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

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.

Regional cerebral perfusion during the premonitory phase of triggered migraine: A double-blind randomized placebo-controlled functional imaging study using pseudo-continuous arterial spin labeling.

OBJECTIVE: To identify changes in regional cerebral blood flow (CBF) associated with premonitory symptoms (PS) of nitroglycerin (NTG)-triggered migraine attacks. BACKGROUND: PS could provide insights into attack initiation and alterations in neuronal function prior to headache onset. METHODS: We undertook a functional imaging study using a double-blind placebo-controlled randomized approach in patients with migraine who spontaneously experienced PS, and in whom PS and migraine-like headache could be induced by administration of NTG. All study visits took place in a dedicated clinical research facility housing a monitoring area with clinical beds next to a 3Tesla magnetic resonance imaging scanner. Fifty-three patients with migraine were enrolled; imaging on at least one triggered visit was obtained from 25 patients, with 21 patients completing the entire imaging protocol including a placebo visit. Whole brain CBF maps were acquired using 3D pseudo-continuous arterial spin labeling (3D pCASL). RESULTS: The primary outcome was that patients with migraine not taking preventive treatment (n = 12) displayed significant increases in CBF in anterior cingulate cortex, caudate, midbrain, lentiform, amygdala and hippocampus (p < 0.05 family-wise error-corrected) during NTG-induced PS. A separate region of interest analysis revealed significant CBF increases in the region of the hypothalamus (p = 0.006, effect size 0.77). Post hoc analyses revealed significant reductions in CBF over the occipital cortices in participants with a history of migraine with underlying aura (n = 14). CONCLUSIONS: We identified significant regional CBF changes associated with NTG-induced PS, consistent with other investigations and with novel findings, withstanding statistical comparison against placebo. These findings were not present in patients who continually took preventive medication. Additional findings were identified only in participants who experience migraine with aura. Understanding this biological and treatment-related heterogeneity is vital to evaluating functional imaging outcomes in migraine research.