Andreas von Leupoldt

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

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.

Dyspnea and pain share emotion-related brain network.

The early detection of stimuli signalling threat to an organism is a crucial evolutionary advantage. For example, the perception of aversive bodily sensations such as dyspnea and pain strongly motivates fast adaptive behaviour to ensure survival. Their similarly threatening and motivating characters led to the speculation that both sensations are mediated by common brain areas, which has also been suggested by neuroimaging studies on either dyspnea or pain. By using functional magnetic resonance imaging (fMRI), we formally tested this hypothesis and compared the cortical processing of perceived heat pain and resistive load induced dyspnea in the same group of participants. Here we show that the perception of both aversive sensations is processed in similar brain areas including the insula, dorsal anterior cingulate cortex, amygdala and medial thalamus. These areas have a documented role in the processing of emotions such as fear and anxiety. Thus, the current study highlights the role of a common emotion-related human brain network which underlies the perception of aversive bodily sensations such as dyspnea and pain. This network seems crucial for translating the threatening character of different bodily signals into behavioural consequences that promote survival.

The Impact of Anxiety and Depression on Outcomes of Pulmonary Rehabilitation in Patients With COPD

BACKGROUND Anxiety and depression are prevalent comorbidities in COPD and are related to a worse course of disease. The present study examined the impact of anxiety and depression on functional performance, dyspnea, and quality of life (QoL) in patients with COPD at the start and end of an outpatient pulmonary rehabilitation (PR) program. METHODS Before and after PR, 238 patients with COPD (mean FEV(1) % predicted = 54, mean age = 62 years) underwent a 6-min walking test (6MWT). In addition, anxiety, depression, QoL, and dyspnea at rest, after the 6MWT, and during activities were measured. RESULTS Except for dyspnea at rest, improvements were observed in all outcome measures after PR. Multiple regression analyses showed that before and after PR, anxiety and depression were significantly associated with greater dyspnea after the 6MWT and during activities and with reduced QoL, even after controlling for the effects of age, sex, lung function, and smoking status. Moreover, before and after PR, anxiety was related to greater dyspnea at rest, whereas depression was significantly associated with reduced functional performance in the 6MWT. CONCLUSIONS This study demonstrates that anxiety and depression are significantly associated with increased dyspnea and reduced functional performance and QoL in patients with COPD. These negative associations remain stable over the course of PR, even when improvements in these outcomes are achieved during PR. The results underline the clinical importance of detecting and treating anxiety and depression in patients with COPD.

Mental disorders in chronic obstructive pulmonary disease (COPD).

Recent research using questionnaire measures has demonstrated high prevalence rates of mental disorders in chronic obstructive pulmonary disease (COPD). However, clinical interviews and clinical rather than healthy control groups have rarely been employed. The aim of the present study was to assess mental disorders in patients with COPD with advanced methodology, to identify moderating factors explaining mental co-morbidities and to compare results with a clinical control group without COPD. A standardized clinical interview (F-DIPS) and a range of questionnaires were used to assess mental disorders, perceived physical symptoms and cognitions in 20 hospitalized patients with mild-to-moderate COPD (mean FEV(1)/VC (%)=61.3). Results were compared with a hospitalized clinical control group without pulmonary dysfunction (CCG; N=20). Results showed that 55% of patients with COPD received a diagnosis of a mental disorder compared to 30% of CCG patients. All principal mental diagnoses in the COPD group were anxiety disorders (especially Panic Disorder with Agoraphobia), while CCG patients received a wider range of diagnoses (anxiety, pain, alcohol abuse). There was no systematic association between anxiety levels and respiratory function in the whole COPD group, but a positive correlation between anxiety levels and perceived physical symptoms (p<0.001) as well as negative cognitions (p<0.001 and p<0.05, respectively) for COPD patients with anxiety disorder (N=11). The present results confirm the high prevalence rate of anxiety in patients with COPD and suggest further that anxiety in COPD patients may be mediated by cognitive processes. These findings are discussed in terms of their implications for treatment.

Down-Regulation of Insular Cortex Responses to Dyspnea and Pain in Asthma

RATIONALE Dyspnea is the impairing cardinal symptom of asthma but its accurate perception is also crucial for timely initiation of treatment. However, the underlying brain mechanisms of perceived dyspnea in patients with asthma are unknown. OBJECTIVES To study brain mechanisms of dyspnea in asthma. METHODS By using functional magnetic resonance imaging we compared the neuronal responses to experimentally induced dyspnea in patients with asthma and healthy controls. These brain activations were compared with neuronal responses evoked by pain to study neuronal generalization processes to another, similarly unpleasant, physiological sensation. MEASUREMENTS AND MAIN RESULTS While lying in the scanner, fourteen patients with mild-to-moderate asthma and fourteen matched healthy controls repeatedly underwent conditions of mild dyspnea, severe dyspnea, mild pain and severe pain. Dyspnea was induced by resistive loaded breathing. Heat pain of similar intensity was induced by a contact thermode. Whereas the sensory intensity of both sensations was rated similar by patients and controls, ratings of the affective unpleasantness of dyspnea and pain were reduced in patients. This perceptual difference was mirrored by reduced insular cortex activity, but increased activity in the periaqueductal gray (PAG) in patients during both increased dyspnea and pain. Connectivity analyses showed that asthma-specific down-regulation of the insular cortex during dyspnea and pain was moderated by increased PAG activity. CONCLUSIONS The results suggest a down-regulation of affect-related insular cortex activity by the PAG during perceived dyspnea and pain in patients with asthma. This might represent a neuronal habituation mechanism reducing the affective unpleasantness of dyspnea in asthma, which generalizes to other unpleasant physiological sensations such as pain.

Sensory and affective aspects of dyspnea contribute differentially to the Borg scale's measurement of dyspnea.

Background:Recent research has shown that distinct dimensions in the perception of dyspnea can be differentiated; however, most studies to date have only used a global rating scale for the measurement of this sensation. Objectives: This study examined the different influence of sensory and affective aspects of perceived dyspnea on the commonly used Borg scale, which measures the global perception of dyspnea. Methods: Dyspnea was induced in 16 healthy volunteers (mean age 26.2 ± 6.3 years) by breathing through an inspiratory resistive load (3.57 kPa/l/s) in two experimental conditions (attention and distraction). After each of the two conditions the experienced intensity (i.e., sensory dimension) and unpleasantness (i.e., affective dimension) of dyspnea were rated on separate visual analog scales (VAS), followed by a global rating of dyspnea on the Borg scale. Hierarchical multiple linear regression models were calculated to analyze the predictive validity of VAS ratings of intensity and unpleasantness on the Borg scale ratings. Results: When subjects attended to their breathing, only VAS intensity scores showed a significant influence on Borg scale ratings (p < 0.05). In contrast, only the VAS unpleasantness scores showed a significant influence on Borg scale ratings (p < 0.05) when subjects were distracted. Conclusions: These findings show that sensory and affective aspects of perceived dyspnea differentially influence the global measure of dyspnea as determined by the Borg scale. A differentiation between these aspects in future studies through the use of separate rating scales could yield more detailed information on the perception and report of dyspnea.

Reduced Perception of Dyspnea and Pain after Right Insular Cortex Lesions

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 cold-pressor 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.

Effects of medical and psychological treatment of depression in patients with COPD – A review

Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory lung disease characterized by progressive and only partially reversible symptoms and by considerable negative consequences such as reductions in functional status and quality of life. Comorbid depression is highly prevalent in patients with COPD and related to a worse course of the disease. Despite its negative impact, depression often remains unrecognized and untreated in COPD patients. This review summarizes the current state of findings from studies examining the effects of antidepressant treatments in patients with COPD. Reviewed treatment options are antidepressant medical therapy and cognitive-behavioral therapy (CBT). Antidepressant medical trials include treatments with selective serotonin reuptake inhibitors (SSRI) or tricyclic antidepressants (TCA); CBT was applied using various components. Across both treatment types, the majority of studies included patients with a wide range of psychiatric conditions and especially comorbid symptoms of anxiety were often not controlled. Furthermore, greatly varying instruments and methods for assessing depressive symptoms, small sample sizes and rather heterogeneous results were observed. This makes the comparison of treatment options rather difficult and prevents definite conclusions. However, some important implications valuable for further research were obtained. Some limited data suggested that SSRI might show fewer side effects than TCA. A few antidepressants as well as beneficial effects in other outcomes were observed after antidepressant medical treatment. More clearly, CBT showed some potential in terms of improvements in depressive symptoms, and also in other outcome measures. Patient compliance seems more promising for CBT than for antidepressant medical treatment. Overall, the reviewed studies suggest some promising effects for both treatment types and effect sizes in studies with significant antidepressant effects were reasonable. However, future randomized controlled trials comparing antidepressant medical and cognitive-behavioral therapy will be essential to assess distinct and most favorable treatment effects. Because recent data is often limited, sound diagnostic criteria of depression and adequate sample sizes are necessary to draw firm conclusions on the effects of these antidepressant treatment options in patients with COPD and comorbid depression.

The impact of anxiety on the neural processing of respiratory sensations.

Previous studies demonstrated that anxiety considerably impacts the reported perceptions of respiratory sensations. A novel feature of the current study is exploring the impact of anxiety on the neural processing of respiratory sensations elicited by short inspiratory occlusions during different affective contexts. Using high-density EEG, respiratory-related evoked potentials (RREP) were recorded in 23 low and 23 matched higher anxious individuals when viewing unpleasant or neutral picture series. Low anxious individuals showed the expected pattern of reduced magnitudes of later RREP components P2 and P3 during the unpleasant compared to the neutral affective context (p<0.05 and p<0.01). In contrast, higher anxious individuals showed greater magnitudes of P2 and P3 during the unpleasant compared to the neutral affective context (ps<0.05). Moreover, higher anxiety levels were correlated with greater magnitudes for P2 (r=0.44, p<0.01) and P3 (r=0.54, p<0.001) during the unpleasant relative to the neutral affective context. Earlier components of the RREP (Nf, P1, N1) were not affected by anxiety. This study demonstrates that anxiety affects the later, higher-order neural processing of respiratory sensations, but not its earlier, first-order sensory processing. These findings might represent a neural mechanism that underlies the increased perception of respiratory sensations in anxious individuals.

Films for eliciting emotional states in children.

Standardized sets of films have been shown to be effective for eliciting emotional states in adults, but no comparable validated stimuli are available for children. We therefore examined the effects of three pre-selected film clips each of 3-min duration in eliciting a pleasant, neutral and unpleasant emotional state in 297 children aged between 6 and 12 years. After the films were presented on a video projector, affective ratings were obtained with the Self-Assessment-Manikin on the emotional dimensions of valence and arousal. Increasing pleasure ratings were observed from the unpleasant to the neutral to the pleasant film. Associated arousal ratings were stronger for the unpleasant and pleasant films compared to the neutral film. Overall, results showed successful elicitation of targeted emotional states only marginally influenced by age, gender or prior experience with the films. The use of these films is therefore suggested for future studies on emotions in children.