title: Neural correlates of cough hypersensitivity in humans: evidence for central sensitisation and dysfunctional inhibitory control.
abstract: BACKGROUND
  Chronic non-productive coughing is a major complication of pulmonary disease and can also occur in many individuals without identifiable underlying pathology. The common clinical link in patients with cough is an enhanced sensitivity of the respiratory system to stimuli that subsequently evoke excessive coughing. The aetiology of this 'cough hypersensitivity syndrome' is unclear but believed to involve hypersensitivity of the sensory neural pathways that innervate the airways and lungs.
  
  
  METHODS
  In the present study, we used functional brain imaging to compare central neural responses to airway stimulation using inhaled capsaicin in healthy people and patients with cough hypersensitivity.
  
  
  RESULTS
  Hypersensitivity in response to inhaled capsaicin coincided with elevated neural activity in the midbrain in a region encompassing the nucleus cuneiformis (left: p<0.001; right: p<0.001) and periaqueductal gray (p=0.008) in comparison to normal sensitivity in controls. The enhanced activity noted in the midbrain is similar to that occurring in patients with chronic pain, thus providing empirical evidence to support the notion that cough and pain share neurobiological similarities. Furthermore, patients with cough hypersensitivity displayed difficulty controlling their cough, which manifested as a failure to suppress cough during capsaicin challenge (ie, reduced cough frequency) in controls compared with patients with cough hypersensitivity (p=0.046). Cough suppression was associated with reduced activity in a forebrain network that included the dorsomedial prefrontal and anterior mid-cingulate cortices. Additionally, cough frequency was correlated with activity in the right inferior frontal gyrus (R(2)=0.6, p<0.001) and right anterior insula (R(2)=0.6, p<0.001), regions previously implicated in voluntary cough suppression.
  
  
  CONCLUSIONS
  These findings provide insight into the central neurobiology of cough hypersensitivity and suggest that both central amplification of cough sensory inputs and reduced capacity to suppress cough motor behaviours define patients with problematic cough.
authors: School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, Australia The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
authors: Ayaka
authors: A
authors: Ando
authors: Department of Respiratory and Sleep Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors: David
authors: D
authors: Smallwood
authors: Department of Respiratory and Sleep Medicine, Austin Hospital, Heidelberg, Victoria, Australia.
authors: Marcus
authors: M
authors: McMahon
authors: Department of Respiratory and Sleep Medicine, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors: Louis
authors: L
authors: Irving
authors: School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, Australia.
authors: Stuart B
authors: SB
authors: Mazzone
authors: Department of Medical Imaging and Radiation Sciences, Monash University, Clayton, Victoria, Australia.
authors: Michael J
authors: MJ
authors: Farrell
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D001315:Australia; D001931:Brain Mapping / Q000379:methods; D002211:Capsaicin / Q000008:administration & dosage*; D016022:Case-Control Studies; D059333:Central Nervous System Sensitization / Q000187:drug effects; D003371:Cough / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D005260:Female; D006801:Humans; D008168:Lung / Q000294:innervation; D008279:Magnetic Resonance Imaging; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000503:physiopathology*; D008875:Middle Aged; D009433:Neural Inhibition; D009434:Neural Pathways / Q000503:physiopathology; D018689:Sensory System Agents / Q000008:administration & dosage*
chemical_list: D018689:Sensory System Agents; D002211:Capsaicin
keywords: Imaging/CT MRI etc; Respiratory Infection