Brain activation after nasal histamine provocation in house dust
mite allergic rhinitis patients
Callebaut I1, Steelant B1, Backaert
W1, Peeters R2-3, Sunaert
S2-3, Van Oudenhove L4-5*, Hellings
PW1*
1Allergy and Clinical Immunology Research Group,
Department of Microbiology, Immunology and Transplantation, KU Leuven,
Leuven, Belgium
2Department of Imaging & Pathology, KU Leuven,
Leuven, Belgium
3Department of Radiology, University Hospitals Leuven,
Leuven, Belgium
4Laboratory for Brain-Gut Axis Studies (LaBGAS),
Translational Research Center for Gastrointestinal Disorders (TARGID),
Department of Chronic Diseases, Metabolism, and Ageing (CHROMETA),
University of Leuven, Belgium
5Cognitive and Affective Neuroscience Laboratory
(CANlab), Center for Cognitive Neuroscience, Department of Psychological
and Brain Sciences, Dartmouth College, Hanover, NH, USA
*Joined senior authorship
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,
rhinorrhoea, 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 paretial 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 metacholine 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.
Eight 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. HDM allergy was
confirmed by a skin prick test. Relevant nasal anatomic abnormalities or
rhinosinusitis were ruled out by nasal endoscopy. Non-allergic HC showed
a negative skin prick test for all the tested allergens, showed no nasal
symptoms and had normal nasal endoscopy. Patients of <18 and
>50 years of age, having used nasal or oral steroid
treatment <6weeks prior to the study or nasal or oral
antihistamine treatment <4weeks 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. Informed consent was signed by all participants. The study
was approved by the local medical ethics committee of the University
Hospitals Leuven (B322201215751).
All HC and AR patients underwent a nasal provocation by means of a
canulla placed under the nose with either nebulized sham solution
(saline) or with histamine for 5 minutes while in 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 canulla by means of air
(8 bar) after 10 minutes of baseline scanning in a pharmacological
(ph)MRI design. This concentration of histamine was chosen as optimal
dose after a pilot study in 3 HCs, 1 birch and grass pollen AR patient
and 1 HDM AR patient where the dose of histamine resulted in a reduction
of 20% in the Peak Nasal Inspiratory Flow (PNIF). Moreover, patients
did not had the urge to sneeze at this concentration, 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). The
best value out of three consecutive measurements with a variability of
<10% was recorded. Changes in PNIF from baseline to
post-provocation were compared between conditons (histamine & saline)
as well as between groups (patients & controls) using marginal linear
mixed models.
phMRI data were preprocessed and analyzed as described previously(8, 9).
The effect of interest for the present study was the group (patient
versus controls)-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<0.05 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.
After nasal provocation with saline, no significant decrease in PNIF was
found compared to baseline in both groups (AR: 135 ± 61.82 l/min vs
137.5 ± 44.88 l/min, p=0.74; HC: 120 ± 36.74 vs 129 ± 31.30, p=0.46).
Nasal provocation with histamine induced a significant decrease in PNIF
in both HDM AR patients (158.8 ± 71.55 l/min vs 112.5 ± 83.67, p=0.0053)
as well as in the HC (134.2 ± 27.64 l/min vs 85.83 ± 40.55, p=0.002).
The analysis on PNIF values showed a significant condition-by-time (pre-
to post-provocation) interaction effect (F(1,11)=28.8, p=0.0002), 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. No significant
group-by-condition-by-time interaction effect was found (F(1,11)=0.09,
p=0.78) indicating that the decrease from baseline after histamine
compared to saline did not differ between patients and controls, with a
significant decrease from baseline after histamine but not saline in
both groups (p=0.002 and p=0.015, respectively).
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 & 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 a stronger
activation in controls 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.