Relief of Dyspnea Involves a Characteristic Brain Activation and a Specific Quality of Sensation

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1 Relief of Dyspnea Involves a Characteristic Brain Activation and a Specific Quality of Sensation Claudine Peiffer 1,2, Nicolas Costes 3, Philippe Hervé 2, and Luis Garcia-Larrea 4 1 Laboratoire de Physiologie Explorations Fonctionnelles Respiratoires, Hôpital Saint-Vincent-de-Paul, Paris, France; 2 Centre Chirurgical Marie-Lannelongue, Le Plessis Robinson, France; 3 Centre d Etude et de Recherche Médicale en Positons, Hôpital Neurologique P. Wertheimer, Lyon, France; and 4 INSERM EMI-342, and Université Lyon 1, Lyon, France Rationale: Central processing of dyspnea relief remains largely unknown. Objectives: To identify physiologic determinants, quality of sensation, and brain activation associated with dyspnea relief. Methods: Dyspnea relief was induced in 10 healthy volunteers by decreasing an adjustable external resistive load (z15 50 cm H 2 O/L/s). Brain imaging (positron emission tomography) was performed during either dyspnea or relief. Measurements and Main Results: Perceived intensity of moderate and high relief was similar to that of its preceding dyspnea (Borg scores vs , and vs , respectively; P > 0.05) and was predominantly related to reversal of dyspneainduced increased mouth pressure/ventilation ratio (r , P, 0.001). Dyspnea relief involved specific, mostly positively valenced descriptors (i.e., breathing-related pleasure and/or reward). Most significant relief-associated brain activation was detected in the left anterior cingulate cortex (Z score 5 4.7, corrected P, 0.05) and additional activation (uncorrected P, ) in the posterior cerebellum and in the temporal and prefrontal cortices. For dyspnea, significant activation was located in the right caudate nucleus, the anterior cerebellum (Z 5 5 and 4.65, respectively; corrected P, 0.05), and the premotor cortex, whereas deactivation occurred in the left prefrontal cortex (Z ). Conclusions: Relief of acute load-induced dyspnea is not simply the neutral perception of dyspnea decrease but rather a strong, positively valenced sensation that is associated with characteristic brain activation distinct from that subserving dyspnea perception and possibly reflecting activation of a dyspnea modulation network. Keywords: breathlessness; relief; perception; functional brain imaging; qualitative word descriptors Relief of dyspnea, the specific sensation of breathing becoming easier, is a very common sensory experience. Indeed, it occurs during recovery from the numerous diseases that are associated with dyspnea and is therefore frequently used in daily clinical practice to assess subjective effects of therapeutic intervention for these conditions. A similar sensation can also occasionally be experienced in normal daily life (e.g., after stopping heavy exercise or volitional breath-holding). Surprisingly, however, despite its high prevalence in the clinical context, fundamental mechanisms and, more specifically, central processing of dyspnea relief have not been extensively investigated so far. Most previous (ReceivedinoriginalformDecember 6, 2006; acceptedinfinal formnovember26, 2007) Supported by a grant from the Association pour l aide à domicile des insuffisants respiratoires (ANTADIR). Correspondenceandrequests for reprints shouldbeaddressed to Dr. ClaudinePeiffer, M.D., Ph.D., Laboratoire de Physiologie EFR, Hôpital Saint-Vincent-de-Paul 82, Avenue Denfert Rochereau, Paris, France. claudinepeiffer@yahoo.fr This article has an online supplement, which is accessible from this issue s table of contents at Am J Respir Crit Care Med Vol 177. pp , 2008 Originally Published in Press as DOI: /rccm OC on November 29, 2007 Internet address: AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Although relief of dyspnea is a very common sensory experience, its general characteristics and especially its central processing remain largely unknown. What This Study Adds to the Field This study shows that relief of dyspnea is a predominantly rewarding sensation, and identifies that dyspnea relief involves characteristic brain activation and that the latter is distinct from areas subserving dyspnea perception. studies of relief were mainly focused on bronchodilator response in patients with asthma and/or chronic obstructive pulmonary disease (COPD) (1 5). Few studies have investigated underlying mechanisms of this sensation and have shown a putative (6 8), although not exclusive (7), role of inhaled nitrous oxide (6), opioid receptors (7), and afferent vagal activity related to stretch receptor activation by lung and/or chest expansion (8). Moreover, in all these previous studies (1 6, 9) except one (7), dyspnea relief was assessed in terms of decrease in dyspnea scores, and its qualitative aspects (albeit in terms of decrease in dyspnea) have thus far been considered in only one study (9). Yet, dyspnea relief is likely to be a specific sensory experience and not only a neutral perception of decrease in dyspnea. Indeed, in most subjects, relief of dyspnea includes a positively valenced component and thus, together with deep sighing or yoga breathing, relief is one of the rare circumstances where the conscious act of breathing may become pleasant and/or rewarding. The study of Nishino and colleagues (7) is currently the only specific investigation of mechanisms underlying the pleasantness component of relief, called respiratory euphoria by the authors, showing that the latter was partially related to endogenous opioids. However, in this study, as in all those mentioned above (1 6, 8, 9), no specific descriptors were used for the subjective experience of dyspnea relief. Most important, however, as opposed to acutely induced dyspnea (10 13), the neural substrates of dyspnea relief remain unknown. Yet, identification of brain structures involved in central processing of dyspnea relief may open new perspectives for the study of the target and the mechanisms of action of various therapeutic maneuvers that alleviate dyspnea. The main objective of the present study was therefore to identify brain activation associated with acute induced relief of dyspnea. In addition, we wanted to determine physiologic and sensory characteristics of relief of dyspnea with special regard to its qualitative aspects. We reasoned that, if relief of dyspnea was a specific sensory experience, it might involve both a specific neural network for its central processing, possibly different from that of dyspnea itself, as well as specific word descriptors for its qualitative assessment. Some of the results of these studies have been previously reported in the form of an abstract (14).

2 Peiffer, Costes, Hervé, et al.: Integration of Dyspnea Relief 441 METHODS A more detailed version of the methods used is given in the online supplement. Subjects Ten healthy male volunteers participated in the study. We informed the subjects that we studied brain activation of respiratory sensations, but they were blinded to the fact that the study was focused on dyspnea relief and to the moment at which the positron emission tomography (PET) scans were performed. The study was approved by the National and Institutional Ethics Committee of our imaging center (Lyons, France). Study Protocol Dyspnea and relief of dyspnea were acutely induced by changing the intensity of an external semilinear resistive load by inflation or deflation of an inflatable ring inserted in an external breathing device. The degree of inflation of the ring (determined in the pilot study) allowed us by its subsequent deflation to induce a relief of dyspnea rated by the whole subject group as a Borg score of about 2.5 and 5, referred to as moderate and high relief, respectively. We studied five different experimental conditions: control condition (C) (unloaded without respiratory sensation), high dyspnea relief (hr) (intensity of dyspnea decreasing from high to 0), moderate dyspnea relief (mr) (intensity of dyspnea decreasing from moderate to 0), high dyspnea (hd) (i.e., similar to that preceding high relief and used for comparison to hr), and augmenting dyspnea (ad) (intensity of dyspnea increasing from 0 to high intensity). The ad condition served as a control for the effect of rapid change in sensory intensity per se and/or nonspecific arousal. Each condition consisted of a first period of 40 seconds (p1) (presence of dyspnea preceding relief in hr and mr), followed by a second period of 60 seconds (p2) during which PET scans were performed (Figure 1). The five experimental conditions were presented twice in random order. For clarity, the periods of PET scanning (p2) of the five experimental conditions are referred to as p2c, p2hd, p2ad, p2hr, and p2mr, respectively. Quantitative and Qualitative Assessment of Respiratory Sensations After each PET scan, the subjects assessed the quantitative and qualitative aspects of respiratory sensations separately for p1 and p2. Perceived intensity of dyspnea and of relief was rated on the French version of the modified Borg scale (15) (represented in the online supplement). Dyspnea and dyspnea relief were defined by the generic terms difficult, uncomfortable breathing and relief from difficult, uncomfortable breathing, respectively (see online supplement for details). For qualitative assessment, the subjects chose appropriate specific word descriptors from a list. For dyspnea relief, the corresponding list consisted of descriptors collected in a preliminary study (see online supplement for details) and included eight different descriptors, two that were neutrally valenced and six that were positively valenced (i.e., with a connotation of pleasantness and/or reward) (Table 1) (the original French version is presented in Table E1 of the online supplement). Experimental Protocols Pilot study. The pilot study was performed before PET scanning to familiarize the subjects with the experimental device and the rating procedure. Functional brain imaging. Regional cerebral blood flow (rcbf) changes, an index of neuronal activity, were assessed by PET using radiolabeled H 2 O ([ 15 O]H 2 O) (16) as previously described (11). Recording of respiratory variables was started 10 seconds before the beginning of p1, and thus 50 seconds before the onset of the rcbf measurement. Data Analysis For both respiratory and sensory data, group averages were calculated separately for p1 and p2. Sensory rating. For each relief condition (hr and mr), we compared sensation intensities (Borg scores) between relief (p2mr, p2hr) and its preceding dyspnea (p1mr, p1hr), and between preceding dyspnea of high relief (p1hr) and p2 of high dyspnea (p2hd) by unpaired and paired t tests, respectively. Qualitative assessment of dyspnea relief was analyzed in terms of frequency of choice (proportion of subjects who chose each given descriptor) and of the number of descriptors selected by each subject. These characteristics were compared between positively and neutrally valenced descriptors and between high and moderate relief by a x 2 and a Mann-Whitney U test, respectively. The relationship between individual intensity scores of dyspnea relief and TABLE 1. SPECIFIC WORD DESCRIPTORS FOR THE QUALITATIVE ASSESSMENT OF DYSPNEA RELIEF* Figure 1. Schematic representation of the study protocol. Dyspnea and relief of dyspnea were acutely induced by changing the intensity of an external resistive load by inflation (Y) or deflation ([) of an inflatable ring present during the entire breathing cycle. The study consisted of five different experimental conditions: four study conditions and an unloaded control condition. Positron emission tomography (PET) scans were all performed during the second period (p2) of the different experimental conditions. The name of the study conditions refers to the sensation present during PET scanning. ad 5 augmenting dyspnea (increase toward a high load during p2); C 5 control condition, no respiratory sensation (unloaded); hd 5 dyspnea of high intensity, present during both p1 and p2 (high load); hr 5 high relief of dyspnea (decrease of a high load during p2); mr 5 moderate relief of dyspnea (decrease of a moderate load during p2). Inflation during ad and deflation during mr and hr were performed progressively (over about 10 s) (Y and [), whereas at the beginning of conditions hd, hr, and mr, the ring was already inflated when the subject was connected to the external device. Neutral valence d Neutral (absence of any specific respiratory sensation) d Simple return to normal breathing Positive valence d Easier to breathe (than during normal breathing) d More comfortable to breathe (than during normal breathing) d Hyperrewarded effort (sensation of getting more air with less effort than during normal breathing) d Real pleasure to breathe (rather than just neutral, normal breathing) d Feeling of respiratory well-being (breathing becomes pleasant and relaxing) d Respiratory release (very strong relief, liberation) The subjects were invited to select one or more of the above-mentioned word descriptors (presented in random order). * Word descriptors are an English translation; the original French version is provided in Table E1 of the online supplement. Sentences between parentheses correspond to additional explanations given for the corresponding descriptor. Sentences between parentheses correspond to additional explanations for unusual expressions in English.

3 442 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL numbers of selected word descriptors was assessed by Spearman s rank correlation test. Respiratory variables. To assess respiratory changes during PET scanning, we calculated the difference between p1 and p2 (p1 2 p2) of averaged breath-by-breath values of amplitude of mouth pressure swings (DPm), end-tidal CO 2 (PET CO2 ), VT, respiratory frequency (f), minute ventilation ( _ VE), and DPm/ _ VE. For the two relief conditions, we further compared p2 values of respiratory variables with those of p1, as well as with those of p2 of the unloaded control condition, by paired t test. Individual and collective contribution of (p1 2 p2) of respiratory variables to the variance of intensity scores of dyspnea relief was determined by simple and by stepwise multiple regression analysis, respectively. Analyses were performed using the StatView statistical package (Abacus Concepts, Berkeley, CA). A P value of less than 0.05 was considered as statistically significant. Functional brain imaging. PET data were analyzed as previously described (11). State-dependent differences in global flow (including that due to CO 2 ) were covaried out using proportional scaling. Change in rcbf, either increase (activation) or decrease (deactivation), was determined for the pooled data of the 10 subjects by separate subtraction analyses for the four study conditions p2hd, p2ad, p2hr, and p2mr and the control condition p2c (i.e., each study condition minus p2c, for activation, and p2c minus each study condition for deactivation). In addition, we compared the two relief conditions, taken together, against p2c [(p2mr 1 p2hr) 2 p2c], and the high relief condition with the high dyspnea condition (p2hr p2hd) (instead of p1hr, which could not be imaged for methodologic reasons outlined in the online supplement). A z score greater than 3.09 (P, 0.001, uncorrected for multiple comparisons) for peak rcbf change and a volume greater than 50 voxels were considered for display. Special emphasis was put upon rcbf changes that remained significant (P, 0.05) after correction for multiple comparisons (corresponding to a z score. 4.58). RESULTS The duration of induction of respiratory sensations by inflation or deflation of the inflatable ring, whose beginning coincided with that of the period of PET scanning (p2), was similar for high relief (p2hr) and augmenting dyspnea (p2ad) ( and s, respectively; P. 0.05), and was slightly shorter for moderate relief (p2mr) ( s). Group mean values (6SD) of respiratory variables, presented separately for the first and second period of the experimental session (p1 and p2), are shown in Table 2 for hr and mr conditions and the unloaded control condition (C), and together with respiratory sensation intensities for all the five experimental conditions in Table E1. The corresponding results showed an important intersubject variation for all these different variables. Except for brain imaging and quantitative perception, results concerning dyspnea are presented in the online supplement. Respiratory Changes During p2mr and p2hr, all respiratory variables returned progressively to their unloaded baseline values. The highest rate of change occurred during the first 20 to 30 seconds for moderate relief and high relief, respectively, the latter being similar to that of augmenting dyspnea (p2ad). As compared with the just preceding period of acute dyspnea (p1mr, p1hr), relief-related respiratory changes, in terms of the group mean of individual differences between p1 and p2 (p1 2 p2) of the corresponding respiratory variables, consisted of a significant decrease in amplitude of mouth pressure swings (DPm) and a parallel increase in VE _ and f, resulting in an important decrease in the DPm/ VE _ ratio. The latter decrease may be considered as the reversal of the just preceding dyspnea-related increase of a crude index of the so-called effort:displacement ratio (17) (i.e., an estimation of the relationship between the respiratory effort and the actual ventilation). The decrease in PET CO2 was statistically significant but actually low in terms of absolute values ( vs mm Hg, and vs mm Hg, for high and moderate relief, respectively; all P, 0.01). There was a large intersubject variation in respiratory changes (p1 2 p2). The highest intersubject variation in amplitude and even in the sense of change (increase in some subjects, decrease in others) was seen for VT, with a coefficient of variance of 148 and 2,500%, for high and moderate relief, respectively, whereas the lowest coefficient of variance was found for DPm (i.e., 64 and 57% for high and moderate relief, respectively). In addition, for DPm and DPm/ _VE, intersubject variation basically mirrored that associated with the preceding dyspnea. Furthermore, during p2 of the two relief conditions (p2mr and p2hr), mean group values of PET CO2, f, and VE _ were similar, whereas those of VT as well as DPm, and thereby DPm/ _VE, remained significantly higher than during the unloaded control condition (p2c) (Table 2), presumably reflecting differences in the time course of return baseline values between the different variables. Sensory Characteristics Quantitative perception of dyspnea and of dyspnea relief. Perceived intensity of high and moderate relief (in terms of group mean Borg scores) wase similar to that of its corresponding just preceding acute dyspnea periods (p1hr and p1mr) ( vs , and vs , respectively; both P. 0.05) (Table E1, Figure 2A). Moreover, group mean values of perceived intensity of dyspnea preceding high relief (p1hr) were similar to that of p2 of the high dyspnea condition (p2hd) TABLE 2. GROUP MEAN VALUES (±SD) OF RESPIRATORY VARIABLES DURING HIGH AND MODERATE RELIEF AS COMPARED WITH THOSE DURING THE PRECEDING ACUTELY INDUCED DYSPNEA AND DURING THE UNLOADED CONTROL CONDITION Control Condition High Relief Condition Moderate Relief Condition Respiratory Variables p1 p2 p1 (high dyspnea) p2 (high relief) p1 (moderate dyspnea) p2 (moderate relief) DPm, cm H 2 O * * PET CO2, mm Hg * * VT, L Respiratory frequency, breaths/min * * _VE, L/min * * DPm/ VE, _ cmh 2 O/L/min * * Definition of abbreviations:pet CO2 5 end-tidal PCO 2 ; DPm 5 amplitude of mouth pressure swings, an index of increased respiratory effort and motor response; p1 5 first period of, and p2 5 second period of the experimental conditions; _ VE 5 minute ventilation. For characteristics of experimental conditions, see Figure 1. * P, 0.05 for the comparison between p2 and p1 for each relief condition. P, 0.05 for the comparison between p2 of each relief condition and p2 of the control condition.

4 Peiffer, Costes, Hervé, et al.: Integration of Dyspnea Relief 443 Figure 2. Perception of respiratory sensations. (A) Group means of perceived intensity (in terms of Borg scores) of acutely induced respiratory sensations showing that there was no significant difference between intensities of high and moderate relief (solid bars) and their corresponding preceding dyspnea (hatched bars), as well as between the dyspnea preceding high relief and that of the second period (p2) of the high relief condition (p2hd) (considered for imaging). (B) Relationship between individual values of intensity scores of dyspnea relief and its two main determinants: intensity scores of the preceding dyspnea (upper panel) and the decrease in DPm/ VE _ (lower panel), which may be considered as the reversal of the preceding dyspnea-related increase of a crude index of the so-called effort:displacement ratio (i.e., an estimation of the relationship between respiratory effort and actual ventilation). Pm 5 mouth pressure. ( vs , P. 0.05) (Table E1, Figure 2A). The similarity in perceived intensity between these two conditions allowed us to compare with confidence brain activation of relief (p2hr) with that of p2hd instead of comparing it with brain activation of p1hr because the latter could not be assessed due to previously mentioned methodologic reasons related to imaging (see the online supplement for details). Determinants of intensity scores of dyspnea relief. As with dyspnea scores, we found large interindividual differences of relief scores (Table E1; Figures 2A and 2B, upper panel). Separate linear regression analyses for the whole subject group showed that relief scores were strongly related to the just preceding dyspnea scores (r , P, 0.001) for the whole study group (Figure 2B, upper panel). Furthermore, relief scores were correlated with various degrees of significance to respiratory change, in terms of (p1 2 p2), of all respiratory variables. Percentages of explained variance (r 2 ) of relief scores were 0.67, 0.32, 0.15, 0.53, 0.68, and 0.88 for DPm (p1 2 p2),pet CO2 (p1 2 p2), VT (p1 2 p2),f (p1 2 p2), _ VE(p1 2 p2), and DPm/ _ VE (p1 2 p2), respectively (all P, 0.05). Moreover, stepwise regression for the whole subject group showed that, taken together, the previously mentioned variables explained 90% of total variance of relief scores, with 88% being explained by a decrease in DPm/ _ VE (Figure 2B, lower panel), which thus was the most important physiologic determinant for perceived intensity of dyspnea relief. Qualitative assessment of dyspnea relief. As with intensity, characteristics of qualitative rating of dyspnea relief greatly varied between subjects, with some overlap between moderate and high relief conditions. Most subjects (66%) chose more than one specific word descriptor to qualify dyspnea relief (median [range]: 2 [1 4]). Interestingly, only one subject chose exclusively neutrally valenced word descriptors for all relief trials. The distribution of selection frequencies of the eight descriptors is shown in Figure 3 for the two relief conditions. For high relief, the most frequently chosen descriptor was hyperrewarded effort (65%), closely followed by real pleasure to breathe and respiratory well-being (50 and 45%, respectively). Moreover, except for one subject, hyperrewarded effort was never selected together with a neutrally valenced descriptor, suggesting that perception of reversal of the dyspnearelated increase in the index of respiratory effort:displacement ratio is a predominantly positively valenced sensory experience. For moderate relief, albeit by a smaller proportion of subjects than for high relief, respiratory well-being was the most frequently chosen descriptor (35%) followed by real pleasure to breathe and hyperrewarded effort (30 and 25%, respectively) (Figure 3). Overall difference of selection frequencies reached the level of statistical significance for global relief (values of high and moderate relief pooled together for each subject) (x 2 [7] , P, 0.01) as well as for high relief alone (x 2 [7] 5 26, P, 0.01), but not for the moderate relief condition alone (x 2 [7] 5 5.5, P. 0.05). Furthermore, for global relief as well as for high relief alone, the selection rate of positively valenced descriptors was significantly higher than for neutral valence (x 2 [2] and 12.3, P, 0.01 for both) (Figure 3). In addition, for global relief, albeit not separately for each relief condition, there was a significant positive correlation between individual numbers of selected positively valenced word descriptors and relief intensity scores (r , P ). Figure 3. Frequency distribution of selected specific word descriptors of dyspnea relief, including neutrally valenced (shaded bars) and positively valenced (black bars) descriptors. Results, expressed by the proportion of subjects (in percentage of their total number) who chose each given word descriptor, are presented separately for moderate and high relief conditions and show that, for the latter condition, positively valenced descriptors were chosen by a significantly (**) higher proportion of subjects than neutrally valenced descriptors (P, 0.01).

5 444 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Functional Brain Imaging Comparison of moderate and high dyspnea relief to the unloaded control condition: (p2hr 2 p2c) and (p2mr 2 p2c). These contrasts allow us to identify brain activation or deactivation specifically associated with central processing of the sensation of relief and its related physiologic (respiratory) changes, as compared with quiet normal breathing, without marked pleasant or unpleasant respiratory sensation. The comparison of high relief versus the unloaded control condition showed a bilaterally distributed set of activation areas (i.e., cerebral regions with significant CBF increase) (Table 3, Figure 4). The most significant rcbf increase (Z 5 4.7, P corrected for multiple comparisons) was detected in the left anterior cingulate cortex (ACC; Brodmann s area [BA] 32/24). Local activation peaked near the upper border of the cingulate sulcus and overlapped bilaterally the limit between two contiguous histologically and functionally different subregions, the pregenual ACC and the posterior ACC (termed anterior midcingulate or amcc by Vogt [18]) (Figure 4). The second most significant activation area was located in the neocerebellum, near the midline in the posterior part of the inferior right semilunar lobule (Crus II) increase (Z , P corrected for multiple comparisons). High relief further involved a distributed set of activation sites with less significant rcbf increase (4.57. Z. 3.42, P, uncorrected for multiple comparisons) in different brain structures, including the third most significant activation area, which was located in a transition zone between two functionally different subregions in the right superior frontal gyrus (BA 10) (Table 3, Figure 4). The remaining activation sites were located in the cerebellum (lateral part of the right superior semilunar lobule, Crus I), the midbrain (meso-diencephalic junction, periventricular gray), as well as bilaterally in different distinct areas in temporal and frontal cortices (Table 3, Figure 4) (additional representations as brain slices of the five most significant brain activation areas are shown in Figure E2). Similarly, the most important increase in rcbf (although of lower statistical significance, Z ) for the comparison of the moderate relief versus the unloaded control condition occurred in the left cingulate sulcus. Furthermore, moderate relief was associated with an additional, albeit less significant activation area (Z ), in the left medial superior frontal lobe (premotor area) (BA 6) (Table 3). When results of both relief conditions were pooled, the comparison with the control condition showed an activation pattern very similar to that associated with high relief. In contrast, no deactivation (significant decrease in rcbf as compared with the unloaded control condition) could be detected for any of the two relief conditions. Comparison of constant high dyspnea and augmenting dyspnea to the unloaded control condition: (p2hd p2c) and (p2ad p2c). These contrasts allow us to identify brain activation or deactivation specifically associated with central processing of the sensation of dyspnea and its related physiologic (respiratory) changes, as compared with quiet normal breathing, without marked pleasant or unpleasant respiratory sensation. p2hd p2c. As compared with the unloaded control condition, main activation areas of constant high dyspnea (p2hd) (Table 4, Figure 5) were seen in the head of the right caudate nucleus and in the cerebellar vermis (culmen) extending into the left anterior quadrangular lobule (Z 5 5 and 4.65, respectively; both P, 0.05 corrected for multiple comparisons). Less significant activation (4.65. Z. 3.7, P, uncorrected for multiple comparisons) was detected bilaterally in the posterior cerebellar hemispheres, right lateral premotor cortex (BA 6), right upper temporal gyrus, midbrain (in the same area as relief), and in the right anterior insula (Table 4, Figure 5) (additional representations as brain slices of the five most significant brain activation areas are shown in Figure E3). Assessment of brain deactivation associated with constant high dyspnea (p2hd) showed only one significant site in the left superior frontal gyrus (BA 6) (Z ) (Table 4, Figure E4). TABLE 3. GROUP RESULTS OF NEURAL ACTIVATION DURING ACUTELY INDUCED MODERATE AND HIGH RELIEF OF DYSPNEA, CHARACTERIZED BY BRAIN AREAS SHOWING A SIGNIFICANT INCREASE IN REGIONAL CEREBRAL BLOOD FLOW AS COMPARED WITH THE UNLOADED CONTROL CONDITION (p2hr 2 p2c AND p2mr 2 p2c)* High Relief of Dyspnea Moderate Relief of Dyspnea Coordinates Coordinates Cluster Size Cluster Size Brain Region x y z (voxels) ZScore Brain Region x y z (voxels) Z Score Left cingulate sulcus (BA 24/32) Left anterior cingulate (BA 24/32) Right cerebellar hemisphere Left medial frontal lobe (BA 6) (inferior semilunar lobule, Crus II) Right superior frontal gyrus (BA 10) Right cerebellar hemisphere (superior semilunar lobule, Crus I) Midbrain (meso-diencephalic junction, periventricular gray) Right superior temporal gyrus (BA 22) Left superior temporal gyrus (BA 22) Left superior temporal gyrus (BA 38) Left middle frontal gyrus (BA 9) Right middle frontal gyrus (BA 9) Left middle cerebellar peduncle Left middle temporal gyrus (BA 21) Right superior frontal gyrus (BA 6) Definition of abbreviations: BA 5 Brodmann s area; rcbf 5 regional cerebral blood flow. Threshold of significance for display: Z scores , P, (uncorrected for multiple comparisons), and a cluster size. 50 voxels (voxel size 5 8mm 3 ). * Brain areas of significant rcbf increase (activation areas) are characterized by their anatomic localization (stereotactic coordinates) and statistical significance (z scores) of their maximal peak of rcbf increase. Coordinates are those of the standard stereotactic space from the atlas of Talairach and Tournoux [51]. x, lateral distance (in mm) right (1) from the midline (interhemispheric line); y, distance anterior (1) or posterior (2) to the vertical line passing through the anterior commissure; z, distance above (1) or below (2) the intercommissural line (AP PC line). Z scores corresponding to a statistical significance of P, 0.05 (corrected for multiple comparisons).

6 Peiffer, Costes, Hervé, et al.: Integration of Dyspnea Relief 445 Figure 4. Brain activation associated with high relief of dyspnea (p2hr) characterized by areas of significant increase in the group average of relative regional cerebral blood flow (rcbf) as compared with the control condition (unloaded, without any respiratory sensation). Results are presented as glass brain views (i.e., projection of statistical parametric maps of significant rcbf increase in the three dimensions of the standard stereotactic space defined by the atlas of Talairach and Tournoux [51]). The brain is viewed from the side (sagittal), from the back (coronal), and from the top (transverse), thus providing a tridimensional view of activation areas. The right hemisphere is on the right side of the coronal view and the lower part of the transverse view. For clarity, only the five clusters with the highest peak activation are labeled: (1) main activation area: left anterior cingulate cortex (BA 32/24); (2) right neocerebellum (inferior semilunar lobule, Crus II); (3) anterior right superior frontal gyrus; (4) right neocerebellum (superior semilunar lobule, Crus I); and (5) midbrain (meso-diencephalic junction, periventricular gray). Display for all maps is thresholded at Z , P, (uncorrected for multiple comparisons), and a cluster size. 50 voxels. The Z values are coded according to increasing statistical significance by an arbitrary gray scale ranging from light gray to black. Activation of area 1 remained significant, and area 2 marginally significant, after correction for multiple comparisons (P and 0.053, respectively. (An additional representation of the five previously mentioned activation areas as statistical parametric maps superimposed onto a section of T1-weighted magnetic resonance image of sagittal, coronal, and transverse slices of a typical canonical brain is shown in the online supplement [Figure E2]). Figure 6. Statistical parametric map of brain activation of the most significant activation area of high dyspnea relief (p2hr) as compared with the unloaded control condition (p2c) (A) and with high dyspnea (p2hd) (B), with its main and secondary activation peak (upper and lower panels, respectively) superimposed onto a section of T1-weighted magnetic resonance image of a typical canonical brain. Note that the cingulate peak of activation in the contrast high relief versus high dyspnea is very close to the main activation peak of the contrast high relief versus unloaded control (i.e., in the left anterior cingulate cortex), suggesting that this activation pattern was, under our experimental conditions, indeed characteristic of dyspnea relief. Display is thresholded at Z , P, (uncorrected for multiple comparisons), and a cluster size. 50 voxels. The Z values are coded by the color scale shown. The main activation peak of both contrasts remained significant after correction for multiple comparisons (P and 0.011, respectively). Figure 5. Brain activation associated with high dyspnea (p2hd), characterized by areas of significant increase in the group average of relative regional cerebral blood flow (rcbf), as compared with the control condition (unloaded, without any respiratory sensation). Results are represented as glass brain views (see Figure 4). Main activation areas of dyspnea were seen in (1) the head of the right caudate nucleus, (2) the cerebellar vermis (culmen) extending into the anterior quadrangular lobule, (3) the right cerebellar hemisphere (posterior quadrangular lobule), (4) right lateral premotor cortex (BA 6), and (5) right lateral superior temporal gyrus (BA 38). Display for all maps is thresholded at Z , P, (uncorrected for multiple comparisons), and a cluster size. 50 voxels. The Z values are coded according to increasing statistical significance by an arbitrary gray scale ranging from light gray to black. Activation of areas 1 and 2 remained significant after correction for multiple comparisons (P and 0.039, respectively). (An additional representation of the five previously mentioned activation areas as statistical parametric maps superimposed onto a section of T1-weighted magnetic resonance image of sagittal, coronal, and transverse slices of a typical canonical brain is shown in the online supplement (Figure E3). This deactivation area was different from all activation sites of dyspnea relief. p2ad p2c. Contrary to expectations, although p2ad was associated with an intense sensation of acute dyspnea and relevant respiratory changes (Table E1), the comparison to the unloaded control condition did not reveal any significant brain activation or deactivation (all P uncorrected for multiple comparisons). Comparison of high relief to high dyspnea (p2hr 2 p2hd). This contrast allows us to identify brain activation associated with the differences between relief and dyspnea of similar intensity regarding their quality of sensation as well as their corresponding related physiologic (respiratory) changes. The comparison of high relief versus high dyspnea showed a distributed bilateral set of activation areas (Table 5, Figure E5A). The most significant rcbf increase involved an activation cluster that partially overlapped the main activation area identified for the contrast of high relief versus unloaded control (p2hr 2 p2c). Local activation peaked in the left superior frontal gyrus (BA 9) (Z , P corrected for multiple comparisons) (Figure 6B, upper panels), whereas a secondary peak was located in the ACC very close to the activation peak of the main activation area identified for the contrast of high relief versus unloaded control (Figures 6 and E5). Less significant activation (3.9. Z. 3.5, P, uncorrected for multiple comparisons) occurred in the right fusiform gyrus (BA 37) in the left frontal cortex (BA 6) and bilaterally in the parietal cortex (BA 7 and 39) (Table 5, Figure E5A) and differed from that identified for the contrast high relief versus unloaded control.

7 446 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL TABLE 4. GROUP RESULTS OF NEURAL ACTIVATION AND DEACTIVATION* DURING ACUTELY INDUCED HIGH DYSPNEA AS COMPARED WITH THE UNLOADED CONTROL CONDITION (p2hd 2 p2c) Coordinates Cluster Size Brain Region x y z (voxels) Z Score Activation Right caudate nucleus (head) Cerebellum (culmen/left anterior , quadrangular lobule) Cerebellum (right posterior quadrangular lobule) Right lateral premotor cortex (BA 6) Right superior temporal gyrus (BA 38) Cerebellum (left posterior quadrangular lobule) Midbrain (meso-diencephalic junction, periventricular gray) Right anterior insula Deactivation Left lateral superior frontal gyrus (BA 8) Definition of abbreviation: BA5 Brodmann s area. For characterization of activation areas, see Table 3. * Brain areas of significant regional cerebral blood flow decrease, characterized in the same way as activation areas; see Table 3. z scores corresponding to a statistical significance of P, 0.05 (corrected for multiple comparisons). DISCUSSION In the present study, we attempted to determine physiologic and sensory characteristics, as well as neural correlates, of relief of acute load-induced dyspnea. The main findings were as follows: (1) the reversal of the dyspnea-induced increase in DPm/ _ VE was the most important physiologic determinant of perceived intensity of dyspnea relief; (2) qualitative assessment of dyspnea relief includes specific, mostly positively valenced word descriptors; and (3) dyspnea relief involves a characteristic brain activation different from that subserving dyspnea perception. Sensory Characteristics of Dyspnea Relief The underlying hypothesis of the present study was that dyspnea relief may be a more complex sensory experience than solely a neutral perception of return to normal breathing. This TABLE 5. GROUP RESULTS OF NEURAL ACTIVATION DURING ACUTELY INDUCED HIGH RELIEF OF DYSPNEA AS COMPARED WITH THE CONSTANT HIGH DYSPNEA CONDITION (p2hr p2hd) Coordinates Cluster Size Brain Region x y z (voxels) Z Score Left superior frontal gyrus (BA 9) * Left cingulate sulcus (BA 24/32) (210) (30) (18) (3.76) Right superior frontal gyrus (BA 6) Left (premotor cortex) middle frontal gyrus (BA 6) Left superior parietal gyrus (BA 40) Left middle frontal gyrus (BA 6) Right temporal fusiform gyrus Right inferior parietal gyrus (BA 39) Left parietal gyrus (BA 7/31) Definition of abbreviation: BA 5 Brodmann s area. For characterization of activation areas, see Table 3. * z scores corresponding to a statistical significance of P, 0.05 (corrected for multiple comparisons). Secondary peak (stereotactic coordinates in parentheses). hypothesis is based on daily clinical observation showing that, in many subjects, dyspnea relief encompasses an additional component of pleasantness and/or reward. Therefore, to take into account all the potential dimensions of relief, we used the generic term of relief for its quantitative assessment rather than to infer the latter from decrease in dyspnea intensity ratings as in almost all previous studies of relief (1 6, 8, 9), and also performed the first study that assessed quality of dyspnea relief by specific word descriptors. Quantitative perception of dyspnea relief: determinants of intensity scores. Our results showed that, when referred to as such, intensity of relief in terms of group mean intensity scores is a sensation as intense as that preceding dyspnea (Figure 2A). In addition, there was a large intersubject variation for relief intensity scores (Table E1). This variation was predominantly related to intensity scores of preceding dyspnea, reflecting the obvious intrinsic relation of relief with its preceding underlying dyspnea (Figure 2B, upper panel). The best physiologic predictor of perceived intensity of relief was the decrease in a composite index, the DPm/ _ VE ratio (Figure 2B, lower panel), reflecting the reversal of the dyspnea-induced increase in the respiratory effort:displacement ratio, which itself indirectly reflects reversal of one of the main characteristics of loaded breathing-induced dyspnea, neuromechanical uncoupling (17). This result suggests that, in the context of loaded breathing, the positive or negative valence of respiratory sensation is primarily determined by perception of the sense of change (decrease or increase) of the DPm/ _ VE ratio and that perceived intensity of relief may ultimately result from central integration of converging sensory information related to achieved pressure (as estimated by DPm) and actual achieved ventilation. More generally, there may exist different types of relief according to the main underlying mechanisms of the preceding dyspnea, which, in the present study, were increased effort of breathing and a small contribution of increased CO 2. Finally, it may be speculated that intersubject differences in the relative contribution of the previously mentioned additional components to the global perception of relief (i.e., pleasantness and/or reward), as well as possible differences in perceived intensity according to the valence, positive or negative, of the sensation, may have contributed to the variance of relief intensity scores that was not explained by intensity of preceding dyspnea and respiratory changes, its two most important determinants. Qualitative assessment of dyspnea relief by specific word descriptors. Only one subject of our study population chose exclusively neutrally valenced word descriptors for all relief trials, suggesting that, according to our initial hypothesis, dyspnea relief is not exclusively a neutral perception of return to normal breathing. Furthermore, our results suggest that, with increasing intensity of dyspnea relief, there is a parallel increase in frequency of choice of positively valenced word descriptors with a concomitant change in quality of the latter (i.e., predominantly breathing-related pleasure for moderate, and reward for high relief, respectively). It may therefore be speculated that both frequency distribution and valence of selected specific word descriptors of dyspnea relief change according to the intensity of relief. However, one has to consider that the present relief descriptors have been selected and used only in our center and thus in a relatively small number of subjects, and that they need to be further validated in a much larger study population. From a more general point of view, our results confirm for dyspnea the daily observation that removal of a noxious stimulus is experienced as pleasant and/or rewarding. Thus, dyspnea relief is one of the rare situations in which breathing may become pleasant. Because the role of pleasure has been recognized for a long time as an important behavioral

8 Peiffer, Costes, Hervé, et al.: Integration of Dyspnea Relief 447 drive (19), it may be speculated that relief may play an adaptive role in behavior in a suffocating condition by adding some reward value to the dyspnea-related flight reaction in this situation. More specifically, in the clinical setting, the rewarding character of relief may contribute to compliance with bronchodilator treatment, especially in asthma. Functional Brain Imaging The most prominent finding of the present study was that relief of dyspnea was associated with a characteristic pattern of brain activation. We considered that the unloaded condition (i.e., quiet, normal breathing without marked pleasant or unpleasant respiratory sensations) was the most appropriate control condition for identifying significant rcbf increase specifically related to dyspnea relief. This contrast identifies brain activation associated with the perception of the sensation but also with its related respiratory changes. However, it may be assumed that these two tightly interrelated components of relief are parts of an integrated sensory-motor response and involve very similar brain activation patterns as previously shown for dyspnea (11). Furthermore, we compared high relief to a second control condition (i.e., high dyspnea), which identifies the effect of the sensory component of relief from a different angle, namely in terms of its qualitative difference with dyspnea, albeit again together with the difference of their corresponding respiratory changes. Nevertheless, it may be assumed that the combined results of these two different control conditions of relief provide at least preliminary insight into the brain structures involved in the central processing of dyspnea relief. For the comparison of high relief versus unloaded control, the highest rcbf increase occurred in the left ACC and overlapped several histologically and functionally different subregions of this brain structure. Activation peaked in the anterior cingulate sulcus close to the rostral cingulate motor area, which has been shown to be involved in complex motor control and execution (20), and therefore may reflect central processing of positively valenced sensation/emotion of relief with its associated respiratory motor responses. Furthermore, activation also extended into the dorsal part of the pregenual ACC and the contiguous rostral part of the dorsal ACC. Individually, each of these two subregions has been previously shown to be predominantly involved in emotional processing (both positive and negative) (17, 21), especially when associated with a cognitive demand (22) and effortful cognitive functions (23) and autonomic responses (24). Interestingly, together these represent most of the multiple aspects of the multidimensional central processing of relief. Indeed, because this sensory experience involves an intense, positively valenced respiratory sensation/emotion its main characteristic but also a change from its inherent preceding unpleasant sensory experience, the central processing of this experience presumably requires additional cognitive processing, such as emotional recall, and thus short-term working memory, comparisons of opposed valences, and perception of change. Most important, activation close to our ACC activation site has been previously shown to be associated with relief of other potentially unpleasant sensations, such as full bladder by micturition (25), thirst (26), and, most important, with relief of pain by various mechanisms such as electrical cerebral stimulation (27), drugs (28), or therapeutic interventions that rely more specifically on motivational, attentional, and/or cognitive aspects of pain integration, such as hypnosis (29), acupuncture (30), or placebo (28). Furthermore, activation in this ACC area has been observed for pleasant sensory experiences like inhalation of NO 2 (31), which also decreases dyspnea (6), and pleasant touch (32). By contrast, any activation in this ACC subregion could be identified in the present study as well as in several previous functional brain imaging studies of dyspnea or of motor aspects of breathing associated with respiratory discomfort (10, 11, 33). Other studies, however, did show dyspnea-related activation in the ACC, but the corresponding activation areas, despite a partial overlap with the site of our relief-related activation site, were predominantly located in a more caudal part of this brain structure (12, 13, 34, 35). We submit the hypothesis that, as previously shown for pain (36, 37), there may be a tendency toward a caudorostral functional segregation of central processing of dyspnea in the ACC with a caudal area devoted to perceptual processing of dyspnea and its associated motor changes, and a rostral modulation area that is specifically activated by the different putative mechanisms that may induce relief, with possible contribution of nonspecific functions such as attention, arousal, and/or emotion. Interestingly, this activation area in the ACC was very close to, and partially overlapped, the most significant activation area of the comparison of high relief to high dyspnea (p2hr 2 p2hd) (Figures 6 and E5, and Table 5), whereas the locations of all the remaining activation areas differed between the two contrasts. Thus, the fact that the most significant activation area for these two contrasts that allows identification of brain activation associated with the sensory component of relief from two different angles was detected in the same brain area suggests that this cerebral structure plays a relevant contributive role in central processing of the different sensory aspects of dyspnea relief. The second and fourth most significant activation areas of relief-related activation versus unloaded control were located in the right inferior and superior semilunar lobule (Crus I and II), which are both parts of the neocerebellum, the phylogenetically most recent part of the cerebellum. There is now increasing evidence from studies in humans during health (38 40) and disease (41) that the neocerebellum, which has bidirectional links with higher order areas of the brain (42), is involved in emotion (41), high-quality sensory acquisition (38), and cognitive functions (41), including memory and learning (39, 40), all of which are likely to be relevant for the previously detailed specific central processing of dyspnea relief. In this respect, it is noteworthy that relief-related activation occurred exclusively in the neocerebellum as opposed to dyspnea, which also activates the phylogenetically more ancient part of the cerebellum (11, 13, 34, 35, 43). However, because the contrast of high relief versus high dyspnea (p2hr 2 p2hd) did not reveal any significant activation in the neocerebellum, it cannot be excluded that increased rcbf in the previously mentioned cerebellar activation areas are also related to relief-related respiratory changes. Most important, our brain imaging results of dyspnea relief did not reveal decreased activation in any of the dyspnearelated activation sites of the present study. Likewise, activation areas of relief differed from the dyspnea-related deactivation site of the present study, as well as from almost all those of previous studies of dyspnea (11, 12, 33). Yet, previous studies of other unpleasant sensations, like pain (28, 44) or thirst (45), have identified a decrease in, or even a virtually instantaneous disappearance (45) of, activity in areas involved in perception of these sensations. We cannot therefore formally exclude that some decrease in activity of dyspnea-related areas occurred too early to be detected in the present study. Nevertheless, our results verify, for dyspnea, that relief of unpleasant sensations does not exclusively consist of decreased activation in brain structures encoding perception of the corresponding sensation. Thus, the present study shows, as it has been previously demonstrated for relief of other unpleasant sensations (25 30, 36, 37), that this sensory experience involves, above all, strong and characteristic activation of several brain areas. We submit the hypothesis that