesiology 8: 1‐14, 1947.
 219.Snider R, Eldred E. Electro‐anatomical studies on cerebro‐cerebellar connections in the cat. J Comp Neurol 95: 1‐16, 1951.
 220.Snyder DW, Liberati NJ, McCarthy MM. Conscious guinea‐pig aerosol model for evaluation of peptide leukotriene antagonists. J Pharmacol Methods 19: 219‐231, 1988.
 221.Somerville LH, Whalen PJ, Kelley WM. Human bed nucleus of the stria terminalis indexes hypervigilant threat monitoring. Biol Psychiatry 68: 416‐424, 2010.
 222.Spiacci A Jr, Vilela‐Costa HH, Sant'Ana AB, Fernandes GG, Frias AT, da Silva GSF, Antunes‐Rodrigues J, Zangrossi H Jr. Panic‐like escape response elicited in mice by exposure to CO2, but not hypoxia. Prog Neuro‐Psychopharmacol Biol Psychiatry 81: 178‐186, 2018.
 223.Stevens J, Dechen T, Sheridan A, O'Donnell C, Schwartzstein RM, Baker K, Howell M, Banzett RB. Patient mortality, readmissions, and resource use associated with dyspnea among hospitalized patients. Am J Respir Crit Care Med 197: 2, 2018.
 224.Stevens JP, Baker K, Howell MD, Banzett RB. Prevalence and predictive value of dyspnea ratings in hospitalized patients: Pilot studies. PLoS One 11: e0152601, 2016.
 225.Stevens JP, Sheridan AR, Bernstein HB, Baker K, Lansing RW, Schwartzstein RM, Banzett RB. A multidimensional profile of dyspnea in hospitalized patients. Chest 156: 507‐517, 2019.
 226.Stevens SS. Mathematics, measurement, and psychophysics. In: Handbook of Experimental Psychology. Oxford, England: Wiley, 1951, p. 1‐49.
 227.Stoeckel MC, Esser RW, Gamer M, Buchel C, von Leupoldt A. Brain mechanisms of short‐term habituation and sensitization toward dyspnea. Front Psychol 6: 748, 2015.
 228.Stoeckel MC, Esser RW, Gamer M, Buchel C, von Leupoldt A. Brain responses during the anticipation of dyspnea. Neural Plast 2016: 6434987, 2016.
 229.Stoeckel MC, Esser RW, Gamer M, von Leupoldt A. Breathlessness amplifies amygdala responses during affective processing. Psychophysiology 55: e13092, 2018.
 230.Strigo IA, Duncan GH, Boivin M, Bushnell MC. Differentiation of visceral and cutaneous pain in the human brain. J Neurophysiol 89: 3294‐3303, 2003.
 231.Sudo T, Hayashi F, Nishino T. Responses of tracheobronchial receptors to inhaled furosemide in anesthetized rats. Am J Respir Crit Care Med 162: 971‐975, 2000.
 232.Supinski G, Dimarco A, Bark H, Chapman K, Clary S, Altose M. Effect of codeine on the sensations elicited by loaded breathing. Am Rev Respir Dis 141: 1516‐1521, 1990.
 233.Tzschentke TM. Conditioned place preference and aversion. In: Stolerman IP, Price LH, editors. Encyclopedia of Psychopharmacology. Berlin, Heidelberg: Springer Berlin Heidelberg, 2015, p. 418‐423.
 234.van Oort J, Tendolkar I, Hermans EJ, Mulders PC, Beckmann CF, Schene AH, Fernandez G, van Eijndhoven PF. How the brain connects in response to acute stress: A review at the human brain systems level. Neurosci Biobehav Rev 83: 281‐297, 2017.
 235.Van Sommers P. Carbon dioxide escape and avoidance behavior in the brown rat. J Comp Physiol Psychol 56: 584‐589, 1963.
 236.Veinante P, Yalcin I, Barrot M. The amygdala between sensation and affect: A role in pain. J Mol Psychiatry 1: 9, 2013.
 237.von Leupoldt A, Sommer T, Kegat S, Baumann HJ, Klose H, Dahme B, Buchel C. The unpleasantness of perceived dyspnea is processed in the anterior insula and amygdala. Am J Respir Crit Care Med 177: 1026‐1032, 2008.
 238.von Leupoldt A, Sommer T, Kegat S, Baumann HJ, Klose H, Dahme B, Buchel C. Dyspnea and pain share emotion‐related brain network. NeuroImage 48: 200‐206, 2009.
 239.von Leupoldt A, Sommer T, Kegat S, Eippert F, Baumann HJ, Klose H, Dahme B, Buchel C. Down‐regulation of insular cortex responses to dyspnea and pain in asthma. Am J Respir Crit Care Med 180: 232‐238, 2009.
 240.Vovk A, Binks AP. Raising end‐expiratory volume relieves air hunger in mechanically ventilated healthy adults. J Appl Physiol 103: 779‐786, 2007.
 241.Weary D, Droege P, Braithwaite V. Behavioral evidence of felt emotions: Approaches, inferences, and refinements. Adv Study Behav 49: 27‐48, 2017.
 242.Webster AB, Fletcher DL. Reactions of laying hens and broilers to different gases used for stunning poultry. Poult Sci 80: 1371‐1377, 2001.
 243.Williams MT, John D, Frith P. Comparison of the dyspnoea‐12 and multidimensional dyspnoea profile in people with COPD. Eur Respir J 49: 12, 2017.
 244.Wong D, Makowska IJ, Weary DM. Rat aversion to isoflurane versus carbon dioxide. Biol Lett 9: 20121000, 2013.
 245.Wright GW, Branscomb BV. The origin of the sensations of dyspnea. Trans Am Clin Climatol Assoc 66: 116‐125, 1954.
 246.Yashiro E, Nozaki‐Taguchi N, Isono S, Nishino T. Effects of different forms of dyspnoea on pain perception induced by cold‐pressor test. Respir Physiol Neurobiol 177: 320‐326, 2011.
 247.Yu L, De Mazancourt M, Hess A, Ashadi FR, Klein I, Mal H, Courbage M, Mangin L. Functional connectivity and information flow of the respiratory neural network in chronic obstructive pulmonary disease. Hum Brain Mapp 37: 2736‐2754, 2016.
 248.Zechman FW Jr, Wiley RL. Afferent inputs to breathing: Respiratory sensation. In: Cherniack NS, Widdicombe JG, editors. Section 3: The Respiratory System. Bethesda, MD: American Physiological Society, 1986, p. 449‐474.
 249.Zhang W, Hayward LF, Davenport PW. Influence of dorsal periaqueductal gray activation on respiratory occlusion reflexes in rats. Auton Neurosci 150: 62‐69, 2009.
Further Reading
 1.Parshall MB, Schwartzstein RM, Adams L, Banzett RB, Manning HL, Bourbeau J, Calverley PM, Gift AG, Harver A, Lareau SC, Mahler DA, Meek PM, O'Donnell DE. An official American Thoracic Society statement: Update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med 185: 435‐452, 2012.

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Robert B. Banzett, Robert W. Lansing, Andrew P. Binks. Air Hunger: A Primal Sensation and a Primary Element of Dyspnea. Compr Physiol 2021, 11: 1449-1483. doi: 10.1002/cphy.c200001