Clinical trial NCT03722849: Functional Magnetic Resonance Imaging of ATP Cough in Chronic Cough Patients
Official title: A Functional Magnetic Resonance Imaging Study to Investigate ATP-sensitive Cough Neural Pathways in Patients With Chronic Cough Hypersensitivity
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Cough
Keywords: functional brain imaging
ATP
Capsaicin
Refractory cough
Lead sponsor: University of Melbourne
Sponsor class: OTHER
Collaborators: name: Imperial College London
name: Queen's University, Belfast
name: Monash University
First posted: 2018-10-29
Enrollment: 58
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The experiment will consist of two sessions. The first session will involve questionnaires, followed by measures of sensitivity and behavioural responses to tussive (cough evoking) stimulation. The second session will involve functional brain imaging measures of responses to tussive stimulation.
Primary purpose: BASIC_SCIENCE

Brief summary: Persistent cough is a distressing symptom for people with respiratory disorders. Patients also often experience an ongoing urge-to-cough that prompts coughing, and which fails to resolve the sensation. Understanding how the brain controls cough and the urge-to-cough could lead to new cough suppressing therapies. The overall objective of this project is to use functional brain imaging (fMRI) to identify brain regions that are involved in the exaggerated urge-to-cough in humans with chronic cough. Our focus will be on the brainstem where information from the airways first arrives in the central nervous system.

Detailed description: Peripheral effects of ATP via P2X3 receptors

ATP has been shown to be a tussive agent particularly on chronic cough patients who were more sensitive than non-cough subjects to inhaled ATP. ATP has been shown to augment the cough response to capsaicin in patients with asthma. Gefapixant at a single oral dose of 50 mg did not modulate capsaicin cough responses in normal volunteers and chronic cough subjects while inhibiting ATP-induced cough particularly in chronic cough subjects. These observations would suggest that ATP has a direct effect on a subset sensory neurons that evoke coughing through the activation of P2X3 receptors.

The use of fMRI to provide insights into the peripheral and central sites of activation by ATP/P2X3 activation We have generated functional brain imaging (fMRI) data to suggest that the different brain circuits in receipt of nodose and jugular ganglia neuron inputs (as identified in animal studies) are conserved in humans. When inhaled, the tussigenic compound capsaicin (from hot chili peppers) indiscriminately stimulates both nodose and jugular chemosensitive afferents and we have published that capsaicin inhalation produces brain activations in the primary sensory, anterior and mid-insula, cingulate, premotor, motor and orbitofrontal cortices. These regions are presumed to encode perceptual awareness of airway irritation, and the associated emotional, cognitive and behavioral (motor) consequences. For example, activity in the human primary sensory cortex (which receives jugular ganglia inputs in animal studies) correlates with an individual's perception of airway irritation (their perceived need/ urge to cough) while activity in the insula (in receipt of nodose inputs) relates closely to the actual magnitude of the delivered stimulus independent of perception. We have now built upon these published findings by using high resolution brainstem fMRI during the inhalation of ATP (expected to only activate P2X2/3 expressing nodose-derived airway afferents) versus capsaicin (expected to activate both jugular and nodose chemosensitive afferents). Our results are striking and reveal that ATP inhalation evokes an in increased signal level in the brainstem regions corresponding to the nTS, while capsaicin inhalation produces activations in both the nTS and in an area of the dorsal spinal trigeminal nucleus on the lateral margins of the brainstem that contains the paratrigeminal nucleus. Indeed, our healthy participants did not cough as much to ATP compared to capsaicin, consistent with studies cough in animals and humans and the relatively poor cough-evoking properties of ATP in healthy humans. However, the perception of airway irritation was identical between ATP and capsaicin stimuli. We believe that cough production will ultimately be dependent upon activation of the neural circuit that integrates in the paratrigeminal nucleus (i.e.' the jugular afferent pathway) and therefore we hypothesize that there is an upregulation of the capacity of ATP to act via jugular ganglia pathways in chronic cough patients.

The fMRI studies described above provide an exciting opportunity to assess for the first time which primary airway afferent pathways are likely excited or sensitized by ATP and, in turn, what aspects of the central processing of airway sensory information is altered by ATP. We have reported previously that patients with chronic cough display functional brain responses consistent with a state of central sensitization that closely resembles the central sensitization accompanying chronic pain.

We will extend upon these findings by determining whether ATP-sensitive pathways in the brainstem and brain are altered in patients with chronic cough, and in doing so provide insight into whether ATP effects vagal afferent processing through an interaction with nodose and/ or jugular neural pathways.

Eligibility criteria: Inclusion Criteria:

* Patients with physician diagnosed chronic refractory cough (cough lasting \>8 weeks).
* \> 18 years of age
* Must be cognitively impaired

Exclusion Criteria:

* People with contraindications to MRI scanning (i.e. metal implants, claustrophobia).
* History of uncontrolled asthma or chronic respiratory disease (other than refractory cough).
* Evidence of an allergic reaction to capsaicin (chilli).
* Pregnant women.
* Smoking, current or recent history (last 6 months).

Primary outcomes:
measure: Brainstem Neural Activations to Capsaicin
timeFrame: fMRI was performed in a single session on the day of the cough challenge testing session and not more than seven days after.
measure: Brainstem Neural Activations to ATP
timeFrame: fMRI was performed in a single session on the day of the cough challenge testing session and not more than seven days after.
Secondary outcomes:
measure: Behavioral Responses During Cough Challenge Testing: Cough Sensitivity to Capsaicin
timeFrame: Thresholds for cough sensitivity were measured during a 1 hr session prior to fMRI scanning
measure: Behavioral Responses During Cough Challenge Testing: Cough Sensitivity to ATP
timeFrame: Thresholds for cough sensitivity were measured during a 1 hr session prior to fMRI scanning
measure: Behavioral Responses to Cough Challenge Testing: Urge to Cough Ratings to Capsaicin and ATP
timeFrame: Urge-to-cough ratings were reported during the 1 hour cough challenge testing session and during the subsequent fMRI scanning session
Other outcomes:
Locations:
city: Parkville
country: Australia
facility: The University of Melbourne
state: Victoria
Study officials:
affiliation: University of Melbourne
name: Stuart Mazzone, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chung KF, Pavord ID. Prevalence, pathogenesis, and causes of chronic cough. Lancet. 2008 Apr 19;371(9621):1364-74. doi: 10.1016/S0140-6736(08)60595-4.
citation: Morice AH, Jakes AD, Faruqi S, Birring SS, McGarvey L, Canning B, Smith JA, Parker SM, Chung KF, Lai K, Pavord ID, van den Berg J, Song WJ, Millqvist E, Farrell MJ, Mazzone SB, Dicpinigaitis P; Chronic Cough Registry. A worldwide survey of chronic cough: a manifestation of enhanced somatosensory response. Eur Respir J. 2014 Nov;44(5):1149-55. doi: 10.1183/09031936.00217813. Epub 2014 Sep 3.
citation: Chung KF, McGarvey L, Mazzone SB. Chronic cough as a neuropathic disorder. Lancet Respir Med. 2013 Jul;1(5):414-22. doi: 10.1016/S2213-2600(13)70043-2. Epub 2013 May 3.
citation: Mazzone SB, McLennan L, McGovern AE, Egan GF, Farrell MJ. Representation of capsaicin-evoked urge-to-cough in the human brain using functional magnetic resonance imaging. Am J Respir Crit Care Med. 2007 Aug 15;176(4):327-32. doi: 10.1164/rccm.200612-1856OC. Epub 2007 Jun 15.
citation: Ando A, Smallwood D, McMahon M, Irving L, Mazzone SB, Farrell MJ. Neural correlates of cough hypersensitivity in humans: evidence for central sensitisation and dysfunctional inhibitory control. Thorax. 2016 Apr;71(4):323-9. doi: 10.1136/thoraxjnl-2015-207425. Epub 2016 Feb 9.
citation: Abdulqawi R, Dockry R, Holt K, Layton G, McCarthy BG, Ford AP, Smith JA. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2015 Mar 28;385(9974):1198-205. doi: 10.1016/S0140-6736(14)61255-1. Epub 2014 Nov 25.