Cough-related neural processing in the brain: a roadmap for cough dysfunction?

Neuroscience and Biobehavioral Reviews 47 (2014) 457–468

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Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev

Review

Cough-related neural processing in the brain: A roadmap for cough dysfunction? Ayaka Ando a,b , Michael J. Farrell a,∗ , Stuart B. Mazzone b a b

The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia School of Biomedical Sciences, University of Queensland, St Lucia, Brisbane, QLD 4072, Australia

a r t i c l e

i n f o

Article history: Received 13 December 2013 Received in revised form 29 June 2014 Accepted 25 September 2014 Available online 6 October 2014 Keywords: Urge-to-cough Cough dysfunction Cough hypersensitivity fMRI

a b s t r a c t Cough is a complex respiratory behavior essential for airway protection, consisting of sensory, motor, affective and cognitive attributes. Accordingly, the cough neural circuitry extends beyond a simple pontomedullary reflex arc to incorporate a network of neurons that are also widely distributed throughout the subcortical and cortical brain. Studies have described discrete regional responses in the brain that likely give rise to sensory discriminative processes, voluntary and urge-related cough control mechanisms and aspects of the emotive responses following airways irritation and coughing. Data from these studies highlight the central nervous system as a plausible target for therapeutic intervention and, consistent with this, a careful appraisal of the many and varied clinical disorders of coughing control would argue that more diversified therapies are needed to treat patients with cough dysfunction. In this paper we explore these concepts in detail to highlight unanswered questions and stimulate discussion for potential research of cough in the future. © 2014 Elsevier Ltd. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The phenomenology of cough . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Defining cough . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. The urge-to-cough . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Cough associated with airway stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Cough in the absence of airway stimulation (voluntary cough) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The representation of cough in the brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Brain circuits involved in generating the urge-to-cough . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Brain circuits involved in cough . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Brain circuits involved in cough suppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cough processing in disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Excessive coughing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Impaired cough in neurological disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Cough processing in the brain in disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1. Hypersensitivity to airway stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.2. Impaired cough suppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.3. Impaired cough initiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.4. Impaired efficacy of cough . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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∗ Corresponding author at: The Florey Institute of Neuroscience and Mental Health, Kenneth Myer Building, 30 Royal Parade (Corner Genetics Lane), University of Melbourne, Parkville, VIC 3010, Australia. Tel.: +61 3 8344 1941; fax: +61 3 9035 3107. E-mail addresses: ayaka.ando@florey.edu.au (A. Ando), michael.farrell@florey.edu.au (M.J. Farrell). http://dx.doi.org/10.1016/j.neubiorev.2014.09.018 0149-7634/© 2014 Elsevier Ltd. All rights reserved.

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A. Ando et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 457–468

Implications for the treatment of cough . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Hypersensitivity to airways stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Impaired cough suppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Impaired efficacy of cough . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The traditional view has held that cough is principally a reflex action controlled by regions in the caudal brainstem (Baekey et al., 2001; Canning and Mori, 2010; Ohi et al., 2005). However, there is increasing recognition that the control of coughing is a complex process influenced by sensory, motor, affective and cognitive mechanisms (Davenport, 2009; Mazzone et al., 2007, 2011b) and contemporary views posit a role for many brain regions in the expanded list of functions that extend beyond the stereotypical cough motor event. Importantly, these contemporary views provide prospective explanations for the expression of cough in clinical contexts and point toward regions in the central nervous system as potential therapeutic targets. There is merit in considering new research directions to develop cough treatments because efforts to antagonize reflex cough often do not produce measurable clinical outcomes and will remain problematic due to the inherent risks of curtailing such an important mechanism for airway clearance. Similarly, inhibitors of cough processing in the brainstem are also problematic given that many of the brainstem cough neural components are integral to normal respiratory rhythm generation and regulation. Although not devoid of possible side effects, the higher brain should be considered as a viable target for treating cough dysfunction in disease. The main objective of this review is to develop a pathway for future research into the central control of coughing in clinical conditions. In order to achieve this objective the review will first explore the sensory, motor, affective and cognitive attributes of cough. The second section of the review will list the brain regions ascribed with a role in cough control and then discuss how activation in these regions can be related to different attributes of cough function. The final two sections will discuss the functional neuroanatomy of cough in the context of clinical conditions and what this means for cough therapies. In doing so, we aim to raise questions for potential future research. 2. The phenomenology of cough 2.1. Defining cough A widely accepted definition of cough is a defensive airway reflex consisting of a modified respiratory act aimed primarily at generating the high flow velocities required for removal of mucus or any other foreign body from the lower respiratory tract. It typically begins with a preparatory inspiratory phase, characterized by an enhanced contraction of the diaphragm and abductor muscles of the larynx, followed by a brief expiration against a closed glottis (compressive phase) and finally a continued forceful contraction of the expiratory muscles with the glottis open (expulsive phase) (Fontana and Lavorini, 2006). However, the definition of cough above merely describes the basic motor events of a typical cough and excludes respiratory responses in which the motor events differ (such as no initial inspiration or partial/absent glottal closure), which for all intents and purposes would be considered a cough in the clinical setting. The definition also excludes entirely the sensory, affective and cognitive

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components of cough. Cough is also often defined or described as a reflex, characterized by the involuntary respiratory motor events described above but occurring as a consequence of sensory inputs to the brainstem arising from the airways. Indeed, reflex cough is the primary defense mechanism that protects the airways from inhaled or locally produced irritants, aspirates and pathogens, thereby maintaining normal pulmonary function (Bessac and Jordt, 2010; Bolser and Davenport, 2002). Although this description includes a sensory component to coughing, it relegates the process to being uncontrollable (i.e., reflex in nature), and devoid of any conscious awareness of airways irritation or behavioral regulation of the cough motor act. This is clearly not the case as there is strong evidence that an awareness of irritation (giving rise to the perceived need to cough) precedes many coughs and furthermore the cough motor output can be voluntarily or subconsciously manipulated with or without concomitant sensory stimulation (Davenport et al., 2002; Mazzone et al., 2011a). Thus, individuals can voluntarily cough, suppress urge-related cough and even have their urge-tocough sensation and cough motor response manipulated through placebo interventions, distractions or alterations to cognitive states (e.g., anxiety) (Davenport and Vovk, 2009; Leech et al., 2012; von Leupoldt et al., 2013). There may be a need to acknowledge that the emphasis on motor events that are employed to define cough do not encompass additional attributes of the human experience of airway clearance that are likely to have a bearing on the expression of cough in health and disease. The more elaborated experience could be thought of as a complex multifaceted respiratory response with sensory, motor, affective and cognitive dimensions (Fig. 1). Indeed, adopting such a viewpoint may help with the understanding of problematic cough in disease, which all too often is simply labeled as a change in cough reflex threshold sensitivity without recognition of the other dimensions of the experience that may also play a role. 2.2. The urge-to-cough The urge-to-cough, a higher brain-dependent sensory experience related to irritation of the airways, constitutes an important component of coughing and several studies have reported urge-tocough measures alongside urge-related cough responses evoked by airway stimulation as indices of cough sensitivity thresholds. Arguably less is known about the phenomenology of the urge-tocough compared to actual coughing, perhaps because studies are confined to human subjects, who can articulate the nature of the sensation. Recently, capsaicin inhalation has been used to model the urge-to-cough in the laboratory setting (Davenport et al., 2002; Mazzone et al., 2007) and the lowest dose to reliably elicit a report of an urge-to-cough without a preceding motor cough event has been dubbed the urge-to-cough threshold (Cu ) (Dicpinigaitis et al., 2012). Whether this experimental model accurately reflects the endogenous urge-to-cough present in respiratory diseases is not clear. Surprisingly there have been no studies explicitly evaluating the phenomenology of urge-to-cough in disease and only a few reports documenting urge-to-cough measures collected in patients in the absence of challenge testing. Nevertheless studies employing urge-to-cough induced by inhaled capsaicin have provided some


Motor

Cognive

Sensory

Cough? Urge-related Cough

YES Urge-toCough

Suppressed Cough

Smulus

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airway stimulation is likely more complex than first thought as there can be considerable variability in perceptual ratings and urgerelated cough from stimulus to stimulus in a single participant or across testing sessions (Farrell et al., 2012). Perhaps related to this is the observation that mood and other affective states (e.g., anxiety) may alter the perception of and/or responses to airway irritation in complex ways (Davenport et al., 2009). However, little is known about whether such processes differentiate distinct attributes of either the urge-to-cough or coughing in health or disease.

NO

2.3. Cough associated with airway stimulation Voluntary Cough

Reflex Cough

YES

Smulus

Fig. 1. Schematic representation of the phenomenology of cough. The model proposed is based on evidence indicating that sensory, cognitive and motor processing steps in the brain differentially regulate the control of cough. Thus, cough motor output may be initiated by a stimulus in the airways which gives rise to the sensation of an urge-to-cough, allowing some level of behavioral control of coughing (urge-related cough versus suppressed cough, for example). Cough can also be voluntarily initiated without an initiating peripheral stimulus or urge-to-cough. Equally, cough may be purely a reflex in which urge-to-cough, cognitive processes and/or behavioral regulations presumably play little or no role in determining the resultant motor output.

interesting insights into this component of coughing (Davenport et al., 2002; Farrell et al., 2012; Mazzone et al., 2007), and have additionally raised many questions that require answers. Consequently, such studies raise the issue of what exactly the urge-to-cough is, and what purpose it serves in the cough process. Tussive stimulation can evoke a sensation of airway irritation akin to scratchiness, burning or itching (sensory discrimination) which can have both intensity and perceptual dimensions, accompanied by some capacity to locate the irritation (spatial discrimination) (Farrell et al., 2012; Mazzone et al., 2007). However, it seems unlikely that the urge-to-cough is purely a sensory processing event in the higher brain. Rather it may reflect a complex integrative phenomenon that serves to link sensations with a range of possible motor outcomes. Coughing in response to the urge-to-cough may produce feelings of relief and satisfaction as a result of removal of the source of stimulation from the airways. Thus, one could argue that the urgeto-cough serves to promote a behavior that is inherently rewarding. There is clear evidence that satiation in other physiological contexts can be rewarding, for example drinking when thirsty or eating when hungry. However, although it is not unreasonable to speculate that successfully clearing an irritation from the airways could be a satisfying outcome, there have been no direct measures of gratification resulting from the act of coughing in response to an urge-to-cough. Furthermore, unlike behaviors such as eating, it seems unlikely that the act of coughing in the absence of any stimulation could be considered inherently rewarding of itself (Bellisle et al., 2012). Finally, it is unclear as to the interdependence of the urgeto-cough and coughing. Reports generally show tight correlations between averaged urge-to-cough ratings and the intensity of tussive stimulation. However, the relationship between the urgeto-cough, stimulus intensity and urge-related cough induced by

A typical urge-related cough is one in which cough is initiated by a stimulus that activates sensory nerve endings innervating the airways. In some limited circumstances stimuli applied to nonairway tissues (such as the pharynx or external auditory meatus) may also initiate coughing (Gupta et al., 1986; Hegland et al., 2011). Regardless of the site of stimulation, a stimulus of sufficient intensity and without warning may initiate purely reflex coughing. In this instance, cough would proceed in an uncontrollable manner and be dependent entirely upon brainstem processing of incoming sensory input from the airways. Although higher brain regions may receive sensory and/or feedback related information, the temporal nature of this would not be sufficiently fast enough to allow any higher order control over the reflex response. A purely reflex cough is easily demonstrated by either mechanical or chemical activation of mechanoreceptors in the larynx or large airways in deeply anesthetized or decerebrated animals (Adcock et al., 1988; Baekey et al., 2001; Biringerova et al., 2013; Canning et al., 2004; Mikus et al., 1997; Usmani et al., 2005) and probably reflects the uncontrollable cough in humans associated with aspiration and other highly invasive stimuli of the airways. Whether all urge-related cough induced by a stimulus is purely a reflex in nature is a subject for debate. For example, the inhalation of tussive substances, such as capsaicin (from hot chilies, commonly used in cough challenge tests) induces not only cough but also the urge-to-cough. Interestingly, human participants can experience the urge-to-cough at capsaicin concentrations that are too low to induce reflex coughing (Davenport, 2008; Davenport et al., 2002). Indeed, many coughs triggered by airway irritants are accompanied by an urge-to-cough, which is often experienced prior to the cough motor event and is perhaps important for initiating behavioral coughing in an attempt to satiate the urge. Thus, the experience of an urge-to-cough may argue against the notion that all urge-related coughing is automatic and involuntary, instead suggesting that a level of volitional control is likely. Studies in experimental animals may support this notion since sleep and general anesthesia has been shown to abolish capsaicin (but not mechanically) related coughing (Canning et al., 2004; Nishino et al., 1990). In addition to the urge-to-cough produced by the actual stimulus, the expectation of receiving a tussive irritant (as is the case with most cough challenge tests) may also induce behaviors that then contribute to the urgerelated response. Indeed, it is well known that central processes associated with expectation and beliefs shape sensory experiences, and this is most readily recognized in placebo suppression studies (Leech et al., 2012) but also apparent in nocebo studies where expectation is used to heighten resultant urge-related responses evoked by a stimulus. For example, focusing on internal sensations related to cough increases the likelihood of coughing (Van den Bergh et al., 2011). Thus, the conscious experience and/or expectation of airway stimulation will introduce added complexity to the resultant cough behavior, in the form of conscious or subconscious attempts to initiate, suppress, augment or attenuate the response. For this reason, coughing in the presence of airway stimulation is perhaps more accurately described as an urge-related cough to make

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a distinction between cough with discretionary influences as compared to the automatic, reflex cough that proceeds involuntarily. Recognizing the difference between reflex and urge-related coughing is more than semantics as it gives insight into cough phenomenology and may have fundamentally important implications for understanding cough and cough challenge data in health and disease. In particular, conscious decisions to initiate, modify or suppress cough as discretionary responses to an urge-to-cough contribute to observed behaviors. It has been noted in healthy people that coughing after inhalation of capsaicin can be purposefully controlled in intensity or suppressed altogether (Hegland et al., 2012; Hutchings et al., 1993c). As in habit cough, some patients with chronic cough may initiate some instances of coughing in an attempt to satiate an ongoing urge-to-cough. 2.4. Cough in the absence of airway stimulation (voluntary cough) Cough like most respiratory maneuvers can be initiated at will, entirely independent of any sensory inputs from the airways to brain. Voluntary cough or cough-like maneuvers can be used as a means of communication (e.g., to gain attention, feign sickness or validate complaints of a genuine illness). In some diseases such as cystic fibrosis, voluntary cough is an important therapeutic strategy to facilitate airway clearance (Lee et al., 2002). There have also been reports of cough “contagion”, whereby one cougher in a crowded room will be imitated by others at predictable frequencies related to the spatial proximity of the instigator and follower (Pennebaker, 1980). Voluntary and urge-related cough differ in more ways than simply the respective absence or presence of a precipitating sensory stimulus. The quality of voluntary versus urge-related cough has been compared directly using measures such as electromyography. Voluntary coughing involves comparable muscle groups to urgerelated coughing, but the recruitment of these muscles shows a sequential order that is not replicated during induced coughing, where expiratory and accessory muscles are activated simultaneously (Lasserson et al., 2006; for review see Magni et al., 2011). Urge-related cough is also associated with a greater peak in intraabdominal pressure compared to voluntary cough (Addington et al., 2008). The disparate muscle actions would suggest that the two coughs are orchestrated by different motor commands in the central nervous system. The contribution of voluntary cough in the manifestation of chronic cough in disease is unclear. A poorly defined subset of chronic coughers are categorized as having psychogenic/habit/tic cough, which is thought to represent a form of voluntary or behavioral coughing. These patients are often, but not exclusively, children and many have additional underlying psychological pathophysiology. Behavioral therapies in these patients typically dissipate the cough; perhaps consistent with the notion that habit cough is voluntary in nature. In airways diseases, there have been very few attempts to assess whether patients’ coughs are voluntarily initiated. Although this may not be true for all coughers, in one study that we are aware of, Vertigan and Gibson (2011) noted that 49% of their patient cohort (diagnosed with chronic refractory cough) reported coughing deliberately in response to perceived irritations in the throat (Vertigan and Gibson, 2011). 3. The representation of cough in the brain Experiments conducted in animals and humans have provided a detailed list of candidate brain regions that comprise the broader neural network involved in sensing and responding to airway stimuli. For example, cytochrome oxidase or c-Fos protein

expression has been used in guinea pigs and cats as markers of neuronal activation following airway sensory stimulation, and somewhat comparable studies have been conducted in humans employing functional brain imaging to monitor regional brain responses following airway irritation or coughing. A general appraisal of the results of these experiments suggests that cough neural pathways represent a widely distributed network in the brain (Canning and Mori, 2010; Davenport and Vovk, 2009; Gestreau et al., 1997; Jakus et al., 2008; Poliacek et al., 2007). Previous studies have identified some of the constituents of the brain circuitry involved in cough-related processing. Although the list of candidate brain regions is extensive, the specific roles of these regions have not been studied in detail and the specific organization (i.e., connectivity) of the circuits has not been determined. Some insight into circuit organization has been provided in neuroanatomical tracing studies employing neurotropic viruses capable of mapping interconnected networks of neurons (McGovern et al., 2012a,b). Vagal sensory nerves innervating the airways terminate in the nucleus of solitary tract and trigeminal sensory nuclei (specifically the paratrigeminal nuclei), and connections from these medullary nuclei can be traced to the parabrachial nuclei in pons, hypothalamus, subthalamic nuclei, thalamus and the amygdala and onto cortical regions including the insula, orbital, cingulate and somatosensory cortices (McGovern et al., 2012a). Using these approaches, at least two ascending airway sensory pathways have been proposed (Mazzone et al., 2013), one which projects from medullary nuclei to the ventrobasal thalamus and onto the somatosensory cortices and another thalamo-limbic pathway projecting via the mediodorsal thalamus onto anterior insula, cingulate and orbital cortices. This is perhaps consistent with the complex phenomenology of cough described above, which would predict the existence of multiple neural circuits in the brain that differentially co-ordinate the unique aspects of sensory, motor, affective and cognitive processing in cough. However, truly defining these distinct neural substrates requires carefully considered methodologies that provide insights into their organization from both an anatomical and functional viewpoint. 3.1. Brain circuits involved in generating the urge-to-cough In behavioral studies, airway irritation is associated with processes that allow for the spatial localization of the stimulus (where is it coming from?) as well as for the assessment of stimulus intensity (how strong is the stimulus?) and the related perceptual consequences (what level of urge do I feel?). It might therefore be expected that different regions of the brain encode these different components of the urge-to-cough. Functional brain imaging in humans during inhalation of capsaicin has been employed to test this hypothesis and has provided a map of the neural correlates of the urge-to-cough. In 2007, our group reported the basic distributed network that was activated during capsaicin inhalation (Mazzone et al., 2007) and have since ‘deconstructed’ this network into distinct components which appear to encode the different sensory discriminative aspects of the urge-to-cough (Farrell et al., 2012) (Fig. 2 and Table 1 for summary of brain regions and relevant references). Brain regions that may play an important role in encoding spatial discrimination are located in the prefrontal and posterior parietal cortices, since responses in these loci are activated by capsaicin inhalation, but independent of the actual or perceived stimulus intensity. This is consistent with other sensory paradigms that similarly suggest that prefrontal and posterior parietal regions are important for determining qualitative rather than quantitative aspects of a stimulus. By contrast, urge-to-cough related brain activations evoked by capsaicin in the sensorimotor and anterior insula cortices are dependent on stimulus intensity measures (Farrell et al., 2012; Mazzone et al., 2007). Specifically,


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(Chan and Davenport, 2009, 2010; Chan et al., 2012; von Leupoldt et al., 2010a,b), and these data may provide additional insights into the mechanisms regulating aspects of cough-related sensory neural processing. For example, breathing against a resistive load elicits the activation of respiratory sensory afferents and subsequently evokes a number of RREP peaks (obtained from the averaged EEG signal) characterized by either early or late onset latencies relative to the stimulus delivery (Davenport et al., 1986). Of particular interest, the early RREP peaks are prominent from scalp positions overlying sensory regions of the brain and are therefore thought to represent first-order sensory processing. Interestingly, and consistent with the fMRI studies described above, the P1 RREP peak is stimulus dependent, correlates with the subjective measures of stimulus intensity and likely reflects the initial arrival of sensory information to the primary sensory cortex (Knafelc and Davenport, 1999). Furthermore, the P1 peak is only measurable when peripheral stimuli exceed the subjective detection threshold, providing additional evidence in support of the notion that subjective measures of the intensity of inputs arising from the respiratory system are encoded at the level of the primary sensorimotor cortex. 3.2. Brain circuits involved in cough

Fig. 2. Overview of the brain regions implicated in (A) the processing sensory inputs arising from the airways, (B) reflex, urge-related and voluntary coughing, and (C) the inhibition or modulation of cough and the urge-to-cough. The regions depicted have been identified in either animal tract tracing or human functional brain imaging studies. Abbreviations (from brainstem to cortex): nucleus of the solitary tract (nTS), paratrigeminal nucleus (Pa5), respiratory central pattern generator (CPG), respiratory motor neurons (MNs), parabrachial nucleus (nPB), hypothalamus (HT), subthalamic nuclei (ST), ventrobasal (VB) thalamus, mediodorsal (MD) thalamus, ventral (V) thalamus, dorsomedial (DM) thalamus, orbitofrontal cortex (OFC), anterior insula (AI), cingulate cortex (CC), mid-cingulate cortex (MCC), prefrontal cortex (PFC), sensorimotor cortex (M1/S1), posterior parietal cortex (PPC), supplementary motor area (SMA), inferior frontal gyrus (IFG), ventromedial prefrontal/anterior cingulate cortices (VMPFC/ACC) and dorsolateral prefrontal cortex (DLPFC). See text for full description of regional functions and Table 1 for summary of regions.

the anterior insula shows responses that are related in magnitude to the dose of inhaled capsaicin (i.e., intensity-dependent) whereas activations in the sensorimotor cortex correlate tightly with an individual’s perception of stimulus intensity (i.e., urge-to-coughdependent). Other groups have investigated sensory and affective processing of respiratory sensations using respiratory-related evoked potentials (RREP) obtained from electroencephalography recordings

Much of the medullary and pontine neural circuitry for reflex cough has been modeled in detail using electrophysiological and pharmacological approaches in decerebrate or deeply anesthetized animals. These studies have elegantly shown how sensory inputs to the brainstem reconfigure the pontomedullary respiratory central pattern generator (CPG), so that normal respiration is converted to that of a cough motor pattern (Baekey et al., 2001, 2003; Canning et al., 2004; Mazzone et al., 2005; McGovern et al., 2012a; Ohi et al., 2004), and argue that intact suprapontine neural circuits are not necessary for the basic reflex response. The primary afferents and medullary circuitry involved in reflex cough has been reviewed elsewhere in detail (Canning, 2011; Haji et al., 2013; Mazzone et al., 2011b; Pantaleo et al., 2002) and there is no compelling reason to reproduce that here. However, it is worth mentioning that a detailed description of the medullary and pontine control of cough in humans has not yet been conducted. This largely reflects the difficulty of obtaining measures of brainstem activity using standard approaches in humans. For example, functional brain imaging experiments are typically optimized for the cortex rather than the brainstem, where signal to noise issues and spatial distortions are problematic. Despite this, capsaicin challenges in healthy humans are associated with an increased activation in the rostral and caudal medulla (Farrell et al., 2012; Mazzone et al., 2011a) which may encompass rhythm generating areas including the ventral respiratory group and the pre-Bötzinger complex (Schwarzacher et al., 2011). Capsaicin also produces a dose-dependent activation in the dorsal pons (Farrell et al., 2012), in a location shown to be activated in humans during brief breath holding and carbon dioxide stimulated respiration (McKay et al., 2010; Pattinson et al., 2009). Nevertheless, further study using optimized functional imaging is necessary to confidently assess regional brainstem responses involved in the control of cough in humans. In humans, urge-related coughing may not only depend on brainstem reflex responses but additionally on the activity in higher order brain regions, including insula, mid-cingulate and sensorimotor cortices (Mazzone et al., 2011a). Although it is not clear what role these regions play in the regulation of urge-related cough, it is conceivable that they contribute to the control of accessory muscles (e.g., laryngeal, trunk, orofacial etc.) during coughing and/or the voluntary regulation of cough. Consistent with this, stimulation of the posterior insula in monkeys evokes contralateral muscle contractions (Shima et al., 1991) and similar activations in the midcingulate cortex have been reported during voluntary coughing,

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Table 1 Summary of the representation of cough in the brain.

A. Sensory processing Tract tracing outcomes

Additional fMRI outcomes

B. Reflex/urge-related/voluntary cough Reflex cough

Urge-related cough

Voluntary cough

C. Modulation of cough sensorimotor processing Spatial discrimination Stimulus intensity Cough suppression

Regions

References

Paratrigeminal sensory nucleus Nucleus of the solitary tract Parabrachial nucleus Hypothalamus Subthalamus Thalamus – ventrobasal and mediodorsal Amygdala Anterior insula Orbitofrontal cortex Cingulate cortex Somatosensory cortex Prefrontal cortex Posterior parietal cortex

Mazzone et al. (2013) McGovern et al. (2012a) McGovern et al. (2012b)

The primary afferents and medullary circuitry involved in reflex cough has been reviewed elsewhere using animal studies. Detailed description of the medullary and pontine control of cough in humans has not yet been conducted. Insula Midcingulate cortex Sensorimotor cortex Cerebellum Thalamus–ventral and mediodorsal Putamen Caudate Insula Orbitofrontal cortex Midcingulate cortex Supplementary motor area Sensorimotor cortex

Canning (2011) Haji et al. (2013) Mazzone et al. (2011b) Pantaleo et al. (2002)

Prefrontal cortex Posterior parietal cortex Anterior insula (intensity-dependent) Sensorimotor cortex (urge-to-cough dependent) Inferior frontal gyrus Anterior insula Ventromedial prefrontal/Anterior cingulate cortices

Farrell et al. (2012)

Farrell et al. (2012) Mazzone et al. (2007) Mazzone et al. (2011a)

Mazzone et al. (2011a) Simonyan et al. (2009) Mazzone et al. (2011a) Mazzone et al. (2011b) Simonyan et al. (2007)

Farrell et al. (2012) Mazzone et al. (2007) Mazzone et al. (2011a)

Summary of the representation of cough in the brain during (A) cough sensory processing, (B) reflex, urge-related and voluntary cough control and (C) modulation of cough sensorimotor processing. Regions and possible functions are deduced from tract tracing studies using animals as well as imaging studies in humans.

sniffing and breathing (Mazzone et al., 2011a; Simonyan et al., 2007). It has also been shown that the mid-cingulate cortex is functionally connected to the laryngeal motor cortex (Simonyan et al., 2009). Interestingly in anesthetized cats, 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) is inhibited by concomitant stimulation of the cingulate gyrus or orbital gyrus (Kase et al., 1984; Kito et al., 1977). However there have been no attempts to modify neural processing in cortical regions during cough in humans. Regardless, these observations give credence to the notion that not all urge-related cough is purely a reflex in nature. The neural correlates of voluntary cough in healthy humans have been assessed in two independent fMRI studies (Mazzone et al., 2011a; Simonyan et al., 2007), both of which have shown activations in the sensorimotor cortex, supplementary motor area, orbitofrontal, insula, mid-cingulate cortices, ventral and mediodorsal thalamus, caudate, putamen and cerebellum. Many of these activations likely represent component processes involved in the planning and control of respiratory and accessory muscles associated with airway muscle movement. Of particular interest is the observation that the descending motor pathway for voluntary cough may bypass the brainstem, whilst urge-related cough

is associated with medullary activations, voluntary cough is not (Mazzone et al., 2011b). Admittedly this study did not have acquisition parameters optimized for brainstem imaging, however the findings are also supported by clinical data obtained from patients with a medulla lesion, some of whom display a diminished cough reflex but can produce a voluntary cough to clear the airways (Addington et al., 1999). This is similar to studies of voluntary breathing control that suggests corticospinal, rather than corticobulbar, pathways regulate conscious respiratory efforts. 3.3. Brain circuits involved in cough suppression Active suppression of urge-related cough is associated with activations in the inferior frontal gyrus, anterior insula and ventromedial prefrontal/anterior cingulate cortices (Mazzone et al., 2011a) and somewhat comparable responses have been reported for voluntary breath holds (McKay et al., 2008). Interestingly, these regions are robustly activated during response inhibition of motor and non-motor tasks, typically studied with go/no-go paradigms (Cai et al., 2014; Duann et al., 2009; Logan and Cowan, 1984; Pawliczek et al., 2013). In particular, the inferior frontal gyrus may serve to initiate response inhibition (rather than directly stopping movement per se) (Hampshire et al., 2010; Sharp et al.,


2010; Verbruggen et al., 2010) and thus, lesions to, or transcranial magnetic stimulation of the inferior frontal gyrus in humans significantly alters successful response inhibition attempts (Chambers et al., 2006; Swick et al., 2008). Two pathways from the inferior frontal gyrus and ventromedial cortex to cortical motor regions have been reported: one via the subthalamic nucleus and globus pallidus (the hyperdirect pathway) and a second via the striatum (indirect pathway), both of which project back to the cortex via the motor thalamus. Whether cough inhibition truly reflects the activation of either of these response inhibition networks is unknown and requires careful appraisal. Other central processes for cough suppression likely exist. For example, beliefs about coughing and the urge-to-cough can also influence the sensory and motor consequences of airway irritation, for example as is the case with placebo inhibition of cough sensorimotor responses (Eccles, 2009; Leech et al., 2012). However, the neural substrates underpinning the suggestive suppression of cough processes are poorly defined. One possible mechanism may be comparable to that reported in studies of placebo analgesia where prominent activations of the dorsolateral prefrontal cortex correlate with placebo suppression of pain (Watson et al., 2009) and this is supported by a recent study from our group (Leech et al., 2013) which additionally showed posterior parietal cortex activation. Nevertheless, precisely where in the central neural circuitry such a mechanism may act to reduce cough and/or the urge-tocough is not presently known. 4. Cough processing in disease The phenomenology of disordered cough in disease is complex. Excessive coughing can be a feature of many diseases, and the most effective way to resolve an unwanted cough is to treat the underlying disease. However, not all diseases associated with coughing admit to a cure and in some cases coughing can be a prominent problem in its own right, seemingly unexplained by any index of underlying pathology (Birring, 2011). Consequently, alternative strategies are needed to control excessive coughing when disease modification is not a viable option. However, antagonism of coughing is not invariably the objective of clinical management. For instance, an effective cough can be critical for the clearance of disease-related mucus in the lungs, in which case the maintenance of an effective cough is an important component of disease management (Foster, 2002). Additionally, coughing can become ineffective in some diseases, particularly neurological disorders affecting motor control, and in these situations the objective is to facilitate effective coughing to reduce the risk of aspiration and infection (Boitano, 2006). Irrespective of the therapeutic objective (i.e., antagonism, maintenance or facilitation of coughing), the central nervous system is a prospective target for treatment. Indeed, the neural processes involved in generating the urge-to-cough or initiating and suppressing cough all constitute potential interfaces between neural activity and disease. Therefore, a consideration of the functional neuroanatomy described above with respect to clinical cough may help develop hypotheses about the contribution of the central nervous system to the expression of cough in disease and identify potential central targets for therapeutic strategies. 4.1. Excessive coughing Frequent, non-productive cough and a recurring urge-to-cough are common clinical problems, and these problems can have negative physical and psychological consequences, particularly when cough symptoms are persistent (Polley et al., 2008). There are many pathogenic factors for chronic cough, but the presentation of cough across different clinical conditions is more remarkable for commonalities rather than disease specificity. Indeed, the relatively

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homogeneous character of chronic cough in many clinical conditions, along with the prevalence of idiopathic cases showing similar cough attributes has led clinicians to the conclusion that chronic cough can be viewed as a syndrome (Morice, 2013). A principal feature of chronic cough, irrespective of etiology, is a decreased threshold to initiate coughing (McGarvey et al., 2009), which has led to the term – Cough Hypersensitivity (syndrome) (Chung, 2011). Cough threshold measures using varied stimuli (capsaicin, citric acid, hypertonic saline) and behavioral end points (C2, C5, C15) have been reported by independent research teams for participants with chronic cough of varied etiology in comparison to healthy controls (Hilton et al., 2013; Koskela et al., 2008; O’Connell et al., 1996; Ziora et al., 2005). Irrespective of the experimental protocol, chronic cough can be associated with a lowering of the cough threshold relative to healthy cohorts. Anecdotal reports have also highlighted the sensitivity of people with chronic cough, including reports of coughing in response to normally inconsequential levels of tussive stimulation (perfume, cold air, cigarette smoke) or even in response to talking or laughing (McGarvey et al., 2009). Reports of urge-to-cough in the absence of any external agency and in response to relatively low levels of extrinsic stimulation are also a feature of cough hypersensitivity (Morice, 2013). The threshold for the urge-to-cough (Cu ) has been measured in otherwise healthy people with an acute upper respiratory tract infection and been reported as significantly lower than measures collected after the infection had resolved (Dicpinigaitis et al., 2011), which indicates that acute airways pathology can cause a shift of the urge-to-cough stimulus/response function. It remains to be seen if lowered Cu thresholds are also a feature of chronic cough, although the anecdotal evidence certainly points in this direction. The same link and logic also applies to observations of transient decreases in the efficacy of cough suppression seen in people with acute upper respiratory tract infections (Hutchings et al., 1993a; Young et al., 2009). However, the hypersensitivity in cough patients may be stimulus specific rather than universal in nature. For example, laughing, speaking, drinking and/or eating may trigger cough in patients with cough hypersensitivity, but purposeful stimulation of the cough reflex with inhaled capsaicin is not always an effective strategy for discriminating cough patients from healthy subjects (Prudon et al., 2005). Although the reason for this discrepancy is unclear, it does highlight the complexity of the neural processes governing cough in disease. 4.2. Impaired cough in neurological disease The ramifications of impaired coughing can be very serious and this risk of adverse outcomes is notably a feature of central nervous system disorders (Boitano, 2006). For instance, ineffective coughing is associated with aspiration leading to pneumonia in people with advanced Parkinson’s disease – the most common cause of death in this clinical group (Ebihara et al., 2003). Poor cough control coupled with dysphagia has also been implicated in the incidence of aspiration pneumonia in people with advanced Alzheimer’s disease and following stroke (Kalia, 2003; Kimura et al., 2013; Smith Hammond et al., 2009). The effects of central nervous system disorders on coughing are likely to be dependent on interactions between the functional neuroanatomy of coughing and the nature and regional distribution of pathological changes associated with particular diseases. A detailed assessment of putative disease-specific effects on coughing is beyond the scope of this review. Instead, a discussion of Parkinson’s disease is offered as an exemplar because empirical reports point toward differential effects of the disease on cough motor control, sensory acuity and cough suppression. The pathology of Parkinson’s disease involves degeneration of dopaminergic cells, most notably in the substantia nigra (Braak and Del Tredici, 2009). The disease is principally a disorder of movement

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control, although non-motor symptoms also occur (Chaudhuri and Odin, 2010). Patients typically present with tremor, slowness of movement, rigidity and impaired balance responses (Jankovic, 2008). Assessments of respiratory function show that the peak flow of cough is decreased in this diagnostic group compared to age-matched controls and that this difference becomes more pronounced as the disease progresses (Ebihara et al., 2003; Fontana et al., 1998). Furthermore, levels of impaired cough among people with Parkinson’s disease are related to objective assessment of aspiration upon swallowing (Pitts et al., 2008). In contradistinction to coughing control, sensitivity to airways irritation appears to be preserved in Parkinson’s disease, in that the citric acid C2 threshold does not differ between most people with the disease and healthy controls (Leow et al., 2012). However, evidence also suggests that cough thresholds is increased with people in advanced stages of Parkinson’s disease as their C2 thresholds was found to be increased in this subgroup compared to healthy people and patients with less advanced disease (Ebihara et al., 2003). 4.3. Cough processing in the brain in disease Previous sections have highlighted the multiple dimensions of cough that include motor, sensory discriminative, affective and cognitive components and the distributed brain regions ascribed with differential roles in the representation of these components of cough. The preceding discussion of disease-related effects also noted highly diverse presentations of cough, incorporating both exaggerated and attenuated motor and sensory behaviors that can seemingly change independently. Collectively, these observations would suggest that regional brain processes could be effected by, or be associated with, or contribute to changes in the expression of cough in ways that reflect the manifestations of clinical disorders. We present a scheme that posits regional brain responses likely to be associated with pathological changes in cough attributes, informed by salient examples from disease states and demographic effects. 4.3.1. Hypersensitivity to airway stimulation An increased level of input from the afferent arm of the cough pathway is likely to trigger an increased response. Consistent with this, electrophysiological measures from airway afferents in animals have provided evidence that heightened cough sensitivity can relate to a lowering of the threshold for activation of primary afferents innervating the airways (Lee and Gu, 2003). However, whether this represents the only mechanism for cough hypersensitivity is unknown. Experience from investigations involving other interoceptive processes in humans, such as pain (Apkarian et al., 2005), would suggest that a distributed neural response, including alterations in the central nervous system, is more likely to characterize hypersensitivity. Many of the brain regions that activate during noxious airway stimulation show responses that are related to the intensity of the stimulus (Farrell et al., 2012). If cough hypersensitivity were associated with increased primary afferent input as a consequence of peripheral sensitization, then most brain regions responding to this input would also be expected to show elevated levels of activation. However, responses in the brain to inputs from sensitized tissues may differ in ways that are not simply reflections of intensity alone. For instance, studies using well controlled psychophysical procedures and measurement of human regional brain responses during the experience of pain have shown differences in activation between stimulation of normal and hyperalgesic skin that are not explained by intensity-related effects of sensitization (Lorenz et al., 2002, 2003). Interpretation of these pain-related behavioral and functional brain imaging outcomes have raised the possibility that sensations arising from injured tissue have

qualitative attributes, appraisals, and motive actions that reflect the unique physiological implications of the inputs. It is not unreasonable to suggest that similar outcomes would also apply to the sensory experience of urge-to-cough in cough hypersensitivity. Hyperalgesia is notable for increased activation in the cingulate and orbitofrontal cortices (Lorenz et al., 2002), which are regions that also show responses that correlate with the unpleasantness of dyspnea. Consequently, the cingulate and orbitofrontal cortices constitute candidate regions likely to show enhanced responses to airway irritation in cough hypersensitivity that would be independent of intensity-related effects. Increased sensitivity to stimulation of the airways could involve responses in the central nervous system that contribute to the initiation and, or maintenance of hypersensitivity. Mechanisms involving descending up-regulation of nociceptive processing in the central nervous system have been identified in animal and human studies (Heinricher et al., 2009), and it is possible that analogous processes could be operable for the processing of airways inputs. Studies of pain processing in humans that contrast responses under normal physiological conditions with hyperalgesic states have implicated midbrain structures as putative pro-nociceptive modulating regions (Iannetti et al., 2005; Lee et al., 2008; Zambreanu et al., 2005). These regions include the periaqueductal gray, nucleus cuneiformis and superior colliculus. There is evidence, principally from animal studies, that the rostral ventromedial medulla is a central relay for pro-nociceptive, descending inputs from the midbrain to the dorsal horn of the spinal cord and homologous bulbar regions (Heinricher et al., 2009). If similar mechanisms operate in people with cough hypersensitivity, then activation in putative modulating regions would be increased in clinical cases compared to healthy controls, and levels of elevated activation could feasibly show a relationship to the severity of hypersensitivity. There are contingencies that would be compatible with testing the effects of cough hypersensitivity on neural representations of urge-to-cough using functional brain imaging measures. For instance, it is feasible to create sensitized cough in healthy people through the inhalation of prostaglandin E2 (Choudry et al., 1989), or to record longitudinal measures from people during and after the resolution of an acute upper respiratory tract infection (Dicpinigaitis et al., 2011), or to contrast responses of clinical populations with responses of healthy people (Koskela et al., 2008). Although yet to be tested, it is likely that protocols involving chronic cough hypersensitivity will be associated with exaggerated levels of urge-to-cough. Akin to studies of pain and hyperalgesia, the design of experiments to assess neural correlates of urge-to-cough associated with hypersensitivity would require careful manipulation of stimulus intensity to allow for meaningful contrasts within or between participants depending on the protocol. Comparisons of responses to like stimuli, or of sensory experiences of equivalent subjective intensity, would have particular utility for the investigation of hypersensitive states. The functional neuroanatomy of cough and urge-to-cough may also afford opportunities to assess the relative contributions of peripheral inputs and higher order processing to up-regulated responses because the projection targets of primary afferents, nuclei in the caudal medulla, are within the field of view of functional brain imaging techniques (Farrell et al., 2012). This situation means that it should be feasible to assess responses in the brain hemispheres after taking account of variance in brainstem responses, effectively allowing comparisons of brain activation in normal and hypersensitive states after consideration of the contribution of peripheral inputs. 4.3.2. Impaired cough suppression Human responses to airway challenges in the context of threshold procedures are discretionary; the probability of a cough


response to a fixed stimulus can be changed markedly by simply asking participants to suppress coughing (Hutchings et al., 1993b). It is possible that decreased efficacy of cough suppression in association with hypersensitivity could occur due to: (i) putative increases in the level of afferent input contingent on peripheral sensitization and associated changes in sensory processing at higher levels of the neuraxis and/or (ii) impairments of the neural mechanisms involved in inhibition of cough motor response. In this regard, it is interesting that functional brain imaging in healthy people have identified a network incorporating the cingulate cortex, inferior frontal gyrus, anterior insula and supplementary motor area that is activated during cough suppression and breath holding (Mazzone et al., 2011a; McKay et al., 2008), which shows comparable activations during other response inhibition tasks such as the go/no-go paradigm (Simmonds et al., 2008). It would be of considerable interest to establish if there is impairment in this inhibitory network in people with cough hypersensitivity. 4.3.3. Impaired cough initiation Reduced sensitivity to tussive stimulation has most commonly been reported in smokers (albeit this is not necessarily a defining feature of all smokers) (Dicpinigaitis, 2003; Kanezaki et al., 2010) but may also occur in patients with cystic fibrosis (Chang et al., 1997). When present, a reduced cough reflex threshold might reflect alterations in the peripheral coding of stimuli (e.g., as a consequence of smoke- or disease-induced changes in sensory receptors within the airway epithelium (Dicpinigaitis et al., 2011)), although this has never been proven. Irrespective of the relative contribution of peripheral components, altered sensitivity to tussive stimulation may also be accompanied by changes in regional brain processing. Again, this has not been investigated to date, but decreased peripheral afferent inputs in other systems are associated with plasticity of central responses, including changes in the primary sensory representation of somatic regions with diminished or absent afferent innervation (Flor et al., 1995; Simoes et al., 2012; Wrigley et al., 2009). These changes are dynamic; transiently blocking peripheral nerves associated with a reversible expansion of the topography of primary somatosensory cortex responses to stimulation of somatic structures neighboring the dermatome of the blocked region (Waberski et al., 2007; Weiss et al., 2004). A possible analogous situation in individuals with a reduced cough threshold would be the alteration of the representation of the airways in the somatosensory cortex in response to tussive stimulation. The salient region of the somatosensory cortex is the most ventral part of the post central gyrus (Brodmann Area 43) and contiguous regions of the parietal operculum (Farrell et al., 2012). A contraction of the airway representation in the somatosensory cortex in smokers would be expected to manifest as a change in the loci of activation in this brain region in response to inhalation of capsaicin or citric acid. 4.3.4. Impaired efficacy of cough The functional neuroanatomy of motor regions involved in the control of cough is dependent upon the presence or absence of contemporaneous tussive stimulation. Voluntary cough appears to be mediated by cortical and subcortical activations without a contribution from bulbar regions (Mazzone et al., 2011a). An urge-related cough in association with tussive stimulation is accompanied by regional brainstem and subcortical activations as well as activation in cortical regions that exceed responses for voluntary cough, such as the posterior cingulate, posterior insula and premotor cortices (Mazzone et al., 2011a). Brain regions involved in the control of purely reflex cough in humans remain unknown, but brainstem activation is likely to be a critical component. Collectively, these observations indicate that cough control is dependent on a highly distributed, functionally diverse sensory-motor network.

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Consequently, the formulation of neuroanatomical hypotheses to explain the effect of neurodegenerative disorders on the efficacy of cough must take account of the circumstances under which coughing occurs. The interaction between Parkinson’s disease and control of coughing shows differential effects depending on whether the action is voluntary or urge-related. The first observation of note is that both forms of cough show reduced levels of peak flow in people with Parkinson’s disease compared to age-matched control participants (Ebihara et al., 2003; Pitts et al., 2008). Secondly, the adverse effect of Parkinson’s disease is more pronounced for urge-related cough compared to voluntary cough (Fontana et al., 1998). These two observations could reflect the staging of Parkinson’s disease and the relative contribution of brainstem regions to the two types of cough. Histological studies of brains collected at autopsy from people with varied duration of Parkinson’s disease at time of death have revealed a region-specific developmental pattern of disposition of Lewy bodies, which are the principle markers of Parkinson’s disease pathology (Braak et al., 2006). The first regions in the brain to consistently show the presence of Lewy bodies are the olfactory bulb and the lower medulla. The dorsal vagal motor nucleus is the most consistently affected region of the medulla in the earliest stages of Lewy body disposition, but the nucleus ambiguus also shows early changes in autopsy samples acquired from people with a history of Parkinson’s disease. The early involvement in Parkinson’s disease of medullary regions could have functional implications for the control of urge-related cough that would be further compounded by later effects on dopaminergic circuits contributing to movement control. Contrasts of regional brain activation during voluntary and urge-related cough could be used to assess the relative impact of Parkinson’s disease on responses in the brainstem and hemispheres. 5. Implications for the treatment of cough In earlier sections of this review we have highlighted the potential for targeting a variety of central processes for novel approaches to cough suppression. However, arguably this concept is not new as compounds with presumed central activity, including opiates (morphine and codeine) and dextromethorphan, have been used clinically for many years to achieve relief in acute and chronic cough (Cass et al., 1954; Mudge, 1778). Although such compounds have some efficacy for cough suppression, their utility is unfortunately limited by significant off-target effects, leading to sedation, nausea, drowsiness, dependence and constipation. Yet this does not debunk the concept of central targets for cough suppression, instead arguing for a better understanding of central processes and the development of more selective centrally acting therapies. Such therapies do not necessarily have to be pharmacological in nature. 5.1. Hypersensitivity to airways stimulation A contribution by the central nervous system to cough hypersensitivity is likely to involve modulation of afferent processing regions at lower levels of the neuraxis, such as the nucleus of the solitary tract and the paratrigeminal nucleus. Analogous modulating circuits implicated in pain and hyperalgesia involve serotonergic and noradrenergic inputs. Pharmacological approaches to the management of pain and hyperalgesia have targeted these modulating circuits, and there is evidence that some of the drugs used for these purposes are also efficacious in the treatment of sensitized cough. Thus far, two adjuvant treatments have been trialed in people with cough: amitriptyline and

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gabapentin. Amitriptyline inhibits the re-uptake of serotonin and has been trialed in two small studies, both of which found that the majority of patients reported a 75–100% reduction of coughing frequency on the basis of subjective judgments (Bastian et al., 2006; Jeyakumar et al., 2006). Gabapentin is an anticonvulsant with analgesic properties that are attributed to the action of the drug on noradrenergic circuits. Early case studies reported favorable outcomes for gabapentin when administered to people with persistent cough (Lee and Woo, 2005; Mintz and Lee, 2006), and a more recent randomized controlled trial has provided further support for gabapentin as a management option in cough hypersensitivity (Ryan et al., 2012). However, the multiple measures used in the randomized trial of gabapentin did not show uniform benefits, with notable absence of effects for urge-to-cough ratings and thresholds of cough challenges (C5), potentially due to wide variability of the data. If the data is correct, these negative outcomes raise doubts about the probable action of gabapentin because antagonism of sensitizing circuits would be expected to down-regulate sensory processing. Investigation of the neural correlates of prospective anti-tussive agents could provide insights into the central actions of these drugs with possible implications for future drug development (Wise and Tracey, 2006). 5.2. Impaired cough suppression A decrease in efficacy of the brain network governing cough inhibition could contribute to impaired cough suppression and strategies that increase functional capacity of the network would consequently be expected to produce a therapeutic benefit. Pharmacological approaches have not been advocated to enhance cough suppression, and the distributed nature of brain regions involved in response inhibition is possibly less amenable to targeted augmentation. However, behavioral therapies have been tested as a strategy to improve the efficacy of cough suppression (Patel et al., 2011; Vertigan et al., 2006). The trials of behavioral therapy have reported benefits in both subjective and objective measures of cough impact and frequency among patients with chronic cough. How behavioral therapies influence regional brain processing of airway afferent inputs and motor control of coughing is an outstanding question. It is possible to hypothesize that training to improve cough suppression is likely to lead to increases in activation levels and internodal network efficiency in regions involved in response inhibition akin to the reported effects of nicotine in abstinent smokers (Giessing et al., 2013). The localization of brain regions showing altered activation subsequent to successful cough-suppression training could present opportunities to further augment benefits through the application of interventions such as transcranial magnetic stimulation (TMS) (Dayan et al., 2013). 5.3. Impaired efficacy of cough The efficacy of behavioral therapy has also been assessed in the management of respiratory function among people with neurological disorders. The majority of studies have involved participants post-stroke, but there have also been reports of training effects on respiration in people with Parkinson’s disease and multiple sclerosis (Pollock et al., 2013). Meta-analysis indicated that training had a positive effect on inspiration pressures but did not show similar effects for peak expiration pressure (Pollock et al., 2013). A study of respiration training in people with Parkinson’s disease measured cough parameters explicitly, and while some attributes of cough production showed improvements, there was an absence of effect on peak expiration pressure (Pitts et al., 2009). There is evidence that noninvasive brain stimulation techniques such as TMS and transcranial direct current stimulation (tDCS) can

enhance training of motor skills in neurological disorders (Webster et al., 2006) and that these benefits are also achievable for muscle groups likely to contribute to cough (Murdoch and Barwood, 2013). 6. Conclusion The concept that cough simply reflects a reflex change in respiratory pattern following airways irritation is now surely outdated, as is the simplistic view that modifying this reflex will directly and uniformly translate into a clinical benefit in disease. Our extensive appraisal of the complexities and nuances of cough sensorimotor responses instead argues in favor of a more critical investigation into the neural mechanisms that generate disordered coughing, as these may be heterogeneously expressed across different patient cohorts. However, it is important to note that much of our understanding of higher brain processes in cough pertain only to the nociceptor (C-fiber) evoked responses due to a complete absence of any studies assessing suprapontine brain responses in animals or humans related to activation of cough-evoking airway mechanoreceptors. The challenge ahead lies in providing a more complete delineation of cough neural pathways in the brain and then disentangling the contribution of central and peripheral neural processes leading to disordered coughing. By doing so novel and tailored strategies for therapeutic intervention will undoubtedly be discovered. Funding The authors are funded by the National Health and Medical Research Council of Australia (Grant Numbers APP1042528 and APP1025589). References Adcock, J.J., Schneider, C., Smith, T.W., 1988. Effects of codeine, morphine and a novel opioid pentapeptide BW443C, on cough, nociception and ventilation in the unanaesthetized guinea-pig. Br. J. Pharmacol. 93, 93–100. Addington, W.R., Stephens, R.E., Gilliland, K.A., 1999. Assessing the laryngeal cough reflex and the risk of developing pneumonia after stroke: an interhospital comparison. Stroke 30, 1203–1207. Addington, W.R., Stephens, R.E., Phelipa, M.M., Widdicombe, J.G., Ockey, R.R., 2008. Intra-abdominal pressures during voluntary and reflex cough. Cough, 4. Apkarian, A.V., Bushnell, M.C., Treede, R.D., Zubieta, J.K., 2005. Human brain mechanisms of pain perception and regulation in health and disease. Eur. J. Pain 9, 463–484. Baekey, D.M., Morris, K.F., Gestreau, C., Li, Z., Lindsey, B.G., Shannon, R., 2001. Medullary respiratory neurones and control of laryngeal motoneurones during fictive eupnoea and cough in the cat. J. Physiol. (Lond.) 534, 565–581. Baekey, D.M., Morris, K.F., Nuding, S.C., Segers, L.S., Lindsey, B.G., Shannon, R., 2003. Medullary raphe neuron activity is altered during fictive cough in the decerebrate cat. J. Appl. Physiol. 94, 93–100. Bastian, R.W., Vaidya, A.M., Delsupehe, K.G., 2006. Sensory neuropathic cough: a common and treatable cause of chronic cough. Otolaryngol. Head Neck Surg. 135, 17–21. Bellisle, F., Drewnowski, A., Anderson, G.H., Westerterp-Plantenga, M., Martin, C.K., 2012. Sweetness, satiation, and satiety. J. Nutr. 142, 1149S–1154S. Bessac, B.F., Jordt, S.E., 2010. Sensory detection and responses to toxic gases: mechanisms, health effects, and countermeasures. Proc. Am. Thorac. Soc. 7, 269–277. Biringerova, Z., Gavliakova, S., Brozmanova, M., Tatar, M., Hanuskova, E., Poliacek, I., Plevkova, J., 2013. The effects of nasal irritant induced responses on breathing and cough in anaesthetized and conscious animal models. Respir. Physiol. Neurobiol. 189, 588–593. Birring, S.S., 2011. New concepts in the management of chronic cough. Pulmon. Pharmacol. Ther. 24, 334–338. Boitano, L.J., 2006. Management of airway clearance in neuromuscular disease. Respir. Care 51, 913–922 (discussion 922-914). Bolser, D.C., Davenport, P.W., 2002. Expiratory motor control during the cough reflex. Eur. Respir. Rev. 12, 243–248. Braak, H., Bohl, J.R., Muller, C.M., Rub, U., de Vos, R.A., Del Tredici, K., 2006. Stanley Fahn Lecture 2005: the staging procedure for the inclusion body pathology associated with sporadic Parkinson’s disease reconsidered. Mov. Disord. 21, 2042–2051. Braak, H., Del Tredici, K., 2009. Neuroanatomy and pathology of sporadic Parkinson’s disease. Adv. Anat. Embryol. Cell Biol. 201, 1–119.

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