Chronic Cough-Related Differences in Brain Morphometry in Adults

BackgroundIndividuals with cough hypersensitivity have increased central neural responses to tussive stimuli, which may result in maladaptive morphometric changes in the central cough processing systems.Research QuestionAre the volumes of the brain regions implicated in cough hypersensitivity different in adults with chronic cough compared with adults without chronic cough?Study Design and MethodsBetween 2009 and 2014, participants in the Rotterdam Study, a population-based cohort, underwent brain MRI and were interviewed for chronic cough, which was defined as daily coughing for at least 3 months. Regional brain volumes were quantified with the use of parcellation software. Based on literature review, we identified and studied seven brain regions that previously had been associated with altered functional brain activity in chronic cough. The relationship between chronic cough and regional brain volumes was investigated with the use of multivariable regression models.ResultsChronic cough was prevalent in 9.6% (No. = 349) of the 3,620 study participants (mean age, 68.5 ± 9.0 years; 54.6% female). Participants with chronic cough had significantly smaller anterior cingulate cortex volume than participants without chronic cough (mean difference, ˗126.16 mm3; 95% CI, −245.67 to −6.66; P = .039). Except for anterior cingulate cortex, there were no significant difference in the volume of other brain regions based on chronic cough status. The volume difference in the anterior cingulate cortex was more pronounced in the left hemisphere (mean difference, −88.11 mm3; 95% CI, −165.16 to −11.06; P = .025) and in male participants (mean difference, −242.58 mm3; 95% CI, −428.60 to −56.55; P = .011).InterpretationIndividuals with chronic cough have a smaller volume of the anterior cingulate cortex, which is a brain region involved in cough suppression.Clinical Trial RegistrationThe Netherlands National Trial Registry (NTR; www.trialregister.nl) and the World Health Organization’s International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/network/primary/en/) under the joint catalogue number NTR6831. Individuals with cough hypersensitivity have increased central neural responses to tussive stimuli, which may result in maladaptive morphometric changes in the central cough processing systems. Are the volumes of the brain regions implicated in cough hypersensitivity different in adults with chronic cough compared with adults without chronic cough? Between 2009 and 2014, participants in the Rotterdam Study, a population-based cohort, underwent brain MRI and were interviewed for chronic cough, which was defined as daily coughing for at least 3 months. Regional brain volumes were quantified with the use of parcellation software. Based on literature review, we identified and studied seven brain regions that previously had been associated with altered functional brain activity in chronic cough. The relationship between chronic cough and regional brain volumes was investigated with the use of multivariable regression models. Chronic cough was prevalent in 9.6% (No. = 349) of the 3,620 study participants (mean age, 68.5 ± 9.0 years; 54.6% female). Participants with chronic cough had significantly smaller anterior cingulate cortex volume than participants without chronic cough (mean difference, ˗126.16 mm3; 95% CI, −245.67 to −6.66; P = .039). Except for anterior cingulate cortex, there were no significant difference in the volume of other brain regions based on chronic cough status. The volume difference in the anterior cingulate cortex was more pronounced in the left hemisphere (mean difference, −88.11 mm3; 95% CI, −165.16 to −11.06; P = .025) and in male participants (mean difference, −242.58 mm3; 95% CI, −428.60 to −56.55; P = .011). Individuals with chronic cough have a smaller volume of the anterior cingulate cortex, which is a brain region involved in cough suppression. The Netherlands National Trial Registry (NTR; www.trialregister.nl) and the World Health Organization’s International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/network/primary/en/) under the joint catalogue number NTR6831. FOR EDITORIAL COMMENT, SEE PAGE 13Take-home PointsStudy Question: Are the volumes of the brain regions implicated in cough hypersensitivity different in adults with chronic cough compared with adults without chronic cough?Results: Adults with chronic cough had smaller anterior cingulate cortex volume than adults without chronic cough. The volume difference in the anterior cingulate cortex was more pronounced in the left hemisphere and in men.Interpretation: The observed volumetric alterations in the anterior cingulate cortex lends credence to the mechanistic relevance of impaired cough suppression in adults with chronic cough. FOR EDITORIAL COMMENT, SEE PAGE 13 Study Question: Are the volumes of the brain regions implicated in cough hypersensitivity different in adults with chronic cough compared with adults without chronic cough? Results: Adults with chronic cough had smaller anterior cingulate cortex volume than adults without chronic cough. The volume difference in the anterior cingulate cortex was more pronounced in the left hemisphere and in men. Interpretation: The observed volumetric alterations in the anterior cingulate cortex lends credence to the mechanistic relevance of impaired cough suppression in adults with chronic cough. Chronic cough, defined as a cough that lasts more than 8 weeks, is one of the most common reasons for a primary care visit because it affects 2% to 18% of people worldwide.1Song W.J. Chang Y.S. Faruqi S. et al.The global epidemiology of chronic cough in adults: a systematic review and meta-analysis.Eur Respir J. 2015; 45: 1479-1481Crossref PubMed Scopus (305) Google Scholar It is associated with significant physical and psychosocial complications, exacerbates underlying medical conditions,2Won H.K. Song W.J. Impact and disease burden of chronic cough.Asia Pac Allergy. 2021; 11: e22Crossref PubMed Scopus (19) Google Scholar, 3Morice A. Dicpinigaitis P. McGarvey L. Birring S.S. Chronic cough: new insights and future prospects.Eur Respir Rev. 2021; 30: 210127Crossref PubMed Scopus (36) Google Scholar, 4Arinze J.T. Hofman A. de Roos E.W. et al.The interrelationship of chronic cough and depression: a prospective population-based study.ERJ Open Res. 2022; 8: 00069-02022Crossref PubMed Scopus (9) Google Scholar and imposes a huge clinical and financial burden on patients and health care systems.5Hull J.H. Langerman H. Ul-Haq Z. Kamalati T. Lucas A. Levy M.L. Burden and impact of chronic cough in UK primary care: a dataset analysis.BMJ Open. 2021; 11e054832Crossref Scopus (14) Google Scholar,6Birring S.S. Currie C.J. Holden S.E. et al.The financial burden of treating patients presenting with acute and chronic cough.Curr Med Res Opin. 2021; 37: 2175-2184Crossref PubMed Scopus (8) Google Scholar The management of chronic cough is challenging given that more than one-half of patients do not respond well to treatment (ie, refractory chronic cough)7Ryan N.M. Vertigan A.E. Birring S.S. An update and systematic review on drug therapies for the treatment of refractory chronic cough.Expert Opin Pharmacother. 2018; 19: 687-711Crossref PubMed Scopus (50) Google Scholar and that almost one-third of chronic cough cases remain unexplained despite a thorough diagnostic work up (ie, unexplained chronic cough).5Hull J.H. Langerman H. Ul-Haq Z. Kamalati T. Lucas A. Levy M.L. Burden and impact of chronic cough in UK primary care: a dataset analysis.BMJ Open. 2021; 11e054832Crossref Scopus (14) Google Scholar After several recommendations from clinical experts and scientific societies, which includes the European Respiratory Society, chronic cough has been recognized as a distinct clinical condition and recently was assigned the International Classification of Diseases, 10th revision, Clinical Modification code R05.3.8World Health Organization, 2022 ICD-10-CM Diagnosis Code R05.3 for Chronic cough, In: International Classification of Diseases version 10, World Health Organization; 2022. Accessed June 1, 2023. https://www.icd10data.com/ICD10CM/Codes/R00-R99/R00-R09/R05-/R05.3Google Scholar The primary putative mechanism of chronic cough in adults, neural hypersensitivity,9Morice A.H. Millqvist E. Belvisi M.G. et al.Expert opinion on the cough hypersensitivity syndrome in respiratory medicine.Eur Respir J. 2014; 44: 1132Crossref PubMed Scopus (259) Google Scholar is sustained by neuroplastic changes, which are functional or structural maladaptation in the central and peripheral cough processing systems caused by repeated tussive stimuli exposure.10Rouadi P.W. Idriss S.A. Bousquet J. et al.WAO-ARIA consensus on chronic cough: part 1: role of TRP channels in neurogenic inflammation of cough neuronal pathways.World Allergy Organ J. 2021; 14100617Abstract Full Text Full Text PDF Scopus (8) Google Scholar Indeed, a study has shown that the density of airway epithelial sensory nerves is increased in chronic cough, which implies that peripheral sensory neuroplasticity plays a role in cough hypersensitivity.11Shapiro C.O. Proskocil B.J. Oppegard L.J. et al.Airway sensory nerve density is increased in chronic cough.Am J Respir Crit Care Med. 2021; 203: 348-355Crossref PubMed Scopus (31) Google Scholar Similarly, several research groups have suggested that brain plasticity might contribute to central hyperexcitability and to inhibitory brain network dysfunction in adults with chronic cough.12Ando A. Mazzone S.B. Farrell M.J. Altered neural activity in brain cough suppression networks in cigarette smokers.Eur Respir J. 2019; 54: 1900362Crossref PubMed Scopus (13) Google Scholar,13Ando A. Smallwood D. McMahon M. Irving L. Mazzone S.B. Farrell M.J. Neural correlates of cough hypersensitivity in humans: evidence for central sensitisation and dysfunctional inhibitory PubMed Scopus Google Scholar evidence of central in chronic cough has shown that cough is brain between and with chronic A. Smallwood D. McMahon M. Irving L. Mazzone S.B. Farrell M.J. 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