Article Figures & Data
Figures
- 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.
Tables
ID no.a Sex Age (years) Session 1 C2 (μm) Session 2 C2 (μm) 1 Male 35 15.63 15.63 2 Female 36 7.81 7.81 3 Male 49 15.63 15.63 4 Female 21 3.91 3.91 5 Female 21 3.91 3.91 6 Female 22 1.95 1.95 9 Male 21 15.63 15.63 10 Male 24 3.91 3.91 11 Male 21 3.91 3.91 12 Male 23 31.25 31.25 13 Male 28 7.81 3.91 14 Female 27 1.95 0.25 15 Female 19 0.98 0.98 16 Male 20 15.63 31.25 17 Male 18 7.81 7.81 18 Male 20 1.95 3.91 19 Male 19 7.81 7.81 20 Female 33 7.81 3.91 21 Male 26 7.81 7.81 Mean Male 25.6 ± 6.2 8.71 ± 1.26b 9.33 ± 1.31b Mean Female 24.5 ± 11.2 3.23 ± 1.35b 2.29 ± 1.41b - Table 2.
Regions showing increased activation associated with saline exhalation, voluntary cough, evoked cough, and suppressed cough
Region Saline challenge Voluntary cough Evoked cough Suppressed cough Peak voxel coordinate Z score Peak voxel coordinate Z score Peak voxel coordinate Z score Peak voxel coordinate Z score x y z x y z x y z x y z Cingulate cortex 0 44 2 3.22 4 38 4 3.04 4 42 2 4.39 4 24 28 3.62 0 −2 38 4.49 6 22 22 4.53 2 26 28 5.29 −2 20 32 2.94 2 2 38 4.35 −2 20 22 4.56 −2 26 22 4.97 0 −16 40 3.58 6 −22 32 3.22 4 −20 30 3.78 −2 −14 40 3.97 −4 −16 30 4.14 −2 −22 30 3.66 Superior frontal gyrus 6 12 58 3.91 −2 26 22 5.29 Middle frontal gyrus 44 12 50 4.04 40 28 34 3.79 36 56 12 4.05 44 22 44 3.40 −34 44 24 4.05 −32 48 22 3.59 −36 28 34 3.34 Pre-SMA 6 34 42 3.50 −2 26 44 2.86 SMA 4 −10 58 3.01 4 2 62 4.88 6 −10 60 3.09 4 8 52 3.37 −6 8 60 2.79 −2 2 60 4.07 −8 −10 68 3.36 0 2 52 2.62 Premotor cortex 54 2 42 3.54 56 2 40 5.16 Sensorimotor cortex 26 −28 62 4.02 22 −30 60 4.13 −22 −34 64 4.27 −20 −34 60 4.03 50 −8 54 3.20 56 −2 40 4.62 −50 −8 46 3.68 46 −10 34 3.83 36 −14 40 4.00 −46 −10 40 4.64 −46 −12 42 3.86 −46 −12 40 3.14 44 −12 30 4.27 44 −8 30 4.57 46 −8 34 2.78 −42 −10 30 4.80 −64 −20 32 5.06 −40 −18 32 3.38 Operculum 58 −14 14 3.68 64 −4 10 5.22 −60 4 10 5.15 −56 −2 10 5.18 −56 −4 12 3.11 −46 −12 18 4.67 64 −4 10 5.12 58 −4 8 5.48 Posterior cingulate cortex 8 −32 42 3.41 6 −26 36 3.49 −14 −38 42 4.28 −2 −22 30 3.66 Inferior parietal lobule 64 −42 26 4.53 64 −34 24 4.17 62 −36 26 4.69 60 −42 42 4.70 −60 −42 40 4.44 −62 −36 30 3.51 −64 −38 34 3.87 −58 −40 46 4.36 Middle temporal gyrus 56 −52 −2 3.10 −50 −62 0 4.06 Anterior insula 38 22 4 2.86 34 14 4 3.40 36 20 2 3.51 −32 10 6 3.41 −34 16 2 3.47 Mid-insula 44 4 0 3.13 36 −12 8 3.12 46 12 −4 3.85 −40 10 2 2.81 −44 2 −2 4.39 −40 −12 8 4.46 −38 10 4 3.84 Posterior insula 40 −8 8 2.98 34 −22 8 3.33 −38 −12 8 4.33 −32 −26 10 3.69 Caudate 16 22 2 3.57 Lentiform nuclei 16 10 −6 3.01 16 12 −6 3.06 Thalamus 10 −18 4 2.99 12 −6 10 2.84 −8 −2 0 3.62 −14 −18 4 3.48 −10 −6 10 3.25 Midbrain 6 −32 −12 3.54 4 −32 −14 3.84 −10 −24 −14 4.27 −8 −26 −14 4.37 Pons 8 −32 −28 3.17 −8 −36 −28 3.86 Rostral medulla 0 −38 −52 2.52 −4 −38 −50 3.40 Caudal medulla 0 −40 −66 2.86 −4 −44 −64 3.26 Cerebellum 20 −70 −22 4.66 4 −46 −24 5.02 −24 −64 −26 4.54 −8 −62 −20 4.58 The coordinates of maximally activated voxels are given in MNI space where x, y, and z coordinates represent the medial-lateral, anterior-posterior, and superior-inferior distances (in millimeters) from the anterior commissure. SMA, Supplementary motor area.
All activations identified at cluster-level significance of p < 0.05 (corrected).
- Table 3.
Regions showing increased activation associated with the contrasts of voluntary cough > saline challenge, evoked cough > saline challenge, and suppressed cough > saline challenge
Region Voluntary cough > saline challenge Evoked cough > saline challenge Suppressed cough > saline challenge Peak voxel coordinate Z score Peak voxel coordinate Z score Peak voxel coordinate Z score x y z x y z x y z Cingulate cortex 2 24 20 5.01 4 22 22 4.74 2 38 10 3.76 4 10 34 3.92 8 8 32 4.20 8 34 20 4.24 4 4 32 3.92 8 −4 40 3.96 12 4 48 3.65 −2 24 20 4.80 −2 22 20 5.15 −2 24 22 4.90 −2 4 38 4.18 −4 10 34 4.34 −6 20 32 4.29 −2 −10 40 3.88 −8 −12 36 4.28 Superior frontal gyrus −12 16 62 3.25 Middle frontal gyrus 12 −12 50 3.43 SMA 0 0 62 4.38 10 −4 62 3.44 10 8 52 2.97 −10 2 52 3.16 −10 6 54 2.88 Premotor cortex 56 0 42 3.25 −62 −4 34 2.91 Sensorimotor cortex 24 −28 60 3.80 22 −28 60 4.03 −20 −32 64 3.84 −22 −32 62 4.27 48 −10 48 3.23 60 −4 42 4.49 40 −10 26 3.81 −50 −6 46 3.15 −62 −8 36 4.80 −40 −16 32 4.81 46 −12 30 4.31 42 −8 30 4.69 42 −6 12 4.13 −40 −10 30 4.97 −40 −14 32 4.66 −52 −8 18 5.06 Operculum 56 −2 16 3.28 56 −10 18 3.82 60 −4 10 4.95 −48 −10 16 4.68 −50 −8 18 4.92 −58 −2 10 4.05 Inferior parietal lobule 56 −30 26 3.58 −52 −42 24 3.56 Paracentral lobule 0 −42 64 3.55 Precuneus 12 −30 44 3.61 −12 −38 46 3.95 Anterior insula 34 12 4 3.14 40 16 −8 4.78 −28 20 2 3.01 −30 12 4 3.35 −32 14 −8 4.60 Mid-insula 40 −10 8 3.25 34 −12 8 3.38 34 12 4 5.24 −36 −10 8 4.72 −36 −14 6 5.28 −30 14 0 4.51 Posterior insula 34 −24 12 2.95 38 −26 12 4.31 38 0 −6 4.60 −32 −22 10 3.13 −32 −26 10 4.34 −32 −12 8 4.33 Caudate 14 16 4 3.30 Thalamus 16 −24 6 3.14 14 −18 2 3.53 8 −16 2 3.06 −18 −20 4 3.28 −14 −22 2 4.11 −10 −16 −2 4.27 −8 −4 0 3.20 8 0 4 2.92 −4 −4 4 2.97 Midbrain 6 −26 −6 3.73 12 −18 −8 4.47 12 −14 −8 3.10 −4 −26 −2 3.74 −10 −20 −6 4.92 −10 −16 −6 3.70 6 −30 −12 4.08 6 −28 −8 4.25 −8 −24 −12 4.40 −4 −28 −10 4.50 Pons 8 −30 −26 2.90 8 −30 −24 3.53 8 −38 −34 3.37 −6 −36 −26 2.99 −8 −34 −28 3.75 −4 −36 −32 3.07 Rostral medulla 10 −38 −54 3.10 6 −40 −52 3.45 −4 −38 −50 3.34 −4 −38 −52 3.45 Caudal medulla 8 −38 −60 4.08 2 −38 −66 4.28 −4 −42 −68 4.65 Cerebellum 20 −70 −24 4.99 4 −46 −24 4.96 4 −52 −18 3.89 −14 −44 −24 4.01 −8 −50 −22 5.05 14 −62 −18 3.89 −24 −64 −26 4.57 −8 −62 −22 5.46 −18 −72 −22 3.58 The coordinates of maximally activated voxels are given in MNI space where x, y, and z coordinates represent the medial-lateral, anterior-posterior, and superior-inferior distances (in millimeters) from the anterior commissure. SMA, Supplementary motor area.
All activations identified at cluster-level significance of p < 0.05 (corrected).
Region Cough Capsaicin Peak voxel coordinate Z score Peak voxel coordinate Z score x y z x y z PMC −12 −24 58 2.97 SMA −8 −10 62 3.57 8 −6 60 2.87 10 −4 50 3.14 aMCC −8 22 22 4.03 0 24 20 4.66 6 16 30 3.82 pMCC −6 −10 36 4.07 0 −6 38 3.60 8 −12 36 4.46 M1 −22 −32 58 4.25 26 −28 58 4.33 15 62 56 4.58 S1 −54 −6 26 4.55 −52 −4 24 3.79 44 −8 30 4.33 52 −2 26 3.96 S2 −48 −10 16 4.41 −56 −6 8 4.52 56 −10 16 3.26 52 −2 8 3.87 pINS −36 −14 8 4.86 −34 −12 4 4.21 42 −8 8 3.00 36 −4 2 4.85 amINS −30 18 6 2.32 −32 12 8 3.45 32 22 4 3.14 Thalamus −14 −22 0 3.45 −10 −16 −2 4.85 16 −20 4 3.30 8 −14 0 3.48 Midbrain −10 −26 −12 4.74 −10 −14 −6 4.38 6 −26 −6 4.37 10 −14 −6 4.19 Pons −6 −36 −26 3.85 −6 −34 −24 3.57 6 −30 −22 3.20 4 −34 −32 3.46 RVM −6 −36 −50 2.95 −2 −34 −56 3.68 CVM −6 −42 −62 4.31 −2 −40 −66 4.30 Cerebellum −6 −62 −22 5.29 −8 −50 −20 3.59 2 −62 22 4.91 4 −50 −24 3.94 The main effect for cough was determined by contrasting coughing events with noncoughing events (evoked cough + voluntary cough > suppressed cough + saline challenge). The main effect for capsaicin was determined by contrasting capsaicin events with saline events (evoked cough + suppressed cough > voluntary cough + saline challenge). The coordinates of maximally activated voxels are given in MNI space where x, y, and z coordinates represent the medial-lateral, anterior-posterior, and superior-inferior distances (in millimeters) from the anterior commissure. PMC, Premotor cortex; SMA, supplementary motor area; aMCC, anterior mid-cingulate cortex; pMCC, posterior mid-cingulate cortex; M1, primary motor cortex; S1, primary somatosensory cortex; S2, secondary somatosensory cortex; pINS, posterior insula cortex; amINS, anterior/mid-insula cortex; RVM, rostral ventral medulla; CVM, caudal ventral medulla.
All activations identified at cluster-level significance of p < 0.05 (corrected).
Region Positive interaction Region Negative interaction Peak voxel coordinate Z score Peak voxel coordinate Z score x y z x y z PMC −18 −26 62 3.12 PFC 26 50 2 3.91 22 −22 62 3.21 aMCC −2 24 32 3.05 60 −2 38 3.22 2 26 32 3.39 M1 −18 −26 58 3.54 SMA 0 0 66 3.97 6 −36 58 3.48 SFG 4 26 56 3.78 SM 62 −12 30 3.47 aINS 42 16 0 3.18 S2 −44 −32 22 3.26 IFG 42 28 −4 3.26 48 −26 24 3.04 pINS −32 −26 14 3.58 38 −32 14 3.22 pMCC −8 −12 36 4.03 8 −10 38 4.15 PCC −8 −32 42 3.87 12 −26 38 3.56 The coordinates of maximally activated voxels are given in MNI space where x, y, and z coordinates represent the medial-lateral, anterior-posterior, and superior-inferior distances (in millimeters) from the anterior commissure. SMA, Supplementary motor area; PMC, premotor cortex; M1, primary motor cortex; SFG, superior frontal gyrus; PFC, prefrontal cortex; aMCC, anterior mid cingulate cortex; pMCC, posterior mid-cingulate cortex; SM, primary somatosensory/motor cortex; S2, secondary somatosensory cortex; aINS, anterior insula; pINS, posterior insula; PCC, posterior cingulate cortex; IFG, inferior frontal gyrus.
All activations identified at cluster-level significance of p < 0.05 (corrected).
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