Cortical and subcortical central neural pathways in respiratory sensations

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Abstract

Respiratory sensations motivate humans to behaviorally modulate their breathing and are the sensory urge component of the respiratory motivation-to-action neural system. Human and animal studies have provided evidence for the neural substrate for afferents in the respiratory tract and muscles to project to the cerebral cortex. Respiratory afferents continually transduce breathing pattern into a sensory neural code. This neural code is transmitted to a subcortical gating area. Respiratory sensory information is then transmitted by respiratory modality specific convergent and divergent subcortical pathways to the cerebral cortex. There are two primary cortical pathways: (1) the discriminative pathway related to respiratory proprioception and (2) the affective pathway related to the qualitative assessment of breathing. Respiratory sensory information is processed by the discriminatory somatosensory-motor cortex and the affective mesocortex resulting in conscious awareness of breathing that can lead to distressing respiratory sensations. The significance of respiratory sensory information processing is the fundamental interoceptive perception of ventilatory status.

Introduction

Respiratory sensations motivate humans to behaviorally modulate their breathing and are the sensory urge component of the respiratory motivation-to-action neural system (Bradley, 2000, Davenport, 2008). Conscious awareness of disrupted breathing motivates patients to seek medical care, severe sensations of respiratory dysfunction produce significant morbidity in patients. The different types of respiratory sensations are due to different patterns of stimulation of afferent mediating respiratory sensory modalities, e.g. mechanical loads, bronchoconstriction, hyperinflation and blood gas changes. When ventilation is obstructed, stimulated, challenged or attended to, cognitive awareness of breathing can occur. Respiratory sensations usually include the various forms of dyspnea (air hunger, chest tightness, effort of breathing); however, other respiratory sensations are common, such as an urge-to-cough, urge-to-sneeze, sense of suffocation and similar cognitive perceptions related to breathing. The effects of respiratory sensations range from a simple awareness of breathing to highly distressing fear and anxiety in both humans and animals. Respiratory sensations of sufficient magnitude can dominate cognitive awareness, hence there has to be a cortical and sub-cortical neural basis for perception of breathing. It follows that appropriate manipulation of these neural processes will provide insight into the mechanisms mediating the specific forms of respiratory sensations, including dyspnea. It has been proposed that respiratory sensations are the result of neural gating into the cerebral cortex of respiratory afferent input eliciting a somatosensory cognitive awareness of breathing and an affective response. Respiratory sensations are the result of sensory activation of subcortical and cortical neural pathways. Some of these pathways are shared across respiratory modalities (convergent) while activation of some neural areas are modality specific (divergent). Convergent neural mechanisms provide generalized respiratory sensation while divergent pathways provide sensation of modality specificity. Subsequent neural processing recruits neural centers in motor pathways to initiate the respiratory compensatory behavior component of the motivation-to-action neural network.

Subcortical and cortical neural pathways mediate respiratory afferent activation of central neural structures. Respiratory sensations are, thus, the result of two subcortical and cortical processes: (1) discriminative processing—awareness of the spatial, temporal and intensity components of the respiratory input (i.e. what is sensed), and (2) affective processing—evaluative and emotional components of the respiratory input (i.e. how it feels). Discriminative processing involves neural pathways resulting in somatosensory cortical activation. Affective processing includes the amygdala and associated structures such as the anterior cingulate and insular cortex. Modality specific activation of cortical neural processing depends on a change in neural activity that gates-in modality specific information to the higher brain centers (Boutros et al., 1991, Boutros et al., 1995, Boutros and Belger, 1999, Arnfred et al., 2001, Grunwald et al., 2003, Kisley et al., 2004). This activation leads to cognitive awareness of the modality. The significance of gating-in and gating-out sensory modalities is the need to attend or ignore essential physiological functions. Changing the status of the respiratory system alters the associated sensory inputs, respiratory information can then be gated-in, eliciting a cognitive awareness of breathing which can be distressing, i.e. dyspnea. The transition between breathing that does not reach consciousness to cognitive awareness of breathing suggests neural information processing similar to non-respiratory sensory modalities. Sensory gating has been demonstrated with inspiratory loads (Davenport et al., 2007, Chan and Davenport, in press) and auditory, visual and somatosensory systems (Boutros et al., 1991, Boutros et al., 1995, Boutros and Belger, 1999, Arnfred et al., 2001, Grunwald et al., 2003, Kisley et al., 2004). The neural gating element is likely the thalamus since it has been implicated in gating sensory information from auditory, visual and somatosensory modalities. The significance of respiratory sensory information processing is the fundamental interoceptive perception of ventilatory status. Self-monitoring of ventilatory state is critical to respiratory disease management and morbidity. In order to investigate respiratory sensations, several things must be considered: the modality mediating the sensation, threshold, magnitude of stimulation, neural processing mechanisms, and motor outcomes/compensations. In the following sections, the human neural areas activated by different respiratory sensation eliciting modalities are summarized. The following section presents human sensory electrophysiological studies that determined the temporal relationship between respiratory mechanical stimuli and brain neural activity. Electrophysiological and anatomical animal studies of brain areas mediating cortical and subcortical respiratory sensory neural pathways are then summarized. These human and animal results are used to develop a model of respiratory sensory gating and an integrated respiratory neural network mediating respiratory cortical and subcortical pathways.

Section snippets

Cerebral cortical processing of respiratory information—human brain imaging

Brain imaging tools, such as functional MRI and PET, have provided valuable insights into the cortical and sub-cortical neural mechanisms that may be involved in processing respiratory sensory information in humans. A drawback of brain imaging tools is that they cannot distinguish between the structures that are involved in discriminative and affective processing, and motor behavioral responses. Thus, the brain activation maps generated represents the entire neural network activated by a

Cerebral cortical processing of respiratory information—human RREP

The respiratory related evoked potential (RREP) is a method used to determine the temporal relationship between respiratory mechanical stimuli and brain neural activity. The RREP is elicited by inspiratory occlusion and inspiratory resistive loads (Davenport et al., 1986, Davenport et al., 1996, Revelette and Davenport, 1990, Bloch-Salisbury and Harver, 1994, Harver et al., 1995, Knafelc and Davenport, 1997, Bloch-Salisbury et al., 1998, Logie et al., 1998, Knafelc and Davenport, 1999, Webster

Cerebral cortical processing of respiratory information—animal electrophysiological studies

What can animal studies tell us about respiratory cognitive sensations and dyspnea? By definition, dyspnea is a cognitive sensory process which requires activation of sensory neural systems to elicit the sensation. Animals and humans have the same respiratory related afferents. In addition, animals have behavioral responses consistent with conscious awareness of respiratory stimuli that are aversive, i.e. hypercapnia and respiratory loads. Dogs have been behaviorally conditioned to signal

Cerebral cortical processing of respiratory information—animal c-Fos anatomical studies

These central neural pathways were further studied in animals using expression of c-Fos protein. The expression of c-FOS in the nucleus of neurons activated by stimulation of afferents has become a useful tool for identifying nuclei that may be part of a central neural pathway. Activation of neurons has been shown to induce an immediate early gene c-FOS which is expressed rapidly and transiently (Solano-Flores et al., 1997). The gene transcription produces mRNA which encode for the protein FOS.

Cortical gating role of the thalamus

Nuclei in the thalamus were activated by all the respiratory modalities and afferent populations (Table 1, Fig. 2). In addition, phasic respiratory motor drive correlated with neural activity has been recorded in the thalamus (Chen et al., 1992) yet similar activity is not recorded in discriminative and affective cortical areas. Neural activity in the thalamus and cortex can be recruited by stimulation of respiratory related afferents. However, cortical activation is suppressed during normal

Conclusion

Respiratory cortical and subcortical sensory neural processing is unique among sensory modalities. Respiratory motor output is a continuous process that occurs over the entire lifetime of humans and animals. This phasic motor drive is continuously monitored by various respiratory related afferents systems that continually provide an input to the central nervous system. One of the unique features of the respiratory system is that while we can perceive our breathing, this continual respiratory

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