Regional brain stem activations during capsaicin inhalation using functional magnetic resonance imaging in humans

Abstract

Coughing is an airway protective behavior elicited by airway irritation. Animal studies show that airway sensory information is relayed via vagal sensory fibers to termination sites within dorsal caudal brain stem and thereafter relayed to more rostral sites. Using functional magnetic resonance imaging (fMRI) in humans, we previously reported that inhalation of the tussigenic stimulus capsaicin evokes a perception of airway irritation (“urge to cough”) accompanied by activations in a widely distributed brain network including the primary sensorimotor, insular, prefrontal, and posterior parietal cortices. Here we refine our imaging approach to provide a directed survey of brain stem areas activated by airway irritation. In 15 healthy participants, inhalation of capsaicin at a maximal dose that elicits a strong urge to cough without behavioral coughing was associated with activation of medullary regions overlapping with the nucleus of the solitary tract, paratrigeminal nucleus, spinal trigeminal nucleus and tract, cardiorespiratory regulatory areas homologous to the ventrolateral medulla in animals, and the midline raphe. Interestingly, the magnitude of activation within two cardiorespiratory regulatory areas was positively correlated ( r2 = 0.47, 0.48) with participants’ subjective ratings of their urge to cough. Capsaicin-related activations were also observed within the pons and midbrain. The current results add to knowledge of the representation and processing of information regarding airway irritation in the human brain, which is pertinent to the pursuit of novel cough therapies. NEW & NOTEWORTHY Functional brain imaging in humans was optimized for the brain stem. We provide the first detailed description of brain stem sites activated in response to airway irritation. The results are consistent with findings in animal studies and extend our foundational knowledge of brain processing of airway irritation in humans.

Altered neural activity in brain cough suppression networks in cigarette smokers

“…Evidence for altered airway sensory processing in the brain of smokers Capsaicin inhalation challenge of both smokers and controls activated brain regions that are consistent with previous reports, and this adds further support to the conclusion that airways irritation and associated processes are represented in a distributed brain network [1,2,7,[22][23][24]. The constituent regions of the network include the prefrontal, cingulate, sensorimotor, posterior parietal and insula cortices, as well as the thalamus, cerebellum, basal ganglia and brainstem.…”

“…Cough is a neural process that plays an important role in airway defence and the maintenance of adequate ventilation. Functional brain imaging studies in humans and neuroanatomical investigations in animals provide insight into the central (brain and brainstem) sensory and motor networks involved in cough under nonpathological circumstances [1][2][3][4][5]. However, cough sensitivity can become altered, especially in disease states and from psychophysical (e.g.…”

Evidence for multiple bulbar and higher brain circuits processing sensory inputs from the respiratory system in humans

“…2018), both of which respond to capsaicin inhalation in humans (Bautista et al . 2019 a ). By contrast, at the same rostrocaudal medullary levels, the bulbar activations induced by the putatively nodose‐selective stimulus ATP were restricted to medially‐located regions of the medulla, consistent with sensory integration confined to the NTS.…”

Peripheral and central mechanisms of cough hypersensitivity

“…The nucleus of the solitary tract and paratrigeminal nucleus connect widely to medullary and pontine networks responsible for cardiorespiratory control and respiratory pattern generation via which automated motor responses, including cough, are encoded (3,34,35). Recent studies using functional brain imaging during tussive challenges, for example with inhaled capsaicin, suggest that similar brainstem circuitry exists in humans, with capsaicin-evoked activations reported within regions encompassing the nucleus of the solitary tract, paratrigeminal nucleus, spinal trigeminal nuclei and cardiorespiratory processing regions equivalent to the ventrolateral medulla and midline raphe (36).…”