Regional brain stem activations during capsaicin inhalation using functional magnetic resonance imaging in humans.

Coughing is an airway protective behavior elicited by airway irritation. Animal studies show that airway sensory information is relayed via vagal sensory fibers to termination sites within dorsal caudal brain stem and thereafter relayed to more rostral sites. Using functional magnetic resonance imaging (fMRI) in humans, we previously reported that inhalation of the tussigenic stimulus capsaicin evokes a perception of airway irritation ("urge to cough") accompanied by activations in a widely distributed brain network including the primary sensorimotor, insular, prefrontal, and posterior parietal cortices. Here we refine our imaging approach to provide a directed survey of brain stem areas activated by airway irritation. In 15 healthy participants, inhalation of capsaicin at a maximal dose that elicits a strong urge to cough without behavioral coughing was associated with activation of medullary regions overlapping with the nucleus of the solitary tract, paratrigeminal nucleus, spinal trigeminal nucleus and tract, cardiorespiratory regulatory areas homologous to the ventrolateral medulla in animals, and the midline raphe. Interestingly, the magnitude of activation within two cardiorespiratory regulatory areas was positively correlated ( r2 = 0.47, 0.48) with participants' subjective ratings of their urge to cough. Capsaicin-related activations were also observed within the pons and midbrain. The current results add to knowledge of the representation and processing of information regarding airway irritation in the human brain, which is pertinent to the pursuit of novel cough therapies. NEW & NOTEWORTHY Functional brain imaging in humans was optimized for the brain stem. We provide the first detailed description of brain stem sites activated in response to airway irritation. The results are consistent with findings in animal studies and extend our foundational knowledge of brain processing of airway irritation in humans.

Brain activity associated with placebo suppression of the urge-to-cough in humans.

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.

Continuous-combined oral estradiol/drospirenone has no detrimental effect on cognitive performance and improves estrogen deficiency symptoms in early postmenopausal women: a randomized placebo-controlled trial.

OBJECTIVE: This study aimed to explore the effects of continuous-combined estradiol 1 mg/drospirenone 2 mg (E2D) on cognitive performance in healthy, recently postmenopausal women. METHODS: A 6-month randomized, double-blind, placebo-controlled study was carried out in a university research center. Participants were 23 healthy postmenopausal women aged 49 to 55 years. Cognitive performance was assessed with a computerized cognitive battery administered to all participants on 0, 12, and 26 weeks. Functional magnetic resonance imaging was performed on 13 participants before and after treatment using tasks of verbal fluency and mental rotation. RESULTS: E2D was not associated with an overall effect on cognitive performance. Functional magnetic resonance imaging results showed no difference between the groups for verbal fluency or mental rotation task performance at baseline. The mental rotation task was associated with increased blood oxygen level-dependent signalling in the placebo group in both occipital lobes and in the left superior parietal lobe after 26 weeks (P < 0.05), with no changes over time seen in the treatment group. The total menopausal symptom and sexual function domain scores improved after treatment in women randomized to E2D compared with the placebo group (both P < 0.05). Similarly, systolic blood pressure, weight, and body mass index were significantly lower in women randomized to E2D at 26 weeks (P < 0.05). CONCLUSIONS: E2D has no detrimental effect on cognitive performance in early postmenopausal women. E2D significantly improves menopausal symptoms, sexual function, systolic blood pressure, and weight.

Sensorimotor circuitry involved in the higher brain control of coughing.

There is an overwhelming body of evidence to support the existence of higher brain circuitries involved in the sensory detection of airways irritation and the motor control of coughing. The concept that cough is purely a reflex response to airways irritation is now superseded by the recognition that perception of an urge-to-cough and altered behavioral modification of coughing are key elements of cough disorders associated with airways disease. Understanding the pathways by which airway sensory nerves ascend into the brain and the patterns of neural activation associated with airways irritation will undoubtedly provide new insights into disordered coughing. This brief review aims to explore our current understanding of higher order cough networks by summarizing data from recent neuroanatomical and functional studies in animals and humans. We provide evidence for the existence of distinct higher order network components involved in the discrimination of signals arising from the airways and the motor control of coughing. The identification of these network components provides a blueprint for future research and the development of targeted managements for cough and the urge-to-cough.

The effect of placebo conditioning on capsaicin-evoked urge to cough.

BACKGROUND: The urge to cough is a clinical symptom of respiratory disease that precedes the motor act of coughing. Although previous studies have shown that cough is particularly susceptible to placebo suppression, it is unclear whether the perception of an urge to cough is also modifiable by placebo. Therefore, we tested the hypothesis that capsaicin-evoked urge to cough could be suppressed by placebo conditioning. METHODS: Eleven healthy participants were unknowingly conditioned to believe that an inert inhaler temporarily suppressed capsaicin-induced urge to cough by deceptively modifying the challenge concentration of capsaicin. In subsequent testing, capsaicin-evoked urge-to-cough subjective ratings were assessed in four challenges with a single dose of inhaled capsaicin following no treatment or the placebo metered-dose inhaler. An additional 10 participants were informed that the inhaler therapy was inert prior to receiving capsaicin challenges with and without inhaler treatment. RESULTS: There was a significant decrease in mean urge-to-cough ratings to capsaicin challenge following placebo compared with no treatment followed by capsaicin challenge (P < .001), with a peak decrease of 45%. The placebo inhaler alone had no effect on urge-to-cough subjective ratings when participants were aware that it contained no active medication. CONCLUSIONS: These data confirm that the urge to cough is susceptible to placebo inhibition. This provides further evidence that higher brain networks are involved in the processing of respiratory sensations related to airway irritation.