Functional neuroimaging of placebo inhibition in capsaicin induced urge-to-cough

Leech, Jennifer (2015). Functional neuroimaging of placebo inhibition in capsaicin induced urge-to-cough PhD Thesis, School of Biomedical Sciences, The University of Queensland. doi:10.14264/uql.2015.297

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Author Leech, Jennifer
Thesis Title Functional neuroimaging of placebo inhibition in capsaicin induced urge-to-cough
School, Centre or Institute School of Biomedical Sciences
Institution The University of Queensland
DOI 10.14264/uql.2015.297
Publication date 2015-01-30
Thesis type PhD Thesis
Open Access Status Other
Supervisor Stuart Mazzone
Michael Farrell
Total pages 117
Language eng
Subjects 110903 Central Nervous System
170101 Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology)
060699 Physiology not elsewhere classified
Formatted abstract
An abnormal or persistent urge-to-cough is a common symptom of respiratory disease with few effective treatments. Evidence suggests that both cough and the urge-to-cough are particularly susceptible to placebo effects, indicating inhibitory processes in the central nervous system that are capable of reducing the urge-to-cough. Little is known about how these circuits are organised in the human brain. Knowledge of the neural basis of placebo inhibition of urge-to-cough may help to develop targets for future antitussive therapies. These studies investigate the effect of placebo on urge-to-cough using behavioural studies and functional magnetic resonance imaging (fMRI).

1) To determine whether placebo conditioning can modulate the perception of capsaicin-evoked urge-to-cough in human subjects.
2) Using fMRI, to establish whether placebo induced reduction of the urge-to-cough causes a commensurate reduction in activity in cortical brain regions involved in sensing capsaicin-evoked urge-to-cough, and to identify regions that may be involved in producing this effect.
3) Using fMRI optimised for the brainstem, to establish if placebo induced reduction of the urge-to-cough also causes inhibition in subcortical regions involved in processing signals from the airways.

Three independent experiments were designed in which healthy adult volunteers underwent a series of inhalations of a substance that causes an urge-to-cough (capsaicin, the active ingredient in hot chilli peppers), preceded by either placebo treatment (via a placebo inert gas inhaler or normal air via a nasal cannula), which participants believed was a local anaesthetic, or no treatment. Participants rated their urge-to-cough following each capsaicin inhalation period. Prior to the sessions participants were conditioned to believe the treatment would be effective by surreptitiously lowering the dose of capsaicin following placebo administration. Three separate cohorts completed the protocol. The first experiment (Chapter 3) optimised a protocol to test whether the psychophysical aspects of capsaicin-evoked urge-to-cough were modifiable by placebo intervention. The second experiment (Chapter 4) then employed this protocol along with blood-oxygen-level dependent (BOLD) fMRI to detect changes in cortical activation that accompanied the placebo response, while the third experiment (Chapter 5) used BOLD fMRI optimised for assessing subcortical and brainstem responses.

Placebo administration resulted in a significant (up to 40 percent) reduction in participants’ ratings of urge-to-cough. fMRI showed capsaicin-evoked activations in a network of regions including primary motor and sensory cortices, supplementary motor area, insula, mid cingulate cortex and orbitofrontal cortex. Placebo administration significantly reduced BOLD signal responses following placebo treatment in a distributed network of cortical regions that are normally activated during capsaicin inhalation, including primary and secondary somatosensory cortex, primary motor cortex, mid cingulate cortex and supplementary motor area. Regions in the dorsolateral prefrontal and posterior parietal cortices that have been implicated in producing placebo analgesia also showed increased activation following placebo treatment. In the dorsolateral prefrontal cortex the magnitude of the activation was significantly correlated with the magnitude of placebo effect in individuals. This reduction in capsaicin-evoked activation following placebo was also observed in the pons and rostral medulla in the brainstem.

These studies are the first to confirm that administration of a placebo can alter perception of experimentally-evoked urge-to-cough. They also provide further evidence that higher brain networks are important in modulating responses to airway irritation. Consistent with subjective reports, placebo administration decreases capsaicin-related activation in brain regions that process incoming sensory signals from the airways. This indicates that placebo treatment is capable of activating endogenous inhibitory networks in the central nervous system that can suppress the sensation of airway irritation. This process is likely to be mediated by higher cortical regions, such as dorsolateral prefrontal cortex, that can suppress processing of incoming sensory signals from the airways by descending inhibition of brainstem respiratory centres.
Keyword Neurosciences
Cough reflex
Placebo Effect
Functional magnetic resonance imaging (fMRI)
Respiratory Diseases

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Created: Fri, 23 Jan 2015, 07:03:10 EST by Jennifer Leech on behalf of Scholarly Communication and Digitisation Service