Advanced visual network and cerebellar hyperresponsiveness to trigeminal nociception in migraine with aura

Background: Despite the growing body of advanced studies investigating the neuronal correlates of pain processing in patients with migraine without aura (MwoA), only few similar studies have been conducted in patients with migraine with aura (MwA). Therefore, we aimed to explore the functional brain response to trigeminal noxious heat stimulation in patients with MwA. Methods: Seventeen patients with MwA and 15 age- and sex-matched healthy controls (HC) underwent whole- brain blood oxygen level–dependent (BOLD) fMRI during trigeminal noxious heat stimulation. To examine the specificity of any observed differences between patients with MwA and HC, the functional response of neural pathways to trigeminal noxious heat stimulation in patients with MwA was compared with 18 patients with MwoA. Secondary analyses investigated the correlations between BOLD signal changes and clinical parameters of migraine severity. Results: We observed a robust cortical and subcortical pattern of BOLD response to trigeminal noxious heat stimulation across all participants. Patients with MwA showed a significantly increased activity in higher cortical areas known to be part of a distributed network involved in advanced visual processing, including lingual gyrus, inferior parietal lobule, inferior frontal gyrus and medial frontal gyrus. Moreover, a significantly greater cerebellar activation was observed in patients with MwA when compared with both patients with MwA and HC. Interestingly, no correlations were found between migraine severity parameters and magnitude of BOLD response in patients with MwA. Conclusion: Our findings, characterized by abnormal visual pathway response to trigeminal noxious heat stimulation, support the role of a functional integration between visual and trigeminal pain networks in the pathophysiological mechanisms underlying migraine with aura. Moreover, they expand the concept of “neurolimbic-pain network” as a model of MwoA including both limbic dysfunction and cortical dys-excitability. Indeed, we suggest a model of “neurolimbic-visual-pain network” in MwA patients, characterized by dysfunctional correlations between pain- modulating circuits not only with the cortical limbic areas but with advanced visual areas as well. Furthermore, the abnormal cerebellar response to trigeminal noxious heat stimulation may suggest a dysfunctional cerebellar inhibitory control on thalamic sensory gating, impinging on the advanced visual processing cortical areas in patients with MwA.