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Sensations and regional brain responses evoked by tussive stimulation of the airways
Respiratory Physiology & Neurobiology 204 (2014) 58–63
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Sensations and regional brain responses evoked by tussive stimulation of the airways夽 M.J. Farrell a,∗ , S.B. Mazzone b a b
The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3010, Australia School of Biomedical Sciences, University of Queensland, St Lucia 4072 Australia
a r t i c l e
i n f o
Article history: Accepted 13 June 2014 Available online 19 June 2014 Keywords: Urge-to-cough Brain Interoceptive
a b s t r a c t Stimuli that evoke cough in humans also elicit a sensation described as the urge-to-cough. This sensation is perceived at levels of stimulation below the threshold for coughing and increases in intensity in response to higher levels of stimulation. Cough in humans can be consciously modified in intensity or suppressed altogether, and the urge-to-cough is likely to contribute to discretionary responses to tussive stimulation. Converging evidence from animal and human experiments have identified a widely distributed network of brain regions that are implicated in the representation of urge-to-cough and the control of coughing. This network incorporates regions that show responses associated with urge-to-cough ratings, such as limbic and somatosensory cortices, as well as paralimbic and premotor regions implicated in response inhibition that activate in association with efforts to suppress cough. The urge-to-cough can be influenced by psychological factors and preliminary findings suggest that these effects could be mediated by topdown influences. There is considerable impetus to understand circuits involved in the modulation of urge-to-cough because it may be possible to antagonise the troubling sensation while preserving the critical cough reflex. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Cough is a motor response that expels particulate matter from the airways, thus contributing to the preservation of airway patency and hence the maintenance of respiratory function. Although cough can be enlisted voluntarily, the typical mode of induction of defensive coughing is reflexively following stimulation of the airways through a pathway involving vagal afferents and processing at the level of the brainstem. This short loop pathway ensures a rapid response to airway irritation that reduces the risk of aspirated substances reaching the airways and lungs as well as aiding with efficient clearance of intrinsically generated material such as secretions. In addition to the motor behaviour, stimuli likely to evoke cough also give rise to a sensory experience, commonly referred to as the urge-to-cough (Davenport et al., 2002). Interest in the character and mechanisms of urge-to-cough is growing as clinicians and researchers recognise that the sensation can be a troublesome symptom of airways disease in its own right, that clinical cough could in part be a discretionary behaviour motivated
夽 This paper is part of a special issue entitled “Non-homeostatic control of respiration”, guest-edited Dr. Eugene Nalivaiko and Dr. Paul Davenport. ∗ Corresponding author. Tel.: +61 421785215. E-mail address: michael.farrell@florey.edu.au (M.J. Farrell). http://dx.doi.org/10.1016/j.resp.2014.06.009 1569-9048/© 2014 Elsevier B.V. All rights reserved.
by a drive to satiate the urge-to-cough, and that antagonism of the urge-to-cough could be a viable treatment strategy that would leave the critical cough reflex intact (Chung, 2011; Mazzone et al., 2011b; Morice, 2013; Morice et al., 2012). This review will discuss recent advances in the understanding of urge-to-cough that have been facilitated by heightened interest in the sensation.
1.1. Sensory attributes of the urge-to-cough The urge-to-cough is a latent process. Psychophysical investigations of the sensation have been confined to experiments involving humans, in whom language provides a means to convey personal experience. Studies of endogenously derived urge-tocough (for example, in airways disease) are limited and have only reported measures of severity rather than investigating mechanistic processes. For this reason we will limit our discussion to experimentally induced urge-to-cough, which typically involves the inhalation of nebulised solutions containing varied doses of tussive substances such as capsaicin (Davenport et al., 2002) and citric acid (Yamanda et al., 2008), or the use of other stimuli such as inhalation of distilled water (fog) (Lavorini et al., 2007) or application of puffs of air (Hegland et al., 2011). The quality of the sensation evoked by tussive stimuli is not well characterised but has been described as itching, scratching or burning, and is usually localised
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to the pharynx and/or larynx. Additionally, the sensation is associated with a desire to cough. There has been speculation that the urge-to-cough is also likely to be invested with a negative emotional valence, or unpleasantness, but evaluations of this attribute have not been reported to date (Farrell et al., 2012). Unlike in disease where the endogenous urge-to-cough can be persistent and difficult to satiate, the duration of experimentally-induced urgeto-cough is relatively short-lived. A single inhalation of a tussive substance will usually give rise to an urge-to-cough during the inhalation and subsequent exhalation, and no longer be noticeable upon the initiation of the next inhalation of fresh air (Farrell et al., 2012). The temporal pattern of urge-to-cough during inhalation of a tussive substance is distinct from other sensations that can feasibly arise in association with stimulation. Whereas urge-to-cough is closely related to the respiratory cycle, other sensations associated with capsaicin inhalation, such as heat in the mouth, taste, watering of the eyes, etc. usually only occur after repeated doses and persist for minutes with no appreciable variability relative to the respiratory cycle (Mazzone et al., 2007). The intensity of urge-to-cough varies according to the intensity of stimulation. Stimulus–response functions for urge-to-cough are typically derived using doubling doses of tussive substances. The lowest dose required to elicit a detectable urge-to-cough has been dubbed the urge-to-cough threshold, or Cu (Dicpinigaitis et al., 2011). The relatively recent appearance in the literature of Cu measures reflects the growing interest in the sensation, and complements the traditional motor-related thresholds such as the C2 and C5, which are the lowest doses of a tussive stimulus that elicit two or five coughs (Choudry and Fuller, 1992). Single breaths of doubling doses of tussive stimuli in excess of the Cu generally evoke monotonic increases in the urge-to-cough in healthy people (Davenport et al., 2002). The stimulus–response function has a decelerating profile when plotted against real stimulus values, and research groups tend to present psychophysical outcomes using logarithmic dose values that display a linear relationship with urge-to-cough ratings. Personal attributes and behaviours systematically influence the slope, but not the intersect of the urge-to-cough stimulus–response function. For instance, the slope of the response function is steeper in women than men, but the Cu does not differ between the sexes (Dicpinigaitis et al., 2012; Gui et al., 2010). The Cu is also comparable among smokers and non-smokers, although smoking is associated with a decrease in the slope of the urge-tocough stimulus–response function (Kanezaki et al., 2012, 2010), which trends towards normal levels when smoking is ceased (Dicpinigaitis et al., 2006). Advancing age is associated with a decrease in the intensity of urge-to-cough at motor thresholds (i.e. C2, C5), which do not show age-related changes, whereas interpolated values of the Cu are stable across groups of disparate age (Ebihara et al., 2011). The general conclusion from these assessments of urge-to-cough is that the level of stimulation requisite for the detection of any urge-to-cough is relatively stable, but that both increased and decreased sensitivity to supra-threshold stimuli can be observed in healthy cohorts depending on age, sex and exposure to cigarette smoke. The urge-to-cough is subject to considerable within-subject variance during repeated presentations of stimuli. Adaptation to tussive stimulation has been observed in experiments involving multiple inhalations of fixed intensity doses (Choudry et al., 1989; Farrell et al., 2012; Mazzone et al., 2007). Indeed, in some individuals a dose initially eliciting a moderate level of urge-to-cough can fail to evoke any appreciable sensation after repeated inhalations during tens of minutes (Mazzone et al., 2007). Psychological factors have demonstrable effects on the urge-to-cough within the same person. An increase in ratings of urge-to-cough occurs when anxiety increases (Davenport et al., 2009) and when attention
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shifts from an exteroceptive to an interoceptive focus (Janssens et al., 2014), whereas administration of a placebo erroneously ascribed with antitussive benefits can dramatically decrease ratings of urge-to-cough under experimental conditions (Leech et al., 2012). Non-systematic variance is also a feature of urge-to-cough responses among participants inhaling capsaicin. Very large coefficients of variation (56–75%) have been reported for intermittent breaths of capsaicin at fixed doses (Farrell et al., 2012), as well as for repeated estimates of urge-to-cough during continuous inhalation of a single dose for several minutes (Farrell et al., 2014). Visceroafferent sensations are generally less reliably described during magnitude estimation procedures compared to sensations arising from cutaneous stimuli, and this inconsistency could be related to differences in the central representation of the viscera in sensory processing regions of the brain (Strigo et al., 2002). However, despite considerable variability within participants, averaging over repeated trials consistently identifies intensity-dependence of urge-to-cough responses to tussive stimuli. 1.2. Urge-to-cough and the likelihood of coughing Perception of an urge-to-cough occurs at levels of stimulation that are typically less than the threshold for coughing (Davenport et al., 2002) (Fig. 1A). It is difficult to provide estimates of the difference between the Cu and cough-motor thresholds by amalgamating outcomes across studies because lack of consistent methods has a bearing on results (Ternesten-Hasseus et al., 2006), but a report from one study of differential scores calculated on a case-by-case basis estimated that the urge-to-cough is elicited at approximately two doses increments lower than the threshold for one or more coughs (Dicpinigaitis et al., 2012). The presence of an urge-to-cough at stimulus levels that do not evoke a cough has important implications for the role of cognitive processes in the control of coughing. Sensitivity to low levels of airways irritation captures attention and provide opportunities to engage in discretionary behaviour (Davenport, 2008). Many aspects of coughing are under conscious control in humans, and an awareness of airways irritation has the potential to interact with motor planning. For instance, coughing can be suppressed or modelled (i.e. actively increased or decreased in intensity or duration) in response to stimuli that evoke an urge-to-cough (Hegland et al., 2012; Hutchings et al., 1993). Indeed, coughing can be initiated voluntarily in the absence of any interoceptive trigger. Voluntary control of coughing impacts on the relationship between intensity of urge-to-cough and the likelihood of coughing. The most readily apparent influence of voluntary control on the association between urge-to-cough and coughing is conscious suppression. In the absence of any motivation to suppress coughing, the delivery of a tussive dose that evokes two coughs (C2) is likely to be associated with a low to moderate level of urge-to-cough (Farrell et al., 2012). However, the simple instruction to participants to suppress coughing can profoundly increase the dose required to evoke an uncontrolled response, despite the reported experience of increasing levels of urge-to-cough (Hutchings et al., 1993). Consequently, this “dynamic motor threshold” (Hegland et al., 2011) means that reported levels of urge-to-cough have limited utility as a predictor of the likelihood of coughing. It may be that participants’ judgements of urge-to-cough under conditions of conscious suppression are representative of the level of effort required to avert coughing, although this proposition is yet to be tested. 1.3. Neural structures implicated in the urge-to-cough 1.3.1. Peripheral receptors and fibres The cell bodies of afferents implicated in cough are located in the nodose and jugular ganglia of the vagal nerves (Canning et al., 2004).
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Fig. 1. (A) Ratings of the urge-to-cough increase linearly in response to the log of doubling doses of tussive stimulation. Low doses elicit an urge-to-cough without evoking cough. Higher doses are associated with both urge-to-cough and coughing, although the incidence of cough can be consciously suppressed (Cough Discretion Zone). At the highest doses the urge-to-cough is at a maximum and coughing occurs despite efforts to suppress. Regional brain responses during tussive stimulation are associated with different aspects of the urge-to-cough stimulus–response function. Responses in brain regions have been associated with the intensity of stimuli or urge-to-cough ratings (Intensity Effects), as well as efforts to suppress cough (Cough Discretion Zone). (B) Contrasts of regional brain responses at two different doses of capsaicin have shown regions with stimulus-related BOLD signal changes (STIMULUS). These regions include bilateral insula cortex, motor cortices, premotor cortices and the midcingulate cortex (MCC). (C) Urge-to-cough ratings show variance that is not explained by stimulus level. Some brain regions activated during inhalation of capsaicin show variance that is closely associated with ratings of urge-to-cough (URGE-to-COUGH). These regions include the primary somatosensory cortex (SI), the posterior insula (Post. Insula), the posterior patietal cortex (PPC), and the midcingulate cortex. The urge-to-cough is modified by psychological factors, such as placebo. It is likely that the dorsolateral prefrontal cortex (DLPFC) plays a role in the modulation of urge-to-cough. (D) The conscious effort to suppress cough decreases the likelihood of coughing to a wide range of tussive stimuli and associated levels of urge-to-cough (Cough Discretion Zone). Efforts to suppress cough are associated with regional brain responses to capsaicin challenge (SUPPRESSION). These regions include right inferior frontal gyrus (R IFG), the right anterior insula (R Ant. Insula), the ventromedial prefrontal cortex (VMPFC), and the midcingulate cortex.
Receptor subtypes in the airways with putative roles in the urge-tocough have been characterised according to their associations with cough evoked by administered airway irritants. Such studies have been performed extensively in animals and other reviews describe the attributes of airway afferents implicated in reflex coughing (Canning, 2011; Mazzone and Canning, 2013). Our discussion will be confined to features that could have a bearing on the experience of an urge-to-cough. The majority of human studies of urge-to-cough involve inhaled chemical stimuli. Chemosensors responding to salient substances (capsaicin, bradykinin, citric acid) have been identified in the epithelium of the airways (Canning et al., 2006), and these C-fibre terminals are likely to be involved in the urge-to-cough. However, chemical stimuli capable of activating the receptors do not evoke cough in unconscious animals (Canning et al., 2004; Tatar et al., 1988), which is the modus operandi for implicating afferent units in the reflex motor response. The absence of reflex responses to chemical stimulation of the airways during anaesthesia has led to speculation that inputs from the C-fibres may be principally contributing to sensations dependent on higher order processing, such as the urge-to-cough, rather than the mediation of motor reflexes (Narula et al., 2014). Coughing is elicited in unconscious animals and humans upon the application of punctate (touch-like) stimuli to the epithelium of the upper airways (e.g., probing with a von Frey filament in animals or intubation in humans) (Mazzone, 2005). Stretch-like stimuli (inflation and deflation) are reportedly ineffective at inducing cough (Chou et al., 2008), which suggests that neither rapidly nor slowly adapting A fibres (stretch receptors) mediate mechanically evoked cough. Rather, a population of A␦ fibres with rapidly adapting receptors, dubbed “cough receptors”, have functional properties that are wholly compatible with a primary role in reflex cough (Canning et al., 2004). Evidence supporting a role for mechanically sensitive afferents in the experience of urge-to-cough is limited.
Chest percussion has been shown to induce an urge-to-cough that is exaggerated in patients with an upper respiratory tract infection, although frequency of responders was reported rather than any measures of subjective intensity, and only a minority of participants in either group reported an urge-to-cough (Lee and Eccles, 2004). A solitary study has reported ratings of urge-to-cough to brief puffs of air applied to the oropharynx (Hegland et al., 2011). Interestingly, both cough frequency and urge-to-cough ratings failed to show intensity-dependence at two levels of air pressure, but instances of stimuli evoking coughing were associated with a stronger urgeto-cough than stimuli that did not elicit a cough. Also of note is the absence of a correlation between cough thresholds derived with capsaicin inhalation versus fog (distilled water, and a likely stimulus for mechanosensitive cough receptors) (Lavorini et al., 2007), which suggests dissociable processing of C and Adelta fibre inputs, although the implications of this dissociation of motor responses for urge-to-cough is a matter for speculation. Further studies will be required to establish the consistency of these observations and to test for any additional distinctions between mechanically and chemically evoked urge-to-cough. 1.3.2. Brainstem regions Human functional brain imaging has provided preliminary indications of the brainstem regions involved in the processing of inputs related to urge-to-cough. Intensity-dependent activations associated with inhalation of graduated doses of capsaicin have been identified in the dorsolateral regions of the rostral pons and rostral medulla (Farrell et al., 2012). Intensity-independent responses have also been shown in the lateral caudal medulla (Farrell et al., 2012). The images used to identify brainstem responses to capsaicin inhalation were not optimal for the region, and consequently it is not feasible to implicate specific neuroanatomical structures as the loci of activations. Nevertheless, the outcomes indicate that capsaicin inhalation activations are
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distributed throughout the brainstem, which might suggest multiple, complimentary functional processes in response to airway irritation. Animal studies have provided neuroanatomical detail of regions implicated in sensory processing of airways afferents, with possible implications for pathways contributing to urge-to-cough. Anterograde transneuronal tracing has been undertaken in rats after inoculation of the extrathoracic trachea with herpes simplex virus to identify brainstem and supra-bulbar regions in receipt of afferent inputs from the upper airways (McGovern et al., 2012a,b). These experiments have implicated the nucleus of the solitary tract and the spinal trigeminal nucleus as the principal regions in the brainstem receiving afferent, monosynaptic inputs from the upper airways. At a delay consistent with a polysynaptic ascending sensory circuit, the parabrachial nuclei, Kölliker-Fuse nuclei, locus coeruleus, periaqueductal grey and neighbouring regions of the pons and midbrain are infected subsequent to inoculation of the trachea (McGovern et al., 2012a). There is converging evidence supporting a primary role for the nucleus of the solitary tract in the transmission of afferent inputs from the airways (Atoji et al., 2005; Haxhiu and Loewy, 1996; Kubin et al., 1991; Perez Fontan and Velloff, 2001), and it seems very likely that this region is part of the circuitry contributing to urge-to-cough. The spinal trigeminal nucleus has been implicated in visceroafference (Ma et al., 2007; Saxon and Hopkins, 2006), and is another candidate region for the transmission of afferent inputs with relevance for the representation of urge-tocough. Further research will be required to establish if the nucleus of the solitary tract and the spinal trigeminal nuclei have distinct, mutual or interacting functions with respect to the relay of afferent information from the airways. The implications of a polysynaptic pathway involving vagal inputs via the nucleus of the solitary tract and/or spinal trigeminal nucleus, and the parabrachial nuclei are not immediately apparent with respect to the representation of urge-to-cough. Spinobulbar nociceptive pathways incorporating the lateral parabrachial nuclei have been identified (Bernard et al., 1989; Bester et al., 2000; Jasmin et al., 1997; Pan et al., 1999), and a similar pathway (albeit vagal, not spinal) may contribute to transmission of nociceptive input from the airways. Indeed, the lateral parabrachial nuclei are in receipt of vagal afferent inputs from the airways (McGovern et al., 2012a,b). The possibility also exists, however, that parabrachial nuclei could be involved in respiratory motor responses to airways challenge (Dutschmann and Dick, 2012). 1.3.3. Cortical and subcortical regions Tussive stimulation of the airways is associated with activation in a widely distributed network in the hemispheres of the human brain. This network includes thalamic nuclei, and primary somatosensory, posterior parietal, premotor, prefrontal, limbic and paralimbic cortices (Farrell et al., 2012; Mazzone et al., 2009, 2007). The brain regions implicated in responses to tussive stimulation are likely to represent multiple functions that include representation of the urge-to-cough and related processes. Dose-dependent thalamic activation in association with tussive stimulation is observed in human studies (Farrell et al., 2012), although the nuclei involved in these responses cannot be accurately localised at the spatial resolution of the constituent images. Transneuronal tract tracing in rodents would suggest that the likely thalamic targets of afferent inputs from the airways are the ventral posterior lateral and mediodorsal nuclei (McGovern et al., 2012a), which are certainly consistent with the projection sites of these nuclei and the cortical structures implicated in urge-to-cough. The network of cortical regions implicated in the urge-to-cough in humans has been ascribed with a range of complementary functions that characterise sensory and motor responses to airways
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challenge. Many of the regions activated during inhalation of capsaicin show intensity-dependence at doses ranging from supra-Cu threshold to the C2 threshold, which would suggest that regions including the insula, anterior midcingulate cortex, rolandic and contiguous primary motor cortices and premotor cortices could contribute to graduated sensory experiences and motor responses that reflect the differential implications of variable levels of nociceptive input (Farrell et al., 2012) (Fig. 1B). Variance in ratings relative to stimuli, described in earlier sections (see final paragraph of “Sensory Attributes of the Urge-to-Cough”), makes it possible to identify brain regions with signal changes that are more closely correlated with the subjective experience of urge-to-cough than the intensity attributes of the evoking stimuli. These “urge-to-cough coding” regions include the primary somatosensory cortex, posterior parietal cortex, posterior insula and the anterior midcingulate cortex (Farrell et al., 2012) (Fig. 1C). Doses at or about the C2 threshold are likely to engage efforts to suppress cough under the type of conditions that operate during functional brain imaging in humans. There are a number of brain regions including the inferior frontal gyrus, anterior insula, ventromedial prefrontal and adjacent anterior cingulate cortex, cerebellum and supplementary motor area, that do not activate at low doses of capsaicin inhalation but are activated at relatively high doses consistent with cough suppression (Farrell et al., 2012) (Fig. 1D). Signals from the majority of these regions also show interactions between tussive stimulation and explicit instructions to suppress cough that more directly implicate their responses in the conscious decision to prevent an evoked cough (Mazzone et al., 2011a). This network of regions has also been implicated in response inhibition to exteroceptive cues (Simmonds et al., 2008), and it would appear that the same regions are involved in conscious decisions to avert preponent behaviours triggered by the interoceptive sensation of urge-to-cough. Alternative suppressive networks (for example that enlisted by placebo described above) may also exist (Leech et al., 2013), and point to the existence of descending modulatory influences of incoming airway afferent signals, perhaps at the level of the brainstem. Descending inhibition, for example via a circuit comprising the nucleus submedius in the thalamus, rostral agranular insula cortex, periaqueductal grey and rostral medial medulla, is widely known to modulate nociceptive afferent processing in the spinal cord (Tang et al., 2009). Interestingly anterograde transneuronal tracing studies in rodents have shown that airway afferent pathways terminate extensively in these same brain regions (McGovern et al., 2012a), providing an anatomic substrate that might subserve descending control over incoming airway afferent inputs. Evidence from neuroimaging of placebo effects suggests that the dorsolateral prefrontal cortex could play an important role in the modulation of urge-to-cough (Leech et al., 2013) (Fig. 1C), possibly through putative descending circuits. Further support for functional sub-networks within the broader network of responses to tussive stimulation has been provided by studies of functional connectivity in humans (Farrell et al., 2014). These experiments involve the demonstration of correlated signal changes among distributed regions ascribed with a common function. Analyses of this nature have shown unique variance among constituent regions ascribed with roles in either intensity-coding, or urge-to-cough coding, or cough suppression that is distinct from any variability shared across the regions collectively. 2. Conclusions The urge-to-cough is elicited by noxious stimulation of the airways at intensities below the threshold for coughing suggesting that the sensation is involved in discretionary actions that lead to the initiation or suppression of coughing. Urge-to-cough is
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dependent on the modality of stimulus, with chemical stimuli more reliably evoking an urge-to-cough than mechanical stimulation, whereas the later more consistently elicits reflex coughing. Different populations of primary afferents mediate chemosensitivity and mechanosensitivity of the airways, thus providing peripheral substrates for differences in the evocation of urge-to-cough and reflex coughing. Tussive stimulation of the airways is associated with regional brain responses in a distributed network that incorporates sub-networks likely involved in stimulus-intensity coding, representation of the urge-to-cough, and cough suppression. Response levels in regions implicated in intensity coding and urge-to-cough show changes associated with psychological states that could indicate a role for endogenous modulating circuits in the processing of respiratory afferent inputs. Newfound knowledge of the urge-to-cough brain network is providing exciting opportunities to develop and test hypotheses that could ultimately deliver safe, effective anti-tussive therapies. Acknowledgements This work was supported by the National Health and Medical Research Council of Australia through the provision of grants to the authors (566734, APP1042528) and a fellowship to S. Mazzone. References Atoji, Y., Kusindarta, D.L., Hamazaki, N., Kaneko, A., 2005. Innervation of the rat trachea by bilateral cholinergic projections from the nucleus ambiguus and direct motor fibers from the cervical spinal cord: a retrograde and anterograde tracer study. Brain Res. 1031, 90–100. Bernard, J.F., Peschanski, M., Besson, J.M., 1989. A possible spino (trigemino)-pontoamygdaloid pathway for pain. Neurosci. Lett. 100, 83–88. Bester, H., Chapman, V., Besson, J.M., Bernard, J.F., 2000. Physiological properties of the lamina I spinoparabrachial neurons in the rat. J. Neurophysiol. 83, 2239–2259. Canning, B.J., 2011. Functional implications of the multiple afferent pathways regulating cough. Pulm. Pharmacol. Ther. 24, 295–299. Canning, B.J., Mazzone, S.B., Meeker, S.N., Mori, N., Reynolds, S.M., Undem, B.J., 2004. Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs. J. Physiol. 557, 543–558. Canning, B.J., Mori, N., Mazzone, S.B., 2006. Vagal afferent nerves regulating the cough reflex. Respir. Physiol. Neurobiol. 152, 223–242. Chou, Y.L., Scarupa, M.D., Mori, N., Canning, B.J., 2008. Differential effects of airway afferent nerve subtypes on cough and respiration in anesthetized guinea pigs. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295, R1572–R1584. Choudry, N.B., Fuller, R.W., 1992. Sensitivity of the cough reflex in patients with chronic cough. Eur. Respir. J. 5, 296–300. Choudry, N.B., Fuller, R.W., Pride, N.B., 1989. Sensitivity of the human cough reflex: effect of inflammatory mediators prostaglandin E2, bradykinin, and histamine. Am. Rev. Respir. Dis. 140, 137–141. Chung, K.F., 2011. Chronic ‘cough hypersensitivity syndrome’: a more precise label for chronic cough. Pulm. Pharmacol. Ther. 24, 267–271. Davenport, P.W., 2008. Urge-to-cough: what can it teach us about cough? Lung 186 (Suppl. 1), S107–S111. Davenport, P.W., Sapienza, C.M., Bolser, D.C., 2002. Psychophysical assessment of the urge-to-cough. Eur. Respir. Rev. 12, 249–253. Davenport, P.W., Vovk, A., Duke, R.K., Bolser, D.C., Robertson, E., 2009. The urge-tocough and cough motor response modulation by the central effects of nicotine. Pulm. Pharmacol. Ther. 22, 82–89. Dicpinigaitis, P.V., Sitkauskiene, B., Stravinskaite, K., Appel, D.W., Negassa, A., Sakalauskas, R., 2006. Effect of smoking cessation on cough reflex sensitivity. Eur. Respir. J. 28, 786–790. Dicpinigaitis, P.V., Bhat, R., Rhoton, W.A., Tibb, A.S., Negassa, A., 2011. Effect of viral upper respiratory tract infection on the urge-to-cough sensation. Respir. Med. 105, 615–618. Dicpinigaitis, P.V., Rhoton, W.A., Bhat, R., Negassa, A., 2012. Investigation of the urgeto-cough sensation in healthy volunteers. Respirology 17, 337–341. Dutschmann, M., Dick, T.E., 2012. Pontine mechanisms of respiratory control. Compr. Physiol. 2, 2443–2469. Ebihara, S., Ebihara, T., Kanezaki, M., Gui, P., Yamasaki, M., Arai, H., Kohzuki, M., 2011. Aging deteriorated perception of urge-to-cough without changing cough reflex threshold to citric acid in female never-smokers. Cough 7, 3. Farrell, M.J., Cole, L.J., Chiapoco, D., Egan, G.F., Mazzone, S.B., 2012. Neural correlates coding stimulus level and perception of capsaicin-evoked urge-to-cough in humans. NeuroImage 61, 1324–1335. Farrell, M.J., Koch, S., Ando, A., Cole, L.J., Egan, G.F., Mazzone, S.B., 2014. Functionally connected brain regions in the network activated during capsaicin-inhalation. Hum. Brain Mapp., http://dx.doi.org/10.1002/hbm.22554.
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Ternesten-Hasseus, E., Johansson, K., Lowhagen, O., Millqvist, E., 2006. Inhalation method determines outcome of capsaicin inhalation in patients with chronic cough due to sensory hyperreactivity. Pulm. Pharmacol. Ther. 19, 172– 178. Yamanda, S., Ebihara, S., Ebihara, T., Yamasaki, M., Asamura, T., Asada, M., Une, K., Arai, H., 2008. Impaired urge-to-cough in elderly patients with aspiration pneumonia. Cough 4, 11.
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Respiratory Physiology & Neurobiology journal homepage: www.elsevier.com/locate/resphysiol
Sensations and regional brain responses evoked by tussive stimulation of the airways夽 M.J. Farrell a,∗ , S.B. Mazzone b a b
The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville 3010, Australia School of Biomedical Sciences, University of Queensland, St Lucia 4072 Australia
a r t i c l e
i n f o
Article history: Accepted 13 June 2014 Available online 19 June 2014 Keywords: Urge-to-cough Brain Interoceptive
a b s t r a c t Stimuli that evoke cough in humans also elicit a sensation described as the urge-to-cough. This sensation is perceived at levels of stimulation below the threshold for coughing and increases in intensity in response to higher levels of stimulation. Cough in humans can be consciously modified in intensity or suppressed altogether, and the urge-to-cough is likely to contribute to discretionary responses to tussive stimulation. Converging evidence from animal and human experiments have identified a widely distributed network of brain regions that are implicated in the representation of urge-to-cough and the control of coughing. This network incorporates regions that show responses associated with urge-to-cough ratings, such as limbic and somatosensory cortices, as well as paralimbic and premotor regions implicated in response inhibition that activate in association with efforts to suppress cough. The urge-to-cough can be influenced by psychological factors and preliminary findings suggest that these effects could be mediated by topdown influences. There is considerable impetus to understand circuits involved in the modulation of urge-to-cough because it may be possible to antagonise the troubling sensation while preserving the critical cough reflex. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Cough is a motor response that expels particulate matter from the airways, thus contributing to the preservation of airway patency and hence the maintenance of respiratory function. Although cough can be enlisted voluntarily, the typical mode of induction of defensive coughing is reflexively following stimulation of the airways through a pathway involving vagal afferents and processing at the level of the brainstem. This short loop pathway ensures a rapid response to airway irritation that reduces the risk of aspirated substances reaching the airways and lungs as well as aiding with efficient clearance of intrinsically generated material such as secretions. In addition to the motor behaviour, stimuli likely to evoke cough also give rise to a sensory experience, commonly referred to as the urge-to-cough (Davenport et al., 2002). Interest in the character and mechanisms of urge-to-cough is growing as clinicians and researchers recognise that the sensation can be a troublesome symptom of airways disease in its own right, that clinical cough could in part be a discretionary behaviour motivated
夽 This paper is part of a special issue entitled “Non-homeostatic control of respiration”, guest-edited Dr. Eugene Nalivaiko and Dr. Paul Davenport. ∗ Corresponding author. Tel.: +61 421785215. E-mail address: michael.farrell@florey.edu.au (M.J. Farrell). http://dx.doi.org/10.1016/j.resp.2014.06.009 1569-9048/© 2014 Elsevier B.V. All rights reserved.
by a drive to satiate the urge-to-cough, and that antagonism of the urge-to-cough could be a viable treatment strategy that would leave the critical cough reflex intact (Chung, 2011; Mazzone et al., 2011b; Morice, 2013; Morice et al., 2012). This review will discuss recent advances in the understanding of urge-to-cough that have been facilitated by heightened interest in the sensation.
1.1. Sensory attributes of the urge-to-cough The urge-to-cough is a latent process. Psychophysical investigations of the sensation have been confined to experiments involving humans, in whom language provides a means to convey personal experience. Studies of endogenously derived urge-tocough (for example, in airways disease) are limited and have only reported measures of severity rather than investigating mechanistic processes. For this reason we will limit our discussion to experimentally induced urge-to-cough, which typically involves the inhalation of nebulised solutions containing varied doses of tussive substances such as capsaicin (Davenport et al., 2002) and citric acid (Yamanda et al., 2008), or the use of other stimuli such as inhalation of distilled water (fog) (Lavorini et al., 2007) or application of puffs of air (Hegland et al., 2011). The quality of the sensation evoked by tussive stimuli is not well characterised but has been described as itching, scratching or burning, and is usually localised
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to the pharynx and/or larynx. Additionally, the sensation is associated with a desire to cough. There has been speculation that the urge-to-cough is also likely to be invested with a negative emotional valence, or unpleasantness, but evaluations of this attribute have not been reported to date (Farrell et al., 2012). Unlike in disease where the endogenous urge-to-cough can be persistent and difficult to satiate, the duration of experimentally-induced urgeto-cough is relatively short-lived. A single inhalation of a tussive substance will usually give rise to an urge-to-cough during the inhalation and subsequent exhalation, and no longer be noticeable upon the initiation of the next inhalation of fresh air (Farrell et al., 2012). The temporal pattern of urge-to-cough during inhalation of a tussive substance is distinct from other sensations that can feasibly arise in association with stimulation. Whereas urge-to-cough is closely related to the respiratory cycle, other sensations associated with capsaicin inhalation, such as heat in the mouth, taste, watering of the eyes, etc. usually only occur after repeated doses and persist for minutes with no appreciable variability relative to the respiratory cycle (Mazzone et al., 2007). The intensity of urge-to-cough varies according to the intensity of stimulation. Stimulus–response functions for urge-to-cough are typically derived using doubling doses of tussive substances. The lowest dose required to elicit a detectable urge-to-cough has been dubbed the urge-to-cough threshold, or Cu (Dicpinigaitis et al., 2011). The relatively recent appearance in the literature of Cu measures reflects the growing interest in the sensation, and complements the traditional motor-related thresholds such as the C2 and C5, which are the lowest doses of a tussive stimulus that elicit two or five coughs (Choudry and Fuller, 1992). Single breaths of doubling doses of tussive stimuli in excess of the Cu generally evoke monotonic increases in the urge-to-cough in healthy people (Davenport et al., 2002). The stimulus–response function has a decelerating profile when plotted against real stimulus values, and research groups tend to present psychophysical outcomes using logarithmic dose values that display a linear relationship with urge-to-cough ratings. Personal attributes and behaviours systematically influence the slope, but not the intersect of the urge-to-cough stimulus–response function. For instance, the slope of the response function is steeper in women than men, but the Cu does not differ between the sexes (Dicpinigaitis et al., 2012; Gui et al., 2010). The Cu is also comparable among smokers and non-smokers, although smoking is associated with a decrease in the slope of the urge-tocough stimulus–response function (Kanezaki et al., 2012, 2010), which trends towards normal levels when smoking is ceased (Dicpinigaitis et al., 2006). Advancing age is associated with a decrease in the intensity of urge-to-cough at motor thresholds (i.e. C2, C5), which do not show age-related changes, whereas interpolated values of the Cu are stable across groups of disparate age (Ebihara et al., 2011). The general conclusion from these assessments of urge-to-cough is that the level of stimulation requisite for the detection of any urge-to-cough is relatively stable, but that both increased and decreased sensitivity to supra-threshold stimuli can be observed in healthy cohorts depending on age, sex and exposure to cigarette smoke. The urge-to-cough is subject to considerable within-subject variance during repeated presentations of stimuli. Adaptation to tussive stimulation has been observed in experiments involving multiple inhalations of fixed intensity doses (Choudry et al., 1989; Farrell et al., 2012; Mazzone et al., 2007). Indeed, in some individuals a dose initially eliciting a moderate level of urge-to-cough can fail to evoke any appreciable sensation after repeated inhalations during tens of minutes (Mazzone et al., 2007). Psychological factors have demonstrable effects on the urge-to-cough within the same person. An increase in ratings of urge-to-cough occurs when anxiety increases (Davenport et al., 2009) and when attention
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shifts from an exteroceptive to an interoceptive focus (Janssens et al., 2014), whereas administration of a placebo erroneously ascribed with antitussive benefits can dramatically decrease ratings of urge-to-cough under experimental conditions (Leech et al., 2012). Non-systematic variance is also a feature of urge-to-cough responses among participants inhaling capsaicin. Very large coefficients of variation (56–75%) have been reported for intermittent breaths of capsaicin at fixed doses (Farrell et al., 2012), as well as for repeated estimates of urge-to-cough during continuous inhalation of a single dose for several minutes (Farrell et al., 2014). Visceroafferent sensations are generally less reliably described during magnitude estimation procedures compared to sensations arising from cutaneous stimuli, and this inconsistency could be related to differences in the central representation of the viscera in sensory processing regions of the brain (Strigo et al., 2002). However, despite considerable variability within participants, averaging over repeated trials consistently identifies intensity-dependence of urge-to-cough responses to tussive stimuli. 1.2. Urge-to-cough and the likelihood of coughing Perception of an urge-to-cough occurs at levels of stimulation that are typically less than the threshold for coughing (Davenport et al., 2002) (Fig. 1A). It is difficult to provide estimates of the difference between the Cu and cough-motor thresholds by amalgamating outcomes across studies because lack of consistent methods has a bearing on results (Ternesten-Hasseus et al., 2006), but a report from one study of differential scores calculated on a case-by-case basis estimated that the urge-to-cough is elicited at approximately two doses increments lower than the threshold for one or more coughs (Dicpinigaitis et al., 2012). The presence of an urge-to-cough at stimulus levels that do not evoke a cough has important implications for the role of cognitive processes in the control of coughing. Sensitivity to low levels of airways irritation captures attention and provide opportunities to engage in discretionary behaviour (Davenport, 2008). Many aspects of coughing are under conscious control in humans, and an awareness of airways irritation has the potential to interact with motor planning. For instance, coughing can be suppressed or modelled (i.e. actively increased or decreased in intensity or duration) in response to stimuli that evoke an urge-to-cough (Hegland et al., 2012; Hutchings et al., 1993). Indeed, coughing can be initiated voluntarily in the absence of any interoceptive trigger. Voluntary control of coughing impacts on the relationship between intensity of urge-to-cough and the likelihood of coughing. The most readily apparent influence of voluntary control on the association between urge-to-cough and coughing is conscious suppression. In the absence of any motivation to suppress coughing, the delivery of a tussive dose that evokes two coughs (C2) is likely to be associated with a low to moderate level of urge-to-cough (Farrell et al., 2012). However, the simple instruction to participants to suppress coughing can profoundly increase the dose required to evoke an uncontrolled response, despite the reported experience of increasing levels of urge-to-cough (Hutchings et al., 1993). Consequently, this “dynamic motor threshold” (Hegland et al., 2011) means that reported levels of urge-to-cough have limited utility as a predictor of the likelihood of coughing. It may be that participants’ judgements of urge-to-cough under conditions of conscious suppression are representative of the level of effort required to avert coughing, although this proposition is yet to be tested. 1.3. Neural structures implicated in the urge-to-cough 1.3.1. Peripheral receptors and fibres The cell bodies of afferents implicated in cough are located in the nodose and jugular ganglia of the vagal nerves (Canning et al., 2004).
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Fig. 1. (A) Ratings of the urge-to-cough increase linearly in response to the log of doubling doses of tussive stimulation. Low doses elicit an urge-to-cough without evoking cough. Higher doses are associated with both urge-to-cough and coughing, although the incidence of cough can be consciously suppressed (Cough Discretion Zone). At the highest doses the urge-to-cough is at a maximum and coughing occurs despite efforts to suppress. Regional brain responses during tussive stimulation are associated with different aspects of the urge-to-cough stimulus–response function. Responses in brain regions have been associated with the intensity of stimuli or urge-to-cough ratings (Intensity Effects), as well as efforts to suppress cough (Cough Discretion Zone). (B) Contrasts of regional brain responses at two different doses of capsaicin have shown regions with stimulus-related BOLD signal changes (STIMULUS). These regions include bilateral insula cortex, motor cortices, premotor cortices and the midcingulate cortex (MCC). (C) Urge-to-cough ratings show variance that is not explained by stimulus level. Some brain regions activated during inhalation of capsaicin show variance that is closely associated with ratings of urge-to-cough (URGE-to-COUGH). These regions include the primary somatosensory cortex (SI), the posterior insula (Post. Insula), the posterior patietal cortex (PPC), and the midcingulate cortex. The urge-to-cough is modified by psychological factors, such as placebo. It is likely that the dorsolateral prefrontal cortex (DLPFC) plays a role in the modulation of urge-to-cough. (D) The conscious effort to suppress cough decreases the likelihood of coughing to a wide range of tussive stimuli and associated levels of urge-to-cough (Cough Discretion Zone). Efforts to suppress cough are associated with regional brain responses to capsaicin challenge (SUPPRESSION). These regions include right inferior frontal gyrus (R IFG), the right anterior insula (R Ant. Insula), the ventromedial prefrontal cortex (VMPFC), and the midcingulate cortex.
Receptor subtypes in the airways with putative roles in the urge-tocough have been characterised according to their associations with cough evoked by administered airway irritants. Such studies have been performed extensively in animals and other reviews describe the attributes of airway afferents implicated in reflex coughing (Canning, 2011; Mazzone and Canning, 2013). Our discussion will be confined to features that could have a bearing on the experience of an urge-to-cough. The majority of human studies of urge-to-cough involve inhaled chemical stimuli. Chemosensors responding to salient substances (capsaicin, bradykinin, citric acid) have been identified in the epithelium of the airways (Canning et al., 2006), and these C-fibre terminals are likely to be involved in the urge-to-cough. However, chemical stimuli capable of activating the receptors do not evoke cough in unconscious animals (Canning et al., 2004; Tatar et al., 1988), which is the modus operandi for implicating afferent units in the reflex motor response. The absence of reflex responses to chemical stimulation of the airways during anaesthesia has led to speculation that inputs from the C-fibres may be principally contributing to sensations dependent on higher order processing, such as the urge-to-cough, rather than the mediation of motor reflexes (Narula et al., 2014). Coughing is elicited in unconscious animals and humans upon the application of punctate (touch-like) stimuli to the epithelium of the upper airways (e.g., probing with a von Frey filament in animals or intubation in humans) (Mazzone, 2005). Stretch-like stimuli (inflation and deflation) are reportedly ineffective at inducing cough (Chou et al., 2008), which suggests that neither rapidly nor slowly adapting A fibres (stretch receptors) mediate mechanically evoked cough. Rather, a population of A␦ fibres with rapidly adapting receptors, dubbed “cough receptors”, have functional properties that are wholly compatible with a primary role in reflex cough (Canning et al., 2004). Evidence supporting a role for mechanically sensitive afferents in the experience of urge-to-cough is limited.
Chest percussion has been shown to induce an urge-to-cough that is exaggerated in patients with an upper respiratory tract infection, although frequency of responders was reported rather than any measures of subjective intensity, and only a minority of participants in either group reported an urge-to-cough (Lee and Eccles, 2004). A solitary study has reported ratings of urge-to-cough to brief puffs of air applied to the oropharynx (Hegland et al., 2011). Interestingly, both cough frequency and urge-to-cough ratings failed to show intensity-dependence at two levels of air pressure, but instances of stimuli evoking coughing were associated with a stronger urgeto-cough than stimuli that did not elicit a cough. Also of note is the absence of a correlation between cough thresholds derived with capsaicin inhalation versus fog (distilled water, and a likely stimulus for mechanosensitive cough receptors) (Lavorini et al., 2007), which suggests dissociable processing of C and Adelta fibre inputs, although the implications of this dissociation of motor responses for urge-to-cough is a matter for speculation. Further studies will be required to establish the consistency of these observations and to test for any additional distinctions between mechanically and chemically evoked urge-to-cough. 1.3.2. Brainstem regions Human functional brain imaging has provided preliminary indications of the brainstem regions involved in the processing of inputs related to urge-to-cough. Intensity-dependent activations associated with inhalation of graduated doses of capsaicin have been identified in the dorsolateral regions of the rostral pons and rostral medulla (Farrell et al., 2012). Intensity-independent responses have also been shown in the lateral caudal medulla (Farrell et al., 2012). The images used to identify brainstem responses to capsaicin inhalation were not optimal for the region, and consequently it is not feasible to implicate specific neuroanatomical structures as the loci of activations. Nevertheless, the outcomes indicate that capsaicin inhalation activations are
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distributed throughout the brainstem, which might suggest multiple, complimentary functional processes in response to airway irritation. Animal studies have provided neuroanatomical detail of regions implicated in sensory processing of airways afferents, with possible implications for pathways contributing to urge-to-cough. Anterograde transneuronal tracing has been undertaken in rats after inoculation of the extrathoracic trachea with herpes simplex virus to identify brainstem and supra-bulbar regions in receipt of afferent inputs from the upper airways (McGovern et al., 2012a,b). These experiments have implicated the nucleus of the solitary tract and the spinal trigeminal nucleus as the principal regions in the brainstem receiving afferent, monosynaptic inputs from the upper airways. At a delay consistent with a polysynaptic ascending sensory circuit, the parabrachial nuclei, Kölliker-Fuse nuclei, locus coeruleus, periaqueductal grey and neighbouring regions of the pons and midbrain are infected subsequent to inoculation of the trachea (McGovern et al., 2012a). There is converging evidence supporting a primary role for the nucleus of the solitary tract in the transmission of afferent inputs from the airways (Atoji et al., 2005; Haxhiu and Loewy, 1996; Kubin et al., 1991; Perez Fontan and Velloff, 2001), and it seems very likely that this region is part of the circuitry contributing to urge-to-cough. The spinal trigeminal nucleus has been implicated in visceroafference (Ma et al., 2007; Saxon and Hopkins, 2006), and is another candidate region for the transmission of afferent inputs with relevance for the representation of urge-tocough. Further research will be required to establish if the nucleus of the solitary tract and the spinal trigeminal nuclei have distinct, mutual or interacting functions with respect to the relay of afferent information from the airways. The implications of a polysynaptic pathway involving vagal inputs via the nucleus of the solitary tract and/or spinal trigeminal nucleus, and the parabrachial nuclei are not immediately apparent with respect to the representation of urge-to-cough. Spinobulbar nociceptive pathways incorporating the lateral parabrachial nuclei have been identified (Bernard et al., 1989; Bester et al., 2000; Jasmin et al., 1997; Pan et al., 1999), and a similar pathway (albeit vagal, not spinal) may contribute to transmission of nociceptive input from the airways. Indeed, the lateral parabrachial nuclei are in receipt of vagal afferent inputs from the airways (McGovern et al., 2012a,b). The possibility also exists, however, that parabrachial nuclei could be involved in respiratory motor responses to airways challenge (Dutschmann and Dick, 2012). 1.3.3. Cortical and subcortical regions Tussive stimulation of the airways is associated with activation in a widely distributed network in the hemispheres of the human brain. This network includes thalamic nuclei, and primary somatosensory, posterior parietal, premotor, prefrontal, limbic and paralimbic cortices (Farrell et al., 2012; Mazzone et al., 2009, 2007). The brain regions implicated in responses to tussive stimulation are likely to represent multiple functions that include representation of the urge-to-cough and related processes. Dose-dependent thalamic activation in association with tussive stimulation is observed in human studies (Farrell et al., 2012), although the nuclei involved in these responses cannot be accurately localised at the spatial resolution of the constituent images. Transneuronal tract tracing in rodents would suggest that the likely thalamic targets of afferent inputs from the airways are the ventral posterior lateral and mediodorsal nuclei (McGovern et al., 2012a), which are certainly consistent with the projection sites of these nuclei and the cortical structures implicated in urge-to-cough. The network of cortical regions implicated in the urge-to-cough in humans has been ascribed with a range of complementary functions that characterise sensory and motor responses to airways
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challenge. Many of the regions activated during inhalation of capsaicin show intensity-dependence at doses ranging from supra-Cu threshold to the C2 threshold, which would suggest that regions including the insula, anterior midcingulate cortex, rolandic and contiguous primary motor cortices and premotor cortices could contribute to graduated sensory experiences and motor responses that reflect the differential implications of variable levels of nociceptive input (Farrell et al., 2012) (Fig. 1B). Variance in ratings relative to stimuli, described in earlier sections (see final paragraph of “Sensory Attributes of the Urge-to-Cough”), makes it possible to identify brain regions with signal changes that are more closely correlated with the subjective experience of urge-to-cough than the intensity attributes of the evoking stimuli. These “urge-to-cough coding” regions include the primary somatosensory cortex, posterior parietal cortex, posterior insula and the anterior midcingulate cortex (Farrell et al., 2012) (Fig. 1C). Doses at or about the C2 threshold are likely to engage efforts to suppress cough under the type of conditions that operate during functional brain imaging in humans. There are a number of brain regions including the inferior frontal gyrus, anterior insula, ventromedial prefrontal and adjacent anterior cingulate cortex, cerebellum and supplementary motor area, that do not activate at low doses of capsaicin inhalation but are activated at relatively high doses consistent with cough suppression (Farrell et al., 2012) (Fig. 1D). Signals from the majority of these regions also show interactions between tussive stimulation and explicit instructions to suppress cough that more directly implicate their responses in the conscious decision to prevent an evoked cough (Mazzone et al., 2011a). This network of regions has also been implicated in response inhibition to exteroceptive cues (Simmonds et al., 2008), and it would appear that the same regions are involved in conscious decisions to avert preponent behaviours triggered by the interoceptive sensation of urge-to-cough. Alternative suppressive networks (for example that enlisted by placebo described above) may also exist (Leech et al., 2013), and point to the existence of descending modulatory influences of incoming airway afferent signals, perhaps at the level of the brainstem. Descending inhibition, for example via a circuit comprising the nucleus submedius in the thalamus, rostral agranular insula cortex, periaqueductal grey and rostral medial medulla, is widely known to modulate nociceptive afferent processing in the spinal cord (Tang et al., 2009). Interestingly anterograde transneuronal tracing studies in rodents have shown that airway afferent pathways terminate extensively in these same brain regions (McGovern et al., 2012a), providing an anatomic substrate that might subserve descending control over incoming airway afferent inputs. Evidence from neuroimaging of placebo effects suggests that the dorsolateral prefrontal cortex could play an important role in the modulation of urge-to-cough (Leech et al., 2013) (Fig. 1C), possibly through putative descending circuits. Further support for functional sub-networks within the broader network of responses to tussive stimulation has been provided by studies of functional connectivity in humans (Farrell et al., 2014). These experiments involve the demonstration of correlated signal changes among distributed regions ascribed with a common function. Analyses of this nature have shown unique variance among constituent regions ascribed with roles in either intensity-coding, or urge-to-cough coding, or cough suppression that is distinct from any variability shared across the regions collectively. 2. Conclusions The urge-to-cough is elicited by noxious stimulation of the airways at intensities below the threshold for coughing suggesting that the sensation is involved in discretionary actions that lead to the initiation or suppression of coughing. Urge-to-cough is
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