Neural fingerprints of Alice in Wonderland Syndrome in patients with migraine with aura

Backgroundthe Alice in Wonderland syndrome (AIWS) is a transient neurological disturbance characterized by visual and somatosensory misperceptions most frequently associated with migraine. The heterogeneity of the etiologies and techniques applied to investigate the reported cases have so far prevented to draw strong conclusions about the origin of AIWS symptoms. Some lines of evidence suggest that AIWS and migraine might share common pathophysiological mechanisms, therefore we set out to investigate the common and distinct neurophysiological alterations associated with these conditions in a population of migraineurs. Methodswe acquired resting-state fMRI data from 12 migraine patients with AIWS, 12 patients with migraine with typical aura (MA) and 24 age-matched healthy controls (HC). We then compared the interictal thalamic seed-to-voxel and ROI-to-ROI cortico-cortical resting-state functional connectivity between the 3 groups. Resultswe found a common pattern of altered thalamic connectivity in MA and AIWS, compared to HC, with more profound and diffuse alterations observed in AIWS. The ROI-to-ROI functional connectivity analysis highlighted an increased connectivity between a lateral occipital region corresponding to area V3 and the posterior part of the superior temporal sulcus (STS) in AIWS, compared to both MA and HC. The posterior STS is a multisensory integration area, while area V3 is considered the starting point of the cortical spreading depression (CSD), the neural correlate of migraine aura. This interictal hyperconnectivity might increase the probability of the CSD to directly diffuse to the posterior STS or trigger a diaschisis phenomenon causing the AIWS symptoms during the ictal phase. Conclusionstaken together, these results suggest that AIWS in migraineurs might be a form of complex migraine aura, characterized by the involvement of associative and multisensory integration areas. The altered connectivity between early visual and multisensory associative areas provides a model for the pathophysiology of AIWS associated with other transient neurological conditions or with a structural etiology.