CHEST Meets Brain: Understanding Chronic Cough Requires Interdisciplinary Thinking.

FOR RELATED ARTICLE, SEE PAGE 169Chronic cough is one of the most frequent chief complaints seen in primary care, with an estimated prevalence of approximately 9% to 33% of the US population.1Chung K.F. Pavord I.D. Prevalence, pathogenesis, and causes of chronic cough.Lancet. 2008; 371: 1364-1374Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar Although there are numerous well-established environmental factors (eg, allergens, smoking) and diseases (eg, interstitial lung disease, COPD, gastroesophageal reflux disease [GERD]) with proven associations with chronic cough, the underlying mechanisms remain largely elusive.2Chung K.F. McGarvey L. Song W.J. et al.Cough hypersensitivity and chronic cough.Nat Rev Dis Primers. 2022; 8: 45Crossref Scopus (29) Google Scholar Our limited understanding of the pathophysiology of chronic cough is partly owed to a high degree of heterogeneity in both potential causes and presentations, as well as to the complex interplay between multiple organ systems, environmental exposures, and individual differences in health and wellness.1Chung K.F. Pavord I.D. Prevalence, pathogenesis, and causes of chronic cough.Lancet. 2008; 371: 1364-1374Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar,2Chung K.F. McGarvey L. Song W.J. et al.Cough hypersensitivity and chronic cough.Nat Rev Dis Primers. 2022; 8: 45Crossref Scopus (29) Google Scholar However, the pathophysiology of cough clearly involves both the peripheral and CNS, including voluntary and autonomic systems, brainstem, and higher cortical functions.1Chung K.F. Pavord I.D. Prevalence, pathogenesis, and causes of chronic cough.Lancet. 2008; 371: 1364-1374Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar,2Chung K.F. McGarvey L. Song W.J. et al.Cough hypersensitivity and chronic cough.Nat Rev Dis Primers. 2022; 8: 45Crossref Scopus (29) Google Scholar Therefore, a complete understanding of this ostensibly pulmonary disease also necessitates a careful study of its underlying neural substrates. FOR RELATED ARTICLE, SEE PAGE 169 MRI has emerged as a versatile tool for investigating the CNS in vivo, because of its use of non-ionizing radiation, superb contrast resolution, and ability to quantitatively measure both structure and function with reasonably high spatial resolution. MRI studies have suggested associations between cough and brain activity in several neuroanatomic regions, including anterior cingulate, insular cortex, inferior frontal gyrus, and cerebellum.3Namgung E. Song W.J. Kim Y.H. An J. Cho Y.S. Kang D.W. Structural and functional correlates of higher cortical brain regions in chronic refractory cough.Chest. 2022; 162: 851-860Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 4Farrell M.J. Cole L.J. Chiapoco D. Egan G.F. Mazzone S.B. Neural correlates coding stimulus level and perception of capsaicin-evoked urge-to-cough in humans.Neuroimage. 2012; 61: 1324-1335Crossref PubMed Scopus (62) Google Scholar, 5Mazzone S.B. Cole L.J. Ando A. Egan G.F. Farrell M.J. Investigation of the neural control of cough and cough suppression in humans using functional brain imaging.J Neurosci. 2011; 31: 2948-2958Crossref PubMed Scopus (130) Google Scholar Structural anomalies with chronic cough have also been previously reported in the frontal lobe.3Namgung E. Song W.J. Kim Y.H. An J. Cho Y.S. Kang D.W. Structural and functional correlates of higher cortical brain regions in chronic refractory cough.Chest. 2022; 162: 851-860Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar However, prior human neuroimaging studies on cough have thus far been few in number and limited by sample sizes well under 50. Small samples are increasingly recognized as particularly problematic for neuroimaging studies of brain-behaviour associations, contributing to elevated false-positive rates and a historical lack of reproducibility in the field.6Marek S. Tervo-Clemmens B. Calabro F.J. et al.Reproducible brain-wide association studies require thousands of individuals.Nature. 2022; 603: 654-660Crossref PubMed Scopus (359) Google Scholar In this issue of CHEST, Arinze et al7Arinze J.T. Vinke E.J. Verhamme K.M.C. et al.Chronic cough-related differences in brain morphometry in adults: a population-based study.Chest. 2023; 164: 169-178Google Scholar report on neuroanatomic associations with chronic cough using data from the Rotterdam Study, a large, prospective, population-based sample. With structural MRI data available on 3,620 subjects, including 349 with chronic cough, this study is by far the largest of its kind. Using FreeSurfer,8Fischl B. FreeSurfer.Neuroimage. 2012; 62: 774-781Crossref PubMed Scopus (4459) Google Scholar one of the most widely used automated segmentation and parcellation image processing pipelines in neuroimaging, the authors measure the volumes of seven cortical regions of interest that have previously been implicated in the pathophysiology in chronic cough. After adjusting for several important covariates, they find a statistically significant 1.7% mean volumetric reduction in the anterior cingulate cortex of individuals with chronic cough compared with the control group. The anterior cingulate cortex has mystified the neuroscience community for decades, playing a role in a myriad of complex tasks, but with its precise function an area of ongoing debate.9Ebitz R.B. Hayden B.Y. Dorsal anterior cingulate: a Rorschach test for cognitive neuroscience.Nat Neurosci. 2016; 19: 1278-1279Crossref Scopus (73) Google Scholar As part of the limbic system, it has strong connectivity to more primitive cortical regions, as well as executive centers in the frontal lobe, and it is part of several canonical brain networks.10Rolls E.T. The cingulate cortex and limbic systems for emotion, action, and memory.Brain Struct Funct. 2019; 224: 3001-3018Crossref PubMed Scopus (283) Google Scholar The anterior cingulate cortex has been implicated in diverse brain functions ranging from attention, reward-based actions, self-control, decision-making, memory, and sensorimotor transformations. The anterior cingulate cortex tends to be most active in situations in which one behavioral response is suppressed in favor of an alternative. The interest in ACC has historically been in its importance to higher cognitive functions; for example, it has been hypothesized to play an instrumental role in selecting between different behavioral plans.11Holroyd C.B. Verguts T. The best laid plans: computational principles of anterior cingulate cortex.Trends Cogn Sci. 2021; 25: 316-329Abstract Full Text Full Text PDF Scopus (29) Google Scholar Regardless of its specific function, numerous functional MRI studies on cough have demonstrated robust activation in the ACC, making this one of the most replicated findings in a relatively sparse literature.4Farrell M.J. Cole L.J. Chiapoco D. Egan G.F. Mazzone S.B. Neural correlates coding stimulus level and perception of capsaicin-evoked urge-to-cough in humans.Neuroimage. 2012; 61: 1324-1335Crossref PubMed Scopus (62) Google Scholar Exactly how the “classic” functions of the anterior cingulate cortex relate to cough remains largely speculative; however, understanding the mechanisms of cough may help inform our understanding of anterior cingulate cortex function more broadly. The findings by Arinze et al7Arinze J.T. Vinke E.J. Verhamme K.M.C. et al.Chronic cough-related differences in brain morphometry in adults: a population-based study.Chest. 2023; 164: 169-178Google Scholar support the role of anterior cingulate cortex in chronic cough, and provide the first large-sample analysis of brain structure in this condition. The study is not without some limitations; for example, group differences in image quality, relatively small effect sizes, and the cross-sectional nature of its design should all be considered when interpreting its results. Nevertheless, this work represents an important step toward understanding the associations between the CNS and the pathophysiology of chronic cough, and it is an example of how interdisciplinary thinking can advance our understanding of heterogeneous, complex diseases.12Mazzone S.B. Chung K.F. McGarvey L. The heterogeneity of chronic cough: a case for endotypes of cough hypersensitivity.Lancet Respir Med. 2018; 6: 636-646Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar None declared. Chronic Cough-Related Differences in Brain Morphometry in Adults: A Population-Based StudyCHESTVol. 164Issue 1PreviewIndividuals with chronic cough have a smaller volume of the anterior cingulate cortex, which is a brain region involved in cough suppression. Full-Text PDF Open Access