Cortico-limbic circuitry and the airways: Insights from functional neuroimaging of respiratory afferents and efferents

Abstract

After nearly two decades of active research, functional neuroimaging has demonstrated utility in the identification of cortical, limbic, and paralimbic (cortico-limbic) brain regions involved in respiratory control and respiratory perception. Before the recent boon of human neuroimaging studies, the location of the principal components of respiratory-related cortico-limbic circuitry had been unknown and their function had been poorly understood. Emerging neuroimaging evidence in both healthy and patient populations suggests that cognitive and emotional/affective processing within cortico-limbic circuitry modulates respiratory control and respiratory perception. This paper will review functional neuroimaging studies of respiration with a focus on whole brain investigations of sensorimotor pathways that have identified respiratory-related neural circuitry known to overlap emotional/affective cortico-limbic circuitry. To aid the interpretation of present and future findings, the complexities and challenges underlying neuroimaging methodologies will also be reviewed as applied to the study of respiration physiology.

Introduction

The act of breathing and the perception of breathing impairment are vital homeostatic functions essential to human life. It is widely accepted that brainstem respiratory centers mediate automatic respiratory rhythm (Feldman and Del Negro, 2006); however, the higher motor-cognitive and emotional centers thought to modulate the intrinsic respiratory rhythm as well as mediate the conscious perception of respiratory sensations remain poorly understood. Cortical, limbic and paralimbic sites for respiratory efferent/afferent processing were first identified by pioneering surgical/electrophysiological work in humans and animal models (as reviewed by Hugelin, 1986). With an acknowledgement of the ongoing debate over anatomical divisions of limbic versus paralimbic architectonics (LeDoux, 2000), the integrated brain regions typically involved in motor-cognitive and emotional processing will be collectively referred to as “cortico-limbic” circuitry in this review of respiratory neuroimaging.

The last 20 years have witnessed an amazing acceleration and expansion of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) technologies. These technological advances have facilitated the non-invasive, in vivo investigation of respiratory-related regional neural activity within cortico-limbic circuitry with spatial resolution on the order of a few millimeters and temporal resolution within fractions of a second. Advanced electroencephalographic event-related potential studies have also contributed to our understanding of cortico-limbic respiratory circuitry but are reviewed elsewhere (Davenport and Vovk, 2009). Prior to these advances in imaging technology, evidence for respiratory-related activity within cortico-limbic circuitry was largely derived from invasive electrophysiological studies of animals and surgical patients (Foerster, 1936, Kaada and Jasper, 1952, Penfield and Faulk, 1955, Frysinger and Harper, 1990).

The findings from recent PET and fMRI studies reviewed here provide intriguing support for longstanding hypotheses regarding cortico-limbic modulation of respiratory control and respiratory sensation. This circuitry shares remarkable homology with cortico-limbic elements known to mediate cognitive and emotional/affective processing (Dolan, 2000, Cabeza and Kingstone, 2001) as well as primal alarm/threat processing (LeDoux, 2000, Denton, 2005). Recent studies which employed hypothesis-driven experimental paradigms involving cognitive (Evans et al., 2009a) and affective (von Leupoldt et al., 2008) breathing tasks provide preliminary evidence of cortico-limbic modulation of respiratory control and respiratory sensation. In view of the wide-reaching implications regarding this shared circuitry, an integrated neural systems model for cortico-limbic influences on respiratory control and respiratory perception is considered as supported by the literature reviewed (Fig. 1).

Our understanding of cortico-limbic circuitry as related to respiratory control and perception should be viewed as a work in progress. Although the identification and function of many of the cortico-limbic elements discussed herein have been validated across imaging modalities and by various experimental designs, several of the recent findings reviewed require replication and should be considered with caution. Scholars within and outside of the field of neuroimaging, as well as the lay press, have voiced growing concern over the persuasive impact of neuroimaging data given its intrinsic vulnerability to Type I Error (Check, 2005, Dolan, 2008, McCabe and Castel, 2008, Poldrack, 2008, Hamilton, 2009). In keeping with this concern, this author is humbled to state that the discipline of respiratory neuroimaging is still in its infancy. The framework provided here is anticipated to serve as a primer on the current knowledge regarding the role of cortico-limbic circuitry in respiratory control and respiratory sensation and also serve as a guide for the interpretation of future findings given the complexities and challenges underlying neuroimaging studies of respiration.