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Published ahead of print on February 8, 2008, doi:10.1164/rccm.200712-1821OC
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American Journal of Respiratory and Critical Care Medicine Vol 177. pp. 1026-1032, (2008)
© 2008 American Thoracic Society
doi: 10.1164/rccm.200712-1821OC

Original Article

The Unpleasantness of Perceived Dyspnea Is Processed in the Anterior Insula and Amygdala

Andreas von Leupoldt1,2, Tobias Sommer2, Sarah Kegat1, Hans Jörg Baumann3, Hans Klose3, Bernhard Dahme1 and Christian Büchel2

1 Department of Psychology, University of Hamburg, Hamburg, Germany; and 2 Department of Systems Neuroscience/Neuroimage Nord and 3 Department of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Correspondence and requests for reprints should be addressed to Andreas von Leupoldt, Ph.D., Department of Psychology, University of Hamburg, Von-Melle-Park 5, 20146 Hamburg, Germany. E-mail: andreas.vonleupoldt{at}uni-hamburg.de


   ABSTRACT
TOP
 ABSTRACT
AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: The subjective perception of dyspnea, which is an impairing symptom in various cardiopulmonary diseases, consists of sensory (intensity) and affective aspects (unpleasantness). However, little is known about the cortical processing of the perception of dyspnea.

Objectives: To investigate the cortical areas associated with the processing of the affective unpleasantness of perceived dyspnea.

Methods: Brain imaging study using functional magnetic resonance imaging in 14 healthy volunteers.

Measurements and Main Results: Dyspnea was induced by inspiratory resistive loaded breathing with concomitant positive and negative emotional stimulation by viewing standardized emotional picture series. The blood oxygen level–dependent contrast was measured as an index of local neuronal activity while respiration was continuously monitored. Negative emotional stimulation during loaded breathing was associated with higher unpleasantness of perceived dyspnea when compared with loaded breathing with concomitant positive emotional stimulation (P < 0.05). The levels of intensity of perceived dyspnea, respiratory responses, and load magnitude were similar between both conditions. Higher unpleasantness of dyspnea was associated with neuronal activations in the limbic system—that is, in the right anterior insula and in the right amygdala (respective Z values = 3.93 and 3.15; P < 0.05).

Conclusions: The results of the present brain imaging study suggest that the unpleasantness of subjectively perceived dyspnea is processed in the right human anterior insula and amygdala.

Key Words: brain • dyspnea • emotions • magnetic resonance imaging • perception



   AT A GLANCE COMMENTARY
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Scientific Knowledge on the Subject
Dyspnea is an impairing symptom in various cardiopulmonary and other diseases, but little is known about the cortical mechanisms underlying the perception of this sensation.

What This Study Adds to the Field
This study indicates that the affective dimension (unpleasantness) of perceived dyspnea in humans is processed in the right anterior insula and the amygdala.

 
Dyspnea, the subjective experience of breathing discomfort, is an unpleasant symptom in various cardiopulmonary and neuromuscular diseases and a cardinal symptom of asthma and chronic obstructive pulmonary disease (COPD) (1). In these patients, the sensation of dyspnea often leads to fear, anxiety, panic, and—in severe cases—fear of death (1). Dyspnea causes considerable limitations to functional status and quality of life and is a considerable socioeconomic burden (1, 2).

Studies have demonstrated that the perception of dyspnea—analogous to the perception of pain—consists of at least two distinct dimensions: a sensory dimension (i.e., intensity) and an affective dimension (i.e., unpleasantness). These dimensions have been shown to be differentiated in retrospective symptom reports (3), during physical exercise (4–6), resistive load breathing (7, 8), histamine-induced bronchoconstriction (9), or in real-life settings (10) by healthy participants and by patients with asthma or COPD. In particular, the affective unpleasantness of perceived dyspnea has been suggested as being specifically relevant for motivating patients to take effective medication or to seek professional help in a timely manner (8, 11).

Previous research has further demonstrated—again analogous to the perception of pain—that psychological factors such as emotions, cognitions, and attention can substantially influence the perception of dyspnea irrespective of the objective respiratory status (11–17). The strongest psychological influence was observed on the perceived unpleasantness of dyspnea when compared with the intensity of dyspnea (4, 8, 9, 17).

However, the cortical mechanisms underlying the perception of dyspnea are far from being understood (2, 18). Results of neuroimaging studies have suggested that distinct brain areas process the perception of dyspnea, among which the right anterior insular cortex seems to be the most consistent structure across studies (18–23). Because of similar prominent insular cortex activity during the subjective perception of other unpleasant experiences such as pain (24), hunger (25), thirst (26), aversive taste (27), or negative emotions (28), a particular role for the insular cortex and other related limbic structures for the processing of the affective unpleasantness of perceived dyspnea has been assumed (29–31), but not yet tested. Therefore, the present neuroimaging study examined the neuronal mechanisms associated with the processing of the unpleasantness of resistive load–induced dyspnea by using functional magnetic resonance imaging (fMRI).


   METHODS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Participants
Fourteen healthy volunteers (7 female) with a mean age of 26.6 (±6.2) years were examined. Acute or chronic complaints concerning the respiratory tract, pregnancy, or any chronic medical condition were exclusion criteria. All volunteers provided informed written consent and underwent a standardized diagnostic interview (32) to exclude psychological disorders. The study protocol was approved by the local ethics committee.

Apparatus and Respiratory Measurements
Volunteers breathed through an external breathing circuit consisting of a tightly fitting face mask (no. 7930; Hans Rudolph, Inc., Kansas City, MO), connected in series by a short rigid tube with an fMRI-compatible pneumotachograph, which also contained ports for recording end-tidal CO2 pressure (PETCO2) and inspiratory mouth pressure (PI), followed by a two-way nonrebreathing valve (no. 2630; Hans Rudolph, Inc.). The inspiratory port of the two-way valve was connected to a tube designed for the easy introduction and removal of inspiratory resistive loads while the expiratory port was left free to prevent rebreathing of CO2. Throughout all experimental conditions, peak PI, tidal volume (VT), breathing frequency (f), minute ventilation (VE), inspiratory time (TI), and PETCO2 were continuously measured with a modified ZAN 600 (ZAN Messgeräte GmbH, Oberhulba, Germany), displayed on a computer monitor and stored to hard disk with event marks precisely relating respiratory variables to individual brain scans.

Induction and Measurement of Perceived Dyspnea
We defined dyspnea to the participants as the sensation of uncomfortable or difficult breathing. Dyspnea was induced by introducing an inspiratory resistive load to the external breathing circuit. The magnitude of the load was estimated in a pre test immediately before the fMRI session, during which various loads were repeatedly presented using the external breathing circuit. The selected load induced a sensation of "severe" dyspnea in more than 50% of the trials, corresponding to a Borg score of 5 or more. Across volunteers, the mean of the used load was 8.22 kPa/L/s (range, 2.87 to 11.75 kPa/L/s). Moreover, we verified that the unloaded baseline condition did not induce any sensation of dyspnea.

In the fMRI session, the same individual load magnitude was used for all loaded breathing conditions. The intensity and unpleasantness of perceived dyspnea were rated after each loaded and unloaded condition on continuous computerized horizontal visual analog scales (VAS-I and VAS-U, respectively) presented in permuted order. VAS were anchored with "not noticeable/unpleasant" on the far left side (equivalent to a numeric value of 0) and "maximally imaginable intensity/unpleasantness" on the far right side (equivalent to a numeric value of 100). The intensity and unpleasantness of perceived dyspnea were rated by moving a bar on the VAS via button presses. The distance from the left anchor to the mark provided a numeric value of the sensation. Both dimensions were explained in detail before testing with standardized examples (4) and the experimenter made sure that the phrases were adequately understood. VAS have interval properties, are well established and validated for measuring physiological as well as psychological sensations, and have been used successfully in and recommended for studies on the perception of dyspnea (1, 6–8, 10, 11, 33, 34).

In addition, the overall quality of perceived dyspnea was rated immediately after the fMRI session on a verbal descriptor list containing 22 German language descriptors of dyspnea, which were rated on a 5-point Likert scale (35).

Manipulation of Perceived Unpleasantness of Dyspnea
In a previous study, we observed that negative emotional stimulation by affective picture series during resistive load breathing leads to increased unpleasantness of dyspnea, whereas positive emotional stimulation leads to decreased unpleasantness of dyspnea without concomitant changes in perceived intensity or ventilatory measures (8). In the present fMRI study, the same paradigm was used to manipulate the unpleasantness of dyspnea while keeping the intensity of perceived dyspnea constant across conditions. For this purpose, eight picture series inducing a negative emotional state and eight picture series inducing a positive emotional state were composed, using pictures from the International Affective Picture System (IAPS) (36), which is a validated standard instrument for the induction of emotional states. Pictures were chosen on the basis of the normative ratings offered in the technical manual of the IAPS. Each series, 24 seconds in length, contained four pictures being presented for 6 seconds in randomized order. The picture series were paralleled regarding various attributes, for example, figure–ground composition, human/animal/landscape content, and light parameters. Six similar picture series inducing a neutral emotional state were composed for the habituation trials (see below).

Functional Brain Imaging
Imaging was performed using a 3-T TRIO-Magnetom scanner (Siemens Medical Solutions, Erlangen, Germany) with a standard head coil. The blood oxygen level–dependent effect (BOLD) was taken as an index of local neuronal activity (37). Thirty-eight continuous axial slices (2-mm thickness with 1-mm gap) were acquired by using a gradient echo, echo-planar T2*-sensitive sequence (TR = 2.32 s, TE = 26 ms; flip angle, 80°; matrix, 72 x 72; field of view, 216 x 216 mm). Stimuli were presented with the software Presentation (Neurobehavioral Systems, Inc., Albany, CA) with affective picture series and VAS-I and VAS-U being projected onto a mirror inside the scanner.

Experimental Protocol
After the presentation of standardized instructions, volunteers underwent the pretest to select the appropriate resistive load. After practicing the use of the computerized VAS-I and VAS-U, the fMRI session followed. The subjects lay supine in the scanner with the head immobilized and the face mask and breathing circuit comfortably positioned. Eleven conditions of loaded breathing (dyspnea) and 11 conditions of unloaded breathing (baseline) were presented in alternating order for 24 seconds each. During the loaded breathing conditions, the load was presented continuously for the whole period of 24 seconds—that is, for multiple breaths. During the first three loaded and unloaded conditions, the six neutral picture series were presented in randomized order. These neutral conditions were included to facilitate respiratory and behavioral habituation to the measurement procedure and were excluded from further analyses. Of the remaining eight loaded conditions, four were presented together with a negative picture series (dyspnea negative) and four together with a positive picture series (dyspnea positive). Of the remaining eight unloaded conditions, four were presented together with a negative picture series (baseline negative) and four together with a positive picture series (baseline positive). Therefore, each subject viewed the same set of picture series with each picture being presented only once, but the order of picture series as well as the order of the four pictures within each series were randomized across participants. After each loaded and unloaded condition, the intensity and unpleasantness of perceived dyspnea were rated. The subjects were instructed to rate only the perceived dyspnea, not the unpleasantness of viewing the picture series or any other sensation (e.g., due to the face mask or uncomfortable position). Immediately after the fMRI session, the overall quality of perceived dyspnea was judged on the verbal descriptor list.

Data Analysis
Respiratory variables and perceived dyspnea.
Results are reported as means ± standard deviations of the mean (SD). For each volunteer, PI, VT, f, VE, TI, PETCO2, VAS-I, and VAS-U were averaged across each experimental condition. The resulting mean values of these parameters were then averaged for the whole study group to obtain means for the four main experimental conditions—that is, dyspnea negative, dyspnea positive, baseline negative, and baseline positive. Group means were analyzed as dependent variables in separate two-way analyses of variance with repeated measures on the factor condition and sex as between-group factor. Analyses were calculated with SPSS 15.0 software (SPSS, Inc., Chicago, IL), using a significance level of P < 0.05.

Functional brain imaging.
Image processing and statistical analyses were performed with SPM5 (http://www.fil.ion.ucl.ac.uk/spm/). All images were realigned to the first image, spatially normalized into standard anatomic space based on the Montreal Neurological Institute (MNI) template and smoothed with an isotropic Gaussian kernel of 10 mm full-width at half-maximum (38).

On the single-subject level, the statistical analysis was performed with the general linear model as implemented in SPM5, which included the four experimental conditions, that is, dyspnea negative, dyspnea positive, baseline negative, and baseline positive. PETCO2 and the global BOLD signal intensity (calculated across the whole brain) were included in the model as confounding regressors to control for possible signal artifacts due to the known effects of arterial CO2 changes on global cortical blood flow and the BOLD signal (22, 39). Two additional regressors coded for the rating responses. A high-pass filter with a cutoff of 128 seconds was applied to remove baseline drifts. After model estimation, the linear contrasts of interest were generated on the basis of the ensuing parameter estimates. The first contrast compared the averaged neuronal activity (BOLD response) across both baseline conditions with the averaged neuronal activity across both dyspnea conditions to examine the main effect of dyspnea induction irrespective of concomitant emotional stimulation. For the second contrast, we hypothesized that the difference in neuronal activity between baseline negative and dyspnea negative would be stronger than the difference between baseline positive and dyspnea positive because of the induced higher unpleasantness during the dyspnea-negative condition. Because the perceived intensity of dyspnea was assumed to remain stable and effects of picture viewing were canceled out in this interaction contrast, the cortical activity related to the unpleasantness of perceived dyspnea could be disentangled.

At the group level, the ensuing contrast images were then entered into the group analysis by a random effects approach, treating intersubject variability as a random factor. The threshold for statistical significance was set to P < 0.05, corrected for multiple comparisons across the whole brain. On the basis of our a priori hypotheses, a reduced spherical search volume was used for multiple comparisons in limbic structures such as the insular cortex and the amygdala by employing an anatomic mask derived from the automated anatomic labeling template (40) and by using a reduced search volume (10-mm-radius sphere), respectively.


   RESULTS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Respiratory Variables and Perceived Dyspnea
Group results concerning respiratory variables and perceived dyspnea are presented in Table 1. When compared with the unloaded baseline positive, there was an expected increase in PI and TI during loaded dyspnea positive as well as a slight but significant increase in PETCO2. This was paralleled by decreases in VT, VE, and to a smaller extent in f. Similar findings were observed for the comparison between baseline negative and dyspnea negative. No difference in any respiratory variable was found between dyspnea positive and dyspnea negative or between the two baseline conditions with the exception of marginally higher f during baseline positive compared with baseline negative (P < 0.05).


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  		TABLE 1. RESPIRATORY VARIABLES AND PERCEIVED DYSPNEA DURING UNLOADED-BASELINE AND LOADED-DYSPNEA CONDITIONS WITH CONCOMITANT EMOTIONAL STIMULATION

 
As expected, VAS-I increased under both dyspnea conditions when compared with the respective baselines, but showed no difference between dyspnea positive and dyspnea negative (Table 1). VAS-U increased under both dyspnea conditions when compared with the respective baselines. However, VAS-U was significantly higher under the dyspnea-negative condition compared with the dyspnea-positive condition (Table 1). No difference in any respiratory variable or VAS ratings was found between male and female volunteers. An exploratory analysis of ratings on the verbal descriptor list revealed that the overall quality of dyspnea during loaded breathing was described mainly as "increased work and effort of breathing."

Functional Brain Imaging
Results of the fMRI analyses are group means and are presented in Figures 1 and 2 as brain activation areas—that is, areas with a significant increase in the BOLD signal because of increased neuronal activity. The first analysis revealed significant brain activations in several areas, which were related to the induction of dyspnea regardless of concomitant emotional stimulation. As indicated in Figure 1, these involved the bilateral sensorimotor cortex (MNI coordinates: 60, –6, 16: Z = 5.75; –60, –6, 16: Z = 5.21; 54, 6, 0: Z = 5.22; –54, –33, 20: Z = 5.31; –54, –9, 30: Z = 4.97; all P values < 0.05; corrected for multiple comparisons), the supplemental motor area (MNI coordinates: 3, –6, 64: Z = 4.24; P < 0.05; corrected for multiple comparisons) and the bilateral insular cortex extending to the frontal inferior orbital cortex (MNI coordinates: 27, 21, –14: Z = 5.03; 45, 3, 0: Z = 3.56; –48, –6, 4: Z = 4.02; all P values < 0.05; corrected for multiple comparisons). Most importantly, the second analysis demonstrated significant brain activations related to the perceived unpleasantness of dyspnea (Figure 2) in two areas of the limbic system: the right anterior insular cortex (MNI coordinates: 30, 18, –10: Z = 3.93; P < 0.05; corrected for multiple comparisons) and the right sublenticular extended amygdala (MNI coordinates: 24, 9, –18: Z = 3.15; P < 0.05; corrected for multiple comparisons).


Figure 1
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  		Figure 1. Brain activations associated with resistive load–induced dyspnea as compared with unloaded baseline conditions (dyspnea and baseline conditions are each averaged across concomitant negative and positive emotional stimulation). Group results are presented as statistical maps superimposed onto the group mean structural T1-weighted magnetic resonance image from a transverse view (z = 0, left), a coronal view (y = –6, middle), and a sagittal view (x = 0, right). Signal intensity is coded by the inserted color scale (thresholded at T = 3.9, P < 0.001 uncorrected). Main activation areas (P < 0.05 corrected for multiple comparisons) are seen in the bilateral sensorimotor cortex (SMC), in the supplemental motor area (SMA), and the bilateral insular cortex (IC). A = anterior; L = left side of brain; R = right side of brain.

 

Figure 2
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  		Figure 2. Brain activations associated with the perceived unpleasantness of resistive load–induced dyspnea. Results represent the difference in cortical activity between dyspnea-negative and baseline-negative conditions compared with the difference in cortical activity between dyspnea-positive and baseline-positive conditions. Group results are presented as statistical maps superimposed onto the group mean structural T1-weighted magnetic resonance image from a transverse view (z = –12, left), a coronal view (y = 18, middle), and a coronal view (y = 9, right). Signal intensity is coded by the inserted color scale (thresholded at T = 3.9, P < 0.001 uncorrected). Main activation areas (P < 0.05 corrected for multiple comparisons) are seen in the right anterior insular cortex (IC) and right amygdala (AM). A = anterior; L = left side of brain; R = right side of brain.

 

   DISCUSSION
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present fMRI study examined the cortical areas associated with the processing of the affective unpleasantness of perceived dyspnea. The results show that our experimental manipulation, that is, resistive load breathing with concomitant positive and negative emotional stimulation by viewing picture series, successfully induced two conditions of similarly intensive dyspnea when compared with the two unloaded baseline conditions of matched emotional stimulation. This was confirmed by similar stimulus magnitude, similar subjective ratings of perceived intensity of dyspnea, and similar respiratory responses under both dyspneic conditions. The only difference between these conditions was the considerably higher unpleasantness of perceived dyspnea during concomitant negative emotional stimulation when compared with concomitant positive emotional stimulation, which converges with previous studies on psychological influences on the perception of dyspnea (4, 8, 17). Our main finding demonstrates that this higher level of perceived unpleasantness of dyspnea was related to increased neuronal activity in the right anterior insular cortex and the right amygdala. In line with previous theoretical assumptions (18, 29–31), we therefore conclude that these two limbic structures are related to the processing of the unpleasantness of perceived dyspnea.

Our results show further that successful induction of dyspnea by resistive load breathing in the fMRI scanner was not only confirmed by increased subjective ratings of dyspnea, but also by increases in PI and TI and decreases in VT and VE, which are commonly reported in studies using resistive loads (8, 21, 41, 42). On the cortical level and in line with previous results (20–22), successful induction of dyspnea, irrespective of concomitant emotional stimulation, was confirmed by bilateral activations in the insular and sensorimotor cortices and in the supplemental motor area. Activity in the latter two cortical motor areas has been shown to drive voluntary breathing in several previous studies (18), including those using resistive load breathing (41). Therefore, these activations seem to reflect the voluntary increase in respiratory muscle effort during induced dyspnea in our study, presumably in concert with afferent feedback from respiratory mechanoreceptors signaling higher workload. Further, these activations might represent corollary discharge, that is, copies of increased efferent respiratory motor command from cortical motor centers to the sensory cortex, which are assumed to lead to the perception of increased work and effort of breathing as described by our volunteers (1, 2, 43).

Our observation of prominent activation in the insular cortex is particularly consistent with the rare previous imaging studies that explicitly examined the perception of dyspnea. Banzett and coworkers (20) and Evans and coworkers (22) induced dyspnea in mechanically ventilated volunteers by restraining tidal volume below spontaneous levels in combination with constantly elevated arterial CO2, while Liotti and coworkers (23) induced dyspnea by inspiration of increased CO2 (8%) with either a face mask or a mouthpiece. Thus, all three studies used stimulation of chemoreceptors with assumed subsequent increases in medullary respiratory motor drive leading to dyspneic sensations such as "air hunger" or "urge to breathe." In contrast, Peiffer and colleagues (21) applied external resistive loads during inspiration and expiration leading to sensations of "increased work and effort of breathing," which is more comparable to the present study. Irrespective of methodologic differences, activations of the right anterior insular cortex were the most prominent across all of these studies, whereas only two studies reported concomitant activations of the amygdala (22, 23); this might be related to differences in the employed imaging procedures. However, no previous study has directly assessed both intensity and unpleasantness of subjectively perceived dyspnea or manipulated these different dimensions. Therefore, the present study extends the previous findings by first demonstrating the particular relevance of the right anterior insula and amygdala for the processing of the affective dimension, but not the sensory dimension of perceived dyspnea. This confirms theoretical assumptions on a dual cortical processing of dyspneic respiratory signals (18, 29, 30). In this regard, one pathway including limbic system areas such as the insula, amygdala, medial dorsal areas of the thalamus, and the cingulate cortex has been suggested as being related to the affective components of experienced dyspnea, whereas the other pathway including ventroposterior thalamic areas and sensorimotor cortices has been assumed to process the sensory aspects of dyspnea.

The present findings are in contrast to some results of the elegant study by Peiffer and coworkers (21), who assumed a role for the posterior cingulate cortex in the processing of the unpleasantness of dyspnea. However, these authors have not separately examined the intensity and unpleasantness of subjectively perceived dyspnea. Their volunteers provided only one intensity rating, which was per instruction defined also to "include the affective component of the sensory experience." Therefore, their study was not designed to differentiate the subjectively perceived unpleasantness of dyspnea from the subjectively perceived intensity of dyspnea, but rather concentrated on the combination of both dimensions.

In line with our findings, an affect-related role of the insular cortex has also been suggested for the perception of pain (24), which is an equally aversive physiological sensation with many similarities to dyspnea (15, 18, 19). For example, by keeping the intensity of perceived tonic pain stable across experimental conditions, Schreckenberger and coworkers (44) demonstrated a significant association of insular activity with pain unpleasantness, which was manipulated by an infusion of acidified phosphate buffer into either the muscles or skin of the hand. These findings are supported by lesion studies in which damage to large parts of the insular cortex has been shown in patients with pain asymbolia (45, 46). Patients with this condition demonstrated reduced affective behavior and did not show affective responses, that is, pain unpleasantness, or withdrawal in response to painful thermal stimulation, despite the fact that their capacity to appreciate the sensory qualities of the painful stimuli was still preserved. Participation in the processing of the affective dimension of perceived pain has also been suggested for the amygdala (24). For example, Bingel and colleagues (47) demonstrated bilateral activations of the amygdala during laser-evoked pain applied to the human hand, which was related to the affective processing of pain, but not to its sensory aspects.

An important role of the insular cortex has further been reported for the perception of various other unpleasant sensations such as hunger (25), thirst (26), aversive taste (27), and negative emotions (28), whereas the amygdala seems to be more closely related to the processing of emotional states, particularly those of negative valence (28, 48). Therefore, the insular cortex and in particular its anterior part has been suggested as being an interoceptive alarm center, alerting the individual to potentially distressing stimuli with negative emotional significance (49). Theories on emotions have extended this view by providing a model with the anterior insula as the main center linking the perception of visceral sensations to the conscious experience of human emotions (50, 51). In fact, previous studies have supported this view by showing strong associations between the perception of physical sensations such as heart beat, anterior insular activity, and the experience of emotional arousal (50–52). Because of its extensive and mostly reciprocal connections to a variety of other sensorimotor, cognitive–motivational, and affective brain areas such as the amygdala and the anterior cingulate cortex, this limbic structure seems to be ideally suited to serve this integrative homeostatic function (50, 53). Because the insular cortex also receives various afferent respiratory signals from respiratory chemoreceptors, mechanoreceptors, and the medullary respiratory oscillator in the brainstem (18, 29), a similar transformation in this brain area of perceived respiratory signals of dyspnea into its affective valuation can be assumed on the basis of our present results and previous theoretical assumptions (18, 29–31). It might further be speculated that the anterior insular cortex, presumably in concert with other limbic structures such as the amygdala, is thereby involved in the processing of the influence of emotions on the perception of dyspnea, which has been observed in several studies (8, 14–16).

However, we found no activations of the anterior cingulate cortex, which were reported in some of the previous studies on the perception of dyspnea (22, 23) and other unpleasant sensations (25, 26). In particular, pain research has demonstrated a high relevance of this limbic structure for the affective dimension of perceived pain (24). This discrepancy might be due to the fact that the anterior cingulate cortex is involved not only in the processing of stimuli with a negative emotional valence, but also of positively valenced stimuli (28). Together with its role in cognitive attention, which was necessary at least to some degree in all our experimental conditions, activity in the anterior cingulate cortex was presumably evident in both negative and positive emotional conditions of the present study and, thus, could not be separated by our contrast analyses. Therefore, future studies in this field would profit from contrasting dyspneic conditions with concomitant negative and positive emotional stimulation with dyspneic conditions with concomitant neutral emotional stimulation.

A potential limitation of the present study is that the use of resistive load breathing for the experimental induction of dyspnea only mirrors some aspects of dyspnea in cardiopulmonary and neuromuscular diseases, that is, the sense of increased work and effort of breathing due to increased cortical motor command and stimulation of respiratory mechanoreceptors. Therefore, future studies are necessary to extend the present findings to other pathomechanisms underlying this multidimensional sensation including stimulation of chemoreceptors or intrapulmonary irritant receptors. However, because the obtained neuronal activations in the present study correspond well with other limbic system activations as found in previous studies (20, 22, 31) using unpleasant inspirations of increased levels of CO2, comparable findings might be assumed for other pathomechanisms of dyspnea. In this regard, the use of regions of interest for limbic structures, as in the present study, might be helpful in future studies for detecting neuronal activations related to the unpleasantness of perceived dyspnea. On the basis of strong a priori hypotheses or prior findings, this established method reduces the number of necessary corrections for multiple comparisons from the whole brain to relevant target brain areas, which limits the risk of false negative findings. Furthermore, the generalizability of our findings is somewhat limited by the inclusion of healthy volunteers in the present study. Although there is little reason to assume that the general cortical mechanisms underlying the perception of dyspnea show pronounced differences between healthy volunteers and cardiopulmonary patients, the prolonged or repeated experience of dyspnea by patients might be associated with habituation or sensitization effects. These effects might, in turn, decrease or increase neuronal activity in dyspnea-relevant cortical areas, which necessitates future studies on this subject in patients groups.

In summary, the results of the present brain-imaging study suggest that the unpleasantness, but not the intensity, of subjectively perceived dyspnea is processed in the human anterior insula and amygdala. These findings underline the importance of a differentiation between the affective and sensory dimensions of perceived dyspnea by suggesting different neuronal pathways for the processing of these dimensions. The present results, therefore, contribute to a better understanding of the mechanisms underlying the perception of dyspnea and might help to improve its clinical management by pointing out the relevance of the affective dimension of this sensation.


   Acknowledgments
 
The authors thank the following people for valuable assistance and helpful comments: Katrin Wendt, Katrin Mueller, Niklas Stein, Eszter Schoell, Falk Eippert, Solveig Nielsen-Klein, Dirk Waschatz, Karl Evans, and all of the volunteers.


   FOOTNOTES
 
Supported by a grant from the Deutsche Forschungsgemeinschaft (DFG LE 1843/5-1) to A.v.L. and a grant from the BMBF to C.B.

Originally Published in Press as DOI: 10.1164/rccm.200712-1821OC on February 8, 2008

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form December 13, 2007; accepted in final form February 1, 2008


   REFERENCES
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. American Thoracic Society. Dyspnea: mechanisms, assessment, and management: a consensus statement. Am J Respir Crit Care Med 1999;159:321–340.[Free Full Text]
  2. 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 2007;4:145–168.[Abstract/Free Full Text]
  3. Lehrer PM, Hochron SM, Isenberg S, Rausch L, Carr R. The asthma symptom profile: a psychophysically based scale for assessment of asthma symptoms. J Psychosom Res 1993;37:515–521.[CrossRef][Medline]
  4. von Leupoldt A, Taube K, Schubert-Heukeshoven S, Magnussen H, Dahme B. Distractive auditory stimuli reduce the unpleasantness of dyspnea during exercise in patients with COPD. Chest 2007;132:1506–1512.[CrossRef][Medline]
  5. Wilson RC, Jones PW. Differentiation between the intensity of breathlessness and the distress it evokes in normal subjects during exercise. Clin Sci 1991;80:65–70.[Medline]
  6. Carrieri-Kohlman V, Gormley JM, Douglas MK, Paul SM, Stulbarg MS. Exercise training decreases dyspnea and the distress and anxiety associated with it: monitoring alone may be as effective as coaching. Chest 1996;110:1526–1535.[CrossRef][Medline]
  7. von Leupoldt A, Dahme B. Differentiation between the sensory and affective dimension of dyspnea during resistive load breathing in normal subjects. Chest 2005;128:3345–3349.[CrossRef][Medline]
  8. von Leupoldt A, Mertz C, Kegat S, Burmester S, Dahme B. The impact of emotions on the sensory and affective dimension of perceived dyspnea. Psychophysiology 2006;43:382–386.[CrossRef][Medline]
  9. De Peuter S, Lemaigre V, Van Diest I, Verleden G, Demedts M, Van den Bergh O. Differentiation between the sensory and affective aspects of histamine-induced bronchoconstriction in asthma. Respir Med 2007;101:925–932.[CrossRef][Medline]
  10. Meek PM, Lareau SC, Hu J. Are self-reports of breathing effort and breathing distress stable and valid measures among persons with asthma, persons with COPD, and healthy persons? Heart Lung 2003;32:335–346.[CrossRef][Medline]
  11. Banzett RB, Dempsey JA, O'Donnell DE, Wamboldt MZ. Symptom perception and respiratory sensation in asthma. Am J Respir Crit Care Med 2000;162:1178–1182.[Free Full Text]
  12. Lavietes MH, Sanchez CW, Tiersky LA, Cherniack NS, Natelson BH. Psychological profile and ventilatory response to inspiratory resistive loading. Am J Respir Crit Care Med 2000;161:737–744.[Abstract/Free Full Text]
  13. Scano G, Stendardi L. Dyspnea and asthma. Curr Opin Pulm Med 2006;12:18–22.[Medline]
  14. De Peuter S, Van Diest I, Lemaigre V, Verleden G, Demedts M, Van den Bergh O. Dyspnea: the role of psychological processes. Clin Psychol Rev 2004;24:557–581.[CrossRef][Medline]
  15. von Leupoldt A, Dahme B. Psychological aspects in the perception of dyspnea in obstructive pulmonary diseases. Respir Med 2007;101:411–422.[CrossRef][Medline]
  16. von Leupoldt A, Riedel F, Dahme B. The impact of emotions on the perception of dyspnea in pediatric asthma. Psychophysiology 2006;43:641–644.[CrossRef][Medline]
  17. von Leupoldt A, Seemann N, Gugleva T, Dahme B. Attentional distraction reduces the affective but not the sensory dimension of perceived dyspnea. Respir Med 2007;101:839–844.[CrossRef][Medline]
  18. von Leupoldt A, Dahme B. Cortical substrates for the perception of dyspnea. Chest 2005;128:345–354.[CrossRef][Medline]
  19. Banzett RB, Moosavi SH. Dyspnea and pain: similarities and contrasts between two very unpleasant sensations. APS Bull 2001;11:1–8.
  20. Banzett RB, Mulnier HE, Murphy K, Rosen SD, Wise RJ, Adams L. Breathlessness in humans activates insular cortex. Neuroreport 2000;11:2117–2120.[Medline]
  21. 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 2001;163:951–957.[Abstract/Free Full Text]
  22. 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 2002;88:1500–1511.[Abstract/Free Full Text]
  23. Liotti M, Brannan S, Egan G, Shade R, Madden L, Abplanalp B, Robillard R, Lancaster J, Zamarripa FE, Fox PT, et al. Brain responses associated with consciousness of breathlessness (air hunger). Proc Natl Acad Sci USA 2001;98:2035–2040.[Abstract/Free Full Text]
  24. Price DD. Psychological and neural mechanisms of the affective dimension of pain. Science 2000;288:1769–1772.[Abstract/Free Full Text]
  25. Tataranni PA, Gautier JF, Chen K, Uecker A, Bandy D, Salbe AD, Pratley RE, Lawson M, Reiman EM, Ravussin E. Neuroanatomical correlates of hunger and satiation in humans using positron emission tomography. Proc Natl Acad Sci USA 1999;96:4569–4574.[Abstract/Free Full Text]
  26. Farrell MJ, Egan GF, Zamarripa F, Shade R, Blair-West J, Fox P, Denton DA. Unique, common, and interacting cortical correlates of thirst and pain. Proc Natl Acad Sci USA 2006;103:2416–2421.[Abstract/Free Full Text]
  27. Small DM, Gregory MD, Mak YE, Gitelman D, Mesulam MM, Parrish T. Dissociation of neural representation of intensity and affective valuation in human gustation. Neuron 2003;39:701–711.[CrossRef][Medline]
  28. Phan KL, Wager T, Taylor SF, Liberzon I. Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage 2002;16:331–348.[CrossRef][Medline]
  29. Davenport PW, Reep RL. Cerebral cortex and respiration. In: Dempsey JA, Pack AI, editors. Regulation of breathing. New York: Marcel Dekker; 1995. pp. 365–388.
  30. Guz A. Brain, breathing and breathlessness. Respir Physiol 1997;109:197–204.[CrossRef][Medline]
  31. Corfield DR, Fink GR, Ramsay SC, Murphy K, Harty HR, Watson JDG, Adams L, Frackoviak RSJ, Guz A. Evidence for limbic system activation during CO2-stimulated breathing in man. J Physiol 1995;488:77–84.[Abstract/Free Full Text]
  32. Wittchen HU, Wunderlich U, Gruschwitz S, Zaudig M. SKID-I: structured clinical interview for DSM-IV. Göttingen, Germany: Hogrefe; 1997.
  33. Grant S, Aitchison T, Henderson E, Christie J, Zare S, McMurray J, Dargie H. A comparison of the reproducibility and the sensitivity to change of visual analogue scales, Borg scales, and Likert scales in normal subjects during submaximal exercise. Chest 1999;116:1208–1217.[CrossRef][Medline]
  34. Muza SR, Silverman MT, Gilmore GC, Hellerstein HK, Kelsen SG. Comparison of scales used to quantitate the sense of effort to breathe in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1990;141:909–913.[Medline]
  35. von Leupoldt A, Balewski S, Petersen S, Taube K, Schubert-Heukeshoven S, Magnussen H, Dahme B. Verbal descriptors of dyspnea in patients with COPD at different intensity levels of dyspnea. Chest 2007;132:141–147.[CrossRef][Medline]
  36. Center for the Study of Emotion and Attention (CSEA-NIMH). The International Affective Picture System: digitised photographs. Gainesville, FL: Center for Research in Psychophysiology, University of Florida; 1999.
  37. Ogawa S, Lee TM, Nayak AS, Glynn P. Oxygenation-sensitive contrast in magnetic resonance image of rodent brain at high magnetic fields. Magn Reson Med 1990;14:68–78.[Medline]
  38. Friston KJ, Ashburner J, Frith CD, Pauline JB, Heather JD, Frackowiak RSJ. Spatial registration and normalisation of images. Hum Brain Mapp 1995;2:165–189.
  39. Giardino ND, Friedman SD, Dager SR. Anxiety, respiration, and cerebral blood flow: implications for functional brain imaging. Compr Psychiatry 2007;48:103–112.[CrossRef][Medline]
  40. Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, Mazoyer B, Joliot M. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 2002;15:273–289.[CrossRef][Medline]
  41. Fink GR, Corfield DR, Murphy K, Kobayashi I, Dettmers C, Adams L, Frackowiak RS, Guz A. Human cerebral activity with increasing inspiratory force: a study using positron emission tomography. J Appl Physiol 1996;81:1295–1305.[Abstract/Free Full Text]
  42. Killian KJ, Bucens DD, Campbell EJ. Effect of breathing patterns on the perceived magnitude of added loads to breathing. J Appl Physiol 1982;52:578–584.[Abstract/Free Full Text]
  43. Thornton JM, Guz A, Murphy K, Griffith AR, Pedersen DL, Kardos A, Leff A, Adams L, Casadei B, Paterson DJ. Identification of higher brain centres that may encode the cardiorespiratory response to exercise in humans. J Physiol 2001;533:823–836.[Abstract/Free Full Text]
  44. Schreckenberger M, Siessmeier T, Viertmann A, Landvogt C, Buchholz HG, Rolke R, Treede RD, Bartenstein P, Birklein F. The unpleasantness of tonic pain is encoded by the insular cortex. Neurology 2005;64:1175–1183.[Abstract/Free Full Text]
  45. Berthier M, Starkstein S, Leiguarda R. Asymbolia for pain: a sensory–limbic disconnection syndrome. Ann Neurol 1988;24:41–49.[CrossRef][Medline]
  46. Greenspan JD, Lee RR, Lenz FA. Pain sensitivity alterations as a function of lesion location in the parasylvian cortex. Pain 1999;81:273–282.[CrossRef][Medline]
  47. Bingel U, Quante M, Knab R, Bromm B, Weiller C, Büchel C. Subcortical structures involved in pain processing: evidence from single-trial fMRI. Pain 2002;99:313–321.[CrossRef][Medline]
  48. Büchel C, Morris J, Dolan RJ, Friston KJ. Brain systems mediating aversive conditioning: an event-related fMRI study. Neuron 1998;20:947–957.[CrossRef][Medline]
  49. Reiman EM, Lane RD, Ahern GL. Neuroanatomical correlates of externally and internally generated human emotion. Am J Psychiatry 1997;154:918–925.[Abstract]
  50. Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci 2002;3:655–666.[Medline]
  51. Critchley HD, Wiens S, Rotshtein P, Öhman A, Rayman JD. Neural systems supporting interoceptive awareness. Nat Neurosci 2004;7:189–195.[CrossRef][Medline]
  52. Pollatos O, Kirsch W, Schandry R. On the relationship between interoceptive awareness, emotional experience, and brain processes. Brain Res Cogn Brain Res 2005;25:948–962.[CrossRef][Medline]
  53. Augustine JR. Circuitry and functional aspects of the insular lobe in primates including humans. Brain Res Brain Res Rev 1996;22:229–244.[CrossRef][Medline]

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