Investigation of the neural control of cough and cough suppression in humans using functional brain imaging

Abstract

Excessive coughing is one of the most common reasons for seeking medical advice, yet the available therapies for treating cough disorders are inadequate. Humans can voluntarily cough, choose to suppress their cough, and are acutely aware of an irritation that is present in their airways. This indicates a significant level of behavioral and conscious control over the basic cough reflex pathway. However, very little is known about the neural basis for higher brain regulation of coughing. The aim of the present study was to use functional brain imaging in healthy humans to describe the supramedullary control of cough and cough suppression. Our data show that the brain circuitry activated during coughing in response to capsaicin-evoked airways irritation is not simply a function of voluntarily initiated coughing and the perception of airways irritation. Rather, activations in several brain regions, including the posterior insula and posterior cingulate cortex, define the unique attributes of an evoked cough. Furthermore, the active suppression of irritant-evoked coughing is also associated with a unique pattern of brain activity, including an involvement of the anterior insula, anterior mid-cingulate cortex, and inferior frontal gyrus. These data demonstrate for the first time that evoked cough is not solely a brainstem-mediated reflex response to irritation of the airways, but rather requires active facilitation by cortical regions, and is further regulated by distinct higher order inhibitory processes.

Figure 1.

Experimental protocol for fMRI studies. Top schematic, An example of the four functional runs that were performed for each subject, consisting of three presentations of each condition. A classic 2 × 2 factorial design (no cough/cough and no capsaicin/capsaicin) was used to assess brain BOLD responses for saline challenge, voluntary cough, capsaicin-evoked cough, suppression of evoked cough, and the interaction between capsaicin challenge and coughing. Bottom schematic, An expanded view of one challenge. A brief visual cue was used to prepare (P) for challenge and to instruct subjects how to respond (i.e., “cough” or “don't cough”), followed by a “Go Cue” during which capsaicin or saline was blindly presented. Challenges were timed so that the nebulized gas reached the subject precisely at the onset of a single maximal inspiratory effort and was then replaced by medical air immediately at the peak of inspiration. Subjects performed the required task and then breathed normally (Rest) until the next preparatory cue. Rest periods were variable in duration between 18 and 36 s.

Figure 2.

Mean time courses of the global BOLD signal changes associated with capsaicin and cough events relative to the analytical model used.

Figure 3.

Representative BOLD signal responses associated with saline challenge and evoked cough, suppressed cough or voluntary cough after contrasting activations with saline challenge. The left side of each map corresponds to the left side of the brain. SM1, Primary sensorimotor cortex; SMA, supplementary motor area; SFG, superior frontal gyrus. See Tables 2 and 3 for a list of activated regions.

Figure 4.

Statistical parametric maps comparing brain regions that showed BOLD signal responses associated with capsaicin challenge only (red), cough only (yellow), or both capsaicin and cough (orange). The left side of each map corresponds to the left side of the brain. MCC, Mid-cingulate cortex; aINS, anterior insula cortex; PCC, posterior cingulate cortex; PtCG, postcentral gyrus; MB, midbrain; Thal, thalamus; SMA, supplementary motor area; PrCG, precentral gyrus; SII, secondary somatosensory cortex. See Table 4 for a list of activated regions.

Figure 5.

Brain regions showing a positive interaction between cough and capsaicin for the following: the posterior insula (pINS) (a), the primary sensory/ motor cortex (SM1) and premotor cortex (BA6) (b), and the posterior mid-cingulate (pMCC) and posterior cingulate (PCC) cortices (c). d, The BOLD signal time course in the pINS during each of the four experimental conditions. The shaded region represents the timing of cough events. e–i, Mean (±SE) percentage BOLD signal changes for each of the conditions for the pINS (e), SM1 (f), BA6 (g), pMCC (h), and PCC (i). See Table 5 for a list of activated regions.

Figure 6.

Brain regions showing a negative interaction between cough and capsaicin. The anterior mid-cingulate cortex (aMCC) showing the BOLD signal time course (a) and the mean (±SE) percentage BOLD signal change (b) during each of the four conditions. The shaded region of a represents the timing of cough events. The statistical parametric maps and percentage BOLD signal change for the supplementary motor area (SMA) (c, d), inferior frontal gyrus (IFG) (e, f), mid/anterior insula (INS) (g, h), and prefrontal cortex (PFC) (i, j). See Table 5 for a list of activated regions.