Visualization of Neural Activity Associated with Dyspnea

Ronald M. Harper

Department of Neurobiology and Brain Research Institute, University of California at Los Angeles, Los Angeles, California

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Peiffer and coworkers, in this issue of the Journal (pp. 951-957 (1), provide a significant step forward in determining the neural mechanisms underlying control of a particular aspect of breathing, namely, negative sensations associated with respiratory loading. Impairment of the perception of loaded breathing is a significant issue in pulmonary disease, with a potential for fatal outcome if the ability to perceive is sufficiently disturbed. Other, different sources of dyspnea are also of concern to pulmonary investigators and may benefit from similar visualization measures; failure to express negative affect and appropriate breathing efforts in response to extreme hypercapnia, such as occurs in congenital central hypoventilation syndrome (CCHS), also carries the potential for significant ventilatory consequences. The study by Peiffer and coworkers uses positron emission tomography (PET) to visualize activation of neural sites associated with negative perceptions accompanying respiratory loading. Of importance in this description is the application of physiological measures to psychological aspects of breathing, the partitioning of affective perceptions from other sensory aspects of the loaded breathing challenge, a demonstration of brain lateralization in the neural processing of the perception, and an indication of participation of brain areas not usually considered as mediating breathing challenges.

Several objective procedures have been used to infer neural structures that mediate responses to loaded breathing. Evoked potentials elicited by both inspiratory and expiratory efforts can be recorded on the scalp over sensorimotor cortical regions, with aspects of the evoked potential waveform, for example, the amplitude of the first positive peak to inspiratory loads, being associated with the magnitude of the load (2). Even the relatively remote-from-neural-site scalp placement of evoked potential electrodes can reveal neural processing abnormalities; Davenport and colleagues demonstrated that a subpopulation of children with life-threatening asthma shows an absence of respiratory-related potentials to inspiratory occlusion (3), suggesting that neural processes involved in loaded breathing have been modified in this group. Visualization studies by PET and functional magnetic resonance imaging (fMRI) could be instrumental in revealing which brain regions, and which sequences of activity, might be unresponsive to particular aspects of the challenges.

An important aspect of the study by Peiffer and coworkers is the demonstration of the multiple brain sites involved in mediating components of a breathing challenge, and the illustration that different neural regions may regulate separate "drives" to breathing. The common emphasis on breathing regulation by chemoreception often overlooks aspects of regulation that require sustained inspiratory or expiratory effort, exaggerated efforts to overcome mechanical difficulties in breathing, or circumstances in which long-term tissue demands mismatch perception of need. Negative perceptions from breathing challenges can occur early in the challenge, as in the case of loaded breathing, or may be late developing, as in cases of hypercapnic challenge, and may be absent in subjects with CCHS. The study by Peiffer and coworkers demonstrates the capability of imaging procedures to differentiate neural structures that activate to separate perceptual aspects of a resistive breathing challenge.

A significant aspect of this PET study is the demonstration of laterality of brain sites responsive to the challenge, a finding different from those of evoked potential studies, which have typically reported bilateral representation of activity (4). Unilateral activation of neural sites to other respiratory or cardiovascular responses from loaded breathing tasks has also been reported (5). Responses to breathing tasks confined to one side of the brain should be considered an important aspect of neural processing for respiratory regulation, and place breathing control in the company of other functions, such as language, sensory reception, motion, and aspects of cardiovascular control, all of which appear to have some degree of unilateral representation. The lateralization of function has significant implications for breathing after stroke, which usually affects neural tissue unilaterally. Unilateral ischemic damage ipsilateral to sites that regulate responses to loaded breathing may pose unique control issues. Disordered breathing, particularly during sleep, characterized by extreme loading (e.g., obstructive sleep apnea), is a frequent consequence of stroke (6); a lack of plasticity in rerouting breathing functions to unaffected contralateral neural areas may be an issue in postischemic breathing control.

The demonstration of activation of the right anterior insular cortex in response to loaded breathing is of particular interest for those who study concomitant cardiovascular changes associated with the challenge. Loaded breathing transiently elevates blood pressure, with accompanying activation of relevant brain areas for cardiovascular control. The insular cortex has been implicated in sympathetic activation (7); the affective component of neural activation from the breathing challenge may share common neural mechanisms with emotional aspects of cardiovascular control.

Cerebellar structures are not normally considered major components in mediation of breathing control, despite older (8) and more recent evidence of such participation, especially in loaded breathing, CO₂ processing, and compensatory efforts to overcome long apnea (9). Peiffer and coworkers found that a cerebellar site, the vermis, activates to the dyspnea associated with resistive challenges. It is unclear whether the vermal response derives from concomitant blood pressure changes accompanying the breathing task (5), or whether the sensory-motor "comparator" role of the cerebellum elicits the perceptual reaction. The findings demonstrate, however, that a cerebellar region frequently overlooked in breathing regulation appears to play a major role in this essential component of respiratory control, and that role may extend beyond simple motor patterning.

Respiratory control investigators now have significantly added to their armamentarium for examining quantifiable aspects of neural processing of breathing challenges, even if those aspects include affective or other psychological attributes. The addition of fast imaging procedures, such as fMRI, should further enhance description of the time course of neural activation recruited after such challenges.

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