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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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The Journal of Headache and Pain (2022) 23:106
Insular functional connectivity inmigraine
Cédric Gollion1,2*, Fleur Lerebours1, Federico Nemmi2, Germain Arribarat2, Fabrice Bonneville2,3,
Vincent Larrue1† and Patrice Péran2†
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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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
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.
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.
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
Number of ROI (x,
y, z)
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
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),
Comparison ofMA andHC withMo byusing ROI‑to‑ROI
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
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)
ROI 1 L – vermis
(Z score)
Duration of migraine
ρ = 0,21; p = 0,36 ρ = 0,09; p = 0,34
Frequency of migraine attack
ρ = -0,40; p = 0,08 ρ = -0,24; p = 0,30
Time since last migraine attack
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.
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.
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.
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.
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.
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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... Totally, 16 FC studies were included in this study. Among them, the seed-points were distributed the middle frontal gyrus (31), precuneus (32), PAG (33,36,44), insulas (35,37,45), thalamus (38,43,46), pons (26,39), lateral geniculate nucleus (40), amygdala (41), and lingual gyrus (42). ...
Full-text available
Objectives: To quantitatively summarize the specific changes in brain structure and function in migraine patients. Methods: A literature screening of migraine was conducted from inception to Sept 1, 2022, in PubMed, Web of Science, Cochrane Library, and Medline databases using the keyword combination of "migraine and MRI." Activation likelihood estimation (ALE) was performed to assess the differentiation of functional connectivity (FC), regional homogeneity (ReHo), and gray matter volume (GMV) of migraine patients. Results: Eleven voxel-based morphometry (VBM) studies and 25 resting-state fMRI (rs-fMRI) studies (16 FC and 9 ReHo studies) were included in this study. ALE analysis revealed the ReHo increase in the brainstem and left thalamus, with no decreased area. Neither increased nor decreased regions were detected in FC and GMV of migraine patients. Conclusions: The left thalamus and brainstem were the significantly activated regions of migraine. It is a meaningful insights into the pathophysiology of migraine. The consistent alterated brain areas of morphometrical and functional in migraine patients were far from reached based on current studies.
... These associations were worthy of further investigation. Seventh, studies have indicated a connection between dysautonomia and certain arrhythmia patterns and different parts of the central nervous system (40)(41)(42). Unfortunately, the MIMIC-IV database does not have information on the location and sizes of the strokes. ...
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Background The relationship of mean heart rate (MHR) with 30-day mortality in ischemic stroke patients with atrial fibrillation in the intensive care unit (ICU) remains unknown. This study aimed to investigate the association between MHR within 24 h of admission to the ICU and 30-day mortality among patients with atrial fibrillation and ischemic stroke.Methods This retrospective cohort study used data on US adults from the Medical Information Mart for Intensive Care-IV (MIMIC-IV, version 1.0) database. Patients with ischemic stroke who had atrial fibrillation for and first time in ICU admission were identified from the MIMIC-IV database. We used multivariable Cox regression models, a restricted cubic spline model, and a two-piecewise Cox regression model to show the effect of the MHR within 24 h of ICU admission on 30-day mortality.ResultsA total of 1403 patients with ischemic stroke and atrial fibrillation (mean [SD] age, 75.9 [11.4] years; mean [SD] heart rate, 83.8[16.1] bpm; 743 [53.0%] females) were included. A total of 212 (15.1%) patients died within 30 days after ICU admission. When MHR was assessed in tertials according to the 25th and 50th percentiles, the risk of 30-day mortality was higher in participants in group 1 (< 72 bpm; adjusted hazard ratio, 1.23; 95% CI, 0.79–1.91) and group 3 (≥82 bpm; adjusted hazard ratio, 1.77; 95% CI, 1.23–2.57) compared with those in group 2 (72–82 bpm). Consistently in the threshold analysis, for every 1-bpm increase in MHR, there was a 2.4% increase in 30-day mortality (adjusted HR, 1.024; 95% CI, 1.01–1.039) in those with MHR above 80 bpm. Based on these results, there was a J-shaped association between MHR and 30-day mortality in ischemic stroke patients with atrial fibrillation admitted to the ICU, with an inflection point at 80 bpm of MHR.Conclusion In this retrospective cohort study, MHR within 24 h of admission was associated with 30-day mortality (nonlinear, J-shaped association) in patients with ischemic stroke and atrial fibrillation in the ICU, with an inflection point at about 80 bpm and a minimal risk observed at 72 to 81 bpm of MHR. This association was worthy of further investigation. If further confirmed, this association may provide a theoretical basis for formulating the target strategy of heart rate therapy for these patients.
Full-text available
Background According to the Global Burden of Disease (GBD) study, headache disorders are among the most prevalent and disabling conditions worldwide. GBD builds on epidemiological studies (published and unpublished) which are notable for wide variations in both their methodologies and their prevalence estimates. Our first aim was to update the documentation of headache epidemiological studies, summarizing global prevalence estimates for all headache, migraine, tension-type headache (TTH) and headache on ≥15 days/month (H15+), comparing these with GBD estimates and exploring time trends and geographical variations. Our second aim was to analyse how methodological factors influenced prevalence estimates. Methods In a narrative review, all prevalence studies published until 2020, excluding those of clinic populations, were identified through a literature search. Prevalence data were extracted, along with those related to methodology, world region and publication year. Bivariate analyses (correlations or comparisons of means) and multiple linear regression (MLR) analyses were performed. Results From 357 publications, the vast majority from high-income countries, the estimated global prevalence of active headache disorder was 52.0% (95%CI 48.9–55.4), of migraine 14.0% (12.9–15.2), of TTH 26.0% (22.7–29.5) and of H15+ 4.6% (3.9–5.5). These estimates were comparable with those of migraine and TTH in GBD2019, the most recent iteration, but higher for headache overall. Each day, 15.8% of the world’s population had headache. MLR analyses explained less than 30% of the variation. Methodological factors contributing to variation, were publication year, sample size, inclusion of probable diagnoses, sub-population sampling (e.g., of health-care personnel), sampling method (random or not), screening question (neutral, or qualified in severity or presumed cause) and scope of enquiry (headache disorders only or multiple other conditions). With these taken into account, migraine prevalence estimates increased over the years, while estimates for all headache types varied between world regions. Conclusion The review confirms GBD in finding that headache disorders remain highly prevalent worldwide, and it identifies methodological factors explaining some of the large variation between study findings. These variations render uncertain both the increase in migraine prevalence estimates over time, and the geographical differences. More and better studies are needed in low- and middle-income countries.
Full-text available
Objective Although the majority of migraine with aura (MwA) patients experiences simple visual aura, a discrete percentage also reports somatosensory, dysphasic or motor symptoms (the so-called complex auras). The wide aura clinical spectrum led to investigate whether the heterogeneity of aura phenomenon could be subtended by different neural correlates, suggesting an increased visual cortical excitability in complex MwA. We aimed to explore whether complex MwA patients are characterized by more pronounced connectivity changes of the visual network and whether functional abnormalities may extend beyond the visual network encompassing also the sensorimotor network in complex MwA patients when compared to simple visual MwA patients. Methods By using a resting state-fMRI approach, we compared the resting state functional connectivity (RS-Fc) of both visual and sensorimotor networks in 20 complex MwA patients in comparison with 20 simple visual MwA patients and 20 migraine without aura (MwoA) patients. Results Complex MwA patients showed a significantly higher RS-Fc of the left lingual gyrus, within the visual network, and of the right anterior insula, within the sensorimotor network, when compared to both simple visual MwA and MwoA patients (p<0.001). The abnormal right anterior insula RS-Fc was able to discriminate complex MwA patients from simple aura MwA patients as demonstrated by logistic regression analysis (AUC: 0.83). Conclusion Our findings suggest that higher extrastriate RS-Fc might promote the CSD onset representing the neural correlate of simple visual aura that can propagate to sensorimotor regions, if an increased insula RS-Fc coexists, leading to complex aura phenotypes.
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Background: Hypothesis-driven functional connectivity (FC) analyses have revealed abnormal functional interaction of regions or networks involved in pain processing in episodic migraine patients. We aimed to investigate the resting-state FC patterns in episodic migraine by combining data-driven voxel-wise degree centrality (DC) calculation and seed-based FC analysis. Methods: Thirty-nine patients suffering from episodic migraine without aura and 35 healthy controls underwent clinical assessment and functional MRI. DC was analyzed voxel-wise and compared between groups, and FC of regions with DC differences were further examined using a seed-based approach. Results: Compared with the control group, the migraine group showed increased and decreased DC in the right posterior insula and left crus I, respectively. Seed-based FC analyses revealed that migraine patients demonstrated increased right posterior insula connections with the postcentral gyrus, supplementary motor area/paracentral lobule, fusiform gyrus and temporal pole. The left crus I showed decreased FC with regions of the default mode network (DMN), including the medial prefrontal cortex (mPFC), angular gyrus, medial and lateral temporal cortex in patients with migraine. Furthermore, pain intensity positively correlated with DC in the right amygdala/parahippocampal gyrus, and migraine frequency negatively correlated with FC between the left crus I and mPFC. Conclusion: Patients with episodic migraine without aura have increased FC with the right posterior insula and decreased FC within the DMN, which may underlie disturbed sensory integration and cognitive processing of pain. The left crus I-mPFC connectivity may be a useful biomarker for assessing migraine frequency.
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The objective of the current study was to investigate whether patients with neurogenic orthostatic hypotension (NOH) secondary to autonomic failure have impaired functional connectivity between the cerebellum and central autonomic structures during autonomic challenges. Fifteen healthy controls (61 ± 14 years) and 15 NOH patients (67 ± 6 years; p = 0.12) completed the following tasks during a functional brain MRI: (1) 5 min of rest, (2) 5 min of lower-body negative pressure (LBNP) performed at − 35 mmHg, and (3) Three, 15-s Valsalva maneuvers (VM) at 40 mmHg. Functional connectivity (Conn Toolbox V18) between central autonomic structures and discrete cerebellar regions involved in cardiovascular autonomic control, including the vermis and posterior cerebellum, was assessed using a regions-of-interest approach during rest, LBNP and VM. Functional connectivity was contrasted between controls and patients with autonomic failure. At rest, controls had significantly more intra-cerebellar connectivity and more connectivity between cerebellar lobule 9 and key central autonomic structures, including: bilateral anterior insula (TR-value: 4.84; TL-value: 4.51), anterior cingulate cortex (T-value: 3.41) and bilateral thalamus (TR-value: 3.95; TL-value: 4.51). During autonomic maneuvers, controls showed significantly more connectivity between cardiovascular cerebellar regions (lobule 9 and anterior vermis) and important autonomic regulatory sites, including the brainstem, hippocampus and cingulate: vermis-brainstem (T-value: 4.31), lobule 9-brainstem (TR-value, 5.29; TL-value, 4.53), vermis-hippocampus (T-value, 4.63), and vermis-cingulate (T-value, 4.18). Anatomical and functional studies in animals and humans substantiate a significant role for the cerebellum in cardiovascular autonomic control during postural adjustments. In the current study, patients with NOH related to autonomic failure showed evidence of reduced connectivity between cardiovascular cerebellar regions and several important central autonomic structures, including the brainstem. The cerebellum is an established structure in cardiovascular autonomic control; therefore, evidence of impaired cerebellar connectivity to other autonomic structures may further contribute to the inability to properly regulate blood pressure during postural changes in NOH patients.
Full-text available
Objective: Compare activation patterns within the cortical autonomic network in patients with neurogenic orthostatic hypotension (NOH) versus healthy age-matched controls during an orthostatic challenge. Methods: Fifteen health controls and 15 NOH patients performed 3 Valsalva maneuvers, and 5-min of lower-body negative pressure (LBNP) during a functional brain MRI. Results: Compared to controls, NOH patients had significantly less activation within the cerebellum during both LBNP and VM. Both groups had significant activation of the bilateral insula and left thalamus during LBNP. No significant differences were found during the recovery phase of LBNP. Conclusions: The cerebellum, which plays an important role in vestibulo-sympathetic reflexes, important for blood pressure adjustments during postural changes, appear to be affected in patients with NOH. The cerebellum also appears to be affected during other baroreflex mediated stressors such as the VM. Significance: Orthostatic reflexes mediated by the cerebellum may be impaired in patients with NOH. The results suggest an additional pathological pathway in patients with autonomic failure.
Full-text available
Third edition of the International Classification of Headache Disorders
The trigeminal nerve and its projections to the intracranial vasculature — the trigeminovascular system — are at the nexus of migraine. Identification of the mechanisms that trigger signals in this system have led to targeted treatments and preventive therapies for migraine.
Background Migraine is associated with syncope. We investigated risk factors for syncope and burden of syncope in migraine patients. Methods Participants were recruited from a headache clinic. All participants provided information on lifestyle, co-morbidity, syncope, headache and suicide, and completed the MIDAS and HADS questionnaires. Genetic data were available for a subset of participants. Risk of syncope in relation to participant’s characteristics and migraine susceptibility loci, and risks of psychological disorders associated with syncope, were calculated using logistic regression. Results Underweight, regular tea intake, diabetes mellitus, and migraine with aura were associated with increased syncope risks, with adjusted ORs of 1.76 (95% CI 1.03–3.03), 1.84 (95% CI 1.22–2.79), 4.70 (95% CI 1.58–13.95), and 1.78 (95% CI 1.03–3.10), respectively. Preliminary results showed that rs11172113 in LRP1 was associated with syncope risks. Comorbid syncope in migraine patients was associated with increased risks of depression (OR 1.95, 95% CI 1.18–3.22) and suicide attempt (OR 2.85, 95% CI 1.48–5.48). Conclusion Our study showed the potential roles of vascular risk factors in the association between migraine and syncope. Modifiable risk factors for syncope in patients with migraine include body mass index and tea intake. The debilitating psychological impact of co-morbid syncope in migraine patients warrants clinical attention of treating physicians.
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.
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.