Dyspnea or breathlessness is the subjective experience

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; 128:345 354) 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, 2004. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Andreas von Leupoldt, PhD, Psychological Institute III, University of Hamburg, Von-Melle-Park 5, 20146 Hamburg, Germany; e-mail: 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. 8 11 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. 18 20 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. www.chestjournal.org CHEST / 128 / 1/ JULY, 2005 345

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

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. 50 52 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 56 59 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. 63 70 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. 66 68 These findwww.chestjournal.org CHEST / 128 / 1/ JULY, 2005 347

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. 73 75 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, 73 75 the PMA, 49,73 75 the SMA, 17,19,49 and somatosensory areas, 17,49 which were all involved during voluntary breathing. 63 70 Additionally, neural activity has been observed in the pons, 17 the putamen, 17,19,73 75 the hypothalamus, 73 75 the hippocampus, 73 75 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

sensory, and motor structures. 76 Studies 77 79 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) 85 88 and during various other aversive sensations (eg, hunger, thirst, unpleasant odors, and negative emotions). 84,89 91 www.chestjournal.org CHEST / 128 / 1/ JULY, 2005 349

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 82,102 105 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. 103 105 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

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. Future neuroimaging studies conducted in different patient groups are required for a better understanding of the cortical substrates that are necessary for the perception of dyspnea. References 1 American Thoracic Society. Dyspnea: mechanisms, assessment, and management; a consensus statement. Am J Respir Crit Care Med 1999; 159:321 340 2 Rao AB, Gray D. Breathlessness in hospitalised adult patients. Postgrad Med J 2003; 79:681 685 3 National Asthma Education and Prevention Program. Expert panel report 2: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health, 1997; Publication No. 97 4051 4 National Institutes of Health. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO workshop report. Bethesda, MD: National Institutes of Health, 2001; Publication No. 2701 5 National Institutes of Health. Global strategy for asthma management and prevention: NHLBI/WHO workshop report. Bethesda, MD: National Institutes of Health, 2002; Publication No. 02 3659 6 Murray CJL, Lopez AD. Evidence-based health policylessons from the global burden of disease study. Science 1996; 274:740 743 7 Dahme B, Schandry R, Leopold C. Symptomwahrnehmung beim Asthma bronchiale. In: Warschburger P, Petermann F, eds. Asthma bronchiale. Göttingen, Germany: Hogrefe, 2000; 99 114 8 Banzett RB, Dempsey JA, O Donnell DE, et al. Symptom perception and respiratory sensation in asthma. Am J Respir Crit Care Med 2000; 162:1178 1182 9 Magadle R, Berar-Yanay N, Weiner P. The risk of hospitalization and near-fatal and fatal asthma in relation to the perception of dyspnea. Chest 2002; 121:329 333 10 Rodrigo GJ, Rodrigo C, Hall JB. Acute asthma in adults: a review. Chest 2004; 125:1081 1102 11 Barnes PJ. Blunted perception and death from asthma. N Engl J Med 1994; 330:1383 1384 12 Davenport PW, Cruz M, Stecenko AA, et al. Respiratoryrelated evoked potentials in children with life-threatening asthma. Am J Respir Crit Care Med 2000; 161:1830 1835 13 Webster KE, Colrain IM. P3-specific amplitude reductions to respiratory and auditory stimuli in subjects with asthma. Am J Respir Crit Care Med 2002; 166:47 52 14 Rubinfeld AR, Pain MC. Perception of asthma. Lancet 1976; 1:882 884 15 Kikuchi Y, Okabe S, Tamura G, et al. Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma. N Engl J Med 1994; 330:1329 1334 16 Gandevia SC, Killian K, McKenzie DK, et al. Respiratory sensations, cardiovascular control, kinaesthesia and transcranial stimulation during paralysis in humans. J Physiol 1993; 470:85 107 17 Peiffer C, Poline JB, Thivard L, et al. Neural substrates for the perception of acutely induced dyspnea. Am J Respir Crit Care Med 2001; 163:951 957 18 Manning HL, Schwartzstein RM. Pathophysiology of dyspnea. N Engl J Med 1995; 333:1547 1553 19 Banzett RB, Mulnier HE, Murphy K, et al. Breathlessness in humans activates insular cortex. Neuroreport 2000; 11: 2117 2120 www.chestjournal.org CHEST / 128 / 1/ JULY, 2005 351

20 Guz A. Brain, breathing and breathlessness. Respir Physiol 1997; 109:197 204 21 Simon PM, Basner RC, Weinberger SE, et al. Oral mucosal stimulation modulates intensity of breathlessness induced in normal subjects. Am Rev Respir Dis 1991; 144:419 422 22 Taguchi O, Kikuchi Y, Hida W, et al. Effects of bronchoconstriction and external resistive loading on the sensation of dyspnea. J Appl Physiol 1991; 71:2183 2190 23 Whitelaw WA, McBride B, Ford GT. Effect of lung volume on breath holding. J Appl Physiol 1987; 62:1962 1969 24 Manning HL, Basner R, Ringler J, et al. Effect of chest wall vibration on breathlessness in normal subjects. J Appl Physiol 1991; 71:175 181 25 Banzett RB, Lansing RW, Brown R, et al. Air hunger from increased Pco 2 persists after complete neuromuscular block in humans. Respir Physiol 1990; 81:1 17 26 Moosavi SH, Golestanian E, Binks AP, et al. Hypoxic and hypercapnic drives to breathe generate equivalent levels of air hunger in humans. J Appl Physiol 2003; 94:141 154 27 Killian KJ, Gandevia SC, Summers E, et al. Effect of increased lung volume on perception of breathlessness, effort, and tension. J Appl Physiol 1984; 57:686 691 28 Chen Z, Eldridge FL, Wagner PG. Respiratory-associated rhythmic firing of midbrain neurones in cats: relation to level of respiratory drive. J Physiol 1991; 437:305 325 29 Chen Z, Eldridge FL, Wagner PG. Respiratory-associated thalamic activity is related to level of respiratory drive. Respir Physiol 1992; 90:99 113 30 Schwartzstein RM, Simon PM, Weiss JW, et al. Breathlessness induced by dissociation between ventilation and chemical drive. Am Rev Respir Dis 1989; 139:1231 1237 31 Simon PM, Schwartzstein RM, Weiss JW, et al. Distinguishable types of dyspnea in patients with shortness of breath. Am Rev Respir Dis 1990; 142:1009 1014 32 Harver A, Mahler DA, Schwartzstein RM, et al. Descriptors of breathlessness in healthy individuals: distinct and separable constructs. Chest 2000; 118:679 690 33 Davenport PW, Reep RL. Cerebral cortex and respiration. In: Dempsey JA, Pack AI, eds. Regulation of breathing. New York, NY: Dekker, 1995; 365 388 34 Harver A, Mahler DA. Perception of increased resistance to breathing. In: Kotses H, Harver A, eds. Self-management of asthma. New York, NY: Dekker, 1998; 35 61 35 Manning HL, Schwartzstein RM. Respiratory sensations in asthma: physiological and clinical implications. J Asthma 2001; 38:447 460 36 Banzett RB, Lansing RW. Respiratory sensations arising from pulmonary and chemoreceptor afferents. In: Adams L, Guz A, eds. Lung biology in health and disease: respiratory sensation (vol 90). New York, NY: Dekker, 1996; 155 180 37 Shea SA, Banzett RB, Lansing RW. Respiratory sensations and their role in the control of breathing. In: Dempsey JA, Pack AI, eds. Regulation of breathing. New York, NY: Dekker, 1995; 923 957 38 De Peuter S, Van Diest I, Lemaigre V, et al. Dyspnea: the role of psychological processes. Clin Psychol Rev 2004; 24:557 581 39 Lehrer P, Feldman J, Giardino N, et al. Psychological aspects of asthma. J Consult Clin Psychol 2002; 7:691 711 40 Rietveld S, Prins PJ. The relationship between negative emotions and acute subjective and objective symptoms of childhood asthma. Psychol Med 1998; 28:407 415 41 Isenberg S, Lehrer P, Hochron S. Defensiveness and perception of external inspiratory resistive loads in asthma. J Behav Med 1997; 20:461 472 42 Feldman JM, Lehrer PM, Hochron SM, et al. Defensiveness and individual response stereotypy in asthma. Psychosom Med 2002; 64:294 301 43 Fritz GK, McQuaid EL, Spirito A, et al. Symptom perception in pediatric asthma: relationship to functional morbidity and psychological factors. J Am Acad Child Adolesc Psychiatry 1996; 35:1033 1041 44 Chetta A, Gerra G, Foresi A, et al. Personality profiles and breathlessness perception in outpatients with different gradings of asthma. Am J Respir Crit Care Med 1998; 157:116 122 45 Lavietes MH, Matta J, Tiersky LA, et al. The perception of dyspnea in patients with mild asthma. Chest 2001; 120:409 415 46 Rietveld S. Symptom perception in chronic asthma: learning for better or worse? In: Brown ES, ed. Advances in psychosomatic medicine: asthma; social and psychological factors and psychosomatic syndromes (vol 24). Basel, Switzerland: Karger, 2003; 115 130 47 Van den Bergh O, Stegen K, Van de Woestijne KP. Learning to have psychosomatic complaints: conditioning of respiratory behavior and somatic complaints in psychosomatic patients. Psychosom Med 1997; 59:13 23 48 Bauldoff GS, Hoffman LA, Zullo TG, et al. Exercise maintenance following pulmonary rehabilitation: effect of distractive stimuli. Chest 2002; 122:948 954 49 Evans KC, Banzett RB, Adams L, et al. BOLD fmri identifies limbic, paralimbic, and cerebellar activation during air hunger. J Neurophysiol 2002; 88:1500 1511 50 Davenport PW, Thompson FJ, Reep RL, et al. Projection of phrenic nerve afferents to the cat sensorimotor cortex. Brain Res 1985; 328:150 153 51 Hallowitz RA, MacLean PD. Effects of vagal volleys on units of intralaminar and juxtalaminar thalamic nuclei in monkeys. Brain Res 1977; 130:271 286 52 O Brien JH, Pimpaneau A, Albe-Fessard D. Evoked cortical responses to vagal, laryngeal and facial afferents in monkeys under chloralose anaesthesia. Electroencephalogr Clin Neurophysiol 1971; 31:7 20 53 Davenport PW, Friedman WA, Thompson FJ, et al. Respiratory-related cortical potentials evoked by inspiratory occlusion in humans. J Appl Physiol 1986; 60:1843 1848 54 Revelette WR, Davenport PW. Effects of timing of inspiratory occlusion on cerebral evoked potentials in humans. J Appl Physiol 1990; 68:282 288 55 Knafelc M, Davenport PW. Relationship between resistive loads and P1 peak of respiratory-related evoked potential. J Appl Physiol 1997; 83:918 926 56 Gandevia SC, Macefield G. Projection of low-threshold afferents from human intercostal muscles to the cerebral cortex. Respir Physiol 1989; 77:203 214 57 Gandevia SC, Rothwell JC. Activation of the human diaphragm from the motor cortex. J Physiol 1987; 384:109 118 58 Maskill D, Murphy K, Mier A, et al. Motor cortical representation of the diaphragm in man. J Physiol 1991; 443:105 121 59 Demoule A, Verin E, Locher C, et al. Validation of surface recordings of the diaphragm response to transcranial magnetic stimulation in humans. J Appl Physiol 2003; 94:453 461 60 Chertkow H, Bub D. Functional activation and cognition: the 15 O PET subtraction method. In: Kertesz A, ed. Localization and neuroimaging in neuropsychology. San Diego, CA: Academic Press, 1994; 152 184 61 Ogawa S, Lee TM, Kay AR. Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc Natl Acad Sci U S A 1990; 87:9868 9872 62 Binder JR, Rao SM. Human brain mapping with functional 352 Reviews

magnetic resonance imaging. In: Kertesz A, ed. Localization and neuroimaging in neuropsychology. San Diego, CA: Academic Press, 1994; 185 212 63 Colebatch JG, Adams L, Murphy K, et al. Regional cerebral blood flow during volitional breathing in man. J Physiol 1991; 443:91 103 64 Ramsay SC, Adams L, Murphy K, et al. Regional cerebral blood flow during volitional expiration in man: a comparison with volitional inspiration. J Physiol 1993; 461:85 101 65 Gozal D, Omidvar O, Kirlew KA, et al. Identification of human brain regions underlying responses to resistive inspiratory loading with functional magnetic resonance imaging. Proc Natl Acad Sci U S A 1995; 92:6607 6611 66 Fink GR, Corfield DR, Murphy K, et al. Human cerebral activity with increasing inspiratory force: a study using positron emission tomography. J Appl Physiol 1996; 81: 1295 1305 67 McKay LC, Evans KC, Frackowiak RS, et al. Neural correlates of voluntary breathing in humans. J Appl Physiol 2003; 95:1170 1178 68 Isaev G, Murphy K, Guz A, et al. Areas of the brain concerned with ventilatory load compensation in awake man. J Physiol 2002; 539:935 945 69 Evans KC, Shea SA, Saykin AJ. Functional MRI localisation of central nervous system regions associated with volitional inspiration in humans. J Physiol 1999; 520:383 392 70 Thornton JM, Guz A, Murphy K, et al. Identification of higher brain centres that may encode the cardiorespiratory response to exercise in humans. J Physiol 2001; 533:823 836 71 Gozal D, Hathout GM, Kirlew KA, et al. Localization of putative neural respiratory regions in the human by functional magnetic resonance imaging. J Appl Physiol 1994; 76:2076 2083 72 Corfield DR, Fink GR, Ramsay SC, et al. Evidence for limbic system activation during CO 2 -stimulated breathing in man. J Physiol 1995; 488:77 84 73 Liotti M, Brannan S, Egan G, et al. Brain responses associated with consciousness of breathlessness (air hunger). Proc Natl Acad Sci U S A 2001; 98:2035 2040 74 Brannan S, Liotti M, Egan G, et al. Neuroimaging of cerebral activations and deactivations associated with hypercapnia and hunger for air. Proc Natl Acad Sci USA 2001; 98:2029 2034 75 Parsons LM, Egan G, Liotti M, et al. Neuroimaging evidence implicating cerebellum in the experience of hypercapnia and hunger for air. Proc Natl Acad Sci U S A 2001; 98:2041 2046 76 Augustine JR. Circuitry and functional aspects of the insular lobe in primates including humans. Brain Res Brain Res Rev 1996; 22:229 244 77 Hanamori T, Kunitake T, Kato K, et al. Convergence of oropharyngolaryngeal, baroreceptor and chemoreceptor afferents onto insular cortex neurons in rats. Chem Senses 1997; 22:399 406 78 Hanamori T, Kunitake T, Kato K, et al. Responses of neurons in the insular cortex to gustatory, visceral, and nociceptive stimuli in rats. J Neurophysiol 1998; 79:2535 2545 79 Gaytan SP, Pasaro R. Connections of the rostral ventral respiratory neuronal cell group: an anterograde and retrograde tracing study in the rat. Brain Res Bull 1998; 47:625 642 80 Henderson LA, Woo MA, Macey PM, et al. Neural responses during Valsalva maneuvers in obstructive sleep apnea syndrome. J Appl Physiol 2003; 94:1063 1074 81 Dawson SL, Panerai RB, Potter JF. Critical closing pressure explains cerebral hemodynamics during the Valsalva maneuver. J Appl Physiol 1999; 86:675 680 82 Price DD. Psychological and neural mechanisms of the affective dimension of pain. Science 2000; 288:1769 1772 83 Birbaumer N, Schmidt RF. Biologische psychologie. Berlin, Germany: Springer, 2003; 328 372 84 Damasio AR, Grabowski TJ, Bechara A, et al. Subcortical and cortical brain activity during the feeling of self-generated emotions. Nat Neurosci 2000; 3:1049 1056 85 Peyron R, Laurent B, Garcia-Larrea L. Functional imaging of brain responses to pain. a review and meta-analysis. Neurophysiol Clin 2000; 30:263 288 86 Treede RD, Kenshalo DR, Gracely RH, et al. The cortical representation of pain. Pain 1999; 79:105 111 87 Casey KL. Forebrain mechanisms of nociception and pain: analysis through imaging. Proc Natl Acad Sci U S A 1999; 96:7668 7674 88 Bushnell MC. Psychophysical and brain imaging approaches to the study of clinical pain syndromes. Can J Anaesth 2002; 49:R1 R5 89 Tataranni PA, Gautier JF, Chen K, et al. Neuroanatomical correlates of hunger and satiation in humans using positron emission tomography. Proc Natl Acad Sci U S A 1999; 96:4569 4574 90 Denton D, Shade R, Zamarippa F, et al. Neuroimaging of genesis and satiation of thirst and an interoceptor-driven theory of origins of primary consciousness. Proc Natl Acad Sci U S A 1999; 96:5304 5309 91 Kinomur S, Kawashima R, Yamada K, et al. Functional anatomy of taste perception in the human brain studied with positron emission tomography. Brain Res 1994; 659:263 266 92 Reiman EM, Lane RD, Ahern GL. Neuroanatomical correlates of externally and internally generated human emotion. Am J Psychiatry 1997; 154:918 925 93 Banzett RB, Moosavi SH. Dyspnea and pain: similarities and contrasts between two very unpleasant sensations. APS Bull 2001;11:1 8 94 Gehlbach BK, Geppert E. The pulmonary manifestations of left heart failure. Chest 2004; 125:669 682 95 Nishino T, Shimoyama N, Ide T, et al. Experimental pain augments experimental dyspnea, but not vice versa in human volunteers. Anesthesiology 1999; 91:1633 1638 96 Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965; 150:971 979 97 Geissner E. Psychologische modelle des schmerzes und der schmerzverarbeitung. In: Geissner E, Jungnitsch G, eds. Psychologie des schmerzes. diagnose und therapie. Weinheim, Germany: Psychologie Verlags Union, 1992; 25 46 98 Geissner E. Die schmerzempfindungs-skala. Göttingen, Germany: Hogrefe, 1996 99 Melzack R. The McGill Pain Questionnaire: major properties and scoring methods. Pain 1975; 1:277 299 100 Wilson RC, Jones PW. Differentiation between the intensity of breathlessness and the distress it evokes in normal subjects during exercise. Clin Sci (Lond) 1991; 80:65 70 101 Lehrer PM, Hochron SM, Isenberg S, et al. The asthma symptom profile: a psychophysically based scale for assessment of asthma symptoms. J Psychosom Res 1993; 37:515 521 102 Ruo M. Efficacy and factors of efficacy in psychological pain therapy: a review. Verhaltenstherapie 1998; 8:14 25 103 Rainville P, Duncan GH, Price DD, et al. Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science 1997; 277:968 971 104 Villemure C, Bushnell MC. Cognitive modulation of pain: www.chestjournal.org CHEST / 128 / 1/ JULY, 2005 353

how do attention and emotion influence pain processing? Pain 2002; 95:195 199 105 Valet M, Sprenger T, Boecker H, et al. Distraction modulates connectivity of the cingulo-frontal cortex and the midbrain during pain-an fmri analysis. Pain 2004; 109:399 408 106 Williamson JW, McColl R, Mathews D. Evidence for central command activation of the human insular cortex during exercise. J Appl Physiol 2003; 94:1726 1734 107 Williamson JW, McColl R, Mathews D, et al. Activation of the insular cortex is affected by the intensity of exercise. J Appl Physiol 1999; 87:1213 1219 108 Bornhövd K, Quante M, Glauche V, et al. Painful stimuli evoke different stimulus-response functions in the amygdala, prefrontal, insula and somatosensory cortex: a single-trial fmri study. Brain 2002; 125:1326 1336 354 Reviews