Dyspnea or breathlessness is the subjective experience

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1 Cortical Substrates for the Perception of Dyspnea* Andreas von Leupoldt, PhD; and Bernhard Dahme, PhD Dyspnea is a common, unpleasant, and impairing symptom in various respiratory diseases and other diseases. Despite growing understanding of the multiple peripheral mechanisms giving rise to dyspnea, little is known about the cortical mechanisms underlying its perception. The results of neuroimaging studies have shown that distinct brain areas process the dyspneic sensation, among which the anterior insular seems to be the most important. Based on the findings of the first relevant neuroimaging studies, this review describes the cortical structures associated with the perception of dyspnea. Moreover, similarities to the perception of pain are discussed, and implications for future research are provided. (CHEST 2005; 128: ) Key words: asthma; brain; breathlessness; COPD; dyspnea; emission-ct; MRI; pain; perception Abbreviations: ACC anterior cingulate cortex; fmri functional magnetic resonance imaging; M1 primary motor cortex; N1 primary negative voltage peak; N2 secondary negative voltage peak; P1 primary positive voltage peak; P2 secondary positive voltage peak; PCC posterior cingulate cortex; PET positron emission tomography; PMA premotor area; RREP respiratory-related evoked potentials; SMA supplementary motor area Dyspnea or breathlessness is the subjective experience of breathing discomfort comprising qualitatively distinct sensations that can vary in their intensity. Like pain, these sensory experiences originate from interactions among multiple physiologic, psychological, social, and environmental factors. 1 Breathlessness is an unpleasant and frightening symptom in a variety of cardiopulmonary and other diseases. 1,2 Particularly in asthma and COPD, it is a cardinal symptom, causing reductions in functional status and quality of life, and an enormous socioeconomic burden. 3 5 The increasing prevalence rates for asthma and COPD will further intensify this major public health problem. 4 6 Besides these facts, the adequate perception of the onset and severity of breathlessness is a very important component of current disease-self-management programs, particularly in patients with asthma. 3,7 A failure to perceive *From the Psychological Institute III, University of Hamburg, Hamburg, Germany. We declare that we have not received any financial support for the present manuscript, that we are not involved in any organization with financial interest in the work to be addressed in this manuscript and that there is no other potential conflict of interest associated with this manuscript. Manuscript received September 7, 2004; revision accepted December 24, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: Andreas von Leupoldt, PhD, Psychological Institute III, University of Hamburg, Von-Melle-Park 5, Hamburg, Germany; andreas.vonleupoldt@unihamburg.de the severity of a developing bronchoconstriction can result in a delay in seeking help and inadequate utilization of effective medications, and might, at worst, lead to avoidable deaths Research over the past decades has examined several possible mechanisms contributing to the perception of dyspnea but has focused predominantly on peripheral levels of the respiratory system. Some studies 12,13 using respiratory-related evoked potentials (RREPs) have suggested that deficits in the neuronal processing of perceptual information in asthmatic patients bear on the perception of dyspnea. This could be an underlying mechanism for the blunted perception of dyspnea, which has been reported for subgroups of asthmatic patients. 14,15 Although the important role of the central processing of sensory information related to breathlessness has been realized, 16,17 little is still known about the cortical structures involved in the perception of dyspnea This review provides an overview of the brain areas that are associated with the perception of breathlessness, with a special focus on the results of the first neuroimaging studies on this topic. Furthermore, similarities to the far better understood cortical processing of pain perception, which is a similarly unpleasant, alarming physical sensation, are discussed. Both dyspnea and pain strongly motivate adaptive behavior to regain homeostasis, 19 and patients often experience both conditions. 2 Based on the reviewed findings, implications for future research are presented. CHEST / 128 / 1/ JULY,

2 Physiologic Mechanisms Past research has shown that a variety of different input mechanisms might lead to the complex sensation of difficult breathing. Afferent signals from pulmonary vagal receptors in the upper and lower airways are one possible source that is triggered by bronchoconstrictions. Pulmonary stretch receptors in the airways smooth muscles are activated as the lung expands, type-j receptors in the walls of alveoli and capillaries are stimulated by increasing intrapulmonary pressure, and irritant receptors in the upper airways and the tracheobronchial walls respond to a variety of mechanical or chemical stimuli. 1 All of these pulmonary receptors provide information about changes in the breathing pattern, airflow, pressure, respired volume, and airway diameter, which can contribute to perceived sensations of breathlessness. 21,22 Another input refers to mechanoreceptors in the chest wall. Respiratory muscles contain a variety of afferents in the joints, tendon organs, and muscle spindles. Specifically, receptors in the intercostal muscles and diaphragm have been shown to be involved in the perception of dyspnea by signaling information regarding respiratory muscle displacement and alterations in length-tension relations. 23,24 These chest wall receptors can be activated during hyperinflation, bronchoconstriction, or mechanical stimulation, weakening the respiratory muscles in order to overcome the associated high elastic, threshold, and resistive loading. 8 Furthermore, changes in arterial blood gas levels (ie, arterial Pco 2 and Po 2 ) and acid-base status can lead to breathlessness by stimulation of the central chemoreceptors in the brainstem medulla, and of the peripheral chemoreceptors in the aortic and carotid bodies. 1 These chemical changes due to hypercapnia or hypoxia might be perceived by direct sensory afferents from the chemoreceptors or due to increased medullary respiratory motor drive. 25,26 A predominant mechanism might arise from the simultaneous activation of sensory cortex areas when efferent respiratory motor command is sent to the respiratory muscles. 1,27 These activations are presumably caused by corollary discharges, which originate from medullary or higher cortical respiratory centers. These have not yet been found in the human cortex, but have been found in studies with cats, 28,29 in which sensory thalamic nuclei were activated by corollary discharges. Furthermore, the attractive unifying concept of afferent mismatch states that breathlessness evolves from a dissociation or mismatch between efferent motor command to the respiratory muscles and afferent feedback from pulmonary and chest wall receptors, which signal the effectiveness of the motor command. 30 Where the afferent mismatch is processed within the brain is currently unknown. Although all of these input mechanisms can contribute to breathlessness, different pathways might be involved in different diseases associated with dyspnea. This might be reflected by distinct verbal phrases that subjects use to describe the qualitative nature of the experience (eg, air hunger, effort of breathing, or chest tightness). 31,32 However, information is still lacking on how sensory information from different receptors is transmitted to higher cortical centers 33,34 and which brain areas are involved in the perception of these sensations. For a detailed review of the mechanisms of dyspnea, the reader is referred to various excellent reviews. 33,35 37 Psychological Mechanisms Besides physiologic mechanisms, the role of psychological factors in the perception of breathlessness has been recognized, 8,38,39 but research on this topic is still at the beginning. To the present time, negative emotions have been shown to be associated predominantly with decreased accuracy of dyspnea perception. 38,40 Furthermore, a repressive-defensive coping style might be related to blunted symptom perception, 41,42 but some findings have not been fully conclusive. 43 Psychopathologic characteristics such as hypochondriasis or somatoform tendencies have not been shown to influence the sensing airflow limitations, 44,45 and there is at present no conclusive evidence that distinct personality profiles predispose a person to the inaccurate perception of dyspnea. 35,43 However, an important influence might arise from learning processes or contextual factors and lead to the overperception of respiratory sensations. 46,47 Alternatively, an attention-distracting context has been shown to reduce the awareness of breathlessness, which might be an effective intervention in patients with some conditions (eg, COPD). 48 Cortical Representation of Dyspnea Despite a growing understanding of the possible pathways leading to breathlessness, relatively little is known about higher brain centers in humans that process this sensation. 20 In particular, the brain areas associated with the perception of the experience have not been well-explored. 18,19 This is in part attributable to a lack of adequate animal models properly simulating human dyspnea perception 49 and, furthermore, is due to an absence of highresolution imaging techniques, which allow a noninvasive study of human brain activity. 346 Reviews

3 Introduction to Findings Without Imaging Techniques Early research 33,36 on experimental animals by means of evoked potentials, which were recorded with cortical surface electrodes after electrical or mechanical stimulation of different respiratory afferents, has demonstrated that afferents from airways and respiratory muscles project to the cerebral cortex in cats and monkeys. Prominent activations have been found in the somatosensory cortex, in the motor cortex and in the mesocortex Results like these have suggested a role for higher cerebral involvement in respiratory sensations besides the pontomedullary respiratory oscillator. Activation of the somatosensory cortex in adult humans by means of RREPs was first shown by Davenport and coworkers. 53 These RREPs were recorded after short inspiratory occlusions by means of scalp surface electrodes placed over the somatosensory region of the cortex measuring electroencephalic activity below the surface, which is similar to the evoked potential techniques in other sensory systems using EEGs. Short states of breathlessness predominantly evoked early RREPs, namely, the primary positive voltage peak (P1), the primary negative voltage peak (N1), the secondary positive voltage peak (P2), and the secondary negative voltage peak (N2), which occur within about 100 ms (P1 and N1) or 200 ms (P2 and N2), after stimulus onset. 53,54 P1, P2, N1, and N2 are peaks in the EEG signal due to dipoles occurring when a cerebral column is depolarized by the arrival of activity from respiratory afferents activated by the inspiratory occlusion. Thus, the obtained components represent the arrival and first processing of respiratory-related afferent sensory information in the somatosensory cortex. A subsequent study demonstrated a positive correlation between the amplitude of P1 and the perceived magnitude of the respiratory load. 55 Other studies conducted by means of percutaneous electrical or transcranial magnetic stimulation have provided further evidence for fast-conducting afferent and efferent connections between the cerebral cortex and respiratory muscles. Another study by Davenport and coworkers 12 using the RREP methodology is important with regard to the reported blunted perception of breathlessness in subgroups of asthmatic patients, specifically those with a history of near-fatal attacks. 14,15 In a group of asthmatic children with a history of life-threatening asthma, they found an absence of the P1 component after respiratory occlusion (ie, the dyspneic sensory signal was not activating the somatosensory cortex). These results suggest a deficit in the neural processing of information related to breathlessness, which in turn might be an important mechanism underlying blunted symptom perception. Further evidence for this assumption has arisen from a study by Webster and Colrain, 13 which was performed by means of RREPs. They demonstrated reduced late tertiary positive voltage peak components (P3) in asthmatic adults when compared to healthy control subjects following midinspiratory occlusion. Most interestingly, these reductions in the P3 amplitude were also obtained after a short auditory stimulus, whereas early P1 components showed comparable amplitudes in both groups. The data suggest the presence of an asthma-specific deficit in the later cortical processing of respiratory load information. A rather speculative interpretation of the findings would be that of a general deficit in the cortical processing of perceptual information in specific groups of asthma patients. However, more research is clearly needed to explore these first results further. Imaging Techniques and Dyspnea The development and increasing availability of high-resolution imaging techniques have provided a great tool for the noninvasive study of brain structures in the conscious human. Specifically, positron emission tomography (PET) scanning and functional MRI (fmri) have been used in a vast variety of scientific contexts. Both methods measure regional cerebral blood flow, which is increased locally during neural activity. While PET scanning requires the IV application of a nuclear tracer (eg, H 15 2 O), 60 fmri employs the blood oxygen level dependence effect 61 to contrast areas of different cerebral blood flow. 62 However, compared to other sensory systems, the proportion of and interest in imaging studies examining sensations of breathlessness is markedly reduced. The first studies in this field have focused primarily on aspects of volitional breathing or compensation of induced breathlessness, while the perception of dyspnea has not been systematically examined Volitional breathing in the PET or fmri scanner has been achieved by voluntary targeted breathing, either with or without added respiratory loads, and has been compared with unloaded spontaneous breathing or passive mechanical ventilation. The predominant activation has been obtained bilaterally in the primary motor cortex (M1), in the right premotor area (PMA), in the supplementary motor area (SMA), in the cerebellum, and in the thalamus. Some studies have reported several further activations in regions of the pontomedullary respiratory oscillator, 65,67 in sensorimotor areas, 66,67,69,70 in anterior cingulate structures, 66,67 in the prefrontal cortex, 69,70 and in the parietal cortex These findwww.chestjournal.org CHEST / 128 / 1/ JULY,

4 ings have demonstrated that higher motor cortex areas are involved in volitional breathing and in the compensation of breathlessness. McKay and coworkers 67 concluded that the voluntary control of breathing is similar to other voluntary movements, and requires the activation of an integrated network of cortical and subcortical areas. Further work has studied the effects of increased inspiratory CO 2 on brain activity, which, as described above, is one known source leading to dyspnea. 71,72 But again, a systematic examination of the perceived sensation of breathlessness has not been provided. However, besides activity in cerebellar, frontal, and occipital regions, hypercapnia was predominantly associated with activations in the limbic system (eg, the hypothalamus, hippocampus, cingulate cortex, and insula). 72 No activations were seen in motor cortex areas that have been shown to be associated with volitional breathing. These results further suggest a participation of brain areas above the pontomedullary respiratory oscillator in the processing of sensory information related to breathlessness. At present, only four imaging studies have been published in six reports, with three reports 17,19,49 explicitly examining the perception of dyspnea, and different aspects of the fourth study having been reported in three different reports Only one of these studies 49 employed fmri, which offers a higher resolution compared to PET scanning. In the studies by Liotti et al, 73 Brannan et al, 74 and Parsons et al, 75 breathlessness was induced in nine healthy volunteers by the inspiration of increased CO 2 (8%) using either a facemask or a mouthpiece. Data from these subjects were contrasted with those of subjects having several other conditions, of which the episodes occurring without dyspnea that were due to facemask breathing of increased O 2 (91%) and inspiration of room air (O 2, 21%) are the most relevant for the present review. Evans and coworkers 49 induced breathlessness in six healthy mechanically ventilated participants by restraining the tidal volume below spontaneous levels in combination with constantly elevating arterial Pco 2 levels by manipulating inspired Pco 2. This methodology was also used in the study by Banzett and coworkers, 19 which included eight healthy volunteers. Both studies compared dyspneic conditions with episodes of higher tidal volume combined with normal arterial Pco 2, which relieved breathlessness. Thus, all three studies 19,49,73 75 stimulated chemoreceptors or induced increases in the respiratory motor drive leading to sensations that were verbally expressed as air hunger, urge to breath, and like breathholding. In contrast, Peiffer and coworkers 17 applied external resistive loads during inspiration and expiration in eight healthy participants. These loads were introduced to a breathing circuit to induce moderate-tosevere breathlessness and were removed during unrestricted control conditions while the volunteers breathed at spontaneous levels. An additional load condition including the inhalation of menthol in order to reduce the dyspneic sensation revealed no prominent effects. The resistive-load technique predominantly stimulates respiratory mechanoreceptors, which, as already described, can lead to breathlessness due to increases in perceived respiratory effort and work. While subjects in all studies were lying in the supine position in the scanner, the different interventions were contrasted with episodes that occurred without breathlessness (ie, isocapnia with normal tidal volume or load-free breathing, respectively). Furthermore, all studies continuously monitored respiratory responses in airflow, volume, end-tidal Pco 2, and mouth pressure to control the effectiveness of experimental stimulation. The perceived degree of breathlessness was assessed directly after interventions with appropriate rating scales and was compared to episodes with unrestricted breathing. Some studies further obtained verbal descriptions of the quality of the perceived sensation. Although the induction of breathlessness and the assessment of respiratory responses in the spatially limited, magnetically sensitive scanner environment are complicated procedures, all four studies overcame these restraints with appropriate designs. However, the small number of included participants is a shortcoming across all of these studies. Despite the use of different intervention techniques, common activations in several brain areas have been demonstrated in at least three of the four studies. Predominant neural activity has been found in the insula, in insular agranular extensions (eg, operculum and frontal cortex areas), the anterior cingulate cortex (ACC), the posterior cingulate cortex (PCC), the cerebellum, the thalamus, and the amygdala. Further activations have been observed in the M1, the PMA, 49,73 75 the SMA, 17,19,49 and somatosensory areas, 17,49 which were all involved during voluntary breathing Additionally, neural activity has been observed in the pons, 17 the putamen, 17,19,73 75 the hypothalamus, the hippocampus, and the frontoparietal network. 49 Among all structures, the anterior insula, a multifunctional sensorimotor integration area, showed strong activations in all four studies, predominantly in the right hemisphere. This fact leads to the assumption that the insula is the crucial component in a larger cortical network underlying the perception of breathlessness. 49 Like the ACC and the amygdala, the insula is part of the limbic network, and has dense connections to other limbic, somato- 348 Reviews

5 sensory, and motor structures. 76 Studies in rats have further demonstrated that the insula receives afferents from respiratory chemoreceptors, from mechanoreceptors, and from projections from the medulla, which underlines its important role in the integration of respiratory sensations. Moreover, data 80 have shown altered activity or response timing patterns within several cortical areas, including the insula, cerebellum, ACC, and hippocampus in patients experiencing obstructive sleep apnea syndrome when compared to control subjects. These patterns were obtained during Valsalva maneuvers, which are associated with breathlessness due to prolonged expiratory effort against a high load. 81 These findings further suggest the presence of neural deficits in the processing of respiratory sensations in patients with pulmonary diseases, specifically in insular, cingulate, and cerebellar areas. Figure 1. Cortical areas involved in the perception of dyspnea. This preliminary scheme is based on the first results of neuroimaging studies and includes two major pathways signaling afferent information from peripheral receptors to the cortex, which have been derived from information from earlier psychophysical studies. The first pathway (black line) arises mainly from respiratory muscle afferents, and the second pathway (dashed line) includes mainly vagal afferents from the lungs and airways. Embedded brain areas represent only their proximate localization. AMYG amygdala; CB cerebellum; MDT medial dorsal thalamus; MO medulla oblongata; PFC prefrontal cortex; PPC posterior parietal cortex; S1 primary somatosensory cortex; S2 secondary somatosensory cortex; VPT ventroposterior thalamus. A Cortical Scheme of Dyspnea Perception Summarizing the work conducted on the different input mechanisms, transmitting pathways, and processing brain areas involved in sensations of breathlessness, a preliminary scheme for the cortical substrates underlying the perception of dyspnea can be derived (Fig 1). For a detailed review of the afferent and efferent pathways between peripheral receptors and the brain, the reader is referred to two excellent reviews. 33,36 Two major pathways have been suggested to process respiratory sensations to the cortex. 33 The first pathway arises predominantly from respiratory muscle afferents, is relayed in the brainstem medulla, and projects to the ventroposterior thalamus area, from where thalamocortical projections ascend to the primary and secondary somatosensory cortex. In accordance with other interoceptive sensations, these structures might process the sensory or intensity aspects of dyspnea. 82,83 The second pathway includes mainly vagal afferents from the lungs and airways, which are relayed in the brainstem medulla. Brainstem projections ascend to the amygdala and medial dorsal areas of the thalamus, and further to the insula and cingulate cortex. This predominantly limbic pathway might further include the hippocampus, operculum, putamen, and other prefrontal areas, and might be more associated with the affective components of the experienced breathlessness. 20,33 Both pathways include final projections to the higher motor cortex (ie, M1, PMA, and SMA), from where efferent motor commands project to the brainstem and/or respiratory muscles. The cerebellum might receive afferents from the pontomedullary respiratory oscillator in the brainstem 79 or from the higher motor cortex, as a similar cerebellar activation has been shown during volitional breathing. Alternatively, the cerebellum might also be involved in affective functions of breathlessness, an idea that has been suggested for other primary sensations. 75,84 However, a clear differentiation between specific sensory and affective functions of brain areas associated with dyspnea still has to be explored. Similarities Between Dyspnea and Pain Perception It has been shown that the anterior insula is a crucial component within a larger brain network underlying the perception of dyspnea. However, it is not exclusively activated during respiratory sensations. Strong insular activation has been found in a variety of predominantly painful sensations (eg, heat, cold, and electrical stimulation) and during various other aversive sensations (eg, hunger, thirst, unpleasant odors, and negative emotions). 84, CHEST / 128 / 1/ JULY,

6 Reiman and coworkers 92 have suggested that the anterior insula is in general an internal alarm center, alerting the individual to potentially distressing interoceptive stimuli and investing them with negative emotional significance. But the anterior insula is not the only component that is commonly activated during the perception of dyspnea and pain. In a variety of pain studies with different stimulus modalities, prominent activation has been observed in medial thalamic nuclei, in the ACC, and in the amygdala, which has been shown to be predominantly associated with the affective dimension of pain. Furthermore, strong activation of the ventroposterior lateral thalamus, and the primary and the secondary somatosensory cortex has been reported, and is primarily related to the sensorydiscriminative aspects of pain. 82,85 88 All of these structures were also found to be activated in the first studies on dyspnea, which is suggestive of the presence of a common neural network underlying the perception of both sensations. While distinct cortical structures and pathways have already been shown to be more involved in either sensory or affective aspects of pain, a similar functional differentiation has not yet been proven for the perception of dyspnea, although it has already been hypothesized. 20,33 However, breathlessness and pain share more than cortical characteristics. As previously explicated by Banzett and Moosavi, 93 both are subjectively perceived physiologic sensations, and both are of an unpleasant nature. The perception of dyspnea and pain warns the conscious brain of a disturbed physiologic state and motivates adaptive behavior to modify the aversive situation. Behavioral plans and motor actions can be initiated following the perceptual process. Furthermore, many patients with different diseases experience both unpleasant symptoms. 2,94,95 Despite many similarities between dyspnea and pain, and the high comorbidity of both sensations, almost nothing is known about the interactions regarding their perception. Only one study 95 has examined this issue and has reported increased dyspnea ratings when tourniquet pain was added, whereas tourniquet pain remained almost unchanged after the additional induction of dyspnea. Implications for Future Research Based on the various similarities between dyspnea and pain, the adoption of successful strategies and methods from pain research, which is much more advanced, for investigations into dyspnea has been suggested. 8,93 A key contribution has been the realization of the multidimensionality of the pain sensation, 96,97 which has led to the development of highly useful pain measurement instruments such as the Schmerzempfindungsskala (SES) 98 and the McGill Pain Questionnaire. 99 Although the first attempts have seemed to suggest a similar multidimensionality for perceived breathlessness, 100,101 this aspect has still received little attention but could be a promising paradigm for future research on dyspnea. 93 As discussed above, distinct cortical structures have been shown 82, to primarily process either sensory or affective fractions of pain, which can be further differentially modified with hypnotic and cognitive interventions. Whether this functional differentiation also exists in the cortical processing of dyspnea still remains to be explored. Peiffer and coworkers 17 have suggested that the PCC/right cingulate sulcus might be more related to the affective dimension of perceived breathlessness. Although this was the first published attempt to separate functional aspects of the dyspneic sensation with imaging techniques, the sensory and affective dimensions were not assessed separately but rather were examined by means of a covariate correlational analysis. Hence, future imaging studies could differentially assess the affective and sensory aspects of perceived breathlessness, and could examine the relation of specifically activated brain areas. Furthermore, pain and dyspnea might be induced in the same individuals to compare the brain areas activated by both stimulus modalities. This would give answers to whether both sensations are processed by the same cortical structures or simply by neighboring cortical structures, 93 and would give insight into possible interactions between dyspnea and pain. In an analogy to pain research, it could further be examined whether affective or cognitive interventions are able to modify the perception of dyspnea, which has already been suggested. 48 In this regard, it might be particularly useful to explore whether these modulations influence the associated cortical processing, as has been shown in pain studies Furthermore, it is not understood how the insula gives rise to the perception of breathlessness. Evans and coworkers 49 have suggested, on the basis of obvious connections between the medulla and insula, that corollary discharges from increased medullary brainstem motor activity could generate the sensation (see the introductory section). Alternatively, increased central motor command from the higher motor cortex to the respiratory muscles might activate the insula, 106,107 presumably even without peripheral afferent feedback from respiratory mechanoreceptors. 70 Moreover, the insula might receive projections from the parietal cortex, which has been reported 82,108 for the processing of other perceptual 350 Reviews

7 sensations, and has been linked to the integration of contextual and attentional aspects. Hence, the concrete involvement of the insular within the perceptual network of dyspnea remains to be established. However, none of the discussed studies included a group of patients who were experiencing dyspnea. Hence, our initial knowledge from neuroimaging studies has been exclusively derived from presumably intact cortical structures in healthy volunteers. Nothing is known about the brain mechanisms processing the perception of breathlessness in patients with pathologic conditions such as COPD or asthma. Particularly for the latter disease, data from studies 12,13 obtained by RREPs, have suggested deficits in the cortical processing of dyspnea perception, which might underlie the blunted perception of the sensation. Similar deficits might be present in patients with other diseases associated with breathlessness. To examine these presumed deficits, it will be necessary to perform neuroimaging studies that include different groups of patients who are experiencing dyspnea. Summary Dyspnea is a common and unpleasant symptom in patients with a variety of pathologic states. The failure to perceive this multidimensional sensation might lead to severe or fatal attacks in obstructive respiratory diseases. Multiple peripheral, central, and psychological mechanisms contribute to breathlessness, but little is known about the cortical processing of its perception. Some findings have suggested the presence of deficits in these central cortical mechanisms, which might be responsible for the blunted perception of dyspnea in asthma patients. The first neuroimaging studies in healthy volunteers have predominantly shown that areas in the thalamus, the somatosensory cortexes, the insula, the operculum, the cingulate cortex, the cerebellum, and the amygdala are activated during induced breathlessness, possibly within two different functional pathways. Of these structures, the anterior insula might be particularly important for the processing of dyspnea. Similar brain areas process the perception of pain. Both are subjectively experienced as unpleasant sensations, which have further common characteristics such as an alarming, behavioral, and motivational functions. Successful methods derived from advanced research on pain could therefore be adopted for research into dyspnea (eg, the separation of affective and sensory aspects of the sensation). Furthermore, the effects of modulatory interventions on dyspnea and on the associated brain structures might be explored. 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