The central regulatory network of cough: a cornerstone of cough management

Introduction

While a cough serves a protective role by clearing foreign particles and secretions from the respiratory tract, unlike a physiological cough, a pathological or persistent cough is often linked to various conditions such as the common cold, respiratory infections, asthma, and chronic obstructive pulmonary disease. Cough is one of the most common symptoms of acute coronavirus disease 2019 (COVID-19) caused by the epidemic virus (SARS-CoV-2, severe acute respiratory syndrome coronavirus 2) a few years ago. For individuals with more severe symptoms, cough can persist for weeks or even months, significantly impacting daily life and work (1). Beyond its discomfort, cough also heightens the risk of spreading disease (2).

Cough hypersensitivity syndrome (CHS) is a clinical syndrome characterized by a cough triggered by low-level stimuli, enhanced sensitivity to cough stimulants (e.g., cold air, odors) (hypertussia), and non-cough stimulants (e.g., changing positions, talking) can also trigger coughing (allotussia) (3). The term hypertussia refers to the phenomenon of abnormal excessive coughing in response to airway irritation and allotussia refers to coughing in response to stimuli not normally provoking cough (4). A prominent characteristic of patients with cough hypersensitivity is the presence of specific triggers for coughing (5). The coughing behavior is triggered by stimuli encountered during routine activities that would not normally induce coughing in the general population, mainly due to the increased sensitivity of the sensory nerves to perceive the stimulus (6). Changes in synaptic excitability and plasticity within the brainstem, spinal cord, and respiratory nerves enhance the cough reflex and can persist in the absence of cough triggers (7). Cough is not merely a reflexive behavior, but a complex process influenced by cognitive mechanisms including sensory, motor, and emotional factors. Various regions within the central nervous system, including higher functional areas of the brain, significantly contribute to its regulation. Nevertheless, our understanding of the mechanisms behind severe and persistent coughs remains limited, resulting in a lack of effective and safe treatments (8). Therefore, an in-depth study of the central mechanisms of cough holds significant importance for the diagnosis and treatment of cough-related diseases.

This paper aims to explore the central regulatory network of cough. It begins by defining and classifying cough. The subsequent sections delve into the physiological and pathological mechanisms of cough, identify the brain regions involved, and discuss factors related to the central regulation of cough. Finally, the paper discusses the importance of effective treatment.

Definition and classification of cough

Coughing is considered a defense reflex mechanism with three phases: phase 1: deep inspiration; phase 2: contraction of the chest wall, diaphragm, and abdominal wall muscles, as well as closure of the vocal folds leading to a rapid rise in intrathoracic pressure; phase 3: sudden opening of the vocal folds, the high intrathoracic pressure generated during the rise in intrathoracic pressure facilitates a high expiratory airflow, producing the characteristic coughing sound. This is a typical behavioral description of the cough reflex and does not take into account the sensory, emotional, and cognitive factors that influence cough (9). Influenced by various factors, coughing is more than a simple reflex behavior; it is a complex respiratory behavior necessary for airway protection, and the neural circuitry for cough is incorporated in a network of neurons widely distributed in the subcortex and cortex. Cough can be reflexively evoked or autonomously triggered, involving both peripheral and central regulation, which reflects the complexity of cough behavior. The center can modulate cough in several ways, including altering the perception, location, and quantification of afferent stimuli, mediating cognitive and emotional responses to these, and managing descending pathways (10,11).

Cough is the most common clinical symptom and is classified according to the duration of symptoms: acute (<3 weeks), subacute (3–8 weeks), and chronic cough (>8 weeks) (12). In the field of cough research, most research has looked at chronic cough. Modulation of the central nervous system has an important effect on cough duration, and this effect may be bidirectional, which involves the physiological and pathological mechanisms of cough.

Physiological and pathological mechanisms of cough

In the clinical management of cough, the conventional view is that cough is a reflex action controlled primarily by the caudal brainstem region (13,14). The nerves associated with cough modulation are also essential for normal respiration. There is a risk that external inhibition of brainstem cough centers and reflexive cough may have serious clinical outcomes. Impairment of reflexive cough, a crucial airway defense mechanism, can compromise airway protection and further affect health (e.g., aspiration pneumonia, atelectasis, etc.). The focus of previous definitions of cough does not include attributes other than airway clearance experience. Influenced by sensory, cognitive, and affective attributes may produce different cough movements, which are associated with the expression of cough in health and disease (8). Pure reflex movements, once precipitated, are inherently uncontrollable. However, many coughing behaviors are amenable to human intervention from start to finish. The perception of external stimuli induces or recognizes the need to cough, generating the urge-to-cough, which in turn voluntarily intervenes in the coughing behavior. Thus, individuals can cough voluntarily, inhibit coughing, and even placebo, distraction, or altered cognitive states (e.g., anxiety) can intervene in the urge-to-cough and the cough motor. This demonstrates the involvement of the cerebral cortex in the regulation of coughing behavior (15,16).

Heterogeneity in the neurobiology of cough

Information from the airway can be encoded as an awareness of having a feeling for airway stimuli, resulting in an urge-to-cough. The urge-to-cough arises before the actual coughing (17). It is a sensation generated by the brain by producing the need to cough and is a subjective feeling that involves higher brain areas. Indicators of cough sensitivity thresholds consist of measures of the urge-to-cough that causes airway irritation together with the associated cough response (8). With the exception of voluntary cough, the production of a cough requires stimuli that reach the cough threshold. Most of the current research on cough threshold and the urge-to-cough has been conducted via provocation tests, with little or no direct testing in the normal state free from artificial interference factors. Some aspects, such as different individual state differences (e.g., mood) and habitual coughing caused by prolonged cough and some psychological factors (tension and anxiety, etc.), can cause involuntary cough in the absence of external stimuli. Differences in perception of different tussive agents affect the perception and response of stimuli, which in turn affects the production and measurement of cough threshold and/or the urge-to-cough.

The complexity of the peripheral and central nervous system that regulates coughing involves numerous primary sensory neurons capable of initiating or promoting coughing, ascending pathways, areas of the brain that contribute to cough sensory discrimination and perception of the urge-to-cough, and descending pathways regarding cough movements (18). The central pattern generator (CPG) of the neural circuit respiratory center that generates respiratory rhythmic motor activity, with the pre-Bötzinger complex (preBötC) as its core, is essential for generating normal respiratory rhythms and patterns (19). Similarly alters the activity of inspiratory and expiratory muscles and intervenes in coughing (20). Therefore, it is unlikely that the mechanisms leading to cough dysregulation in disease are homogeneous. It has been suggested that changes in the excitability of primary sensory neurons, abnormalities in the integration of sensory inputs into the central nervous system, and changes in descending control may all contribute to cough dysregulation (18). Cough hypersensitivity reflected by multiple cough triggers (including feeding triggers, mechanical triggers, etc.) is a common feature of chronic cough. The cough challenge test is by far the most established and commonly used method for assessing cough sensitivity, while the cough suppressor test evaluates the center’s ability to suppress cough (21). However, distinct etiologies present specific features of cough triggers that may not be comprehensively evaluated through the cough challenge test (22). Current cough challenge tests are mostly limited to specific tussive agents, with fewer experiments assessing cough reflex sensitivity by mechanical stimulation, and the validity needs to be further explored (23), with no or little consideration of heterogeneity, which is perhaps a key direction for future research.

Cough reflex pathway

Coughing is a reflex that requires minimal conscious control, generated through stimulating sensory nerve fibers (e.g., Aδ and C-fibres) located in the respiratory tract and the diaphragm, external ear, and esophagus, mainly in the extrapulmonary airways (7,24). Different stimuli are transmitted to the vagus nerve by a subtype of sensory neuron, the airway mechanoreceptor or simply the cough receptor, originating in the nodal vagus ganglia (25,26), and by another subtype of sensory neuron, the bronchopulmonary chemoreceptor or injury receptor, originating in the jugular vagal ganglia (18,27). The first are sensitive to bronchospasm, lung hyperextension, mucus overproduction and edema. The latter are sensitive to capsaicin, bradykinin, and prostaglandins. And both of them are sensitive to the acidity of the environment (28). Impulses transmit to the nucleus of tractus solitarius (NTS) and the paratrigeminal nucleus (Pa5), located in the medulla oblongata of the brainstem, at which they are involved in the processing of sensory information in the airway for coordination (29-31). Airway sensory neurons of nodal origin project almost exclusively to the NTS, and jugular ganglion origin project to the Pa5 (24,32-36).

The presence of two medullary processing nuclei suggests that different vagus nerves afferent to different ascending pathways. Nodal afferent pathways are widely integrated into the limbic system and autonomic circuits, whereas jugular afferent pathways resemble those involved in somatosensation (33). These second-order neurons ascend to the brainstem respiratory circuits required for participating in the generation of reflex cough, as well as the subcortical and cortical neural networks involved in sensory discrimination (including the generation of cough impulses) and autonomic cough modulation (voluntary cough induction and suppression) (37,38): ascending the neuraxis with terminating substantively in the parabrachial nucleus (PBN), the ventral postero-medial (VPM) and reticular thalamic nucleus (TRN), the paraventricular nucleus of the hypothalamus (PVN), the zona incerta (ZI), the central amygdala (CeA), and ultimately in the somatosensory cortex (SC), the anterior agranular insular cortex (aAIC), and diffusely throughout the rostro caudal extent of the cingulate cirtex (Figure 1A) (29,35). The act of cough succeeds the perception of the elicited airway stimulus (“urge-to-cough”), accompanied by activation in widely distributed brain networks, including the primary motor cortex (MC), SC, insular cortex (IC), prefrontal cortex (PFC), and posterior parietal cortex (PPC) (Figure 1B) (30). The descending pathways of the reflex arc include the cough center through the vagus, phrenic, and spinal motor nerves to the diaphragm, abdominal wall, and muscles to elicit a coughing movement (7,24).

Figure 1 Overview of the brain regions implicated in (A) the cough reflex pathway, (B) the urge-to-cough, and the cough suppression related. aAIC, anterior agranular insular cortex; CB, cerebellum; CeA, central amygdala; CPG, central pattern generator; MC, motor cortex; NTS, nucleus of the solitary tract; Pa5, paratrigeminal nucleus; PBN, parabrachial nucleus; PC, parietal cortex; PFC, prefrontal cortex; PPC, posterior parietal cortex; PVN, paraventricular nucleus of the hypothalamus; rACC, rostral anterior cingulate cortex; rDLPFC, right dorsolateral prefrontal cortex; SC, somatosensory cortex; TRN, thalamic reticular nucleus; VPM, ventral posteromedial nucleus; ZI, zona incerta.

Difference between jugular and nodal vagal afferent

One study explored differences in cough afferent nerves using functional magnetic resonance imaging (fMRI). Capsaicin activation of the jugular and the nodal vagus further activated the dorsal medial and dorsal lateral regions of the medulla oblongata within the NTS and Pa5. Selective stimulation of nodal neurons and dorsomedial areas of the medulla oblongata, including the NTS, by serotonin, adenosine, and adenosine triphosphate (ATP) produced significantly less cough and stimulated different subjective sensory sites than capsaicin did (39). Further studies have revealed that the higher regions of the human brain activated by capsaicin include localized areas of the IC, SC, cingulate cortex (CC), PFC, and PPC. ATP activation is fully localized in this wider network, with no specific regional response (40). Interestingly, studies have revealed that airway C-fibres from the jugular ganglia of guinea pigs initiate and/or sensitize the cough reflex. In contrast, intrapulmonary C-fibres from the nodose ganglion actively inhibit coughing upon activation (41). The different region responses provide insight into the unique aspects of higher brain regions for different afferent processing.

Central regulation of cough

Central modulation of cough is divided into three main components: (I) brainstem processing of incoming information, (II) organization of the brainstem control network, and (III) higher brain (both subcortical and cortical) circuits that support the role of consciousness, perception, and expression of emotion in cough (24).

Cough is more than a protective reflex cough and involves higher levels of brain regulation. Much of the research and understanding of the central regulation of cough has come from animal models, with human studies mainly conducted using fMRI. There are limitations to current research, and improved methods to study central neuronal expression, function, and synaptic transmission may be needed to determine the transformation potential of previous animal model findings (30,42). There are many previous animal-based studies: there are species differences in the neural networks for cough control in cats and rabbits (43): (I) The rostral NTS (rNTS) of cats was significantly related to the regulation of cough magnitude and phase timing (44), in which the GABAergic inhibitory mechanism could regulate coughing in anesthetized cats, whereas the caudal NTS (cNTS) had a more limited regulation of coughing; the GABAA and glycine receptor effects of acetylcholine on the cNTS of rabbits could effectively inhibit respiration and cough reflexes. (II) There are multiple airway afferent processing pathways in the rodent brain, and the response areas in the higher-order cortex that receive different inputs are different. One study using fMRI during inhalation of capsaicin and ATP has shown that similar sensory processing exists in the human brain (40,45-48). (III) Neuronal activity in the brain during gastroesophageal reflux-associated cough (GERC) was investigated by hydrochloric acid infusion and citric acid-induced cough rat model. The induced airway inflammation is modulated by the dorsal vagus nerve complex (DVC), and neurons in the medulla oblongata, NTS, dorsal motor nucleus of the vagus, Pa5, and intermediate reticular nucleus may be involved in the coughing process. These animal experiments suggest both heterogeneity and similar mechanisms for different causes of cough (49,50). The efficient transformation of research discoveries on cough mechanisms into cough therapies relies on the proper utilization and innovation of cough models (51). The second flawed aspect is the means of measurement. fMRI detection of Blood Oxygenation Level Dependent (BOLD) signals in the brain may be adversely affected by other sources of physiological noise and may behave differently in different individuals, with some studies of human brainstem modulation of coughing finding that in individuals who cough, the baseline noise estimates of the composite measure were higher (52). Perhaps further improvements in the measurements are needed to increase the accuracy of the experiment.

Previous animal studies have demonstrated that cough is elicited in decerebrate or deeply anesthetized animals (25,53). These findings suggest that modulation above the brainstem level, or even supra-medullary modulation, may not be essential for generating fundamental reflexive cough movements. Typically, when coughing falls within the spectrum from purely reflexive to purely voluntary, it is almost always accompanied by perceptible sensations that drive the desire (or impulse) to cough. This sensory process needs to transcend to the parts primarily integrated into the regulation of cough within the brainstem. Cough is initiated and suppressed autonomously, with cortical and subcortical participant regions playing an important role. These regions work together to form a center regulation cough network, associating with perceptual feedback from the respiratory tract, modulating emotional behavioral responses, and providing important descending regulatory control of cough motor events (39,54,55) (Figure 1 and Table 1 for summary of brain regions).

Voluntary cough

The voluntary production of a cough likewise gives rise to the urge-to-cough, which involves the cerebral cortex (61). More intense cough stimuli are required to trigger coughing when pathways between the cortex and brainstem are affected. It indicates dysfunctional control of coughing, especially voluntary coughing, in higher brain regions. Like most neurodegenerative diseases (e.g., stroke and Parkinson’s disease), they can interfere with voluntary coughing (62). Urge-to-cough-associated insulae show reduced activation and atrophy in dementia with Lewy bodies (DLB), with worse cough reflex sensitivity and perception of urge-to-cough (63). Secondly, habitual cough and Tourette’s syndrome are both considered to be cortical-mediated. Some studies have shown that placebos and many complementary medicine-based treatments are effective in suppressing cough (61,64,65). Additionally, cough is significantly suppressed or decreased during sleep and anesthesia (61). When the doses of inhaled capsaicin in healthy individuals are insufficient to cause coughing, the stimulus, although falling short of the cough threshold, still causes a transient urge-to-cough, which commonly provokes a voluntary cough. This impulse activates various related brain regions, including SC, MC, IC, the orbitofrontal cortex (OFC), the discrete regions of the anterior cingulate cortex (ACC), and the cerebellum (CB) (Figure 1B) (39).

The link between body rhythms and neural activity and the influence of both perceptual and cognitive functions has raised questions about many potential mechanisms. There are articles describing in detail the endosensory rhythms of the brain (66). Among these, respiratory interoception relates to the pre-Bötzinger complex and the peripheral nuclei and limbic system in the ventral medulla oblongata of the brainstem in the central nervous system (19,67,68). Also, including the pulmonary vagus nerve, the primary endosensory transmitter nuclei of the NTS and PBN, as well as the thalamus (TH) (69) and the locus coeruleus (LC) (68), and the interoceptive-related subcortices, cortices such as the amygdala and cingulate motor areas (70), these central and peripheral routes are associated with respiratory interoception. Coupling among some neural activities has also been associated with the modulation of memory performance and human emotional appraisal, which partially or fully overlap with the central cough network. Integrating interoception and exteroception signals raises central questions about neural coding (8,66), which provides novel thinking for studying neural coding of coughs at all levels.

Cough suppression

Research has demonstrated that different neural networks are responsible for placebo-intervened cough regulation and autonomic cough suppression. The cough impulse persists during autonomous cough suppression but not during placebo-intervened cough (15). Brain activity in the PFC and PPC increased when participants believed they were receiving cough-suppressing treatment, which may be an essential part of the placebo inhibition network (56). It has been indicated that the dorsal peduncular nucleus (DPn), an almost entirely unexplored area of the ventral prefrontal cortex (vPFC) in which express vesicular glutamate transport 2 neuronal population (DPnvGlut2 neurons) projects to the PBN, is associated with an aversive response to opioids (71). Opioids such as codeine have an antitussive effect (72). It may have something to do with it. Inhibitory control, one of the three components of executive function, occurs primarily in the PFC. Inhibitory control is associated with attention and perception, including controlled and focused attention, usually to self-controlled processing behaviors that gain benefit by delaying conflict or behavior (73). One study manipulated attentional focus through the dual-task paradigm, which could alter the motor and sensory dimensions of urge-to-cough and reflexive coughing, suggesting that changes in attentional processing can alter supramedullary influences on coughing from the top down (74). It contributes to furthering research on cough suppression.

Inhibitory process-related brain regions: inhibitory process that is likely mediated by PFC, parietal cortex (PC), and CB. Activity in the right dorsolateral prefrontal cortex (rDLPFC) seems to have a special significance (Figure 1B) (56). Electrical stimulation of the rDLPFC significantly increased cough reflex and impulse thresholds (57); Nevertheless, the contralateral brain region (lDLPFC) did not show the same inhibitory effect, which may be related to intercortical DLPFC interactions. In contrast, stimulation of the right primary somatosensory cortex (rS1) significantly lowered cough reflex thresholds and increased urge-to-cough sensitivity (58).

Activation of GABAB receptors in the central system will inhibit cough (75). Second-order relay neurons of slowly adapting receptors (SARs) located in the nucleus of the solitary tract are known as pump cells. Includes a group of inhibitory neurons that are essentially GABAergic, some of which may co-release GABA and glycine (76). Studies have shown that cough suppression relies on the descending projections of GABAergic pump cells to rapidly adaptive receptors (RARs) relay neurons in the NTS ganglionic subnucleus (Figure 2A) (77,78).

Figure 2 Overview of the neurotransmission involved. (A) Cough suppression: (I) The M4 subtype of mAChRs mediates the cholinergic inhibitory control mechanism of the cough reflex. Other sources of cholinergic projections to the NTS: the dorsal motor vagal nucleus and the nucleus ambiguus, the ponto-mesencephalic tegmental cholinergic complex. (II) The cough-like reflex activates the l/vlPAG-NTS circuit, inhibiting cough-like behaviors by GABAergic neurotransmission. (III) The descending projections of GABAergic pump cells to RARs relay neurons. (B) Vagal-cNTS immune axis: LPS and cytokines induce activation of glutamatergic neuron clusters expressing DBH genes in the cNTS, i.e., DBH neurons, through two conduits. The TRPA1-expressing vagal neurons as a conduit for relaying anti-inflammatory signals to reinforce the anti-inflammatory state. The CALCA-expressing neurons in the vagal ganglia as another conduit for relaying inhibit pro-inflammation signals to reinforce the anti-inflammatory state. (C) Central sensitization: enhanced sensory signals are transmitted to the brainstem for prolonged periods, leading to the recruitment and activation of glial cells and the release of large amounts of inflammatory mediators (including CK, brain-derived neurotrophic factor, and growth factors), and inflammatory or immune signals can also reach brain regions directly via blood-borne pathways. This further leads to CREB-mediated gene transcription inducing long-term synaptic plasticity, increased excitatory glutamatergic neurotransmission, and decreased inhibitory GABAergic neurotransmission (including endocytosis of GABA_A receptors). CALCA, calcitonin-related polypeptide-α; CK, cytokines; CREB, cAMP-response element binding protein; cNTS, caudal nucleus of the solitary tract; DBH, dopamine β-hydroxylase; l/vlPAG, lateral and ventrolateral periaqueductal gray; LPS, lipopolysaccharide; mAChRs, muscarinic acetylcholine receptors; NTS, nucleus of the solitary tract; PAG, periaqueductal gray; RARs, rapidly adapting receptors; TRPA1, transient receptor potential ankyrin 1.

Circuit mechanisms in the midbrain and surrounding regions that regulate coughing

Anxiety states often lead to disease symptoms in a negative direction. NTS neurons project to many sensory-related brain regions, including the LC, PBN, TH, and CeA (33,34). Reduced functional connectivity between the NTS and ACC may contribute to anxiety in patients with cough, and activation of the ACC may alleviate anxiety symptoms in patients with chronic cough (79).

The lateral and ventrolateral periaqueductal grey (l/vlPAG) receives inputs from many different sensory-related regions, which include the PFC, amygdala, PBN, and the spinal cord, and plays a critical role in somatosensory and multiple respiratory functions. It serves as a hub for integrating multiple sensory information and regulates the interactions between different sensations (59). Animal studies have shown that l/vlPAG GABAergic neurons form inhibitory synapses with NTS neurons, i.e., the l/vlPAG-NTS circuit (Figure 2A). The cough-like reflex activates l/vlPAG, which exerts top-down control over its downstream target, the NTS, inhibiting cough-like behaviors. Continuous airway stimulation induces a disinhibitory effect on the l/vlPAG-NTS circuit, leading to an increase in NTS neuronal activity, which in turn causes cough hypersensitivity (60). It provides novel ideas for cough treatment.

Some animal studies have shown that the M4 subtype of muscarinic acetylcholine receptors (mAChRs) located in the caudal part of the cNTS mediates the cholinergic inhibitory control mechanism of the cough reflex. The dorsal motor vagal nucleus and the nucleus ambiguus, as well as the ponto-mesencephalic tegmental cholinergic complex, periaqueductal grey (PAG), may be the source of cholinergic projections to the NTS. Intervention with the M4 subtype blocked muscarinic-inhibited respiratory activity and cough reflexes without serious adverse effects, suggesting its potential for down-regulation of cough (Figure 2A) (46,80). May serve as a potential pharmacological target.

Excessive coughing

The primary central cause of excessive coughing is the up-regulation of cough sensory processing and/or the down-regulation of inhibitory mechanisms in the brain. The plasticity of the nervous system dictates that stimulation of peripheral nerve fibres leads to changes in their excitability: through alterations in receptor expression and synaptic transmission, resulting in changes in the system’s response to stimulation. This process involves multiple pathways, and a single mechanism may predominate, but not alone. The term “peripheral and central sensitization” was used in the neuropathic pain literature to describe alterations in the function of the cough nerves (81,82), suggesting that a link exists between the two. There are mechanism studies on cough in patients with idiopathic pulmonary fibrosis (IPF) that have found no significant increase in TRPV-1 and TRPA-1 receptor expression in the central airways of IPF patients at the gene or protein level. It indicates that cough behaviors involve many receptors and interactions and is also associated with complex regulation at the central level (83).

Stimulation of peripheral inflammation can induce changes in neurons and glial cells in areas of the brain that control respiration and autonomic processing, such as the NTS. Lung inflammation alone may not be sufficient to drive central sensitization of the cough in all patients; thus, multiple processes are probably involved (37). The main pathway may be through enhanced sensory neurotransmission, or like the NTS lies in the vicinity of near periventricular organs that do not have an intact blood-brain barrier, and inflammatory or immune signals can reach the central region directly via a blood-borne pathway (84). An overactive pro-inflammatory state always leads to immune dysregulation, resulting in various inflammatory responses that trigger uncomfortable symptoms. Inflammatory mechanisms of central sensitization exist (85), and previous studies have noted significant similarities in the clinical manifestations of cough, pain, and itch hypersensitivity (86), with the possibility of similar central mechanisms (Figure 2C). During lung inflammation, enhanced sensory signals are transmitted to the brainstem, driving higher-than-normal levels of synaptic activity. Over time, this leads to the recruitment and/or activation of glial cells. Activated glial cells release large amounts of inflammatory factors, including cytokines and brain-derived neurotrophic (87) and growth factors (37,88,89), which induce central sensitization through distinct and overlapping synaptic mechanisms. Long-term synaptic plasticity may be further induced by cAMP-response element binding protein (CREB)-mediated gene transcription. Tumor necrosis factor-alpha (TNFα) promotes preferential efflux of glutamate receptor 2-lacking AMPA receptors. It also enhances NMDA-mediated currents and induces endocytosis of GABAA receptors (90). Interleukin-1beta (IL-1beta) enhances NMDA receptor phosphorylation in the trigeminal nucleus (91) and inhibits GABA- and glycine-mediated currents (92). The net effect of neuroinflammation is an increase in excitatory (glutamatergic) and a decrease in inhibitory (GABAergic) neurotransmission, with a prominent role for NMDA receptor (a subtype of ionotropic glutamate receptor) signaling in cough coding (77). These activities may make the central nervous circuits more sensitive to sensory neural inputs and weaken cough inhibition, promoting irreversible sensitization, and even when peripherally reinforced sensory inputs are lost, cough hypersensitivity and hyper cough do not disappear (37).

Neurotransmitter-like substances likewise play an essential role in central sensitization. For example, prostaglandin E2 (PGE2) activates the NaV1.8 channel, a voltage-gated sodium channel in the NTS, which enhances citric acid-induced cough centrally and is not associated with the activation of other sensitizing channels, such as transient resistance potential (TRP) channels. It indicates that PGE2 plays an essential role in the central sensitization of cough and that central PGE2 receptors and NaV1.8 channels are significant components of the enhanced cough signaling pathway (93). Related drugs such as lidocaine are already under development (94).

In addition to the brainstem and cortex, cough-related regions exist in other central regions like the mesencephalon, which may be part of the connectivity pathway between the brainstem and cortex or directly involved in cough mechanisms.

Body-brain axis, gut-brain axis

The body-brain axis manifests an essential role in balancing immune function: the activity of central neurons regulates peripheral inflammation in both directions, activating body-brain circuit in the absence of an immune challenge has no effect on cytokine levels, suggesting it plays a role in monitoring and regulating an immune response rather than initiating it (95). There is a vagal-cNTS immune axis. cNTS, as the main channel of the body-brain axis and the primary projection point of the vagus nerve, is activated by immune damage (96), whereas the rNTS is not. At the same time, the area postrema (AP) will be active, and this area is associated with physical discomfort (97). cNTS neurons expressing the dopamine β-hydroxylase (DBH) gene receive direct input from two signaling lines in the vagus ganglia: on the one hand, it carries anti-inflammatory signals and helps to enhance anti-inflammation through positive feedback regulation by releasing anti-inflammatory cytokines; on the other hand, it carries pro-inflammatory signals and helps to inhibit pro-inflammation through negative feedback regulation by releasing pro-inflammatory cytokines (Figure 2B). Body-brain circuits are specific in that neurons in the vagal ganglia respond selectively to proinflammatory, and activation of other vagal populations has no significant effect on LPS-induced inflammatory responses (95,98).

The gut-brain axis, as an integrated system of bi-directional regulation comprising immune, endocrine, and neuronal components (99), regulates the complex interplay of respiratory, neurological, and gastrointestinal functions through the vagus nerve as well as the immune, enteric nervous, endocrine, and circulatory systems. The impact on the central nervous system is critical. Studies have shown that SARS-CoV-2 infiltrates the central nervous system, disrupting the blood-brain barrier and neuronal synapses, further causing brainstem inflammation and neurodegeneration, obstructing efferent signals, leading to impairment of anti-inflammatory signals, normal respiratory and gastrointestinal functions. At the same time, infection of intestinal cells results in intestinal damage, microbiota dysbiosis, and the transporter of bacteria and their products across the compromised epithelial barrier, and the reciprocal malignant feedback exacerbates the local and systemic inflammation (100,101). Some reviews discuss comprehensively the microbiota-gut-brain axis and its mechanisms of intervention and therapeutic applications in neurodegenerative diseases (102). As mentioned earlier, neurodegenerative diseases are closely related to cough behavior and modulation (103). Some studies have examined the role of the microbial gut-lung axis in refractory chronic cough (RCC). RCC refers to permanently increased cough reflex sensitivity, with the cough persistent despite the underlying condition (e.g., upper respiratory disease, asthma) improved. Alterations in the gut and oral microbiota and levels of their metabolites may affect the gut-lung-brain axis. This axis involves bidirectional communication between the three, in which short-chain fatty acids (SCFA), which are microbial-derived metabolites, play a key mediating role (104).

The body-brain axis and the gut-brain axis regulate immune homeostasis through multiple systems and regions as a whole. However, relying on the current study to establish a definitive causal relationship between these mechanisms and cough remains challenging as it is difficult to determine whether the observed alterations are causative, consequential, or merely a bystander response to the disease. Demand caution and rationally understand the causal implications of these findings (102). Central loops and the neuronal populations involved in this serve as pharmacological targets that may yield new approaches to treat diseases caused by immune disorders.

The quest for effectiveness in treatment

Clinical perspective

An understanding of the cough pathophysiological mechanisms is helpful in clarifying the etiology of the cough and in the search for new clinical therapeutic concepts. Acute cough caused by diseases such as the common cold, exacerbation of chronic obstructive pulmonary disease, is induced by a variety of stimuli, most prominently respiratory secretions, which act directly on the reflex zones of the pharyngeal mucosa, and inflammatory mediators, which act on peripheral sensory endings of the respiratory tract (82). Inflammatory or other factors may affect the central nervous system, inducing a hypersensitivity response. In an investigation, healthy subjects had greater control of the urge-to-cough than subjects with the common cold (82). Cough sometimes occurs voluntarily even when there is no risk of any foreign body being present in the airway or the cough threshold is not reached. This highlights the intervention of cortical region. Subacute cough is as self-limiting as acute cough. The subacute cough is caused by slowly resolving viral and post-viral sinusitis, Bordetella pertussis or Mycoplasma pneumoniae infections, or temporary bronchial hyperreactivity after infection (105). The patients who developed postinfectious cough had a higher sensitivity of the cough reflex (106). The common causes of chronic cough are upper airway cough syndrome, gastro-oesophageal reflux disease, asthma, and infections, while some are neurogenic or drug-induced (20,107). As a clinical condition, usually accompanied by cough hypersensitivity, characterized by a cough induced by exposure to low levels of sensory stimuli and excessive coughing in response to innocuous stimuli (38), driven primarily by dysfunction of central and peripheral neural pathways (42,52,54).

Structural and functional plasticity of central neural networks is the fundamental mechanism of cough hypersensitivity (52). When cough behavior was equivalent, chronic cough patients showed significantly less neural activation in the medulla oblongata region known to integrate airway sensory inputs. Neural activation in cortical areas encoding the sensation of coughing did not differ significantly from normal individuals, i.e., low levels of peripheral sensory input could amplify or evoke coughing more effectively. However, significantly increased activation was observed in midbrain regions (the nucleus cuneiformis and the PAG). It resembles the inflammatory and neurological processes that lead to the development of chronic pain (86), supporting the idea that cough and pain have neurobiological similarities (52,54) while providing evidence for the midbrain as an amplifier of cough sensory input. Other causes cannot be ruled out, such as dysfunction of the descending regulatory pathways that may induce dysregulation of cough suppression (52).

Now chronic (refractory or idiopathic) cough is recognized as a disease entity, whereas cough as a symptom of many respiratory (e.g., asthmatic, chronic obstructive pulmonary disease, postinfectious cough) and non-respiratory diseases (e.g., gastroesophageal reflux) (105). The paradigm shift from regarding cough as a symptom to cough as a disease allows for many advantages in both diagnosis and therapy of this condition. The cough reflex hypersensitivity is clinically regarded as the cause of chronic idiopathic or refractory cough. Diseases such as reflux, rhinosinusitis, chronic obstructive pulmonary disease, asthma and pulmonary fibrosis are considered triggers of chronic cough (108). There may be similarities in their central mechanisms (7). In central hypersensitivity, neuronal plasticity plays a central role, and little is known about the more precise molecular pathophysiology (105). The advantage of cough hypersensitivity as a diagnosis is that by focusing on a unifying pathological feature, it points the way to possible therapeutic avenues. And the diagnosis of CHS facilitates communication with patients. Cough hypersensitivity as a disease, objective evidence of it relies on challenge experiments. In the clinic, there is limited utility in performing cough challenge to demonstrate cough hypersensitivity since it is only roughly correlated with the clinical perception of cough (107). Although these perceptions are often reported by patients, lack specificity for the diagnosis of CHS (3). Overall speaking, the identification of cough hypersensitivity is certainly of major importance to boost research on cough and progress in the care of patients whose health status is severely impaired by related symptoms.

Drugs research

The discussion of progress in developing targeted drugs was in another review (109). In particular, the development of a wide range of new drugs for diseases such as RCC is promising. Medicine development requires identify the central locations involved (e.g., neuropeptides), aiming for efficacy without compromising vital protective mechanisms. However, less is known about the pharmacology of drug-induced alterations in central neural circuit transmission processes. Filling these gaps is critical for optimizing therapeutic strategies.

ATP receptors (P2X3) and substance P receptors (NK-1) are emerging as potential targets for targeted antitussive therapy. Several compounds targeting neuronal channels and receptors, such as P2X3 (12) and NK-1 receptor antagonists, have shown the most potential in clinical trials so far. Some studies have found that interventions on the vagal signaling process in the jugular vein at different levels of the neuraxis may be a promising line of research: antagonising P2X3 (110,111), which is present in jugular ganglion, and NK-1, which is present in Pa5 neurons (112,113); Modulatory neural circuits of higher brain regions associated with the jugular vein vagus nerve. The submedius thalamic nucleus and the ventrolateral orbital cortex are the core regions of this circuit. Targeted increased activity of this network inhibits the processing of jugular venous nociceptors in Pa5 (114,115). Multiple neurons in the paratrigeminal circuit that mediate jugular ganglia-evoked respiratory reflexes are involved in the respiratory reflex (115), and they show potential to be new target receptors. Although intervention in a single process does not affect other pathways, improvement in cough symptoms may be limited (116), and therapeutic options are restricted.

Currently, symptomatic treatment of cough is very limited both in terms of the evidence base and its efficacy or side effects. The clinical need for central-targeted treatments for cough, especially those that suppress pathological cough without affecting the protective cough reflex, remains high. And the right choice of drug needs to consider the patients’ heterogeneity. The benefit/risk balance of these drugs also needs to be considered because of the inevitable side effects. Innovative therapies are expected to provide better efficacy and may mitigate the adverse effects associated with currently recommended treatments (42). For example, the goal of behavioral cough suppression therapy is not to make patients good at suppressing cough, but rather to stimulate a reduction in cough sensitivity through neuroplasticity (117). Effective control of cough requires not only controlling the disease causing the cough but also desensitisation of cough pathways.

Conclusions

The complexity of the neural mechanisms of cough results in the possibility of marked or subtle heterogeneity of presentation in different patient groups. This variability highlights the need to tailor individualized treatments. The current study, including the ideas and experimental methodologies, is still insufficient. Typically, both the urge-to-cough and coughing change simultaneously with increasing sensitivity. However, coughing can occur even with normal sensitivity when sensory input is low, possibly due to central inhibition disorders (52). It remains unclear whether this reflects a specific change in sensitivity, the activation of cough inhibitory mechanisms, or other underlying causes. To address these questions, further refinement of the central cough neural network, including physiopathology and mechanisms of change following pharmacological intervention, is required. To achieve the goal of suppressing unnecessary coughing (excessive pathologic) without interfering with necessary coughing behavior.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2262/prf

Funding: This study was supported by Shandong Province Taishan Industry Leading Talent Project (tscx202408120), Key R&D Program of Shandong Province, China (2022CXGC020514), Shandong Province Science and Technology based Small and Medium sized Enterprises Innovation Capability Enhancement Project (2022TSGC2593).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2262/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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