Reduced Perception of Dyspnea and Pain after Right Insular Cortex Lesions

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1 Reduced Perception of Dyspnea and Pain after Right Insular Cortex Lesions Daniela Schön 1, Michael Rosenkranz 2, Jan Regelsberger 3, Bernhard Dahme 1, Christian Büchel 4, and Andreas von Leupoldt 1,4 1 Department of Psychology, University of Hamburg; 2 Center for Clinical Neurosciences-Department of Neurology, University Medical Center Hamburg-Eppendorf; 3 Center for Clinical Neurosciences-Department of Neurological Surgery, University Medical Center Hamburg-Eppendorf; and 4 Department of Systems Neuroscience/Neuroimage Nord, University Medical Center Hamburg-Eppendorf, Germany Rationale: The perception of dyspnea and pain show many similarities. Initial imaging studies suggested an important role of the insular cortex for the perception of both sensations. However, little is known about the cortical processing of dyspnea. Objectives: This study investigated the influence of lesions of the insular cortex on the perception of dyspnea and pain. Methods: Dyspnea was induced by resistive loaded breathing in four patients with right-hemispheric insular cortex lesions, as assessed with computer tomography or magnetic resonance imaging, and four matched healthy control subjects. Pain was induced by a coldpressor test. Perceived intensity and unpleasantness of both sensations were rated on visual analog scales. Measurements and Main Results: In contrast to healthy control subjects, patients with lesions demonstrated reduced perceptual sensitivity for dyspnea, in particular for the unpleasantness of dyspnea (P, 0.05). This was paralleled by reduced sensitivity for pain in patients with lesions, as reflected by smaller ratings of intensity and unpleasantness, higher sensory pain-thresholds, and, in particular, higher affect-related pain tolerance times (P, 0.05). Conclusions: The results suggest that lesions of the right insular cortex are associated with reduced sensitivity for the perception of dyspnea and pain, in particular for their perceived unpleasantness. This underlines the importance of the insular cortex for the perception of both sensations. Keywords: brain; dyspnea; insular cortex lesion; pain; perception Dyspnea is the subjective experience of uncomfortable breathing and a major symptom in various cardiopulmonary and neuromuscular diseases. Perceived dyspnea is associated with fear and panic, considerable limitations to functional status and quality of life, and significant socio-economic costs (1). Recent work has emphasized that dyspnea shares many characteristics with pain (2 4). Both are subjectively perceived physiologic sensations with an unpleasant, alarming, and frightening character, and both contain an affective (unpleasantness) and a sensory dimension (intensity) (5 9). Their perception motivates adaptive behavior to modify the aversive condition to regain homeostatic balance. The affective unpleasantness of perceived dyspnea has been suggested as being particularly important for motivating patients to initiate adaptive behavior in a timely manner (i.e., medication intake or physician visits) (Received in original form May 14, 2008; accepted in final form September 3, 2008) Supported by grants from the Deutsche Forschungsgemeinschaft (DFG LE 1843/ 6-1, LE 1843/5-1) (A.v.L.). Correspondence and requests for reprints should be addressed to Andreas von Leupoldt, Ph.D., Department of Psychology, University of Hamburg, Von- Melle-Park 5, Hamburg, Germany. andreas.vonleupoldt@ uni-hamburg.de Am J Respir Crit Care Med Vol 178. pp , 2008 Originally Published in Press as DOI: /rccm OC on September 5, 2008 Internet address: AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The perception of dyspnea and pain share many characteristics, which presumably include similarities in activated brain areas. Little is known about the cortical processing of dyspnea. What this Study Adds to the Field This study suggests that lesions of the right insular cortex are associated with reduced perceptual sensitivity for dyspnea and pain and emphasize the important role of this brain area for the perception of unpleasant physiologic sensations. (10). In addition, dyspnea and pain often coexist in patients (11, 12). Despite these similarities, only a few studies have investigated the interactions between the perceptions of both sensations within one experimental context (13 16). Schön and colleagues recently demonstrated that the perceived unpleasantness of dyspnea was correlated with the perceived unpleasantness of pain in the same healthy volunteers, which was further related to negative affectivity (16). No such association was found for the intensity dimension. Accordingly, the authors suggested that common brain areas might process the unpleasantness of both sensations, in particular, areas of the affectrelated limbic system, such as the insular cortex. Initial imaging studies have suggested, besides other cortical areas, limbic system activation during the perception of dyspnea (17 23), with the right insular cortex being the most consistently activated structure across studies (4). Similar limbic activations with a predominant role of the insular cortex have been shown in various studies on the perception of pain (24, 25), which has been examined to a greater extent than dyspnea, and these activations have specifically been linked to the unpleasantness dimension of pain (26, 27). In a recent study using functional magnetic resonance imaging (fmri), we demonstrated a similar association of the right anterior insular cortex with the unpleasantness dimension of perceived dyspnea (23). In the present study, we sought to confirm and extend our previous fmri findings by studying the effects of a specific brain lesion, which is an important and unique methodology complementary to the correlative approach in neuroimaging techniques (28). We examined whether patients with right-hemispheric insular cortex lesions show reduced perception of dyspnea, particularly for its unpleasantness, when compared with healthy control subjects. We also studied whether this lesion affects the perception of pain in a similar way.

2 1174 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL TABLE 1. BASELINE CHARACTERISTICS OF PARTICIPANTS Characteristics Patients with insular lesion Control subjects Age, yr Sex, female/male* 4/0 4/0 Weight, kg Height, cm Body mass index Depressive symptoms State anxiety Trait anxiety * Values are given as number of subjects, all other data are presented as mean 1 SD. Score in the Beck Depression Inventory (29). Score in the State-Trait-Anxiety Inventory (30). MATERIALS AND METHODS Participants Four female patients with ischemic lesions of the right insular cortex and four healthy control subjects matched for gender, age, height, weight, body mass index, depression, and anxiety were studied (Table 1). Depression was assessed with the Beck Depression Inventory (29), which is a widely used 21-question self-report inventory measuring the current depression s severity by a total score (range, 0 63). Anxiety was assessed with the widely used State-Trait-Anxiety Inventory (30). This questionnaire comprises two separate self-rating scales for measuring state anxiety and trait anxiety. Each scale contains 20 items, which are summarized to a total state score and a total trait score (range, 20 80). On average, patients were studied 146 days after stroke (i.e., after having regained a stable condition). Acute complaints of the respiratory tract and any chronic medical conditions such as cardiopulmonary or pain conditions were exclusion criteria. Patients were recruited from the Neurology Department when demonstrating an ischemic stroke lesion centered in the right insular cortex with only marginal extensions to neighboring areas. As evident in diagnostic post-stroke computer tomography or MRI scans (Figure 1), which were performed immediately after hospital admission, all lesions involved anterior parts of the insular cortex with extensions to the mid-insular cortex in two patients (Figure 1A and 1C), to parts of the precentral cortex in three patients (Figure 1A, 1B, and 1D), and to prefrontal areas in one patient (Figure 1B). The primary sensory cortex was not involved in any of the patients. Based on thorough medical and neurologic examination by a neurologist, no patient demonstrated significant signs of hypoesthesia or neglect, and no patients or control subjects showed vascular, neurocognitive, or linguistic deficits. All volunteers provided informed written consent. The study was approved by the local ethics committee. Induction of Dyspnea Participants breathed through a mouthpiece connected in series with a pneumotachograph (Biopac Systems Inc., Santa Barbara, CA) and Figure 1. (A, B) Post-stroke computer tomography or (C, D) MRI scans of each patient with a right-hemispheric lesion of the insular cortex. Dark (A, B) or light areas (C, D) in the right hemisphere indicate the location of the lesion.

3 Schön, Rosenkranz, Regelsberger, et al.: Perception of Dyspnea and Pain 1175 a two-way valve (Jaeger Toennies GmbH, Germany) with the nose occluded by a clip. Dyspnea was induced by introducing inspiratory resistive loads to the inspiratory port of the system (total dead space, 650 ml). Seven loads of increasing magnitude (0.99, 1.21, 1.43, 1.75, 2.07, 2.19, and 2.33 kpa/l/s) were presented for 1 minute each, separated by 1-minute baseline epochs without presentation of loads. Participants were unaware of the increasing magnitude of the presented resistive loads. Breathing frequency (f), VT, and _ VE were measured continuously with a MP30 biosignal recording unit (Biopac Systems Inc.). Induction of Pain Pain was induced with the cold-pressor test, which leads to cutaneous vasoconstriction and stimulation of subcutaneous nociceptors (31). After a 2-minute baseline epoch with the nondominant hand in water (378C), the hand was immersed into circulating ice water (38C) until pain became intolerable or for a maximum of 3 minutes. Heart rate (HR) was continuously monitored (MP30; Biopac Systems Inc.). Measurement of Perceived Dyspnea and Pain The experienced levels of intensity (sensory) and unpleasantness (affective) of dyspnea and pain, respectively, were rated on separate horizontal visual analog scales (D-VAS-I, D-VAS-U, P-VAS-I, and P-VAS-U, respectively) (32) ranging from 0 to 10 cm (0 5 not noticeable/unpleasant; 10 5 maximally imaginable intensity/unpleasantness). D-VAS-I and D-VAS-U were presented after each of the seven loaded and unloaded conditions in randomized order. P-VAS-I and P-VAS-U were presented after the baseline epoch and every 10 seconds during the ice-water epoch in randomized order. Both dimensions were explained in detail before testing with standardized examples (33), and the experimenter made sure that the phrases were adequately understood. The pain threshold (i.e., time [in seconds] from hand immersion into ice-water until first noticeable pain sensation) and pain tolerance (i.e., time [in seconds] from first noticeable pain until pain became intolerable) were measured as perceptual indicators of the sensory pain intensity and affective pain unpleasantness, respectively (34). Experimental Protocol After the completion of the Beck Depression Inventory (29) and State- Trait-Anxiety Inventory (30), standardized instructions (31) were presented, and subjects were familiarized with all instruments and experimental procedures. After the subjects were seated in a recliner, the resistive loaded breathing test and the cold-pressor test were presented in randomized order, separated by a resting period. Subjects were free to withdraw at any time during the tests and were debriefed after the last condition. Data Analysis Results are presented as means 1 SD. D-VAS-I, D-VAS-U, f, VT, and _VE during resistive loaded breathing were averaged across the baseline epochs and across the loaded breathing epochs for each group. P-VAS-I, P-VAS-U, HR, pain threshold, and pain tolerance during the cold-pressor test were averaged across the baseline epoch and across the ice-water epochs for each group. Difference scores were calculated for D-VAS-I, D-VAS-U, P-VAS-I, and P-VAS-U by subtracting the averaged baseline value during the resistive loaded breathing test and the cold-pressor test, respectively, from the value during the highest resistive load and the last tolerated ice-water epoch, respectively. These difference scores (DD-VAS-I, DD-VAS-U, DP-VAS-I, and DP-VAS-U) were compared between the patient and control group with nonparametric Mann-Whitney U tests. In addition, Cohen s d was calculated as a measure of effect size. All analyses were calculated with SPSS 15.0 software (SPSS Inc., Chicago, IL) using a significance level of P, RESULTS Resistive Loaded Breathing Loaded breathing induced increases in mean D-VAS-I and D-VAS-U and decreases in mean f, VT, and _ VE when compared with the baseline in patients and in control subjects (Table 2). Patients demonstrated significantly smaller DD-VAS-U when compared with control subjects (P, 0.05; d ) (Figures 2 and 3). This was paralleled by smaller DD-VAS-I in patients, which did not reach statistical significance (P. 0.05; d ). Figure 4 presents the individual dyspnea ratings of the patients. Cold-Pressor Test Cold pain induced increases in mean P-VAS-I, P-VAS-U, and HR when compared with the baseline in patients and in control subjects (Table 2). Patients demonstrated a tendency for smaller DP-VAS-I and DP-VAS-U when compared with control subjects, but these differences did not reach statistical significance (P. 0.05; d and 20.49) (Figure 2). Patients showed a significantly higher affective pain tolerance than control subjects ( seconds versus seconds; P, 0.05; d ) and a nonsignificant trend for a higher sensory pain threshold ( seconds versus seconds; P. 0.05; d ). Figure 4 presents the individual pain ratings of the patients. DISCUSSION This study examined the role of the right insular cortex in the perception of dyspnea and pain by investigating the effects of right-hemispheric ischemic insular cortex lesions on the perception of resistive load induced dyspnea and cold-pressor pain. The results show a successful experimental induction of dyspnea and pain in patients with lesions and in matched control subjects, as witnessed in increased ratings of mean intensity and unpleasantness of both sensations. These were paralleled by decreases in breathing frequency, VT, and VE, _ which are commonly observed in studies using resistive loads (18, 22, 23, 35, 36), and by increases in heart rate, which are frequently Figure 2. Ratings of perceived dyspnea and pain. Top: Group means and SDs for increases in perceived intensity and unpleasantness of dyspnea during resistive loaded breathing from baseline to highest resistive load in patients with an insular cortex lesion and control subjects. Bottom: Group means and SDs for increases in perceived intensity and unpleasantness of pain during the cold-pressor test from baseline to last tolerated ice-water epoch in patients with an insular cortex lesion and control subjects.

4 1176 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Figure 3. Ratings of perceived dyspnea. Top: Group means and SDs for perceived unpleasantness of dyspnea at each inspiratory resistive load in patients with an insular cortex lesion and control subjects. Bottom: Group means and SDs for perceived intensity of dyspnea at each inspiratory resistive load in patients with an insular cortex lesion and control subjects. r 5 the group mean of the individually calculated correlations (Spearman rho) between ratings for unpleasantness and intensity, respectively, and resistive loads. There was no statistically significant difference in r values between patient and control group. reported in studies using cold-pressor pain (16, 29, 37). Compared with control subjects, patients with insular lesions demonstrated a general tendency for reduced perceptual sensitivity for dyspnea and pain, as reflected by smaller increases in ratings of intensity and unpleasantness of both sensations and by higher sensory pain thresholds and affective pain tolerance. The most pronounced and statistically significant differences were observed in the ratings of unpleasantness of dyspnea and in the affective pain tolerance. In line with previous theoretical assumptions (4, 21, 24, 25, 38, 39), our findings suggest that the right insular cortex plays an important role for the cortical processing of the perception of dyspnea and pain, in particular for the affective unpleasantness of both sensations. When interpreting the present results, it is important to notice that the smaller increases in the patients ratings of both sensations mainly resulted from their relatively high baseline ratings, whereas their absolute ratings at maximum stimulus intensities were more similar to those from the control group. Therefore, it seems rather the sensitivity to discriminate between the different nonnoxious and noxious levels of dyspneic and painful stimulation that is affected in these patients. In other words, their threshold for detecting changes in stimulus intensities is presumably higher than in healthy control subjects. This view is supported by the individual ratings of the patients (Figure 4), where the lack of a consistent linear increase with increasing stimulus intensity was clearly apparent in at least two patients. The small sample size did not allow us to link this lack to a specific lesion focus within the insular cortex. However, the higher baseline ratings and cardiorespiratory variables of the patients are difficult to explain. Differences in psychological characteristics, such as higher anxiety or negative affectivity in the patients, seem less plausible because scores in respective measures were comparable with the control group. It might be speculated that the higher baseline ventilation of the patients might have led to a higher effective resistance of the breathing circuit and to the resultant higher baseline ratings of dyspnea. This view does not explain the higher baseline ratings for perceived pain. Alternatively, the insular cortex might have a stabilizing or inhibitory influence on autonomic control and/or perception of autonomic processes, particularly during unloaded resting states, which needs to be addressed in future studies. The high baseline ratings and the averaged ratings for dyspnea and pain across all resistive loaded epochs and across all tolerated ice-water epochs indicate that insular lesions were not associated with a complete loss of the patient s ability to perceive dyspnea and pain. In addition, no patient showed clinical signs of hypoesthesia or neglect. Thus, our findings support previous notions (4, 18, 19) that the insular cortex is not processing the perception of dyspnea in an isolated fashion, but rather within a broader network of brain areas that seem to have preserved at least the general ability to perceive dyspnea in the present patients with insular cortex lesions. The present findings are consistent with the limited number of previous imaging studies that examined the perception of dyspnea by using positron emission tomography (PET) (17, 18, 20, 22) or fmri (19, 23). The most consistent activation across these studies was observed in the right-hemispheric insular cortex. In a recent fmri study, we could extend these findings Figure 4. Individual ratings of perceived dyspnea and pain in patients with insular cortex lesion. Top: Perceived unpleasantness and intensity of dyspnea at each inspiratory resistive load. Bottom: Perceived unpleasantness and intensity of pain at each measurement during the cold-pressor test.

5 Schön, Rosenkranz, Regelsberger, et al.: Perception of Dyspnea and Pain 1177 by showing that the anterior part of the right insular cortex together with the right extended amygdala is relevant for the processing of the perceived unpleasantness of dyspnea (23). However, the results of these studies are inferred from neuronal activations in intact brains of healthy subjects with PET and fmri and thus with imaging techniques that come with their own disadvantages. For example, a particular task can correlate with measured activity in a particular brain area, but it remains unclear whether this area is necessary to perform this task (28). The present method of studying brain lesions complements the findings from imaging studies, and summarizing the findings from both types of methodologies reduces the potential limitations of each single methodology (28). This means that, for the present study, a specific dysfunction of the right insular cortex after an ischemic stroke seems to be associated with reduced perceptual sensitivity for induced dyspnea, which improves the strength of the available evidence from imaging studies regarding the important role of this brain area for the perception of dyspnea. Our observation of similarly reduced perceptual sensitivity for induced pain supports the many previous imaging studies in the pain domain. Virtually all of these PET or fmri studies have reported prominent activations of the insular cortex during experimental pain induction (24, 25) and have linked these activations, in particular in the anterior parts of the insular cortex, to the affective unpleasantness of pain (24 27). These imaging results are supported by lesion studies in which damage to large parts of the insular cortex has been demonstrated in patients with pain asymbolia (40, 41). Similar to the present results, patients with this condition showed reduced affective behavior and did not demonstrate affective responses (i.e., pain unpleasantness or withdrawal in response to painful thermal stimulation). However, although their capacity to appreciate the sensory qualities of the painful stimuli was preserved, the patients in the present study demonstrated strong tendencies for reduced sensory processing for pain and dyspnea, which is also reflected by high effect sizes in the respective analyses. This discrepancy in terms of additional sensory deficits in the present patients is presumably caused by differences between studies in the localization of the lesions within the insular cortex. Although all of our patients demonstrated damage of the anterior insular cortex, some of them showed an extension or even center of the lesion into mid or posterior insular parts. In particular, the posterior insular and overlaying opercular cortex have been demonstrated to be involved in the processing of sensory aspects of perceived pain (42, 43), which might explain the additional sensory deficits observed in our patients. The present findings further extend the knowledge regarding various similarities between the perception of dyspnea and pain, which have been emphasized in previous work (2 4, 13 16, 44). For example, a direct experimental comparison of dyspnea and pain in healthy volunteers recently demonstrated similarities in the verbal description of the unpleasant character of both sensations (15). In a previous study, we observed a significant correlation between perceived unpleasantness of dyspnea with the perceived unpleasantness of pain in one sample of healthy subjects, whereas no such association was found for the intensity dimension. The unpleasantness of perceived pain was further related to the level of self-reported negative affectivity and heart rate changes during emotional picture viewing (16). The most likely explanation for these findings is that common brain areas might process the unpleasantness of both sensations, in particular areas of the affect-related limbic system, such as the insular cortex (2 4, 23). The present lesion study supports this assumption by showing that a dysfunction of this area seems to be associated with reduced perceptual sensitivity for dyspnea and pain, with the most pronounced deficits observed in the perceived affective unpleasantness of both sensations. Our observation of particular reductions in the affective unpleasantness of perceived dyspnea and pain after an insular cortex lesion is consistent with research on the cortical processing of emotions. Various imaging studies have confirmed that limbic structures, such as the insular cortex, play an important role in emotion processing (45 47). Moreover, prominent activations of the insular cortex have been reported for the perception of other unpleasant sensations, such as hunger (48), thirst (49), and aversive taste (50). Therefore, recent theories on emotions have provided a model with the anterior insular cortex as a key structure linking the perception of visceral sensations to the conscious experience of emotions in humans (51, 52). Previous studies have supported this model by showing strong relationships between the perception of physical sensations such as heart beat, anterior insular cortex activity, and the experience of emotional arousal (51 53). The observed reductions in the affective unpleasantness of perceived dyspnea and pain in patients with an insular cortex lesion in the present study therefore support this model. This assumed integrative homeostatic function of the anterior insular cortex is physiologically well based on its extensive and mostly reciprocal connections to various other sensorimotor, cognitive-motivational, and affective brain areas (i.e., the amygdala, anterior cingulate cortex, orbitofrontal cortex) (51, 54). The insular cortex also receives a variety of afferent respiratory signals from respiratory chemoreceptors, mechanoreceptors, and the brainstem medullary respiratory oscillator (4, 54). Based on the present results, recent fmri findings (23), and previous theoretical assumptions (4, 21, 38, 39), these connections seem to suggest a similar transformation of per- TABLE 2. PHYSIOLOGIC MEASURES AND PERCEIVED DYSPNEA AND PAIN DURING THE RESISTIVE LOADED BREATHING TEST AND THE COLD-PRESSOR PAIN TEST WITH RESPECTIVE BASELINES* Baseline Dyspnea Dyspnea Baseline Pain Pain L C L C L C L C VT, L f, breaths/min _VE, L/min Pain threshold, s Pain tolerance, s HR, beats/min Perceived intensity Perceived unpleasantness Definition of abbreviations: C 5 control subjects; f 5 breathing frequency; HR 5 heart rate; L 5 patients with insular lesions. * Results are group mean values 1 SD averaged across the loaded breathing epochs, across the ice-water epochs, and across the respective baseline epochs.

6 1178 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL ceived respiratory signals of dyspnea into its affective unpleasantness in the insular cortex. Thus, our present findings support recent theoretical assumptions on a dual cortical processing of respiratory signals of dyspnea (4, 38, 39), with one pathway being related to the affective unpleasantness of perceived dyspnea and including areas of the limbic system, such as the insular cortex, amygdala, medial nuclei of the thalamus, and the cingulate cortex. The other pathway, including lateral thalamic areas and sensorimotor cortices, has been suggested to process the sensory aspects of dyspnea. It seems reasonable to assume that intact areas from this network other than the insular cortex are responsible for the preserved general ability to perceive the dyspneic and painful stimulation in the present patients with insular lesions. A potential limitation of the present study is the small sample size, which is due to the fact that isolated lesions of the insular cortex without pronounced extensions into other brain areas are rare. Related to this circumstance is the fact that the present brain lesions were not limited to the anterior and thus presumably affective insular cortex, but some of them involved the middle and posterior insular areas. This might explain the observed deficits in the processing of the sensory intensity in addition to the affective unpleasantness of perceived dyspnea and pain. Furthermore, this study included only patients with right-hemispheric insular cortex lesions, which prevents conclusions regarding the influence of the left hemisphere. However, previous imaging studies found the strongest insular activations for perceived dyspnea in the right hemisphere (17 23), which suggests a more pronounced role of the right insular cortex. In addition, the generalizability of our findings is somewhat limited by the relatively old age of subjects in the present study, which is related to the circumstance that ischemic strokes are more prominent in elderly patients. The fact that all our participants were female further limits the generalizability of the results. Although there is little reason to assume gender differences in the general pattern of cortical processing of perceived dyspnea and pain, future studies with male subjects are necessary to rule out any such gender effects. In addition, because we cannot exclude changes in extent of the lesion and in functional recovery over the time between structural scans and functional tests, future studies with repeated structural and functional measurements are needed to examine any such effects of neuroplasticity. 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