Chest Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (18)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by von Leupoldt, A.
Right arrow Articles by Dahme, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by von Leupoldt, A.
Right arrow Articles by Dahme, B.
(Chest. 2005;128:345-354.)
© 2005 American College of Chest Physicians

Cortical Substrates for the Perception of Dyspnea*

Andreas von Leupoldt, PhD and Bernhard Dahme, PhD

* From the Psychological Institute III, University of Hamburg, Hamburg, Germany.

Correspondence to: Andreas von Leupoldt, PhD, Psycho- logical Institute III, University of Hamburg, Von-Melle-Park 5, 20146 Hamburg, Germany; e-mail: andreas.vonleupoldt{at}uni-hamburg.de


   Abstract
TOP
 Abstract
Introduction
 Physiologic Mechanisms
 Psychological Mechanisms
 Cortical Representation of...
 Similarities Between Dyspnea and...
 Implications for Future Research
 Summary
 References
 
Dyspnea is a common, unpleasant, and impairing symptom in various respiratory diseases and other diseases. Despite growing understanding of the multiple peripheral mechanisms giving rise to dyspnea, little is known about the cortical mechanisms underlying its perception. The results of neuroimaging studies have shown that distinct brain areas process the dyspneic sensation, among which the anterior insular seems to be the most important. Based on the findings of the first relevant neuroimaging studies, this review describes the cortical structures associated with the perception of dyspnea. Moreover, similarities to the perception of pain are discussed, and implications for future research are provided.

Key Words: asthma • brain • breathlessness • COPD • dyspnea • emission-CT • MRI • pain • perception


   Introduction
TOP
 Abstract
 Introduction
Physiologic Mechanisms
 Psychological Mechanisms
 Cortical Representation of...
 Similarities Between Dyspnea and...
 Implications for Future Research
 Summary
 References
 
Dyspnea or breathlessness is the subjective experience of breathing discomfort comprising qualitatively distinct sensations that can vary in their intensity. Like pain, these sensory experiences originate from interactions among multiple physiologic, psychological, social, and environmental factors.1 Breathlessness is an unpleasant and frightening symptom in a variety of cardiopulmonary and other diseases.12 Particularly in asthma and COPD, it is a cardinal symptom, causing reductions in functional status and quality of life, and an enormous socioeconomic burden.345 The increasing prevalence rates for asthma and COPD will further intensify this major public health problem.456 Besides these facts, the adequate perception of the onset and severity of breathlessness is a very important component of current disease-self-management programs, particularly in patients with asthma.37 A failure to perceive the severity of a developing bronchoconstriction can result in a delay in seeking help and inadequate utilization of effective medications, and might, at worst, lead to avoidable deaths.891011 Research over the past decades has examined several possible mechanisms contributing to the perception of dyspnea but has focused predominantly on peripheral levels of the respiratory system. Some studies1213 using respiratory-related evoked potentials (RREPs) have suggested that deficits in the neuronal processing of perceptual information in asthmatic patients bear on the perception of dyspnea. This could be an underlying mechanism for the blunted perception of dyspnea, which has been reported for subgroups of asthmatic patients.1415 Although the important role of the central processing of sensory information related to breathlessness has been realized,1617 little is still known about the cortical structures involved in the perception of dyspnea.181920

This review provides an overview of the brain areas that are associated with the perception of breathlessness, with a special focus on the results of the first neuroimaging studies on this topic. Furthermore, similarities to the far better understood cortical processing of pain perception, which is a similarly unpleasant, alarming physical sensation, are discussed. Both dyspnea and pain strongly motivate adaptive behavior to regain homeostasis,19 and patients often experience both conditions.2 Based on the reviewed findings, implications for future research are presented.


   Physiologic Mechanisms
TOP
 Abstract
 Introduction
 Physiologic Mechanisms
Psychological Mechanisms
 Cortical Representation of...
 Similarities Between Dyspnea and...
 Implications for Future Research
 Summary
 References
 
Past research has shown that a variety of different input mechanisms might lead to the complex sensation of difficult breathing. Afferent signals from pulmonary vagal receptors in the upper and lower airways are one possible source that is triggered by bronchoconstrictions. Pulmonary stretch receptors in the airways smooth muscles are activated as the lung expands, type-J receptors in the walls of alveoli and capillaries are stimulated by increasing intrapulmonary pressure, and irritant receptors in the upper airways and the tracheobronchial walls respond to a variety of mechanical or chemical stimuli.1 All of these pulmonary receptors provide information about changes in the breathing pattern, airflow, pressure, respired volume, and airway diameter, which can contribute to perceived sensations of breathlessness.2122

Another input refers to mechanoreceptors in the chest wall. Respiratory muscles contain a variety of afferents in the joints, tendon organs, and muscle spindles. Specifically, receptors in the intercostal muscles and diaphragm have been shown to be involved in the perception of dyspnea by signaling information regarding respiratory muscle displacement and alterations in length-tension relations.2324 These chest wall receptors can be activated during hyperinflation, bronchoconstriction, or mechanical stimulation, weakening the respiratory muscles in order to overcome the associated high elastic, threshold, and resistive loading.8

Furthermore, changes in arterial blood gas levels (ie, arterial PCO2 and PO2) and acid-base status can lead to breathlessness by stimulation of the central chemoreceptors in the brainstem medulla, and of the peripheral chemoreceptors in the aortic and carotid bodies.1 These chemical changes due to hypercapnia or hypoxia might be perceived by direct sensory afferents from the chemoreceptors or due to increased medullary respiratory motor drive.2526

A predominant mechanism might arise from the simultaneous activation of sensory cortex areas when efferent respiratory motor command is sent to the respiratory muscles.127 These activations are presumably caused by corollary discharges, which originate from medullary or higher cortical respiratory centers. These have not yet been found in the human cortex, but have been found in studies with cats,2829 in which sensory thalamic nuclei were activated by corollary discharges. Furthermore, the attractive unifying concept of afferent mismatch states that breathlessness evolves from a dissociation or mismatch between efferent motor command to the respiratory muscles and afferent feedback from pulmonary and chest wall receptors, which signal the effectiveness of the motor command.30 Where the afferent mismatch is processed within the brain is currently unknown.

Although all of these input mechanisms can contribute to breathlessness, different pathways might be involved in different diseases associated with dyspnea. This might be reflected by distinct verbal phrases that subjects use to describe the qualitative nature of the experience (eg, air hunger, effort of breathing, or chest tightness).3132 However, information is still lacking on how sensory information from different receptors is transmitted to higher cortical centers3334 and which brain areas are involved in the perception of these sensations. For a detailed review of the mechanisms of dyspnea, the reader is referred to various excellent reviews.33353637


   Psychological Mechanisms
TOP
 Abstract
 Introduction
 Physiologic Mechanisms
 Psychological Mechanisms
Cortical Representation of...
 Similarities Between Dyspnea and...
 Implications for Future Research
 Summary
 References
 
Besides physiologic mechanisms, the role of psychological factors in the perception of breathlessness has been recognized,83839 but research on this topic is still at the beginning. To the present time, negative emotions have been shown to be associated predominantly with decreased accuracy of dyspnea perception.3840 Furthermore, a repressive-defensive coping style might be related to blunted symptom perception,4142 but some findings have not been fully conclusive.43 Psychopathologic characteristics such as hypochondriasis or somatoform tendencies have not been shown to influence the sensing airflow limitations,4445 and there is at present no conclusive evidence that distinct personality profiles predispose a person to the inaccurate perception of dyspnea.3543 However, an important influence might arise from learning processes or contextual factors and lead to the overperception of respiratory sensations.4647 Alternatively, an attention-distracting context has been shown to reduce the awareness of breathlessness, which might be an effective intervention in patients with some conditions (eg, COPD).48


   Cortical Representation of Dyspnea
TOP
 Abstract
 Introduction
 Physiologic Mechanisms
 Psychological Mechanisms
 Cortical Representation of...
Similarities Between Dyspnea and...
 Implications for Future Research
 Summary
 References
 
Despite a growing understanding of the possible pathways leading to breathlessness, relatively little is known about higher brain centers in humans that process this sensation.20 In particular, the brain areas associated with the perception of the experience have not been well-explored.1819 This is in part attributable to a lack of adequate animal models properly simulating human dyspnea perception49 and, furthermore, is due to an absence of high-resolution imaging techniques, which allow a noninvasive study of human brain activity.

Introduction to Findings Without Imaging Techniques
Early research3336 on experimental animals by means of evoked potentials, which were recorded with cortical surface electrodes after electrical or mechanical stimulation of different respiratory afferents, has demonstrated that afferents from airways and respiratory muscles project to the cerebral cortex in cats and monkeys. Prominent activations have been found in the somatosensory cortex, in the motor cortex and in the mesocortex.505152 Results like these have suggested a role for higher cerebral involvement in respiratory sensations besides the pontomedullary respiratory oscillator.

Activation of the somatosensory cortex in adult humans by means of RREPs was first shown by Davenport and coworkers.53 These RREPs were recorded after short inspiratory occlusions by means of scalp surface electrodes placed over the somatosensory region of the cortex measuring electroencephalic activity below the surface, which is similar to the evoked potential techniques in other sensory systems using EEGs. Short states of breathlessness predominantly evoked early RREPs, namely, the primary positive voltage peak (P1), the primary negative voltage peak (N1), the secondary positive voltage peak (P2), and the secondary negative voltage peak (N2), which occur within about 100 ms (P1 and N1) or 200 ms (P2 and N2), after stimulus onset.5354 P1, P2, N1, and N2 are peaks in the EEG signal due to dipoles occurring when a cerebral column is depolarized by the arrival of activity from respiratory afferents activated by the inspiratory occlusion. Thus, the obtained components represent the arrival and first processing of respiratory-related afferent sensory information in the somatosensory cortex. A subsequent study demonstrated a positive correlation between the amplitude of P1 and the perceived magnitude of the respiratory load.55 Other studies56575859 conducted by means of percutaneous electrical or transcranial magnetic stimulation have provided further evidence for fast-conducting afferent and efferent connections between the cerebral cortex and respiratory muscles.

Another study by Davenport and coworkers12 using the RREP methodology is important with regard to the reported blunted perception of breathlessness in subgroups of asthmatic patients, specifically those with a history of near-fatal attacks.1415 In a group of asthmatic children with a history of life-threatening asthma, they found an absence of the P1 component after respiratory occlusion (ie, the dyspneic sensory signal was not activating the somatosensory cortex). These results suggest a deficit in the neural processing of information related to breathlessness, which in turn might be an important mechanism underlying blunted symptom perception. Further evidence for this assumption has arisen from a study by Webster and Colrain,13 which was performed by means of RREPs. They demonstrated reduced late tertiary positive voltage peak components (P3) in asthmatic adults when compared to healthy control subjects following midinspiratory occlusion. Most interestingly, these reductions in the P3 amplitude were also obtained after a short auditory stimulus, whereas early P1 components showed comparable amplitudes in both groups. The data suggest the presence of an asthma-specific deficit in the later cortical processing of respiratory load information. A rather speculative interpretation of the findings would be that of a general deficit in the cortical processing of perceptual information in specific groups of asthma patients. However, more research is clearly needed to explore these first results further.

Imaging Techniques and Dyspnea
The development and increasing availability of high-resolution imaging techniques have provided a great tool for the noninvasive study of brain structures in the conscious human. Specifically, positron emission tomography (PET) scanning and functional MRI (fMRI) have been used in a vast variety of scientific contexts. Both methods measure regional cerebral blood flow, which is increased locally during neural activity. While PET scanning requires the IV application of a nuclear tracer (eg, H215O),60 fMRI employs the blood oxygen level dependence effect61 to contrast areas of different cerebral blood flow.62 However, compared to other sensory systems, the proportion of and interest in imaging studies examining sensations of breathlessness is markedly reduced.

The first studies in this field have focused primarily on aspects of volitional breathing or compensation of induced breathlessness, while the perception of dyspnea has not been systematically examined.6364656667686970 Volitional breathing in the PET or fMRI scanner has been achieved by voluntary targeted breathing, either with or without added respiratory loads, and has been compared with unloaded spontaneous breathing or passive mechanical ventilation. The predominant activation has been obtained bilaterally in the primary motor cortex (M1), in the right premotor area (PMA), in the supplementary motor area (SMA), in the cerebellum, and in the thalamus. Some studies have reported several further activations in regions of the pontomedullary respiratory oscillator,6567 in sensorimotor areas,66676970 in anterior cingulate structures,6667 in the prefrontal cortex,6970 and in the parietal cortex.666768 These findings have demonstrated that higher motor cortex areas are involved in volitional breathing and in the compensation of breathlessness. McKay and coworkers67 concluded that the voluntary control of breathing is similar to other voluntary movements, and requires the activation of an integrated network of cortical and subcortical areas.

Further work has studied the effects of increased inspiratory CO2 on brain activity, which, as described above, is one known source leading to dyspnea.7172 But again, a systematic examination of the perceived sensation of breathlessness has not been provided. However, besides activity in cerebellar, frontal, and occipital regions, hypercapnia was predominantly associated with activations in the limbic system (eg, the hypothalamus, hippocampus, cingulate cortex, and insula).72 No activations were seen in motor cortex areas that have been shown to be associated with volitional breathing. These results further suggest a participation of brain areas above the pontomedullary respiratory oscillator in the processing of sensory information related to breathlessness.

At present, only four imaging studies have been published in six reports, with three reports171949 explicitly examining the perception of dyspnea, and different aspects of the fourth study having been reported in three different reports.737475 Only one of these studies49 employed fMRI, which offers a higher resolution compared to PET scanning.

In the studies by Liotti et al,73 Brannan et al,74 and Parsons et al,75 breathlessness was induced in nine healthy volunteers by the inspiration of increased CO2 (8%) using either a facemask or a mouthpiece. Data from these subjects were contrasted with those of subjects having several other conditions, of which the episodes occurring without dyspnea that were due to facemask breathing of increased O2 (91%) and inspiration of room air (O2, 21%) are the most relevant for the present review. Evans and coworkers49 induced breathlessness in six healthy mechanically ventilated participants by restraining the tidal volume below spontaneous levels in combination with constantly elevating arterial PCO2 levels by manipulating inspired PCO2. This methodology was also used in the study by Banzett and coworkers,19 which included eight healthy volunteers. Both studies compared dyspneic conditions with episodes of higher tidal volume combined with normal arterial PCO2, which relieved breathlessness. Thus, all three studies1949737475 stimulated chemoreceptors or induced increases in the respiratory motor drive leading to sensations that were verbally expressed as air hunger, urge to breath, and like breathholding. In contrast, Peiffer and coworkers17 applied external resistive loads during inspiration and expiration in eight healthy participants. These loads were introduced to a breathing circuit to induce moderate-to-severe breathlessness and were removed during unrestricted control conditions while the volunteers breathed at spontaneous levels. An additional load condition including the inhalation of menthol in order to reduce the dyspneic sensation revealed no prominent effects. The resistive-load technique predominantly stimulates respiratory mechanoreceptors, which, as already described, can lead to breathlessness due to increases in perceived respiratory effort and work.

While subjects in all studies were lying in the supine position in the scanner, the different interventions were contrasted with episodes that occurred without breathlessness (ie, isocapnia with normal tidal volume or load-free breathing, respectively). Furthermore, all studies continuously monitored respiratory responses in airflow, volume, end-tidal PCO2, and mouth pressure to control the effectiveness of experimental stimulation. The perceived degree of breathlessness was assessed directly after interventions with appropriate rating scales and was compared to episodes with unrestricted breathing. Some studies further obtained verbal descriptions of the quality of the perceived sensation. Although the induction of breathlessness and the assessment of respiratory responses in the spatially limited, magnetically sensitive scanner environment are complicated procedures, all four studies overcame these restraints with appropriate designs. However, the small number of included participants is a shortcoming across all of these studies.

Despite the use of different intervention techniques, common activations in several brain areas have been demonstrated in at least three of the four studies. Predominant neural activity has been found in the insula, in insular agranular extensions (eg, operculum and frontal cortex areas), the anterior cingulate cortex (ACC), the posterior cingulate cortex (PCC), the cerebellum, the thalamus, and the amygdala. Further activations have been observed in the M1,737475 the PMA,49737475 the SMA,171949 and somatosensory areas,1749 which were all involved during voluntary breathing.6364656667686970 Additionally, neural activity has been observed in the pons,17 the putamen,1719737475 the hypothalamus,737475 the hippocampus,737475 and the frontoparietal network.49

Among all structures, the anterior insula, a multifunctional sensorimotor integration area, showed strong activations in all four studies, predominantly in the right hemisphere. This fact leads to the assumption that the insula is the crucial component in a larger cortical network underlying the perception of breathlessness.49 Like the ACC and the amygdala, the insula is part of the limbic network, and has dense connections to other limbic, somatosensory, and motor structures.76 Studies777879 in rats have further demonstrated that the insula receives afferents from respiratory chemoreceptors, from mechanoreceptors, and from projections from the medulla, which underlines its important role in the integration of respiratory sensations. Moreover, data80 have shown altered activity or response timing patterns within several cortical areas, including the insula, cerebellum, ACC, and hippocampus in patients experiencing obstructive sleep apnea syndrome when compared to control subjects. These patterns were obtained during Valsalva maneuvers, which are associated with breathlessness due to prolonged expiratory effort against a high load.81 These findings further suggest the presence of neural deficits in the processing of respiratory sensations in patients with pulmonary diseases, specifically in insular, cingulate, and cerebellar areas.

A Cortical Scheme of Dyspnea Perception
Summarizing the work conducted on the different input mechanisms, transmitting pathways, and processing brain areas involved in sensations of breathlessness, a preliminary scheme for the cortical substrates underlying the perception of dyspnea can be derived (Fig 1 ). For a detailed review of the afferent and efferent pathways between peripheral receptors and the brain, the reader is referred to two excellent reviews.3336



View larger version (36K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1.. Cortical areas involved in the perception of dyspnea. This preliminary scheme is based on the first results of neuroimaging studies and includes two major pathways signaling afferent information from peripheral receptors to the cortex, which have been derived from information from earlier psychophysical studies. The first pathway (black line) arises mainly from respiratory muscle afferents, and the second pathway (dashed line) includes mainly vagal afferents from the lungs and airways. Embedded brain areas represent only their proximate localization. AMYG = amygdala; CB = cerebellum; MDT = medial dorsal thalamus; MO = medulla oblongata; PFC = prefrontal cortex; PPC = posterior parietal cortex; S1 = primary somatosensory cortex; S2 = secondary somatosensory cortex; VPT = ventroposterior thalamus.

 
Two major pathways have been suggested to process respiratory sensations to the cortex.33 The first pathway arises predominantly from respiratory muscle afferents, is relayed in the brainstem medulla, and projects to the ventroposterior thalamus area, from where thalamocortical projections ascend to the primary and secondary somatosensory cortex. In accordance with other interoceptive sensations, these structures might process the sensory or intensity aspects of dyspnea.8283 The second pathway includes mainly vagal afferents from the lungs and airways, which are relayed in the brainstem medulla. Brainstem projections ascend to the amygdala and medial dorsal areas of the thalamus, and further to the insula and cingulate cortex. This predominantly limbic pathway might further include the hippocampus, operculum, putamen, and other prefrontal areas, and might be more associated with the affective components of the experienced breathlessness.2033 Both pathways include final projections to the higher motor cortex (ie, M1, PMA, and SMA), from where efferent motor commands project to the brainstem and/or respiratory muscles. The cerebellum might receive afferents from the pontomedullary respiratory oscillator in the brainstem79 or from the higher motor cortex, as a similar cerebellar activation has been shown during volitional breathing. Alternatively, the cerebellum might also be involved in affective functions of breathlessness, an idea that has been suggested for other primary sensations.7584 However, a clear differentiation between specific sensory and affective functions of brain areas associated with dyspnea still has to be explored.


   Similarities Between Dyspnea and Pain Perception
TOP
 Abstract
 Introduction
 Physiologic Mechanisms
 Psychological Mechanisms
 Cortical Representation of...
 Similarities Between Dyspnea and...
Implications for Future Research
 Summary
 References
 
It has been shown that the anterior insula is a crucial component within a larger brain network underlying the perception of dyspnea. However, it is not exclusively activated during respiratory sensations. Strong insular activation has been found in a variety of predominantly painful sensations (eg, heat, cold, and electrical stimulation)85868788 and during various other aversive sensations (eg, hunger, thirst, unpleasant odors, and negative emotions).84899091 Reiman and coworkers92 have suggested that the anterior insula is in general an internal alarm center, alerting the individual to potentially distressing interoceptive stimuli and investing them with negative emotional significance.

But the anterior insula is not the only component that is commonly activated during the perception of dyspnea and pain. In a variety of pain studies with different stimulus modalities, prominent activation has been observed in medial thalamic nuclei, in the ACC, and in the amygdala, which has been shown to be predominantly associated with the affective dimension of pain. Furthermore, strong activation of the ventroposterior lateral thalamus, and the primary and the secondary somatosensory cortex has been reported, and is primarily related to the sensory-discriminative aspects of pain.8285868788 All of these structures were also found to be activated in the first studies on dyspnea, which is suggestive of the presence of a common neural network underlying the perception of both sensations. While distinct cortical structures and pathways have already been shown to be more involved in either sensory or affective aspects of pain, a similar functional differentiation has not yet been proven for the perception of dyspnea, although it has already been hypothesized.2033

However, breathlessness and pain share more than cortical characteristics. As previously explicated by Banzett and Moosavi,93 both are subjectively perceived physiologic sensations, and both are of an unpleasant nature. The perception of dyspnea and pain warns the conscious brain of a disturbed physiologic state and motivates adaptive behavior to modify the aversive situation. Behavioral plans and motor actions can be initiated following the perceptual process. Furthermore, many patients with different diseases experience both unpleasant symptoms.29495 Despite many similarities between dyspnea and pain, and the high comorbidity of both sensations, almost nothing is known about the interactions regarding their perception. Only one study95 has examined this issue and has reported increased dyspnea ratings when tourniquet pain was added, whereas tourniquet pain remained almost unchanged after the additional induction of dyspnea.


   Implications for Future Research
TOP
 Abstract
 Introduction
 Physiologic Mechanisms
 Psychological Mechanisms
 Cortical Representation of...
 Similarities Between Dyspnea and...
 Implications for Future Research
Summary
 References
 
Based on the various similarities between dyspnea and pain, the adoption of successful strategies and methods from pain research, which is much more advanced, for investigations into dyspnea has been suggested.893 A key contribution has been the realization of the multidimensionality of the pain sensation,9697 which has led to the development of highly useful pain measurement instruments such as the Schmerzempfindungsskala (SES)98 and the McGill Pain Questionnaire.99 Although the first attempts have seemed to suggest a similar multidimensionality for perceived breathlessness,100101 this aspect has still received little attention but could be a promising paradigm for future research on dyspnea.93

As discussed above, distinct cortical structures have been shown82102103104105 to primarily process either sensory or affective fractions of pain, which can be further differentially modified with hypnotic and cognitive interventions. Whether this functional differentiation also exists in the cortical processing of dyspnea still remains to be explored. Peiffer and coworkers17 have suggested that the PCC/right cingulate sulcus might be more related to the affective dimension of perceived breathlessness. Although this was the first published attempt to separate functional aspects of the dyspneic sensation with imaging techniques, the sensory and affective dimensions were not assessed separately but rather were examined by means of a covariate correlational analysis. Hence, future imaging studies could differentially assess the affective and sensory aspects of perceived breathlessness, and could examine the relation of specifically activated brain areas.

Furthermore, pain and dyspnea might be induced in the same individuals to compare the brain areas activated by both stimulus modalities. This would give answers to whether both sensations are processed by the same cortical structures or simply by neighboring cortical structures,93 and would give insight into possible interactions between dyspnea and pain. In an analogy to pain research, it could further be examined whether affective or cognitive interventions are able to modify the perception of dyspnea, which has already been suggested.48 In this regard, it might be particularly useful to explore whether these modulations influence the associated cortical processing, as has been shown in pain studies.103104105

Furthermore, it is not understood how the insula gives rise to the perception of breathlessness. Evans and coworkers49 have suggested, on the basis of obvious connections between the medulla and insula, that corollary discharges from increased medullary brainstem motor activity could generate the sensation (see the introductory section). Alternatively, increased central motor command from the higher motor cortex to the respiratory muscles might activate the insula,106107 presumably even without peripheral afferent feedback from respiratory mechanoreceptors.70 Moreover, the insula might receive projections from the parietal cortex, which has been reported82108 for the processing of other perceptual sensations, and has been linked to the integration of contextual and attentional aspects. Hence, the concrete involvement of the insular within the perceptual network of dyspnea remains to be established.

However, none of the discussed studies included a group of patients who were experiencing dyspnea. Hence, our initial knowledge from neuroimaging studies has been exclusively derived from presumably intact cortical structures in healthy volunteers. Nothing is known about the brain mechanisms processing the perception of breathlessness in patients with pathologic conditions such as COPD or asthma. Particularly for the latter disease, data from studies1213 obtained by RREPs, have suggested deficits in the cortical processing of dyspnea perception, which might underlie the blunted perception of the sensation. Similar deficits might be present in patients with other diseases associated with breathlessness. To examine these presumed deficits, it will be necessary to perform neuroimaging studies that include different groups of patients who are experiencing dyspnea.


   Summary
TOP
 Abstract
 Introduction
 Physiologic Mechanisms
 Psychological Mechanisms
 Cortical Representation of...
 Similarities Between Dyspnea and...
 Implications for Future Research
 Summary
References
 
Dyspnea is a common and unpleasant symptom in patients with a variety of pathologic states. The failure to perceive this multidimensional sensation might lead to severe or fatal attacks in obstructive respiratory diseases. Multiple peripheral, central, and psychological mechanisms contribute to breathlessness, but little is known about the cortical processing of its perception. Some findings have suggested the presence of deficits in these central cortical mechanisms, which might be responsible for the blunted perception of dyspnea in asthma patients. The first neuroimaging studies in healthy volunteers have predominantly shown that areas in the thalamus, the somatosensory cortexes, the insula, the operculum, the cingulate cortex, the cerebellum, and the amygdala are activated during induced breathlessness, possibly within two different functional pathways. Of these structures, the anterior insula might be particularly important for the processing of dyspnea. Similar brain areas process the perception of pain. Both are subjectively experienced as unpleasant sensations, which have further common characteristics such as an alarming, behavioral, and motivational functions. Successful methods derived from advanced research on pain could therefore be adopted for research into dyspnea (eg, the separation of affective and sensory aspects of the sensation). Furthermore, the effects of modulatory interventions on dyspnea and on the associated brain structures might be explored. Future neuroimaging studies conducted in different patient groups are required for a better understanding of the cortical substrates that are necessary for the perception of dyspnea.


   Footnotes
 
Abbreviations: ACC = anterior cingulate cortex; fMRI = functional magnetic resonance imaging; M1 = primary motor cortex; N1 = primary negative voltage peak; N2 = secondary negative voltage peak; P1 = primary positive voltage peak; P2 = secondary positive voltage peak; PCC = posterior cingulate cortex; PET = positron emission tomography; PMA = premotor area; RREP = respiratory-related evoked potentials; SMA = supplementary motor area

We declare that we have not received any financial support for the present manuscript, that we are not involved in any organization with financial interest in the work to be addressed in this manuscript and that there is no other potential conflict of interest associated with this manuscript.

Received for publication September 7, 2004. Accepted for publication December 24, 2004.


   References
TOP
 Abstract
 Introduction
 Physiologic Mechanisms
 Psychological Mechanisms
 Cortical Representation of...
 Similarities Between Dyspnea and...
 Implications for Future Research
 Summary
 References
 

  1. . American Thoracic Society. (1999) Dyspnea: mechanisms, assessment, and management; a consensus statement. Am J Respir Crit Care Med 159,321-340[Free Full Text]
  2. Rao, AB, Gray, D Breathlessness in hospitalised adult patients. Postgrad Med J 2003;79,681-685[Abstract/Free Full Text]
  3. National Asthma Education and Prevention Program.. Expert panel report 2: guidelines for the diagnosis and management of asthma. 1997 National Institutes of Health. Bethesda, MD: Publication No. 97–4051
  4. National Institutes of Health.. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO workshop report. 2001 National Institutes of Health. Bethesda, MD: Publication No. 2701
  5. National Institutes of Health.. Global strategy for asthma management and prevention: NHLBI/WHO workshop report. 2002 National Institutes of Health. Bethesda, MD: Publication No. 02–3659
  6. Murray, CJL, Lopez, AD Evidence-based health policy-lessons from the global burden of disease study. Science 1996;274,740-743[Free Full Text]
  7. Dahme, B, Schandry, R, Leopold, C Symptomwahrnehmung beim Asthma bronchiale. Warschburger, P Petermann, F eds. Asthma bronchiale 2000,99-114 Hogrefe. Göttingen, Germany:
  8. Banzett, RB, Dempsey, JA, O’Donnell, DE, et al Symptom perception and respiratory sensation in asthma. Am J Respir Crit Care Med 2000;162,1178-1182[Free Full Text]
  9. Magadle, R, Berar-Yanay, N, Weiner, P The risk of hospitalization and near-fatal and fatal asthma in relation to the perception of dyspnea. Chest 2002;121,329-333[Abstract/Free Full Text]
  10. Rodrigo, GJ, Rodrigo, C, Hall, JB Acute asthma in adults: a review. Chest 2004;125,1081-1102[Abstract/Free Full Text]
  11. Barnes, PJ Blunted perception and death from asthma. N Engl J Med 1994;330,1383-1384[Free Full Text]
  12. Davenport, PW, Cruz, M, Stecenko, AA, et al Respiratory-related evoked potentials in children with life-threatening asthma. Am J Respir Crit Care Med 2000;161,1830-1835[Abstract/Free Full Text]
  13. Webster, KE, Colrain, IM P3-specific amplitude reductions to respiratory and auditory stimuli in subjects with asthma. Am J Respir Crit Care Med 2002;166,47-52[Abstract/Free Full Text]
  14. Rubinfeld, AR, Pain, MC Perception of asthma. Lancet 1976;1,882-884[ISI][Medline]
  15. Kikuchi, Y, Okabe, S, Tamura, G, et al Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma. N Engl J Med 1994;330,1329-1334[Abstract/Free Full Text]
  16. Gandevia, SC, Killian, K, McKenzie, DK, et al Respiratory sensations, cardiovascular control, kinaesthesia and transcranial stimulation during paralysis in humans. J Physiol 1993;470,85-107[Abstract/Free Full Text]
  17. Peiffer, C, Poline, JB, Thivard, L, et al Neural substrates for the perception of acutely induced dyspnea. Am J Respir Crit Care Med 2001;163,951-957[Abstract/Free Full Text]
  18. Manning, HL, Schwartzstein, RM Pathophysiology of dyspnea. N Engl J Med 1995;333,1547-1553[Free Full Text]
  19. Banzett, RB, Mulnier, HE, Murphy, K, et al Breathlessness in humans activates insular cortex. Neuroreport 2000;11,2117-2120[ISI][Medline]
  20. Guz, A Brain, breathing and breathlessness. Respir Physiol 1997;109,197-204[CrossRef][ISI][Medline]
  21. Simon, PM, Basner, RC, Weinberger, SE, et al Oral mucosal stimulation modulates intensity of breathlessness induced in normal subjects. Am Rev Respir Dis 1991;144,419-422[ISI][Medline]
  22. Taguchi, O, Kikuchi, Y, Hida, W, et al Effects of bronchoconstriction and external resistive loading on the sensation of dyspnea. J Appl Physiol 1991;71,2183-2190[Abstract/Free Full Text]
  23. Whitelaw, WA, McBride, B, Ford, GT Effect of lung volume on breath holding. J Appl Physiol 1987;62,1962-1969[Abstract/Free Full Text]
  24. Manning, HL, Basner, R, Ringler, J, et al Effect of chest wall vibration on breathlessness in normal subjects. J Appl Physiol 1991;71,175-181[Abstract/Free Full Text]
  25. Banzett, RB, Lansing, RW, Brown, R, et al Air hunger from increased PCO2 persists after complete neuromuscular block in humans. Respir Physiol 1990;81,1-17[CrossRef][ISI][Medline]
  26. Moosavi, SH, Golestanian, E, Binks, AP, et al Hypoxic and hypercapnic drives to breathe generate equivalent levels of air hunger in humans. J Appl Physiol 2003;94,141-154[Abstract/Free Full Text]
  27. Killian, KJ, Gandevia, SC, Summers, E, et al Effect of increased lung volume on perception of breathlessness, effort, and tension. J Appl Physiol 1984;57,686-691[Abstract/Free Full Text]
  28. Chen, Z, Eldridge, FL, Wagner, PG Respiratory-associated rhythmic firing of midbrain neurones in cats: relation to level of respiratory drive. J Physiol 1991;437,305-325[Abstract/Free Full Text]
  29. Chen, Z, Eldridge, FL, Wagner, PG Respiratory-associated thalamic activity is related to level of respiratory drive. Respir Physiol 1992;90,99-113[CrossRef][ISI][Medline]
  30. Schwartzstein, RM, Simon, PM, Weiss, JW, et al Breathlessness induced by dissociation between ventilation and chemical drive. Am Rev Respir Dis 1989;139,1231-1237[ISI][Medline]
  31. Simon, PM, Schwartzstein, RM, Weiss, JW, et al Distinguishable types of dyspnea in patients with shortness of breath. Am Rev Respir Dis 1990;142,1009-1014[ISI][Medline]
  32. Harver, A, Mahler, DA, Schwartzstein, RM, et al Descriptors of breathlessness in healthy individuals: distinct and separable constructs. Chest 2000;118,679-690[Abstract/Free Full Text]
  33. Davenport, PW, Reep, RL Cerebral cortex and respiration. Dempsey, JA Pack, AI eds. Regulation of breathing 1995,365-388 Dekker. New York, NY:
  34. Harver, A, Mahler, DA Perception of increased resistance to breathing. Kotses, H Harver, A eds. Self-management of asthma 1998,35-61 Dekker. New York, NY:
  35. Manning, HL, Schwartzstein, RM Respiratory sensations in asthma: physiological and clinical implications. J Asthma 2001;38,447-460[CrossRef][ISI][Medline]
  36. Banzett, RB, Lansing, RW Respiratory sensations arising from pulmonary and chemoreceptor afferents. Adams, L Guz, A eds. Lung biology in health and disease: respiratory sensation (vol 90) 1996,155-180 Dekker. New York, NY:
  37. Shea, SA, Banzett, RB, Lansing, RW Respiratory sensations and their role in the control of breathing. Dempsey, JA Pack, AI eds. Regulation of breathing 1995,923-957 Dekker. New York, NY:
  38. De Peuter, S, Van Diest, I, Lemaigre, V, et al Dyspnea: the role of psychological processes. Clin Psychol Rev 2004;24,557-581[CrossRef][ISI][Medline]
  39. Lehrer, P, Feldman, J, Giardino, N, et al Psychological aspects of asthma. J Consult Clin Psychol 2002;7,691-711[CrossRef]
  40. Rietveld, S, Prins, PJ The relationship between negative emotions and acute subjective and objective symptoms of childhood asthma. Psychol Med 1998;28,407-415[CrossRef][ISI][Medline]
  41. Isenberg, S, Lehrer, P, Hochron, S Defensiveness and perception of external inspiratory resistive loads in asthma. J Behav Med 1997;20,461-472[CrossRef][ISI][Medline]
  42. Feldman, JM, Lehrer, PM, Hochron, SM, et al Defensiveness and individual response stereotypy in asthma. Psychosom Med 2002;64,294-301[Abstract/Free Full Text]
  43. Fritz, GK, McQuaid, EL, Spirito, A, et al Symptom perception in pediatric asthma: relationship to functional morbidity and psychological factors. J Am Acad Child Adolesc Psychiatry 1996;35,1033-1041[CrossRef][ISI][Medline]
  44. Chetta, A, Gerra, G, Foresi, A, et al Personality profiles and breathlessness perception in outpatients with different gradings of asthma. Am J Respir Crit Care Med 1998;157,116-122
  45. Lavietes, MH, Matta, J, Tiersky, LA, et al The perception of dyspnea in patients with mild asthma. Chest 2001;120,409-415[Abstract/Free Full Text]
  46. Rietveld, S Symptom perception in chronic asthma: learning for better or worse? Brown, ES eds. Advances in psychosomatic medicine: asthma; social and psychological factors and psychosomatic syndromes (vol 24) 2003,115-130 Karger. Basel, Switzerland:
  47. Van den Bergh, O, Stegen, K, Van de Woestijne, KP Learning to have psychosomatic complaints: conditioning of respiratory behavior and somatic complaints in psychosomatic patients. Psychosom Med 1997;59,13-23[Abstract/Free Full Text]
  48. Bauldoff, GS, Hoffman, LA, Zullo, TG, et al Exercise maintenance following pulmonary rehabilitation: effect of distractive stimuli. Chest 2002;122,948-954[Abstract/Free Full Text]
  49. Evans, KC, Banzett, RB, Adams, L, et al BOLD fMRI identifies limbic, paralimbic, and cerebellar activation during air hunger. J Neurophysiol 2002;88,1500-1511[Abstract/Free Full Text]
  50. Davenport, PW, Thompson, FJ, Reep, RL, et al Projection of phrenic nerve afferents to the cat sensorimotor cortex. Brain Res 1985;328,150-153[CrossRef][ISI][Medline]
  51. Hallowitz, RA, MacLean, PD Effects of vagal volleys on units of intralaminar and juxtalaminar thalamic nuclei in monkeys. Brain Res 1977;130,271-286[CrossRef][ISI][Medline]
  52. O’Brien, JH, Pimpaneau, A, Albe-Fessard, D Evoked cortical responses to vagal, laryngeal and facial afferents in monkeys under chloralose anaesthesia. Electroencephalogr Clin Neurophysiol 1971;31,7-20[CrossRef][ISI][Medline]
  53. Davenport, PW, Friedman, WA, Thompson, FJ, et al Respiratory-related cortical potentials evoked by inspiratory occlusion in humans. J Appl Physiol 1986;60,1843-1848[Abstract/Free Full Text]
  54. Revelette, WR, Davenport, PW Effects of timing of inspiratory occlusion on cerebral evoked potentials in humans. J Appl Physiol 1990;68,282-288[Abstract/Free Full Text]
  55. Knafelc, M, Davenport, PW Relationship between resistive loads and P1 peak of respiratory-related evoked potential. J Appl Physiol 1997;83,918-926[Abstract/Free Full Text]
  56. Gandevia, SC, Macefield, G Projection of low-threshold afferents from human intercostal muscles to the cerebral cortex. Respir Physiol 1989;77,203-214[CrossRef][ISI][Medline]
  57. Gandevia, SC, Rothwell, JC Activation of the human diaphragm from the motor cortex. J Physiol 1987;384,109-118[Abstract/Free Full Text]
  58. Maskill, D, Murphy, K, Mier, A, et al Motor cortical representation of the diaphragm in man. J Physiol 1991;443,105-121[Abstract/Free Full Text]
  59. Demoule, A, Verin, E, Locher, C, et al Validation of surface recordings of the diaphragm response to transcranial magnetic stimulation in humans. J Appl Physiol 2003;94,453-461[Abstract/Free Full Text]
  60. Chertkow, H, Bub, D Functional activation and cognition: the 15O PET subtraction method. Kertesz, A eds. Localization and neuroimaging in neuropsychology 1994,152-184 Academic Press. San Diego, CA:
  61. Ogawa, S, Lee, TM, Kay, AR Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc Natl Acad Sci U S A 1990;87,9868-9872[Abstract/Free Full Text]
  62. Binder, JR, Rao, SM Human brain mapping with functional magnetic resonance imaging. Kertesz, A eds. Localization and neuroimaging in neuropsychology 1994,185-212 Academic Press. San Diego, CA:
  63. Colebatch, JG, Adams, L, Murphy, K, et al Regional cerebral blood flow during volitional breathing in man. J Physiol 1991;443,91-103[Abstract/Free Full Text]
  64. Ramsay, SC, Adams, L, Murphy, K, et al Regional cerebral blood flow during volitional expiration in man: a comparison with volitional inspiration. J Physiol 1993;461,85-101[Abstract/Free Full Text]
  65. Gozal, D, Omidvar, O, Kirlew, KA, et al Identification of human brain regions underlying responses to resistive inspiratory loading with functional magnetic resonance imaging. Proc Natl Acad Sci U S A 1995;92,6607-6611[Abstract/Free Full Text]
  66. Fink, GR, Corfield, DR, Murphy, K, et al Human cerebral activity with increasing inspiratory force: a study using positron emission tomography. J Appl Physiol 1996;81,1295-1305[Abstract/Free Full Text]
  67. McKay, LC, Evans, KC, Frackowiak, RS, et al Neural correlates of voluntary breathing in humans. J Appl Physiol 2003;95,1170-1178[Abstract/Free Full Text]
  68. Isaev, G, Murphy, K, Guz, A, et al Areas of the brain concerned with ventilatory load compensation in awake man. J Physiol 2002;539,935-945[Abstract/Free Full Text]
  69. Evans, KC, Shea, SA, Saykin, AJ Functional MRI localisation of central nervous system regions associated with volitional inspiration in humans. J Physiol 1999;520,383-392[Abstract/Free Full Text]
  70. Thornton, JM, Guz, A, Murphy, K, et al Identification of higher brain centres that may encode the cardiorespiratory response to exercise in humans. J Physiol 2001;533,823-836[Abstract/Free Full Text]
  71. Gozal, D, Hathout, GM, Kirlew, KA, et al Localization of putative neural respiratory regions in the human by functional magnetic resonance imaging. J Appl Physiol 1994;76,2076-2083[Abstract/Free Full Text]
  72. Corfield, DR, Fink, GR, Ramsay, SC, et al Evidence for limbic system activation during CO2-stimulated breathing in man. J Physiol 1995;488,77-84[ISI][Medline]
  73. Liotti, M, Brannan, S, Egan, G, et al Brain responses associated with consciousness of breathlessness (air hunger). Proc Natl Acad Sci U S A 2001;98,2035-2040[Abstract/Free Full Text]
  74. Brannan, S, Liotti, M, Egan, G, et al Neuroimaging of cerebral activations and deactivations associated with hypercapnia and hunger for air. Proc Natl Acad Sci USA 2001;98,2029-2034[Abstract/Free Full Text]
  75. Parsons, LM, Egan, G, Liotti, M, et al Neuroimaging evidence implicating cerebellum in the experience of hypercapnia and hunger for air. Proc Natl Acad Sci U S A 2001;98,2041-2046[Abstract/Free Full Text]
  76. Augustine, JR Circuitry and functional aspects of the insular lobe in primates including humans. Brain Res Brain Res Rev 1996;22,229-244[CrossRef][Medline]
  77. Hanamori, T, Kunitake, T, Kato, K, et al Convergence of oropharyngolaryngeal, baroreceptor and chemoreceptor afferents onto insular cortex neurons in rats. Chem Senses 1997;22,399-406[Abstract/Free Full Text]
  78. Hanamori, T, Kunitake, T, Kato, K, et al Responses of neurons in the insular cortex to gustatory, visceral, and nociceptive stimuli in rats. J Neurophysiol 1998;79,2535-2545[Abstract/Free Full Text]
  79. Gaytan, SP, Pasaro, R Connections of the rostral ventral respiratory neuronal cell group: an anterograde and retrograde tracing study in the rat. Brain Res Bull 1998;47,625-642[CrossRef][ISI][Medline]
  80. Henderson, LA, Woo, MA, Macey, PM, et al Neural responses during Valsalva maneuvers in obstructive sleep apnea syndrome. J Appl Physiol 2003;94,1063-1074[Abstract/Free Full Text]
  81. Dawson, SL, Panerai, RB, Potter, JF Critical closing pressure explains cerebral hemodynamics during the Valsalva maneuver. J Appl Physiol 1999;86,675-680[Abstract/Free Full Text]
  82. Price, DD Psychological and neural mechanisms of the affective dimension of pain. Science 2000;288,1769-1772[Abstract/Free Full Text]
  83. Birbaumer, N, Schmidt, RF Biologische psychologie. 2003,328-372 Springer. Berlin, Germany:
  84. Damasio, AR, Grabowski, TJ, Bechara, A, et al Subcortical and cortical brain activity during the feeling of self-generated emotions. Nat Neurosci 2000;3,1049-1056[CrossRef][ISI][Medline]
  85. Peyron, R, Laurent, B, Garcia-Larrea, L Functional imaging of brain responses to pain. a review and meta-analysis. Neurophysiol Clin 2000;30,263-288[ISI][Medline]
  86. Treede, RD, Kenshalo, DR, Gracely, RH, et al The cortical representation of pain. Pain 1999;79,105-111[CrossRef][ISI][Medline]
  87. Casey, KL Forebrain mechanisms of nociception and pain: analysis through imaging. Proc Natl Acad Sci U S A 1999;96,7668-7674[Abstract/Free Full Text]
  88. Bushnell, MC Psychophysical and brain imaging approaches to the study of clinical pain syndromes. Can J Anaesth 2002;49,R1-R5[Free Full Text]
  89. Tataranni, PA, Gautier, JF, Chen, K, et al Neuroanatomical correlates of hunger and satiation in humans using positron emission tomography. Proc Natl Acad Sci U S A 1999;96,4569-4574[Abstract/Free Full Text]
  90. Denton, D, Shade, R, Zamarippa, F, et al Neuroimaging of genesis and satiation of thirst and an interoceptor-driven theory of origins of primary consciousness. Proc Natl Acad Sci U S A 1999;96,5304-5309[Abstract/Free Full Text]
  91. Kinomur, S, Kawashima, R, Yamada, K, et al Functional anatomy of taste perception in the human brain studied with positron emission tomography. Brain Res 1994;659,263-266[CrossRef][ISI][Medline]
  92. Reiman, EM, Lane, RD, Ahern, GL Neuroanatomical correlates of externally and internally generated human emotion. Am J Psychiatry 1997;154,918-925[Abstract]
  93. Banzett, RB, Moosavi, SH Dyspnea and pain: similarities and contrasts between two very unpleasant sensations. APS Bull 2001;11,1-8
  94. Gehlbach, BK, Geppert, E The pulmonary manifestations of left heart failure. Chest 2004;125,669-682[Abstract/Free Full Text]
  95. Nishino, T, Shimoyama, N, Ide, T, et al Experimental pain augments experimental dyspnea, but not vice versa in human volunteers. Anesthesiology 1999;91,1633-1638[CrossRef][ISI][Medline]
  96. Melzack, R, Wall, PD Pain mechanisms: a new theory. Science 1965;150,971-979[Free Full Text]
  97. Geissner, E Psychologische modelle des schmerzes und der schmerzverarbeitung. Geissner, E Jungnitsch, G eds. Psychologie des schmerzes. diagnose und therapie 1992,25-46 Psychologie Verlags Union. Weinheim, Germany:
  98. Geissner, E Die schmerzempfindungs-skala. 1996 Hogrefe. Göttingen, Germany:
  99. Melzack, R The McGill Pain Questionnaire: major properties and scoring methods. Pain 1975;1,277-299[CrossRef][ISI][Medline]
  100. Wilson, RC, Jones, PW Differentiation between the intensity of breathlessness and the distress it evokes in normal subjects during exercise. Clin Sci (Lond) 1991;80,65-70[Medline]
  101. Lehrer, PM, Hochron, SM, Isenberg, S, et al The asthma symptom profile: a psychophysically based scale for assessment of asthma symptoms. J Psychosom Res 1993;37,515-521[CrossRef][ISI][Medline]
  102. Ruoß, M Efficacy and factors of efficacy in psychological pain therapy: a review. Verhaltenstherapie 1998;8,14-25
  103. Rainville, P, Duncan, GH, Price, DD, et al Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science 1997;277,968-971[Abstract/Free Full Text]
  104. Villemure, C, Bushnell, MC Cognitive modulation of pain: how do attention and emotion influence pain processing? Pain 2002;95,195-199[CrossRef][ISI][Medline]
  105. Valet, M, Sprenger, T, Boecker, H, et al Distraction modulates connectivity of the cingulo-frontal cortex and the midbrain during pain-an fMRI analysis. Pain 2004;109,399-408[CrossRef][ISI][Medline]
  106. Williamson, JW, McColl, R, Mathews, D Evidence for central command activation of the human insular cortex during exercise. J Appl Physiol 2003;94,1726-1734[Abstract/Free Full Text]
  107. Williamson, JW, McColl, R, Mathews, D, et al Activation of the insular cortex is affected by the intensity of exercise. J Appl Physiol 1999;87,1213-1219[Abstract/Free Full Text]
  108. Bornhövd, K, Quante, M, Glauche, V, et al Painful stimuli evoke different stimulus-response functions in the amygdala, prefrontal, insula and somatosensory cortex: a single-trial fMRI study. Brain 2002;125,1326-1336