Brain activation after nasal histamine provocation in house dust mite allergic rhinitis patients
Authors: Ina Callebaut, Brecht Steelant, Wout Backaert, Ronald Peeters, Stefan Sunaert, Lukas Van Oudenhove, Peter W Hellings
Journal: Allergy (2020)

To the Editor, The nasal mucosa is armed with a complex nervous system of sensory, sympathetic, and parasympathetic nerves, allowing swift defensive responses to physical and chemical stimuli. In allergic rhinitis (AR) patients, nasal allergen deposition leads to mast cell activation with release of allergic mediators such as histamine. Apart from its direct effects on the surrounding tissue, histamine also activates sensory nerve endings giving rise to symptoms like sneezing, rhinorrhea, and/or congestion.1 Activated nasal sensory nerves transmit action potentials to their cell bodies in the trigeminal ganglion and further to the midbrain where secondary synapses lead to the generation of central reflex signals. Despite activation of neural pathways in AR,2 it is not known which particular regions in the brain are activated by different nasal stimuli. Clinical studies using positron emission tomography scans indicate that there is no isolated itch center in the brain but that different cortical centers are involved in the processing of itch.3, 4 Activation of the anterior cingulate cortex (ACC), the supplementary motor area (SMA), and the inferior parietal lobe partly explains the connection between itching and the related reflex of scratching.4 Using functional magnetic resonance imaging (fMRI), the activation of the superior temporal gyrus, insula, and nucleus caudate following painful intranasal trigeminal stimulation has been shown.5 When asthmatic patients are challenged with methacholine or allergens, activity in ACC and insula was associated with markers of bronchial inflammation and obstruction.6 To fill the abovementioned knowledge gap, a prospective, single-blind, cross-over study was designed to investigate brain responses to nasal histamine provocation in healthy volunteers and AR patients. In this proof-of-concept study, 8 house dust mite (HDM) AR patients and 7 non-allergic healthy controls (HC) were recruited at the outpatient clinic for Otorhinolaryngology of University Hospitals Leuven. HC had a negative skin prick test, no nasal symptoms, and had no nasal anatomic abnormalities or rhinosinusitis as confirmed by nasal endoscopy. AR patients had a positive skin prick test for D. pteronyssinus and/or D. farinae >5 mm. Two out of 8 AR patients were mono-sensitized to HDM, and the other 6 AR patients were poly-sensitized with sensitizations to cat (n = 6), dog (n = 5), tree pollen (n = 4), or grass pollen (n = 5). Patients using nasal or oral steroid treatment <6 weeks or nasal or oral antihistamine treatment <4 weeks prior to the study were excluded, as well as those with past or ongoing immunotherapy for HDM, asthma, smoking, and clinical signs of rhinosinusitis or anatomic nasal deformities. All study participants were between 18 and 50 years old and provided written informed consent. The study was approved by the local medical ethics committee of the University Hospitals Leuven (B322201215751). HC and AR patients underwent a nasal provocation through a cannula placed under the nose with either nebulized sham solution (saline) or with histamine for 5 minutes while in a supine position in the MR scanner on 2 separate days with a minimum of 1 week in between and in a single-blinded and random order. An aerosol of 10 mL histamine HCl (16 mg/mL) or 10 mL saline was delivered via the cannula using air (8 bar) after 10 minutes of baseline scanning in a pharmacological (ph)MRI design. This concentration of histamine was chosen as the optimal dose after a pilot study in 3 HCs and 2 AR patient where this dose of histamine resulted in a reduction of 20% in the peak nasal inspiratory flow (PNIF). Patients did not have the urge to sneeze at this concentration and hence, interfering with the (ph)MRI read-out, as was the case for the dose of 32 mg/mL. PNIF values were used for measuring nasal flow at baseline and after the nasal provocation at the end of the phMRI scan, as recommended.7 For each PNIF measurement, we repeated the PNIF at 3 times with a short interval of 30 seconds and with less than 10% variation in measured values. The highest PNIF value of 3 values was chosen, irrespective of control or patients. A marginal linear mixed model, more specifically a 2 (substance, histamine vs. saline, within-subject) × 2 (time, pre- versus poststimulation, within-subject) × 2 (group, AR versus HC, between-subject) ANOVA, was performed. phMRI data were preprocessed and analyzed as described previously.8, 9 The effect of interest for the present study was the group (AR patients versus HC)-by-substance (histamine versus saline)-by-time interaction effect, comparing the time course of the brain response to histamine vs saline provocation between AR patients and controls. A whole-brain voxel-wise FWE-corrected threshold of P < .05 was used combined with an extent threshold of k = 10 voxels (corresponding to pFWE < 0.001 at cluster level). In total, 8 HDM AR patients (5 females and 3 males) and 7 HC (5 females and 2 males) were recruited with a mean age of 22.5 ± 0.72 and 23.8 ± 1.11 years, respectively. One female HDM AR and two female HC were excluded due to excessive head movement during MR scanning. The analysis on PNIF values showed a significant substance-by-time (pre- to postprovocation) interaction effect (F(1,11) = 28.8, P = .0002), driven by a significant decrease in PNIF after histamine (−47.30 ± 8.87, pHolm = 0.0004), but not after saline (−5.81 ± 5.96, pHolm = 0.35) in the entire sample (Supplementary Figure S1). No significant group-by-substance-by-time interaction effect was found (F(1,11) = 0.09, P = .78) indicating that the decrease from baseline after histamine compared to saline did not differ between AR and HC, with a significant decrease from baseline after histamine but not saline in both groups (P = .002 and P = .015, respectively). Besides being considered as one the key mediators of allergic inflammation, histamine plays a major role in the regulation of autonomic functions, including energy balance, sleep, and the regulation of body temperature. In addition, histamine is an important mediator involved in nasal itch and in the diagnosis of nasal hyperreactivity, possibly attributing to the effects observed in HC here. Brain regions showing a differential response to histamine versus saline in AR patients versus HCs included bilateral mid-/posterior insula, right anterior insula, bilateral postcentral/superior temporal gyrus/rolandic operculum (including secondary somatosensory cortex), bilateral putamen, left cerebellum (crus 1 and 2), right mid-occipital gyrus, bilateral medial orbital gyrus/gyrus rectus, and right middle/superior frontal gyrus (ventrolateral prefrontal cortex) (Table 1, Figure 1). Most of these differential responses were due to stronger activation in HCs vs AR patients, except for the right anterior insula, right middle occipital gyrus, right middle/superior frontal gyrus, and left cerebellum, where a stronger activation was observed in AR patients. Left postcentral gyrus left Rolandic operculum left superior temporal gyrus Right posterior insula right superior temporal gyrus/pole Right superior temporal gyrus right supramarginal gyrus Left mid insula left putamen medial orbital gyrus gyrus rectus Right Rolandic operculum right superior temporal gyrus Our pilot study shows for the first time that, besides known differences in local mucosal responses, brain responses to nasal histamine provocation also differ between HDM AR patients versus HCs. More specifically, we found differences in regions that are known to be broadly involved in interoception (ie, monitoring and perceiving the physiological state of the body)10, 11 and in itch perception,12 implicating toward both the perception of symptoms and their putative emotional impact and allergic disease and health. Our proof-of-concept study holds some limitations: firstly, the small number of participants; secondly, the mild disease severity of AR patients limits our understanding of histamine-activated brain regions in patients with severe AR; and thirdly, differences in brain activity measured with fMRI does not allow to distinguish whether this difference is due to differential activation of histamine receptors in the brain or to differences in afferent signals from the nose or their processing at the brain level. Molecular imaging studies based on positron emission tomography with tracers for the histamine system would be needed to verify the presence of different histamine receptors (ie, H1R, H2R, and H4R). In conclusion, our results show for the first time activation of different brain regions upon nasal histamine provocation in AR patients versus HC. Further research in a larger group of patients might be useful to investigate brain responses in severe AR patients and to better understand the psycho-emotional impact of chronic allergic inflammation. The authors declare no conflict of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.