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Insular functional connectivity in migraine with aura

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Introduction Insula plays an integrating role in sensory, affective, emotional, cognitive and autonomic functions in migraine, especially in migraine with aura (MA). Insula is functionally divided into 3 subregions, the dorsoanterior, the ventroanterior and the posterior insula respectively related to cognition, emotion, and somatosensory functions. This study aimed at investigating functional connectivity of insula subregions in MA. Methods Twenty-one interictal patients with MA were compared to 18 healthy controls (HC) and 12 interictal patients with migraine without aura (MO) and were scanned with functional MRI during the resting state. Functional coupling of the insula was comprehensively tested with 12 seeds located in the right and left, dorsal, middle, ventral, anterior and posterior insula, by using a seed-to-voxel analysis. Results Seed-to-voxel analysis revealed, in MA, a strong functional coupling of the right and left antero-dorsal insula with clusters located in the upper cerebellum. The overlap of these cerebellar clusters corresponded to the vermis VI. These functional couplings were not correlated to duration of MA, frequency of MA attacks nor time since last MA attack, and were not found in MO. Discussion The anterior insula and superior cerebellum, including vermis VI, are components of the central Autonomic Nervous System (ANS) network. As these regions are involved in the control of cardiovascular parasympathetic tone, we hypothesize that this connectivity may reflect the cardiovascular features of MA. Conclusion The anterior dorsal insula is connected with vermis VI in MA patients in the resting state. This connectivity may reflect the cardiovascular features of MA. Trial registration NCT02708797.
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Gollionetal.
The Journal of Headache and Pain (2022) 23:106
https://doi.org/10.1186/s10194-022-01473-1
RESEARCH
Insular functional connectivity inmigraine
withaura
Cédric Gollion1,2*, Fleur Lerebours1, Federico Nemmi2, Germain Arribarat2, Fabrice Bonneville2,3,
Vincent Larrue1† and Patrice Péran2†
Abstract
Introduction: Insula plays an integrating role in sensory, affective, emotional, cognitive and autonomic functions in
migraine, especially in migraine with aura (MA). Insula is functionally divided into 3 subregions, the dorsoanterior, the
ventroanterior and the posterior insula respectively related to cognition, emotion, and somatosensory functions. This
study aimed at investigating functional connectivity of insula subregions in MA.
Methods: Twenty-one interictal patients with MA were compared to 18 healthy controls (HC) and 12 interictal
patients with migraine without aura (MO) and were scanned with functional MRI during the resting state. Functional
coupling of the insula was comprehensively tested with 12 seeds located in the right and left, dorsal, middle, ventral,
anterior and posterior insula, by using a seed-to-voxel analysis.
Results: Seed-to-voxel analysis revealed, in MA, a strong functional coupling of the right and left antero-dorsal insula
with clusters located in the upper cerebellum. The overlap of these cerebellar clusters corresponded to the vermis
VI. These functional couplings were not correlated to duration of MA, frequency of MA attacks nor time since last MA
attack, and were not found in MO.
Discussion: The anterior insula and superior cerebellum, including vermis VI, are components of the central Auto-
nomic Nervous System (ANS) network. As these regions are involved in the control of cardiovascular parasympathetic
tone, we hypothesize that this connectivity may reflect the cardiovascular features of MA.
Conclusion: The anterior dorsal insula is connected with vermis VI in MA patients in the resting state. This connectiv-
ity may reflect the cardiovascular features of MA.
Trial registration: NCT02708797.
Keywords: MRI, Functional MRI, Insula, Migraine, Migraine with aura, Cerebellum vermis
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Introduction
Migraine is a disabling disorder affecting up to 15% of
the global population, and is the second leading cause of
years lived with disability [1, 2]. Migraine pain is related
to the involvement of the trigeminovascular system [3],
but migraine is not only a pain, as it is also accompa-
nied by several sensory, autonomic, affective and cog-
nitive disorders. ese symptoms are posited to result
from multiple brain networks involvement within the
brainstem, the subcortical and cortical areas, beyond
the trigemino-vascular system [4]. In about one third of
migraine patients, migraine attacks are accompanied by
an aura which is a transient progressive and fully revers-
ible central neurological symptom, most often visual,
occuring before the headache. e insula is involved in
Open Access
The Journal of Headache
and Pain
Vincent Larrue and Patrice Péran these authors contributed equally to the
paper.
*Correspondence: gollion.c@chu-toulouse.fr
1 Department of Neurology, University Hospital of Toulouse, 31059 cedex 9
Toulouse, France
Full list of author information is available at the end of the article
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Gollionetal. The Journal of Headache and Pain (2022) 23:106
multiple cerebral functions such as sensorymotor pro-
cessing, pain, taste, interoception, autonomic control,
emotions, attention or salience which refers to the ability
to select the most relevant information among multiple
internal and external stimuli [5]. Parcellation of insula
resulted in two architectonic subdivisions (posterior
granular area and anterior dysgranular area) to thirteen
multi-modal MRI subdivisions [5, 6]. Nevertheless, data-
driven meta-analysis of human functional imaging stud-
ies supported a tripartite subdivision of the insula into a
ventroanterior area, a dorsoanterior area and a posterior
area. e ventroanterior insula is functionally coupled
with limbic areas and is associated with emotion, chem-
osensation and autonomic functions. e dorsoanterior
insula is connected to the anterior cingulate cortex and
the dorsolateral prefrontal cortex and plays a role in cog-
nitive tasks and executive control. Conversely, the pos-
terior insula is connected to the somatosensory cortex
and the suplementary motor area resulting in pain and
somatosensory functions involvement [7]. Evidences sup-
port the involvement of the insula in several features of
migraine pathophysiology from the ictal phase to chroni-
cisation. During the ictal phase of spontaneous migraine
attacks, Positron Emission Tomography (PET) studies
revealed activation of bilateral insula cortex as well as
other cortical areas, brainstem and diencephalic nuclei
[8, 9]. In addition, functional MRI studies during the ictal
phase showed a stronger activation of the anterior insula
in response to olfactory stimulations, but a decreased
functional connectivity (FC) of the anterior insula with
the medial prefrontal cortex within the Default Mode
Network (DMN) inversely proportional to the pain inten-
sity [10, 11]. Another study showed a higher FC between
the right thalamus and the left insular cortex during
spontaneous migraine attacks [12]. During the intercital
phase of migraine without aura (MO), the right poste-
rior insula was identified as a hub of FC more strongly
connected to the supplementary motor cortex and the
paracentral lobule among other brain areas [13]. In high
frequency migraine, defined by 8 to 14 monthly migraine
days, compared to low frequency migraine, heat pain-
ful stimulations of the hand induced lower controlateral
anterior insula and bilateral inferior insula activations,
but a higher connectivity of bilateral insula with the left
post central gyrus [14]. In chronic migraine, number of
years of chronic migraine were correlated to the resting
state FC between bilateral anterior insula and the right
mediodorsal thalamus, as well as to the FC between the
right anterior insula and the periaqueductal grey mat-
ter (PAG) [15]. Overall, the insula is posited to play a key
role in migraine, acting as a «hub» of integration of auto-
nomic, sensory, affective and cognitive functions [16].
Insula in migraine with aura (MA) is of specific interest as
previous studies have found specific alterations of insular
connectivity in MA. e anterior insula had a reduced
connectivity with occipital areas in MA compared to
MO and Healthy Controls (HC), and the connectivity
changes between the left anterior insula and occipital
areas were negatively correlated with headache severity
in MA only [17]. In a study investigating cognitive func-
tions in migraine and assessing the DMN, patients with
MA presented an increased FC between the right insu-
lar cortex, the left angular gyrus, the left supramarginal
gyrus, the right precentral gyrus and the right postcentral
gyrus compared to MO. In patients with complex MA,
defined by more than visual symptoms, the right ante-
rior insula was more strongly connected within the sen-
sorimotor network compared to simple visual aura and
MO, and this increased FC could discriminate between
complex MA and simple visual aura [18]. Moreover, in a
PET/MRI brain study, uptake of [11C]PBR28, a glial acti-
vation maker, in the right posterior insula was correlated
to the number of MA attacks [19]. However, this result
was not compared to MO.ese observations suggested
that the insula exhibited altered connectivity in MA,
however these studies have not taken into account the
functional division of the insula. In fact, the studies have
focused either on the salience network, which includes
the anterior insula [17, 20, 21], or on the somato-sensory
network, which includes the posterior insula [18] or to a
few regions of interest that did not explore the insula in
its subdivisions. To our knowledge, the FC of the insula’s
functional subdivisions has not yet been comprehensively
studied in MA. erefore, in the present study, we aimed
at investigating the bilateral insular connectivity in MA
using seeds in the anterior, posterior, dorsal, middle and
ventral insula.
Methods
Design andpopulation
is study was retrospectively conducted from images
acquired in a previous MRI protocol (Trial registration:
NCT02708797). Twenty-three patients with MA patients
aged 30 to 55 without history of neurological disease were
compared to 23 age and sex matched HC. Volunteers
were excluded in case of abnormal neurological examina-
tion or abnormal MRI. Diagnosis of MA was confirmed
by a trained neurologist according to the ICHD-3 criteria
[22]. Patients with MA were included during a pain-free
period for at least 8days. Age at migraine onset and aura
onset, frequency of migraine attacks in the past twelve
months, type of aura (visual, sensory, dysphasic or other),
frequency of aura among all migraine attacks, time since
last migraine attack, and preventive treatment were
recorded. To appraise the specificity of results found in
patients with MA, a post-hoc analysis was conducted in
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Gollionetal. The Journal of Headache and Pain (2022) 23:106
twelve patients with episodic MO from another study
previously conducted in our center. is previous study
compared the brain FC of patients with chronic migraine
to patients with episodic migraine [23]. e fMRI proto-
col was the same and the patients with MO were scanned
during a pain-free period of at least 72h.
Ethics
e study was approved by the local institutional Ethics
Committee (Comité de protection des personnes Sud-
Ouest I). All participants gave written informed consent.
Images acquisition
MRI images were acquired on a 3T MR imager (Philips
Achieva dStream 3 T 32-channel coils). All MRI were
interpreted by a senior neuroradiologist. All volunteers
were evaluated during the resting state, awake and eyes
closed. No activation task was performed. For the rest-
ing-state functional MRI (rs-fMRI), Blood Oxygen Level
Dependent (BOLD) sequence was assessed with the fol-
lowing parameters: 160 volumes, TR = 3000ms, TE = 30,
acquisition matrix 80 × 78, slices = 45, flip angle = 90°,
spatial resolution voxel size = 3 × 3 × 3 mm3. A 3D
T1-weighted sequence was also acquired with the fol-
lowing parameters: TR = 8.1ms; TE = 3.7ms , acquisition
matrix 240 × 240, slices = 170, flip angle = 8°, resolution
voxel size = 1 × 1 × 1 mm3.
Rs‑fMRI analysis
e analysis of the rs-fMRI was processed using Statis-
tical Parametric Mapping (SPM) 12 software (https://
www. fil. ion. ucl. ac. uk/ spm/), running under MATLAB,
and conn toolbox. Pre-processing consisted in spatially
realignment, normalization in the Montreal Neurological
Institute (MNI) space, smoothing using a 8mm Gauss-
ian kernel. We performed seed-to-voxels analysis of insu-
lar connectivity in MA. e seeds corresponded three
Region Of Interest (ROI) dorsal, middle and ventral were
placed in the left and right anterior and posterior insu-
lar cortex accounting for a total of 12 ROI (Fig.1). MNI
coordinates were derived from Cauda et al., NeuroImage
2011 [24] and are given in Table1. We thus conducted
a seed-to-voxel analysis between each of these insular
ROI, considered as seeds, and the voxels in the whole
brain. An average time-course was obtained from the
seeds. Correlation maps were generated for each subject
in a first level analysis, estimating the correlation coef-
ficient between the whole brain voxels and seeds-time
series. e connectivity maps were then introduced in
a second level analysis comparing the resting-state FC
between patients with MA and HC using a two-sample
t-test. e statistical maps were thresholded at p < 0.001
and only clusters of more than 10 voxels were retained.
Connectivity was assumed significant at p < 0.05 cor-
rected for multiple comparisons using the family wise
error rate (FWE). A secondary ROI-to-ROI analysis was
conducted to precise results of the seed-to-voxels anal-
ysis. e average time course was extracted from each
ROI and connectivity value was calculated (Fischer Z
scores). In ROI-to-ROI analysis, functional coupling was
assumed significant at p < 0.05. Results were presented
with mricron software. Significant results found in MA
were afterward compared in patients with MO in order
to evaluate the specificity of this result in MA.
Fig. 1 Region of interest (ROI) located in the dorsal (A), middle (B)
and ventral(C) insula. These ROI were considered as seeds in the
seed-to-voxel analysis. MNI coordinates are given in Table 1
Table 1 MNI coordinates of the insular ROI (Region of interest)
R right, L Left
Right
Number of ROI (x,
y, z)
Left
Number of ROI (x, y, z)
Antero-dorsal insula ROI 1 R (31, 12, 8) ROI 1 L (-31, 12, 8)
Postero-dorsal insula ROI 2 R (36, -9, 7) ROI 2 L (-36, -9, 7)
Anterior middle insula ROI 3 R (36, 19, 1) ROI 3 L (-36, 19, 1)
Posterior middle
insula ROI 4 R (40, -5, 0) ROI 4 L (-40, -5, 0)
Antero-ventral insula ROI 5 R (36, 16, -8) ROI 5 L (-36, 16, -8)
Postero-ventral insula ROI 6 R (40, -2, -8) ROI 6 L (-40, -2, -8)
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Gollionetal. The Journal of Headache and Pain (2022) 23:106
Statistics ofclinical data
Qualitative and continuous variables were presented as
percentages and arithmetic medians with their corre-
sponding interquartile range. Qualitative variables were
compared using the Chi-squared test and continuous
variable by using the Wilcoxon-Mann–Whitney test.
Correlations between clinical data and the strength of
FC, figured as a Z score, were evaluated with the Spear-
man correlation coefficient. Statistical analyses were per-
formed with the statistical R software (v.4.0.0). All tests
were considered significant at the 0.05 level.
Data availability
Anonymized data not published within this article will be
made available on reasonable request from any qualified
investigator.
Results
Subjects
Two patients with MA and five HC were excluded
because of motion artifacts on BOLD sequence. Func-
tional MR images were thus available in 21 patients with
MA, 12 patients with MO and 18 HC. e included
volunteers had no significant medical history and were
similar in age (MA, median age (IQR): 39.0 (12.0) years;
MO: 42 (18.7) years; HC: 39 (9.5) years), P > 0.05 and
sex (81% women in MA; 75% in MO and 72% in HC),
P > 0.05. Seven patients with MA were under preventive
therapy (2 betablocker, 2 topiramate, 1 valproic acid, 1
valproic acid and aspirin, 1 oxetorone). All patients with
MA had visual aura, 8 of them also had sensory aura and
seven dysphasic aura. In MA, median (IQR) duration of
migraine was 25 [13] years, annual frequency of attacks
was 15 [17] attacks/year and time since last migraine
attack was 19 [24] days. No patient with MO was under
preventive therapy. In MO, median (IQR) duration of
migraine was 21 (10.5) years and monthly migraine days
was 3.5 (1.25) days.
MA vs HC: seed‑to‑voxel analysis
ROI 1 R presented an increased FC in MA with a clus-
ter encompassing vermis 6 (31% volume of the clus-
ter), lingual gyrus left (21%), lingual gyrus right (18%),
cerebellum 6 right (18%) and cerebellum 6 left (12%).
Size of the cluster: 257, size p-FWE = 0.015, p eak
p-FWE = 0.043, MNI coordinates (x, y, z) = (06, -72,
-12), T = 6,24, p-FDR < 0,001 (Fig.2). ROI 1 L presented
an increased FC in MA with a cluster encompassing
cerebellum crus 1 left (20%), vermis 7 (18%), cerebel-
lum Crus 2 left (17%), vermis 6 (13%), cerebellum 6 left
(11%), lingual gyrus left (10%), cerebellum Crus 1 right
(5%), cerebellum 6 right (2%). Size of the cluster 218,
size p-FWE = 0.027, peak p-FWE = 0.806, MNI coordi-
nates (x, y, z) = (-02, -78, -18), T = 5,02, p-FDR < 0,001
(Fig. 2). No significant difference was found between
MA and HC for other insular ROI. en both ROI 1
R and 1 L, corresponding respectively to right and left
antero-dorsal insular cortex, presented an increased FC
Fig. 2 Increased connectivity between ROI 1, antero-dorsal insula, right (A) and left (B) with cerebellum in MA
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Gollionetal. The Journal of Headache and Pain (2022) 23:106
with a cerebellum area. e anatomical labelisation was
carried out with SUIT toolbox [25]. e overlapping of
the two cerebellar regions connected with the antero-
superior insula corresponded to the vermis VI, MNI
coordinates (x, y, z) = (00, -76, -17), size of the cluster
86 (Fig.3).
MA vs HC: ROI‑to‑ROI analysis
Althought the overlap functionally coupled to the antero-
dorsal insula corresponded to vermis VI, it is noteworthy
that right and left lingual cortices were part of the clus-
ters. As the lingual cortices are involved in MA, we con-
ducted ROI-to-ROI analysis between lingual cortices and
insula and between vermis VI and insula. It revealed no
FC between the right or the left lingual cortices and ROI
1R or ROI 1L. In contrast, we confirmed the strong FC
between the right and left antero-dorsal insula with the
vermis VI: T (48) = 3.27; p-FDR = 0.002, Fig.4.
Correlation withclinical data inMA
Neither the FC between ROI 1 R and vermis VI nor
the FC between ROI 1 L and vermis VI were correlated
to clinical features (duration of migraine, frequency of
migraine attacks and time since last migraine attack),
Table2.
Comparison ofMA andHC withMo byusing ROI‑to‑ROI
analysis
We compared the FC of vermis VI to ROI 1R and ROI
1L between MO and HC and between MO and MA. No
difference of functional coupling was found between MO
and HC. When MA was compared to MO, vermis VI
was functionally coupled to ROI 1R but not to ROI 1L,
T(48) = 2.96; p-FDR = 0.004.
Fig. 3 Overlap (purple) of areas highly connected to the right (red)
and left (blue) antero-dorsal insula, corresponding to vermis VI
Fig. 4 ROI-to-ROI functional coupling of vermis VI with right (ROI 1 R) and left (ROI 1 L) antero-dorsal insula. HC = healthy controls. MA = migraine
with aura
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Gollionetal. The Journal of Headache and Pain (2022) 23:106
Discussion
is explorative study aimed at investigating whether insula
exhibits differences in FC in patients with MA using a com-
prehensive seed-to-voxel analysis of right and left insula with
six seeds located within the anterior, posterior, dorsal, middle
and ventral insula. We found an increase connectivity of both
right and left antero-dorsal insula with the cerebellar vermis
VI in patients with MA. is increased FC was not found in
patients with MO. Previous studies in migraine have shown
that insula exhibits alterations of FC with brain structures
involved in pain processing such as thalamus [12], PAG [26,
27], somatosentory cortex [18], or cognitive function such as
the default mode network [21, 28] or salience network [17, 20,
21]. In MA specifically, insula exhibited altered FC with
occipital cortex and somatosensoriel cortex only in complex
MA [17, 18]. However, these findings relied mostly on inves-
tigations of other brain areas or partial explorations of insula.
To the best of our knowledge, our result is new and its origi-
nality could be explained by the methods which consisted of a
comprehensive insular FC analysis by distinguishing insula
subdivions from each other. Other methodological differ-
ences with previous studies should be considered. Previous
studies showing an increased FC of the insula with the thala-
mus involved MO during spontaneous migraine attacks [12],
an increased connectivity of insula with the PAG involved
patients with allodynia [26, 27], an increased connectivity of
insula with the somatosensory cortex involved patients with
complex auras [18]. One study showing a lower correlation
with the visual cortex set a less conservative threshold of sig-
nificance for statistical maps [17]. Our study showing an
increased FC of both right and left antero-dorsal insula with
the cerebellar vermis VI provides a new perpective on the
role of insula in MA. Because our study did not demonstrate
a correlation between this FC and clinical features of MA, we
acknowledge that the clinical significance of our finding is
currently undetermined. However, knowledge on the func-
tion of the insula and the vermis VI allowed us to postulate
two hypotheses to explain this increased FC: one related to
the central integration of pain, the other to the control of the
parasympathetic autonomic nervous system. Animals and
humans studies have highlighted the involvement of the cere-
bellum in pain [29]. Indeed, studies in healthy volunteers,
using fMRI showed an activation of cerebellar lobule VI,
VIIIa, crus I and vermal lobule VIIIa evoked by painful stimu-
lation of the left nostril. e cerebellum presented an
increased FC with structures involved in pain processing
such as rostral pons, PAG, thalamus and cortices regions
including insula and face area in the precentral gyrus [30].
Compared to HC, migraine patients presented a higher acti-
vation of PAG and left cerebellum crus I in response to nocic-
eptive trigeminal stimulations. Moreover the vermis VI
belonged to a cluster that comodulated with migraine-phase
[31]. Moreover, functional MR studies revealed cerebellar
activation evoked by heat painful stimulations in migraine
[3234]. Although these evidences stressed the role of cere-
bellum in trigeminal pain processing in migraine, our result
did not support clearly a role of vermis-insula FC in pain
because this FC was not correlated to migraine feature and
was not found in patients with MO. e insula is part of the
autonomic nervous system (ANS) network, as well as the
anterior cingulate cortex, the pre-frontal cortex and the
amygdala [35]. Some studies have suggested that the cerebel-
lum is also involved in the regulation of the cardiovascular
ANS. Functional neuroimaging studies in human confirmed
that cerebellum is activated during tasks challenging cardio-
vascular ANS and both anterior insula and vermis cerebellum
seem to be involved in the regulation of parasympathetic tone
[3638]. A meta-analysis published in 2013 included studies
analysing peripheral signals in response to ANS stimulation
by cognitive, affective and somatosensory autonomic nervous
system tasks in conjunction with brain imaging in healthy
subjects. e ANS response was classified as sympathetic or
parasympathetic based on measures of heart rate variability
and electrodermal activity. is meta-analysis showed para-
sympathetic activation of the dorsoanterior insula and vermis
VI in addition to other brain structures such as the amygdala
or posterior cingulate cortex [38]. e shared role of the cere-
bellum and insula in the regulation of the cardiovascular ANS
is also supported by two activation studies and a connectivity
study during ANS stimulation tasks: in a PET study, Critchley
etal. have explored the cerebral activation during isometric
exercise and mental arithmetic stressor tasks. ese tasks
induced variation in mean arterial blood pressure (MAP) and
heart rate (HR) and were accompanied by an activation of the
midline cerebellum, the brainstem in the region of the pon-
tine reticular nuclei and the right dorsal cingulate cortex. In a
conjunction analysis, the activation of both the cerebellar ver-
mis and the insular cortex covariated with MAP and HR [39].
Baker etal., in an fMRI study, showed that lower-body nega-
tive pressure maneuver (LBNP) induced activation of bilat-
eral insula. e cerebellum and the bilateral insula were
Table 2 Correlation between antero-dorsal insula – vermis
VI connectivities and characteristics of migraine (Spearman
correlation coefficients)
Connectivity ROI
1 R – vermis VI
(Z score)
Connectivity
ROI 1 L – vermis
VI
(Z score)
Duration of migraine
(years)
ρ = 0,21; p = 0,36 ρ = 0,09; p = 0,34
Frequency of migraine attack
(/year)
ρ = -0,40; p = 0,08 ρ = -0,24; p = 0,30
Time since last migraine attack
(days)
ρ = 0,34; p = 0,13 ρ = 0,22; p = 0,69
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Gollionetal. The Journal of Headache and Pain (2022) 23:106
activated during the recovery phase of LBNP [40]. A further
analysis revealed that vermis VI was part of a cerebellar con-
nectome functionally coupled with bilateral insula, as well as
anterior cingulate cortex, bilateral thalamus and bilateral
putamen [41]. ese previous observations supported the
hypothesis that the increased FC between dorsoanterior
insula and vermis VI in MA could be related to the cardiovas-
cular parasympathetic ANS control. However, our study was
unable to confirm this hypothesis as no recording of cardio-
vascular parameters was performed during the MR scan.
Nevertheless, this hypothesis is likely given the cardiovascu-
lar autonomic disorders observed in MA. It has previously
been shown that both MA and MO are at increased risk of
syncope and orthostatic intolerance [42]. However, one study
found that only MA was associated with increased risk of
syncope after adjustment on confounders [43]. A review of
studies assessing cardiovascular autonomic balance in
migraine showed a trend toward greater autonomic dysfunc-
tion in MA than in MO, with sympathetic dysfunction being
more common than parasympathetic dysfunction [44]. ese
previous observations supported the hypothesis of ANS-
related alteration of FC between dorsoanterior insula and
vermis VI in MA. e strengths of our study were the com-
prehensive exploration of the insula in a seed-to-voxel analy-
sis. e result remained significant after correction for
multiple comparisons and was found bilaterally. A random
result seemed thus unlikely. ROI-to-ROI analysis excluded
the involvement of the lingual cortex in the vicinity and con-
firmed the functional coupling of the vermis VI with the
antero-dorsal insula. Some limitations should be mentioned.
e study involved a small sample of volunteers, which may
have underestimated differences in connectivity with other
brain areas. Although a previous study suggested gender dif-
ferences of insular connectivity in pain [45], our study sample
did not allow for testing gender differences of insular connec-
tivity in migraine. Patients with MO were included from
another study previously conducted at our center but the
MRI protocol was the same as in the study including patients
with MA and HC. Finally, assessment of the cardiovascular
ANS during fMRI was not performed which mitigate the
interpretation of our result. Further studies are warranted to
determine whether the increased functional coupling of
antero-dorsal insula with vermis VI reflected an increased
parasympathetic tone as we may hypothesize.
Conclusion
In MA, the bilateral antero-dorsal insula was strongly func-
tionally coupled with the cerebellar vermis IV. Because
both regions are involved in the control of the parasym-
pathetic cardiovascular ANS, this functional connectivity
could reflect the cardiovascular features of MA. Further
research is needed to explore this hypothesis.
Abbreviations
ANS: Autonomic nervous system; BOLD: Blood oxygen level dependent; DMN:
Default mode network; FC: Functional connectivity; FEW: Family wise error;
fMRI: Functional MRI; HC: Healthy controls; HR: Heart rate; ICHD: International
classification of headache disorders; IQR: Interquartile range; LBNP: Lower-
body negative pressure maneuver; MAP: Mean arterial blood Pressure; MA:
Migraine with Aura; MNI: Montreal neurological institute; MO: Migraine with-
out aura; MRI: Magnetic resonance imaging; PAG: PeriAqueductal grey matter;
PET: Positron tomography emission; ROI: Region of Interest; SPM: Statistical
parametric mapping; Rs-fMRI: Resting functional MRI.
Acknowledgements
We thank the INSERM/UPS UMR1214 Technical Platform for performing the
MRI scans.
Author contributions
C.G. and F.L. contributed to the inclusion of participants. C.G., F.N., G.A. and
P.P. contributed to MR processing and statistical analysis. F.B. read MR images.
C.G. wrote the main manuscript text and prepared tables and figures. V.L. and
P.P. contributed to study design and proofread the manuscript. All authors
reviewed the manuscript.
Funding
No funding.
Availability of data and materials
Anonymized data and materials not published within this article will be made
available on reasonable request from any qualified investigator.
Declarations
Ethical approvaland consent to participates
The study was approved by the local institutional Ethics Committee (Comité
de protection des personnes Sud-Ouest I). All participants gave written
informed consent.
Competing interests
Authors report no disclosure related to this paper.
Author details
1 Department of Neurology, University Hospital of Toulouse, 31059 cedex 9
Toulouse, France. 2 Toulouse NeuroImaging Center, ToNIC, University of Tou-
louse III, Inserm, Toulouse, France. 3 Department of Neuroradiology, University
Hospital of Toulouse, Toulouse, France.
Received: 12 July 2022 Accepted: 9 August 2022
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Objective: To determine if migraine with aura is associated with neuroinflammation, which has been suggested by preclinical models of cortical spreading depression (CSD) as well as imaging of human pain conditions. Methods: Thirteen migraineurs with aura and 16 healthy controls received integrated PET/MRI brain scans with [11C]PBR28, a radioligand that binds to the 18 kDa translocator protein, a marker of glial activation. Standardized uptake value ratio (SUVR) was compared between groups, and regressed against clinical variables, using region of interest and whole-brain voxelwise analyses. Results: Compared to healthy controls, migraineurs demonstrated SUVR elevations in nociceptive processing areas (e.g., thalamus and primary/secondary somatosensory and insular cortices) as well as in areas previously shown to be involved in CSD generation (visual cortex). SUVR levels in frontoinsular cortex, primary/secondary somatosensory cortices, and basal ganglia were correlated with frequency of migraine attacks. Conclusions: These findings demonstrate that migraine with aura is associated with neuroimmune activation/neuroinflammation, and support a possible link between CSD and glial activation, previously observed in animals.
Article
Objective: To investigate the functional connectivity of the hypothalamus in chronic migraine compared to interictal episodic migraine in order to improve our understanding of migraine chronification. Methods: Using task-free fMRI and ROI-to-ROI analysis, we compared anterior hypothalamus intrinsic connectivity with the spinal trigeminal nucleus in patients with chronic migraine (n = 25) to age- and sex-matched patients with episodic migraine in the interictal phase (n = 22). We also conducted a seed-to-voxel analysis with anterior hypothalamus as a seed. Results: All patients with chronic migraine had medication overuse. We found a significant connectivity (T = 2.08, p = 0.024) between anterior hypothalamus and spinal trigeminal nucleus in the chronic group, whereas these two regions were not connected in the episodic group. The strength of connectivity was not correlated with pain intensity (rho: 0.09, p = 0.655). In the seed-to-voxel analysis, three regions were more connected with the anterior hypothalamus in the chronic group: The spinal trigeminal nuclei (MNI coordinate x = 2, y = -44, z = -62), the right dorsal anterior insula (MNI coordinate x = 10, y = 10, z = 18), and the right caudate (MNI coordinate x = 12, y = 28, z = 6). However, these correlations were no longer significant after whole brain FWE correction. Conclusion: An increased functional connectivity between the anterior hypothalamus and the spinal trigeminal nucleus, as previously reported in preictal episodic migraine, was demonstrated in chronic migraine with medication overuse. This finding confirms a major role of the anterior hypothalamus in migraine and suggests that chronic migraineurs are locked in the preictal phase.