Comments
Abstract
Rationale: Antitussive therapies are accompanied by a substantial placebo effect, indicating that inhibitory circuits in the brain have a significant capacity to regulate cough neural processing. However, essentially nothing is known about the identity of these inhibitory circuits or how they reduce coughing. Understanding these processes may help develop more effective antitussive therapies in the future.
Objectives: To identify regional changes in human brain activity related to the urge-to-cough after placebo antitussive administration.
Methods: Seventeen healthy participants undertook functional magnetic resonance imaging while completing a series of inhalations of capsaicin to induce the urge-to-cough. The resultant brain responses associated with capsaicin inhalation without any treatment were compared with those induced by capsaicin after placebo antitussive administration.
Measurements and Main Results: There was a significant decrease in participants’ ratings of urge-to-cough after the placebo antitussive administration. Brain activity associated with capsaicin inhalation was less in the somatosensory, primary motor, insula, and cingulate cortices during placebo antitussive trials compared with no treatment control subjects. By contrast, placebo trials were associated with increased activation in the prefrontal and left parietal cortices.
Conclusions: Placebo-related decreases in urge-to-cough are accompanied by commensurate decreases in several brain regions activated during capsaicin inhalation, suggesting that beliefs about treatment can modify the central processing of inputs arising from the airways. The prefrontal cortex and posterior parietal cortex are likely to play an active role in the modification of airway sensory processing after administration of a placebo.
Placebo antitussives are very effective in reducing cough and the urge-to-cough in clinical settings and under experimental conditions. There have been no studies investigating the neural mechanisms that contribute to the antitussive placebo effect.
Capsaicin inhalation induces a reproducible urge-to-cough in healthy humans, which is markedly diminished after placebo antitussive administration. Reductions in the urge-to-cough are accompanied by decreased activation in some brain regions that respond to capsaicin inhalation. An increase in activity in the prefrontal cortex likely contributes to the placebo-antitussive effects.
The urge-to-cough is recognized as an important clinical symptom that accompanies chronic cough hypersensitivity disorders (1, 2). It is characterized by sensory nerve-dependent perception of airways irritation and the resultant desire to cough. Understanding mechanisms that regulate urge-to-cough may therefore reveal opportunities to help relieve chronic cough in respiratory disease.
Like cough, the urge-to-cough is subject to regulatory processes that play an important role in shaping its magnitude or characteristics. For example, coughing and the urge-to-cough are markedly reduced by placebo antitussive treatments, suggesting the presence of inhibitory neural pathways that can modify processing of airway sensory inputs. In both clinical and experimental settings the magnitude of this reduction seems to be greater and more consistent than in placebo analgesia (3, 4), although the reasons for this are as yet unclear. Eccles (5) concluded that the placebo antitussive effect is associated with improvements in cough-related symptoms averaging 85% of the benefits seen for active treatments in clinical trials. Perhaps most tellingly, we have shown that a placebo antitussive reduces the urge-to-cough by 45% in healthy people inhaling a tussive agent under controlled experimental conditions (6). It seems plausible that this reduction in urge-to-cough contributes significantly to the effectiveness of placebos and/or therapeutics in reducing coughing in disease. Therefore, understanding the mechanisms underlying these large placebo antitussive effects could have important implications for future development of active antitussive treatments.
Despite repeated observations of an unusually large placebo antitussive response there has surprisingly been no published research into the underlying neurologic basis of this effect. We have previously described the neural networks involved in generating the urge-to-cough in humans using functional brain imaging (7), showing regional brain responses that are related to the intensity of tussive stimuli and magnitude of the perceived urge-to-cough (8). A logical prediction is that these brain responses should show selective decreases after placebo antitussive administration corresponding with changes in the perceived urge-to-cough. Therefore, in the present study we set out to define the effects of placebo antitussive administration on the cough neural network and describe possible brain regions that generate placebo modulation of the urge-to-cough in humans. Some of the results of these studies have been previously reported in the form of an abstract (9).
Healthy adult volunteers with no history of smoking, chronic respiratory disease, or recent respiratory infections were recruited. One subject was excluded because of gross neurologic abnormalities identified during magnetic resonance imaging (MRI), which would have precluded accurate registration and interpretation of imaging data. Data analysis was performed on the remaining 17 subjects (10 male; mean age, 23.4 ± SD 6.6 yr). Written informed consent was obtained by a modified “authorized deception” consent form (10), containing the following information: “Research designs often require that the full intent of the study not be explained prior to participation. Although we have described the general nature of the tasks that you will be asked to perform, the full intent of the study will not be explained to you until after the completion of the study.”
A full debriefing was provided to participants at the conclusion of each session and they were given the option to withdraw their data if they wished. No participant chose to use this option. All aspects of this study were approved by the Melbourne Health Human Research Ethics Committee (2011.100).
Individual cough thresholds were determined using single maximum capacity inhalations of doubling doses of nebulized capsaicin (6, 11). After each inhalation participants rated their urge-to-cough on a modified Borg scale ranging from zero (no discernible urge) to 10 (maximal urge). The “high dose” of capsaicin for each individual was defined as the highest concentration that evoked a strong urge-to-cough but was not associated with reflex coughing when repeatedly inhaled during 16 seconds of continuous stimulation. The “low dose” was one-quarter of this concentration and used for conditioning as described next.
As previously described (6), participants were informed they would on occasion receive lidocaine hydrochloride, a commonly used local anesthetic that would substantially but briefly reduce their urge-to-cough during capsaicin challenges. The expectation of receiving an active treatment was enhanced using an information leaflet outlining possible side effects and contraindications of lidocaine. Participants were informed that they would receive capsaicin to induce the urge-to-cough and that there would be two types of trials: “lidocaine” and “no treatment,” differentiated by instructions projected on a screen in either green or red text, respectively. The “lidocaine” was in fact normal air (i.e., placebo antitussive), passively inhaled by a nasal cannula. To control for breathing-related artifacts, participants were instructed to use the same pattern of inhalation during no treatment trials. During conditioning placebo trials, participants unknowingly received the low dose of capsaicin. During functional MRI the high dose of capsaicin was given for all trials. After the session participants were asked if they suspected they were not actually receiving lidocaine. All participants believed they received an active treatment.
Images were acquired with a Siemens Trio 3T scanner (Siemens, Erlangen, Germany) at the Murdoch Children’s Research Institute (Melbourne, Australia), as described elsewhere (7, 8, 11). Participants completed four runs, each consisting of randomized placebo, control trials, and conditioning trials (Figure 1). Behavioral analyses were performed using repeated measures analysis of variance. MRI analysis was performed using approaches previously described (see the Methods section in the online supplement for details) (8, 11). Regional brain activations were identified for control trials, placebo trials, and the contrasts of control greater than placebo and placebo greater than control trials. The association between participants’ behavior and regional signal changes was tested by analyzing the shared variance between placebo effects (urge-to-cough ratings during control trials minus ratings during placebo trials) and the levels of activation identified by the contrast of placebo greater than control trials. All statistical maps were thresholded to include voxels with a z value greater than 2.3 and a cluster probability of P less than 0.05, corrected for multiple comparisons using gaussian random field theory cluster-based correction as implemented in FEAT (fMRI Expert Analysis Tool) (12).
Figure 1. Participants inhaled either a low or high dose of nebulized capsaicin for 16 seconds during six stimulus trials throughout a single run of functional brain image acquisition lasting 7 minutes and 12 seconds. All participants completed four scanning runs. Air was inhaled through a nasal cannula before each stimulus trial. A visual cue to participants indicated if lidocaine or normal air would be delivered through the nasal cannula. However, participants only ever received normal air through the nasal cannula. Low doses of capsaicin preceded by placebo lidocaine were used to sustain the conditioned belief that the treatment was effective. High doses of capsaicin preceded by normal air constituted control trials. Placebo antitussive trials consisted of high doses of capsaicin preceded by placebo lidocaine. At the conclusion of each trial, participants were asked to indicate their rating of maximum urge-to-cough for the preceding stimulus using the fingers of the right hand (scale 0–10).
[More] [Minimize]Repeated measures analysis of variance of urge-to-cough ratings during control and placebo trials showed a significant main effect of condition (F [1,16] = 71.11; P < 0.001). On average there was a 42% decrease in urge-to-cough ratings in placebo compared with control trials and a placebo antitussive effect was seen in all individuals (Figure 2). The geometric means of low and high capsaicin doses were 0.39 μM and 1.66 μM, respectively. The high stimuli were a dose increment less than the geometric mean of participants’ C2 doses (3.91 μM), which relates to increased levels of urge-to-cough and likelihood of coughing when participants inhaled capsaicin repeatedly compared with a single breath (see Table E1 in the online supplement for individual scanning doses and C2 thresholds).
Figure 2. Participants’ ratings of the urge-to-cough were averaged across the functional brain imaging runs for control trials and placebo antitussive trials. The figure shows the pair of ratings from individual participants represented as unbroken lines. A downward slope to the right indicates a placebo-related decrease in the urge-to-cough. All participants showed placebo-related decreases, and the average effect across the group is represented by the filled triangles connected by a broken line. The variance bars on the triangles are standard errors of the mean.
[More] [Minimize]Capsaicin inhalation during control trials was associated with widespread activation in a distributed urge-to-cough neural network, comparable with findings that we have previously reported (7, 8). Thus, activations in the cerebral cortex included loci in the precentral and postcentral gyri (primary motor and sensory cortices, respectively), the insula, mid-cingulate cortex, and orbitofrontal cortices, and the supplementary motor area (Table 1). In subcortical regions, discrete activations were noted in the thalamus, midbrain, pons, medulla, and cerebellum (see Table E2).
| Region | BA | Side | MNI Coordinates* | Z Score | ||
|---|---|---|---|---|---|---|
| x | y | z | ||||
| Mid-cingulate cortex | 32 | Right | 4 | 18 | 42 | 5.01 |
| 24 | Left | −6 | 18 | 32 | 5.12 | |
| 24 | Right | 4 | 16 | 32 | 4.46 | |
| Medial frontal gyrus | 6 | Left | −4 | 30 | 32 | 4.21 |
| Supplementary motor area | 6 | 0 | −4 | 60 | 3.31 | |
| Superior frontal gyrus | 6 | Left | −16 | −4 | 68 | 3.98 |
| 6 | Right | 26 | 2 | 66 | 3.94 | |
| 9 | Left | −30 | 46 | 28 | 4.50 | |
| 9 | Right | 30 | 54 | 30 | 4.68 | |
| Middle frontal gyrus | 6 | Right | 42 | 8 | 60 | 3.88 |
| 46 | Left | −36 | 40 | 26 | 4.53 | |
| 46 | Right | 46 | 38 | 26 | 4.76 | |
| 46 | Right | 38 | 32 | 22 | 4.60 | |
| 10 | Left | −32 | 38 | 20 | 4.84 | |
| 10 | Right | 36 | 44 | 0 | 5.86 | |
| Orbitofrontal cortex | 11 | Left | −44 | 44 | −14 | 3.67 |
| 11 | Right | 46 | 48 | −16 | 4.37 | |
| Inferior parietal lobule | 40 | Right | 52 | −40 | 46 | 4.26 |
| Cuneus | 18 | 0 | −88 | 28 | 4.15 | |
| Precentral gyrus | 6 | Left | −54 | −10 | 36 | 4.31 |
| 6 | Left | −42 | −16 | 32 | 3.97 | |
| 6 | Right | 40 | −14 | 32 | 3.70 | |
| 6 | Left | −44 | −12 | 22 | 3.64 | |
| 6 | Right | 40 | −14 | 26 | 4.53 | |
| 6 | Right | 58 | 4 | 18 | 5.04 | |
| Postcentral gyrus | 2 | Left | −66 | −18 | 28 | 3.44 |
| 1 | Right | 60 | −16 | 22 | 3.98 | |
| Central operculum | Left | −56 | 0 | 8 | 4.73 | |
| Right | 60 | 2 | 10 | 4.56 | ||
| Superior temporal gyrus | 22 | Left | −56 | 8 | −2 | 4.26 |
| Insula | 13 | Left | −36 | 16 | −2 | 5.16 |
| 13 | Right | 36 | 20 | 0 | 6.09 | |
| 13 | Left | −40 | 4 | −0 | 5.24 | |
| 13 | Right | 38 | 4 | −6 | 5.37 | |
In general, regions activated during placebo antitussive trials were similar to the network seen for control stimulus periods (see Table E3). Mixed-effects analysis showed significantly greater activation during control trials compared with placebo antitussive trials in regions including the primary and secondary somatosensory cortices, primary motor cortices, mid-cingulate cortices, and supplementary motor area (P < 0.05, cluster corrected) (Figure 3, Table 2). Conversely, there was greater activation in placebo antitussive trials versus control trials in several brain regions including the dorsolateral prefrontal cortices in the middle frontal gyri, the precentral gyri, the inferior frontal gyri, the left inferior parietal lobule, and the cerebellum (P < 0.05, cluster corrected) (Figure 4, Table 3). The levels of increased activation during placebo antitussive compared with control trials in the right middle frontal gyrus were positively correlated with placebo-related changes in urge-to-cough ratings (P < 0.05, cluster corrected).
Figure 3. Brain regions showing activation during control trials are rendered in red–yellow on an average of participants’ structural brain images that were warped to the standard dimensions of the Montreal Neuroscience Institute template brain. A contrast was made between control and placebo antitussive trials to show regions where the level of activation was decreased after placebo lidocaine compared with control, the results of which have been rendered in blue on top of the structural image and control activations. (A) Sagittal slice through the left hemisphere shows placebo antitussive-related decreases in capsaicin activation in the supplementary motor area (SMA) and anterior cingulate cortex (ACC). These placebo antitussive-related decreases also occurred in the right hemisphere (not shown). (B) The secondary somatosensory cortex (SII) in the parietal operculum showed bilateral decreases in capsaicin activation during placebo antitussive trials. (C) The insula (INS) was activated in both hemispheres during control stimulus periods, but showed placebo antitussive-related decreased activation exclusively in the right hemisphere. (D) Control activations in the primary motor (MI) and somatosensory (SI) cortices were reduced bilaterally during placebo antitussive stimulus periods. A similar decrease was seen in the right superior frontal gyrus (SFG), but the same region in the left hemisphere did not show placebo antitussive-related decreases.
[More] [Minimize]| Region | BA | Side | MNI Coordinates* | Z Score | ||
|---|---|---|---|---|---|---|
| x | y | Z | ||||
| Mid-cingulate cortex | 24 | Left | −2 | 2 | 42 | 3.88 |
| 24 | Right | 4 | 22 | 24 | 3.70 | |
| Pregenual cingulate cortex | 32 | Left | −2 | 38 | 8 | 3.68 |
| Superior frontal gyrus | 6 | Left | −18 | −4 | 62 | 3.84 |
| 6 | Right | 14 | −8 | 64 | 3.62 | |
| 9 | Right | 30 | 44 | 28 | 3.67 | |
| Supplementary motor area | 6 | 0 | −4 | 58 | 3.95 | |
| Precentral gyrus | 6 | Left | −52 | −4 | 26 | 3.23 |
| 6 | Right | 54 | −6 | 28 | 3.32 | |
| Postcentral gyrus | 3 | Left | −50 | −18 | 36 | 3.48 |
| 3 | Right | 52 | −20 | 30 | 3.29 | |
| 3 | Left | −56 | −14 | 24 | 3.50 | |
| 43 | Left | −60 | −12 | 22 | 3.21 | |
| 43 | Right | 58 | −8 | 20 | 3.10 | |
| Central operculum | Left | −60 | −10 | 12 | 3.26 | |
| Right | 54 | 2 | 8 | 3.77 | ||
| Parietal operculum | Left | −54 | −22 | 22 | 3.25 | |
| Right | 50 | −24 | 28 | 3.21 | ||
| Cuneus | 18 | Right | 4 | −92 | 20 | 3.27 |
| Superior temporal gyrus | 22 | Left | −54 | 8 | −2 | 3.74 |
| Insula | 13 | Right | 40 | 8 | 2 | 3.41 |
| 13 | Right | 42 | −8 | 2 | 3.07 | |
Figure 4. Voxels shaded in green indicate regions where capsaicin activation was increased during placebo antitussive trials compared with control trials. Blue voxels denote regions where the size of the placebo antitussive increase in brain response was correlated with the size of the behavioral measures of placebo effects. Regions that showed placebo antitussive-related increases in capsaicin activations and correlations with the behavioral measures are shown in red. (A) The posterior parietal cortex (PPC) in the left hemisphere and the precentral gyrus (PreC) bilaterally showed increased levels of placebo antitussive trial activation compared with control trials. The middle frontal gyrus (MFG) in the right hemisphere showed placebo antitussive-related levels of activation that correlated with the size of behavioral placebo effects measured with urge-to-cough ratings. (B) Placebo antitussive trial-related increases in activation greater than control trials were seen bilaterally in the middle frontal gyri (MFG) in this axial slice 52 mm above the anterior commissure. These symmetrical regions of activation did not show levels of activation that correlated with behavioral measures of the placebo antitussive effect. (C) An extensive region of the right middle frontal gyrus (MFG) in the dorsolateral prefrontal cortex showed levels of placebo antitussive greater than control trial activation that was correlated with behavioral measures of placebo effects. (D) The mean ratings of urge-to-cough by a participant for placebo antitussive trials during a scanning run were subtracted from the mean of the control trials in the same run to derive a behavioral measure of placebo effect (ΔUrge-to-Cough). Blood oxygen level–dependent (BOLD) signal changes for the contrast of placebo greater control trials (Δ%BOLD Signal Change) were extracted for voxels showing correlation with the behavioral placebo effect. The relationship between behavior and regional brain activation is represented in the scattergram where the four runs were ranked according to behavioral placebo effects from smallest to largest and then plotted against the mean BOLD signal changes for the corresponding runs.
[More] [Minimize]| Region | BA | Side | MNI Coordinates* | Z Score | ||
|---|---|---|---|---|---|---|
| X | Y | Z | ||||
| Middle frontal gyrus | 6 | Left | −36 | 10 | 54 | 3.32 |
| 6 | Right | 40 | 6 | 50 | 3.44 | |
| 9 | Left | −40 | 20 | 36 | 3.35 | |
| 9 | Right | 46 | 26 | 34 | 3.52† | |
| 9 | Right | 46 | 32 | 28 | 3.19† | |
| Inferior frontal gyrus | 45 | Left | −40 | 22 | 22 | 3.75 |
| 9 | Left | −46 | 12 | 26 | 3.46 | |
| 9 | Right | 40 | 8 | 26 | 3.15 | |
| Precentral gyrus | 6 | Left | −40 | 4 | 34 | 3.20 |
| 6 | Right | 36 | 4 | 34 | 3.22 | |
| Inferior parietal lobule | 40 | Left | −50 | −54 | 50 | 3.53 |
| 40 | Left | −34 | −56 | 46 | 3.11 | |
| Middle temporal gyrus | 39 | Left | −32 | −58 | 32 | 3.24 |
| Cerebellum | Right | 26 | −88 | −34 | 3.84 | |
The brain plays an important role in the processing of incoming sensory information arising from the airways and lungs and in generating motor outputs that contribute to the behavioral regulation of respiration. These central processes are not confined to the brainstem but rather involve all levels of the neuraxis (13, 14). With respect to cough, information from the airways can be encoded into a conscious awareness of airway irritations leading to the generation of an urge-to-cough (15), which may then facilitate behavioral or evoked coughing to help clear the airways (16). Components of this higher brain circuitry also comprise inhibitory mechanisms that can be consciously or subconsciously recruited to suppress cough neural processing in the brain (11). This suppression may lead to either a reduction in the encoding of incoming sensory information, which would predictably lower the urge-to-cough, or a reduction in the outgoing motor commands that lead to a top down inhibition of coughing. Indeed, the available evidence indicates that central inhibitory mechanisms are capable of an impressive level of cough suppression (5, 17), suggesting that opportunities may exist to harness or mimic these processes as novel therapeutic approaches to achieve cough suppression in disease.
In the present study we confirmed our previous findings (6) that the perceptual component of airway sensory irritation (urge-to-cough) is significantly modifiable by placebo antitussive treatments. Thus, the belief in a therapeutic is seemingly sufficient to reduce the encoding of urge-to-cough intensity in the brain. In support of this, the results from our functional brain imaging studies revealed that the magnitude of brain activations in a number of central loci involved in generating the urge-to-cough were significantly reduced by placebo antitussive administration. Furthermore, we showed that when participants believed that they were receiving an antitussive treatment, brain activity was increased in regions of the prefrontal and parietal cortices that may represent important components of the placebo suppression network (18, 19). These data represent the first insights into the neurobiologic mechanisms that contribute to placebo antitussive responses and reinforce the notion that multiple central inhibitory mechanisms exist for modifying cough in humans.
The urge-to-cough is an important component of coughing that serves to inform individuals of the presence of irritants in the airways. Studies in the laboratory have shown that common tussive challenges (e.g., capsaicin) can be used to evoke an urge-to-cough in a dose-dependent fashion (8, 15). Furthermore, the urge-to-cough typically precedes the motor act of coughing, perhaps arguing that it plays a pivotal role in governing whether patients cough or not in response to sensory input from the airways (20).
In the present study we noted a 42% reduction in the mean capsaicin-evoked urge-to-cough ratings after placebo antitussive administration. This response is highly comparable with our previous work, which was performed using an entirely separate cohort of participants (6). In both studies we used a standard conditioning strategy to reinforce expectations that the placebo treatment was in fact an efficacious antitussive therapy. Using this strategy we have yet to identify any participants who do not report a decrease in urge-to-cough ratings after placebo antitussive trials. These experimental data resemble data obtained from clinical trials that report a high rate of placebo responses to antitussive therapies (5), adding support to our assertions that cough is particularly amenable to suggestive suppression. Indeed, cough may be more susceptible than pain to the effects of placebo, because placebo analgesia studies typically report that only around 50% of subjects experience a modest reduction in pain scores (21).
It is unclear at present why cough neural networks display such a high sensitivity to placebo antitussive suppression. It is worth noting that behavioral aspects of placebo suppression have not been studied in detail for cough. In this regard, we do not know whether the magnitude of placebo antitussive suppression varies depending on the magnitude of the initial stimulus. In other words, it is plausible that the placebo effect diminishes in participants when evoked cough approaches challenge thresholds that would elicit uncontrollable reflex coughing (and therefore very strong urge-to-cough sensations). Furthermore, it is simply not known whether patients with a cough disorder are equally sensitive to placebo antitussive suppression. Nevertheless, the size of the urge-to-cough reduction reported in our studies of healthy participants is not dissimilar to the magnitude of placebo contribution to cough suppression reported in many clinical trials of antitussive therapies, including in patients with chronic cough (22–24).
It has been speculated that decreased anxiety or attention may play a role in placebo analgesia (25). Indeed, our paradigm shares some similarities with “threat of pain” studies (26). Most notably, the preparatory cues used in our study could have primed emotional responses in anticipation of stimuli. However, it is difficult to make direct comparisons between the activation outcomes of the other studies and our own because threat of pain studies focus on adverse, anxiety-related responses, whereas our study investigated expectations of relief. Nevertheless, given that anxiety is known to influence cough (27), then reduction in anxiety may have played a role in producing the placebo antitussive effects observed in this study, and indeed could feasibly also contribute to the placebo effects seen in clinical trials.
This study used a conditioning strategy common to experimental placebo manipulations (21, 28), where rather than using an active drug, conditioning was achieved by means of pairing a visual cue with a reduced level of stimulus. As an initial investigation into the neural mechanisms underlying placebo in urge-to-cough, our design incorporated enhanced expectation and conditioning to maximize the size of the observed effect. Further investigation into the behavioral and neural responses to either conditioning or expectation alone may be instructive in elucidating the relative contributions of each to the behavioral effect, and also whether activation changes in similar cortical regions are involved. Although it is possible to design studies dissecting the relevant contributions of these mechanisms toward experimental placebo effects, it may be more difficult to conceptually separate them in clinical settings. For example, prior experience using ineffective antitussives may lead not only to negative expectations surrounding treatment, but may indeed be thought of as a form of conditioning, whereby patients are conditioned to associate treatment with a lack of effect (29).
The urge-to-cough relies on subcortical and cortical processing of incoming sensory information from the airways (7, 8, 30). We have previously reported that subcomponents of this broader urge-to-cough network can be delineated that show activations encoding for the sensory discriminative, cognitive, and motor aspects of airways irritation. For example, based on differential responses to varying levels of tussive stimuli, we have shown that distinct parts of the network activated by capsaicin inhalation are responsible for grading stimulus intensity (e.g., anterior insula cortex), determining urge-to-cough intensity (e.g., primary sensory cortex) and processing spatial or higher-order processes, such as those related to attention and motivation (e.g., the inferior parietal lobule and prefrontal cortex) (14). We have also identified discrete regions within the right inferior frontal gyrus and anterior insula as forming part of an endogenous cough-suppression network that can be voluntarily recruited to reduce motor outputs driven by the urge-to-cough (11) and the mid-cingulate cortex as a key hub area that may help integrate all of these functions of the urge-to-cough network (8).
The results of the present study suggest that the different components of the urge-to-cough network do not respond uniformly in response to placebo antitussive administration. For example, capsaicin-related activations after placebo antitussive administration were significantly reduced in several sensory and motor regions, including the insula, anterior cingulate cortex, primary somatosensory and motor cortices, and the supplementary motor area. By contrast, placebo increased the activity in the middle frontal gyri (specifically in the region containing the dorsolateral prefrontal cortex, Brodmann area 9) and in the inferior parietal lobule and precentral gyrus. These findings might reflect regional responses that are responsible for the behavioral outcomes after placebo antitussive administration. Thus, the reduction in urge-to-cough ratings reported by participants after placebo presumably reflects the relatively lower amount of activation seen in the urge-to-cough sensorimotor brain regions. Furthermore, these reductions may be related to the heightened activity noted elsewhere in the urge-to-cough network. Indeed, placebo analgesia studies similarly report elevated brain activity in the dorsolateral prefrontal cortex and inferior parietal lobule, suggesting that these regions may play an important role in regulating sensorimotor responses in the brain (31). Consistent with this, the magnitude of the activation in the right dorsolateral prefrontal cortex in the present study was significantly correlated with the magnitude of the reported placebo antitussive effect. Alternatively, regions including the right ventral inferior frontal gyrus, neighboring anterior insula, and the more anterior extent of mid-cingulate activation, regions that have been implicated in cough and breathing suppression (11, 32), did not show differences between placebo and control trials.
These results point to similarities in the mechanism of action of placebos between pain and urge-to-cough. The decreases in activation in capsaicin inhalation networks can be compared with results from placebo analgesia studies, where the network of pain-related brain regions shows decreased activation in response to painful stimuli after placebo (29, 33, 34). Studies of placebo effects in pain have also shown increased activation in the dorsolateral prefrontal cortex (29, 30) in the placebo condition. Furthermore, placebo analgesia is abolished when transcranial magnetic stimulation is used to block neural transmission in this region (22).
Interestingly, there were no statistically significant decreases in brain activity noted in thalamic or subcortical structures when responses after placebo antitussive administration were compared with no-treatment responses. This might suggest that placebo antitussive circuits function by selectively reducing cortical processing of incoming sensory information. However, the data might also reflect the scanning parameters used, which were optimized for whole-brain imaging rather than discrete imaging of subcortical and lower brain structures. Consistent with this, several thalamic and brainstem regions displayed responses approaching statistical significance after placebo antitussive administration, which may be better resolved using an acquisition protocol optimized for this purpose.
Placebo antitussives have a strong influence on coughing and the urge-to-cough. The outcomes of this study have shown that the substantial reductions in urge-to-cough after placebo are matched by a parallel decrease in brain responses to capsaicin inhalation in regions coding sensation and processing motor outputs. This confluence of behavior and brain activity points toward an active inhibitory process that is likely mediated by the prefrontal cortex, parietal cortex, and the cerebellum. Of those regions implicated in the placebo antitussive effect, activity in the right dorsolateral prefrontal cortex seems to have a special significance and constitutes a promising target for future studies. The study of higher brain mechanisms in cough has the potential to expand the understanding of a number of clinical conditions, such as chronic idiopathic cough or chronic cough, associated with chronic obstructive pulmonary disease. In addition, it is highly likely that these mechanisms are involved in excessive cough syndromes with a psychological or behavioral component including psychogenic or habit cough, and disorders of abnormal cough down-regulation or suppression, such as Lady Windermere syndrome (27, 35, 36). Because these disorders are particularly difficult to treat, understanding the neurologic basis of placebo suppression of urge-to-cough may be a promising avenue for developing or evaluating tools, such as biofeedback, cognitive behavioral therapy, or perhaps other behavioral therapy (e.g., speech therapy) that aim to establish a normal cough reflex. Further research may also prove useful for developing novel central nervous system drug targets.
| 1. | Chung KF. Chronic “cough hypersensitivity syndrome”: a more precise label for chronic cough. Pulm Pharmacol Ther 2011;24:267–271. |
| 2. | Morice AH, McGarvey LP, Dicpinigaitis PV. Cough hypersensitivity syndrome is an important clinical concept: a pro/con debate. Lung 2012;190:3–9. |
| 3. | Hróbjartsson A, Gøtzsche PC. Unsubstantiated claims of large effects of placebo on pain: serious errors in meta-analysis of placebo analgesia mechanism studies. J Clin Epidemiol 2006;59:336–338, discussion 339–341. |
| 4. | Vase L, Petersen GL, Riley JL III, Price DD. Factors contributing to large analgesic effects in placebo mechanism studies conducted between 2002 and 2007. Pain 2009;145:36–44. |
| 5. | Eccles R. The powerful placebo in cough studies? Pulm Pharmacol Ther 2002;15:303–308. |
| 6. | Leech J, Mazzone SB, Farrell MJ. The effect of placebo conditioning on capsaicin-evoked urge to cough. Chest 2012;142:951–957. |
| 7. | Mazzone SB, McLennan L, McGovern AE, Egan GF, Farrell MJ. Representation of capsaicin-evoked urge-to-cough in the human brain using functional magnetic resonance imaging. Am J Respir Crit Care Med 2007;176:327–332. |
| 8. | Farrell MJ, Cole LJ, Chiapoco D, Egan GF, Mazzone SB. Neural correlates coding stimulus level and perception of capsaicin-evoked urge-to-cough in humans. Neuroimage 2012;61:1324–1335. |
| 9. | Leech J, Farrell MJ, Mazzone SB. The effect of placebo conditioning on regional brain blood oxygen-level dependent signal changes during capsaicin-evoked urge-to-cough. Presented at the Australian Neuroscience Society Annual Conference. February 3–6, 2013, Melbourne, Australia. ORAL-20-08. |
| 10. | Miller FG, Wendler D, Swartzman LC. Deception in research on the placebo effect. PLoS Med 2005;2:e262. |
| 11. | Mazzone SB, Cole LJ, Ando A, Egan GF, Farrell MJ. Investigation of the neural control of cough and cough suppression in humans using functional brain imaging. J Neurosci 2011;31:2948–2958. |
| 12. | Worsley KJ, Evans AC, Marrett S, Neelin P. A three-dimensional statistical analysis for CBF activation studies in human brain. J Cereb Blood Flow Metab 1992;12:900–918. |
| 13. | Davenport PW, Vovk A. Cortical and subcortical central neural pathways in respiratory sensations. Respir Physiol Neurobiol 2009;167:72–86. |
| 14. | Mazzone SB, McGovern AE, Yang SK, Woo A, Phipps S, Ando A, Leech J, Farrell MJ. Sensorimotor circuitry involved in the higher brain control of coughing. Cough 2013;9:7. |
| 15. | Davenport PW, Sapienza CM, Bolser DC. Psychophysical assessment of the urge-to-cough. Eur Respir Rev 2002;12:249–253. |
| 16. | Hegland KW, Bolser DC, Davenport PW. Volitional control of reflex cough. J Appl Physiol (1985) 2012;113:39–46. |
| 17. | Hutchings HA, Morris S, Eccles R, Jawad MS. Voluntary suppression of cough induced by inhalation of capsaicin in healthy volunteers. Respir Med 1993;87:379–382. |
| 18. | Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta JK. Neurobiological mechanisms of the placebo effect. J Neurosci 2005;25:10390–10402. |
| 19. | Krummenacher P, Candia V, Folkers G, Schedlowski M, Schönbächler G. Prefrontal cortex modulates placebo analgesia. Pain 2010;148:368–374. |
| 20. | Davenport PW. Urge-to-cough: what can it teach us about cough? Lung 2008;186:S107–S111. |
| 21. | Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, Kosslyn SM, Rose RM, Cohen JD. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science 2004;303:1162–1167. |
| 22. | Kuhn JJ, Hendley JO, Adams KF, Clark JW, Gwaltney JM Jr. Antitussive effect of guaifenesin in young adults with natural colds. Objective and subjective assessment. Chest 1982;82:713–718. |
| 23. | Lee PCL, Jawad MS, Eccles R. Antitussive efficacy of dextromethorphan in cough associated with acute upper respiratory tract infection. J Pharm Pharmacol 2000;52:1137–1142. |
| 24. | Parvez L, Vaidya M, Sakhardande A, Subburaj S, Rajagopalan TG. Evaluation of antitussive agents in man. Pulm Pharmacol 1996;9:299–308. |
| 25. | Flaten MA, Aslaksen PM, Lyby PS, Bjorkedal E. The relation of emotions to placebo responses. Philos Trans R Soc Lond B Biol Sci 2011;366:1818–1827. |
| 26. | Ploghaus A, Narain C, Beckmann CF, Clare S, Bantick S, Wise R, Matthews PM, Rawlins JNP, Tracey I. Exacerbation of pain by anxiety is associated with activity in a hippocampal network. J Neurosci 2001;21:9896–9903. |
| 27. | Van den Bergh O, Van Diest I, Dupont L, Davenport PW. On the psychology of cough. Lung 2012;190:55–61. |
| 28. | Watson A, El-Deredy W, Iannetti GD, Lloyd D, Tracey I, Vogt BA, Nadeau V, Jones AK. Placebo conditioning and placebo analgesia modulate a common brain network during pain anticipation and perception. Pain 2009;145:24–30. |
| 29. | Colloca L, Benedetti F. How prior experience shapes placebo analgesia. Pain 2006;124:126–133. |
| 30. | Wheeler-Hegland K, Pitts T, Davenport PW. Cortical gating of oropharyngeal sensory stimuli. Front Physiol 2010;1:167. |
| 31. | Amanzio M, Benedetti F, Porro CA, Palermo S, Cauda F. Activation likelihood estimation meta-analysis of brain correlates of placebo analgesia in human experimental pain. Hum Brain Mapp 2013;34:738–752. |
| 32. | McKay LC, Adams L, Frackowiak RS, Corfield DR. A bilateral cortico-bulbar network associated with breath holding in humans, determined by functional magnetic resonance imaging. Neuroimage 2008;40:1824–1832. |
| 33. | Lui F, Colloca L, Duzzi D, Anchisi D, Benedetti F, Porro CA. Neural bases of conditioned placebo analgesia. Pain 2010;151:816–824. |
| 34. | Lu HC, Hsieh JC, Lu CL, Niddam DM, Wu YT, Yeh TC, Cheng CM, Chang FY, Lee SD. Neuronal correlates in the modulation of placebo analgesia in experimentally-induced esophageal pain: a 3T-fMRI study. Pain 2010;148:75–83. |
| 35. | Widdicombe J, Singh V. Physiological and pathophysiological down-regulation of cough. Respir Physiol Neurobiol 2006;150:105–117. |
| 36. | Weinberger M. The habit cough syndrome and its variations. Lung 2012;190:45–53. |
Supported by the National Health and Medical Research Council of Australia (566734, APP1042528, and APP1025589).
Author Contributions: J.L. contributed to study design, data collection, analysis, and manuscript preparation. M.J.F. contributed to study design, analysis, and manuscript preparation. S.B.M. contributed to study design and manuscript preparation.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201306-1079OC on October 4, 2013
Author disclosures are available with the text of this article at www.atsjournals.org.
