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). Migraine pain is related to the involvement of the trigeminovascular system (2), but migraine is not only a pain, as it is also accompanied by several sensory, autonomic, affective and cognitive disorders. These symptoms are posited to result from multiple brain networks involvement within the brainstem, the subcortical and cortical areas, beyond the trigemino-vascular system (3). In about one third of migraine patients, migraine attacks are accompanied by an aura which is a transient progressive and fully reversible central neurological symptom, most often visual, occuring before the headache.
The insula is involved in multiple cerebral functions such as sensorymotor processing, 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 (4). Parcellation of insula resulted in two architectonic subdivisions (posterior granular area and anterior dysgranular area) to thirteen multi-modal MRI subdivisions (4, 5). Nevertheless, data-driven meta-analysis of human functional imaging studies supported a tripartite subdivision of the insula into a ventroanterior area, a dorsoanterior area and a posterior area. The ventroanterior insula is functionally coupled with limbic areas and is associated with emotion, chemosensation and autonomic functions. The dorsoanterior insula is connected to the anterior cingulate cortex and the dorsolateral prefrontal cortex and plays a role in cognitive tasks and executive control. Conversely, the posterior insula is connected to the somatosensory cortex and the suplementary motor area resulting in pain and somatosensory functions involvement (6).
Evidences support the involvement of the insula in several features of migraine pathophysiology from the ictal phase to chronicisation. 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 (7, 8). 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 intensity (9, 10). Another study showed a higher FC between the right thalamus and the left insular cortex during spontaneous migraine attacks (11). During the intercital phase of migraine without aura (MO), the right posterior insula was identified as a hub of FC more strongly connected to the supplementary motor cortex and the paracentral lobule among other brain areas (12). In high frequency migraine, defined by 8 to 14 monthly migraine days, compared to low frequency migraine, heat painful 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 (13). 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 matter (PAG) (14). Overall, the insula is posited to play a key role in migraine, acting as a « hub » of integration of autonomic, sensory, affective and cognitive functions (15).
Insula in migraine with aura (MA) is of specific interest as previous studies have found specific alterations of insular connectivity in MA. The 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 (16). In a study investigating cognitive functions in migraine and assessing the DMN, patients with MA presented an increased FC between the right insular 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 anterior insula was more strongly connected within the sensorimotor network compared to simple visual aura and MO, and this increased FC could discriminate between complex MA and simple visual aura (17). Moreover, in a PET/MRI brain study, uptake of [11C]PBR28, a glial activation maker, in the right posterior insula was correlated to the number of MA attacks (18). However, this result was not compared to MO.
These 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 (16, 19, 20), or on the somato-sensory network, which includes the posterior insula (17) 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. Therefore, 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.