Table_1_Neuroimaging markers of Alice in Wonderland syndrome in patients with migraine with aura.docx

BackgroundThe Alice in Wonderland syndrome (AIWS) is a transient neurological disturbance characterized by sensory distortions most frequently associated with migraine in adults. 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 migraineurs.MethodsWe conducted a case–control study acquiring 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.ConclusionThe 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 deactivating it, causing the AIWS symptoms during the ictal phase. Taken 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.</p

Table_3_Neuroimaging markers of Alice in Wonderland syndrome in patients with migraine with aura.docx

BackgroundThe Alice in Wonderland syndrome (AIWS) is a transient neurological disturbance characterized by sensory distortions most frequently associated with migraine in adults. 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 migraineurs.MethodsWe conducted a case–control study acquiring 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.ConclusionThe 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 deactivating it, causing the AIWS symptoms during the ictal phase. Taken 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.</p

Brain regions that showed significant activation (red) and deactivation (blue) during passive right hand movement in three groups of subjects: healthy controls (HC), relapsing-remitting MS patients (RRMS) and secondary progressive MS patients (SPMS).

<p>Maps obtained by one sample t-test, corrected for age and gender at p<0.05 FWE (cluster level) are superimposed to a rendered T1 brain image. Cluster maxima for activation (red) included cerebellum and vermis, left pre- and postcentral gyri and inferior parietal lobule in all groups. In both RRMS and SPMS groups the left sensorimotor activation extended to include the adjacent parietal and temporal cortex and additional foci were observed in the supplementary motor area bilaterally and in the right (ipsilateral) cortical areas. In SPMS patients, activation was even more extended and involved additional cortical foci, i.e. the middle frontal gyrus, insula and temporal pole bilaterally. Significant deactivation (blue) was observed in the ipsilateral motor areas (arrow) in HC but not in either MS group. Deactivation in cortical areas outside the motor system, i.e. cuneus, precuneus and temporal areas, was present in HC and extended in RRMS MS patients. No foci of deactivation were observed in the SPMS group at this level of significance (for more details see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065315#pone-0065315-t002" target="_blank">Tables 2</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065315#pone-0065315-t003" target="_blank">3</a>).</p

Brain regions that showed significant activation during passive right hand movement within each of the 3 study groups.

<p>L = left; R = Right; Bi = Bilateral; MNI = Montreal Neurological Institute.</p><p>HC = Healthy Controls; RRMS = Relapsing Remitting MS patients; SPMS = Secondary Progressive MS patients.</p><p>Results obtained from a one-sample t-test after correcting for age, <i>p</i><0.05 FWE corrected.</p

Foci of activation (red) and deactivation (blue) that showed a positive and negative correlation, respectively (p<0.05 FWE corrected at cluster level) with T2-LV, superimposed to a rendered T1 brain image.

<p>The T2-LV positively correlated with activation in clusters located in the left supramarginal gyrus (Z = 5.85, MNI coordinates: −52, −42, 24), right SMA (Z = 5.04, MNI coordinates: 4, 8, 56) and right superior temporal gyrus (Z = 4.18, MNI coordinates: 56, −30, 16). The T2-LV negatively correlated (p<0.05 FWE corrected at cluster level) with deactivation in the precuneus and paracentral lobule bilaterally with the activity peak centered in the right paracentral lobule (Z = 3.90, MNI coordinates: 2, −34, 58).</p

Demographic and clinical/radiological characteristics of 31 MS patients (13 RRMS, 18 SPMS) and 15 HC enrolled in the study.

<p>EDSS = Expanded Disability Status Scales; T2-LV = T2-hyperintense lesion volume; F = Females M = Males; HC = Healthy Controls; RRMS = Relapsing Remitting MS patients; SPMS = Secondary Progressive MS patients; SD = Standard Deviation.</p>*<p>significantly lower than SPMS group by unpaired t-test (p<0.05).</p

Brain regions that showed significant deactivation during passive right hand movement within each of the three groups.

<p>L = left; R = Right; Bi = Bilateral; MNI = Montreal Neurological Institute.</p><p>HC = Healthy Controls; RRMS = Relapsing Remitting MS patients; SPMS = Secondary Progressive MS patients; n.s. = not statistically significant.</p><p>Results obtained from a one-sample t-test after correcting for age, p<0.05 FWE corrected.</p

Correlation between mean Z-score of maximum activation cluster in left sensorimotor cortex and mean Z-score of maximum deactivation in the posterior corical areas overlapping the Default Mode Network (DMN).

<p>R² values and corresponding linear regression estimate lines for healthy controls (HC) in blue, relapsing-remitting MS patients (RRMS) in light green and secondary progressive (SPMS) in red, are reported. Significant correlation was found in HC (R² = 0.88, p<0.001), in RRMS (R² = 0.52, p<0.01), but not in SPMS.</p

Plots of contrast estimates of brain activity in three groups of subjects: healthy controls (HC), relapsing-remitting (RRMS) MS patients and secondary progressive (SPMS) MS patients, centered on the activity peaks of the average effect of conditions (activation in red, deactivation in blue) by ANOVA (p<0.05 FWE corrected at cluster level).

<p>Plots show that significant differences in brain activation between groups in the left precentral (cluster maxima at −36, −30, 60) cortex and in the left supplementary motor area (SMA) (cluster maxima at 4, −6, 66) was due to increased activation in SPMS than in RRMS and in RRMS than in HC (top). Plots show that significant differences in brain deactivation between groups in the left precuneus (cluster maxima at −24, −90, 34) was due to greater deactivation in the RRMS than in the other two groups whereas in the ipsilateral motor cortex (cluster maxima at 36, −12, 36), deactivation was greater in HC rather than in patients (bottom). (All coordinates refer to the MNI standard brain).</p

Brain regions that showed significant differences between groups in activation (red) and deactivation (blue) during passive right hand movement.

<p>Maps obtained by two sample t-test, corrected for age and gender at p<0.05 FWE (cluster level) are superimposed to a rendered T1 brain image. HC = healthy controls, RRMS = relapsing-remitting MS patients; SPMS = secondary progressive MS patients.</p