Abnormal Glutamatergic and Serotonergic Connectivity in Visual Snow Syndrome and Migraine with Aura

• Published in: Annals of neurology 2023-11, Vol.94 (5), p.873-884
• Main Authors: Puledda, Francesca, Dipasquale, Ottavia, Gooddy, Benjamin J. M., Karsan, Nazia, Bose, Ray, Mehta, Mitul A., Williams, Steven C. R., Goadsby, Peter J.
• Format: Article
• Language: English
• Subjects: Brain; Brain mapping; Cortex (cingulate); Cortex (parietal); Cortex (temporal); Dopamine; Dopamine transporter; Enrichment; Functional magnetic resonance imaging; Glutamatergic transmission; Glutamic acid receptors (ionotropic); Headache; Magnetic resonance imaging; Migraine; N-Methyl-D-aspartic acid receptors; Networks; Neural networks; Neuroimaging; Neurotransmitters; Noradrenaline; Norepinephrine; Receptor density; Receptors; Serotonin; Serotonin S1 receptors; Serotonin S2 receptors; Subgroups; Visual pathways; γ-Aminobutyric acid
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.26745

Objective Neuropharmacological changes in visual snow syndrome (VSS) are poorly understood. We aimed to use receptor target maps combined with resting functional magnetic resonance imaging (fMRI) data to identify which neurotransmitters might modulate brain circuits involved in VSS. Methods We used Receptor‐Enriched Analysis of Functional Connectivity by Targets (REACT) to estimate and compare the molecular‐enriched functional networks related to 5 neurotransmitter systems of patients with VSS (n = 24), healthy controls (HCs; n = 24), and migraine patients ([MIG], n = 25, 15 of whom had migraine with aura [MwA]). For REACT we used receptor density templates for the transporters of noradrenaline, dopamine, and serotonin, GABA‐A and NMDA receptors, as well as 5HT1B and 5HT2A receptors, and estimated the subject‐specific voxel‐wise maps of functional connectivity (FC). We then performed voxel‐wise comparisons of these maps among HCs, MIG, and VSS. Results Patients with VSS had reduced FC in glutamatergic networks localized in the anterior cingulate cortex (ACC) compared to HCs and patients with migraine, and reduced FC in serotoninergic networks localized in the insula, temporal pole, and orbitofrontal cortex compared to controls, similar to patients with migraine with aura. Patients with VSS also showed reduced FC in 5HT2A‐enriched networks, largely localized in occipito‐temporo‐parietal association cortices. As revealed by subgroup analyses, these changes were independent of, and analogous to, those found in patients with migraine with aura. Interpretation Our results show that glutamate and serotonin are involved in brain connectivity alterations in areas of the visual, salience, and limbic systems in VSS. Importantly, altered serotonergic connectivity is independent of migraine in VSS, and simultaneously comparable to that of migraine with aura, highlighting a shared biology between the disorders. ANN NEUROL 2023;94:873–884