Mapping supramedullary pathways involved in cough using functional brain imaging: Comparison with pain

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Abstract

Several indications suggest that supramedullary brain regions receive sensory information from the airways and provide motor control to the brainstem neurons that control coughing. However, the organization of this circuitry has not been described in any detail. In this short review we will discuss how state-of-the-art functional brain imaging techniques in humans and animals will enable unprecedented insights into the supramedullary brain regions that help control coughing. In addition we will describe the likely similarities between cough-related higher brain networks and those involved in the processing of other aversive sensory modalities, such as pain.

Introduction

Cough can be evoked in decerebrated animals indicating that the most basic components of the cough reflex do not include any neural processing above the level of the brainstem [1], [2]. However, it is clear that higher brain regions are not without involvement in the cough reflex. Humans can voluntarily cough and reflex evoked coughing can be suppressed either consciously or via placebo inhibition. In the clinic, psychogenic cough (in which there is presumably no peripheral stimulus) accompanies some psychiatric conditions and this is best treated with behavioral, rather than pharmacological, therapy [3]. These observations point to the existence of higher brain motor pathways that provide descending inputs to the brainstem components of the basic cough reflex. Furthermore, supramedullary brain regions also likely receive input from airway sensory pathways. In support of this, humans report that airway irritation (especially from the larynx) is preceded by an awareness of the irritating stimulus resulting in a perceived urge-to-cough [4], [5]. Consequently, the ongoing feeling of an ‘itchy’ or ‘scratchy’ throat that often accompanies cough disorders not only causes significant discomfort in coughers, but may lead to voluntary (behavioral) coughing in an attempt to relieve the irritating sensation.

The existence of higher brain modulation of coughing has clear clinical significance. However, relatively little is known about the neuronal circuitry involved. Limited physiological studies in cats have shown that, cough-like efforts can be evoked following electrical stimulation of the suprasylvian gyrus or amygdala, and reflex cough (evoked by electrical stimulation of sensory nerves in the superior laryngeal nerves) can be inhibited by stimulating the cingulate gyrus or orbital gyrus [6], [7]. Nevertheless, there have been no reports of cough in humans following brain stimulation, although such experiments are obviously difficult to rigorously conduct in human subjects.

Section snippets

Functional brain imaging

The obvious limitations that prevent invasive physiological experimentation in humans have necessitated the development of non-invasive approaches to understanding human brain function. With the rapid advances in the field of brain imaging, it has been possible to gain insights into the functional neural circuitry involved in any number of biological processes. Several functional imaging approaches are available for studying human brain activity, the use of which depends on the question at

Functional brain imaging and voluntary cough in humans

Coughing, by its nature, consists of head movements that can be problematic for fMRI purposes. Movement of the head during echo planar imaging produces artifacts that can mask or mimic BOLD signal changes associated with neuronal activity, especially when the task of interest is strongly correlated with motion. However, carefully designed imaging studies can overcome these motion problems and provide insights into brain regions involved in cough. For example, the impact of movement artifacts

Functional brain imaging and the urge-to-cough in humans

Activation of subsets of sensory receptors in the airways evokes reflex coughing that can be preceded by an awareness of the irritating stimulus and a perceived urge-to-cough. This urge-to-cough occurs frequently in individuals with coughing disorders and can be evoked in healthy individuals by inhaling capsaicin and other cough provoking chemicals [4], [5]. Interestingly, capsaicin-evoked urge-to-cough always precedes the cough motor event, and the sensitivity of airway peripheral receptors

Comparison between brain activations associated with cough and pain

Whilst our data have identified brain activations following capsaicin inhalation, at present we can only speculate as to the role of these brain regions in sensing and responding to airway irritations. This speculation is facilitated by looking at the role ascribed to particular brain regions from imaging and physiological studies of other sensory driven processes. The well documented [reviewed in [13]] similarities between the sensory components of cough and pain makes for an ideal comparison,

Limitations of functional brain imaging in humans

As with many brain imaging studies, it is difficult to precisely identify the key brain regions involved in either voluntary cough or the urge-to-cough from the limited experiments described above. The studies do, however, highlight the importance of experimental design when conducting functional brain imaging studies. Controlling fMRI studies is often very difficult and data sets will usually contain unwanted brain activations associated with events that are not related to the question at

Functional brain imaging in laboratory animals

Functional brain imaging is an ideal tool for identifying brain regions involved in the higher level control of coughing in humans. Only humans can provide quantitative and qualitative measures of an urge-to-cough, readily and repeatedly evoke or suppress cough voluntarily or be easily manipulated with suggestive placebo suppression. However, human studies do not afford the ability to ask specific questions about the physiological significance of a given brain region that is activated in the

Conclusions

It is now somewhat outdated to consider cough as a simple reflex response to airway irritation, thereby if the reflex can be blocked then the problem is solved. We now know that coughing involves a series of more complex events. There are likely multiple primary and secondary sensory pathways involved, unique brainstem processing mechanisms and higher brain contributions that all help shape the response. In the clinical setting, a persistent urge-to-cough is the underlying symptom of many cough

Acknowledgments

SBM is supported by grants from the National Health and Medical Research Council of Australia (454776, 350333) and the Angior Family Foundation. MJF is supported by a University of Melbourne Sir Randal Heymanson Research Fellowship.

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