New directions for structural and functional neuroimaging markers in migraine

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Migraine is a common primary headache disorder, yet the exact cause and processes underlying the disease are not fully clear. Neuroimaging markers have proven useful in tracking the disease course and acquiring information about the pathomechanism. However, questions remain about the background of identified alterations and their connection to other biomarkers. In this work, we aim to place established alterations of white matter microstructure in the context of neurochemical alterations. Furthermore, we set out to identify new potential functional markers for migraine employing temporal features of functional connectivity that potentially complement current approaches. In the first study, we use tract-based spatial statistics to investigate how microstructural alterations of the white matter relate to interictal serum levels of PACAP38, a neuropeptide implicated in migraine pathogenesis, in a cohort of 26 migraine patients. In the second study, we investigate how temporal features of functional connectivity in the salience network differ between healthy controls (n=32), migraine with (n=20) and migraine without aura patients (n=37), using dynamic conditional correlation. We then proceed to describe the effects of connectivity variability on large-scale network interactions using spectral Granger’s causality. Serum levels of PACAP38 correlated with mean, axial and radial diffusivity in Study 1 (p<0.018, p<0.043, p<0.042, respectively). These findings were located mainly in the left optic radiation and the left posterior corpus callosum, reaching into the parietal and temporal white matter tracts. When we included disease duration in the regression model, the spatial pattern of findings relocated to the left thalamus (mean and axial diffusivity: p<0.01). In Study 2, the temporal variance of correlation was higher in the aura group compared to migraine without aura and healthy controls between the right anterior insula and dorsal anterior cingulate cortex (p<0.011 and p<0.026) and also higher in the aura group compared to healthy controls between the left prefrontal cortex and dorsal anterior cingulate cortex (p<0.021). The sum of causality from the salience to the dorsal attention network in the 0.01-0.05 Hz range was lower in migraine with aura compared to migraine without aura and healthy controls (p<0.032 in both cases). In migraine without aura, the variance of right and left prefrontal cortex connectivity and right anterior insula – right prefrontal cortex connectivity diminished with increasing attack frequency (R= -0.516, p<0.003 and R= -0.456, p<0.012). Causal interaction power in the 0.01-0.05 Hz range between the default mode and dorsal attention networks diminished with longer disease duration in the migraine with aura group (R= -0.525, p<0.036). We also found a relationship between right prefrontal cortex – dorsal anterior cingulate cortex connectivity variance and salience-default mode network causality in the migraine with aura group (R= -0.564, p<0.045). We identified a link between microstructural characteristics of the white matter and serum levels of PACAP38 in the interictal term in migraine patients, which connects neuroimaging and neurochemical markers of migraine, further emphasizing the values of both markers. The second study showed that temporal features of connectivity might be an alternative to current functional connectivity markers in migraine and presents evidence that pathophysiological differences between the main subtypes might manifest in altered brain network function that can be used to objectively differentiate between them.

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