Neuroimaging developments have provided highly sensitive and non invasive approaches to investigate the neural mechanisms of brain alterations associated with several disorders. Although advances in migraine research contributed to improve the disease understanding, the use of advanced MRI techniques allowed the accurate investigation of migraine patients. Migraine is not only relate to pain occurring intermittently or constantly, but a process that over time affects the brain acting on a predisposed brain (genetic) and modifining it the function or morphology. Several fMRI studies revealed abnormalities of resting state functional connectivity in pain network involved in migraine pathophysiology [6,10,11]. Abnormalities have been reported in multiple brain areas as evidenced by VBM. It is an ongoing matter of debate whether the changes are cause or consequence of migraine, but in many VBM studies the changes correlated with disease duration argues in favor of the latter. The exact underlying mechanisms, leading to alterations in grey matter density as evidenced by VBM, are not clear. These alterations may reflect modifications of dendritic complexity or changes in the numbers of synapses or simply in water content. These changes may be an index of the disorder, its progression or an effective therapy. Migraine patients showed significant GM abnormalities of several brain regions involved in central pain processing [12-13]. In particular, VBM data established that the GMV was decreased in the anterior cingulate cortex, insula, amygdala, parietal operculum, middle and inferior frontal gyrus . In addition, regions with less grey matter density are located in bilateral insula, motor premotor, prefrontal, cingulate cortex, right posterior parietal cortex and orbitofrontal cortex .
In this study, we applied the VBM approach to MwA and MwoA patients and HS. We observed that MwA and MwoA subjects had a significant reduction of GMV compared to HS in cerebellum, and frontal and temporal lobe. Our previous study  analyzed the resting state findings in the same patient sample and we found an hyperactivity increase of cortical activity in bilateral fusiform and cingulate gyrus of MwoA subjects compared with controls. In this study, the VBM approach showed a reduction in the volumes of same cerebral areas. Although the volume of bilateral fusiform and cingulate gyrus is descreased, the hyperactivity of cortical activity could be ascribed to the fusiform gyrus that seems to be hyperactive in migraineurs for it involvment in the cognitive pain treatment, while the cingulate gyrus is involved in the transformation process of migraine from “an episodic” to “a chronic brain disorder” . Fusiform gyrus is involved in nociception/antinociception and neurocognitive aspects of pain processing. In idiopathic or primary headaches, including migraine, tension-type headaches, and cluster headaches, the accepted view is that these conditions are due to abnormal brain function that occurs with normal brain structure. A decrease in GMV suggest that the central reorganization processes in chronic pain syndromes may involve degeneration of anti-nociceptive brain areas.
In addition, the cerebellum of migraineurs and controls differs structurally. In a study of Mehnert  the GMV and the neuronal activity, in response to trigeminal pain, increased in posterior part of the cerebellum (crus). Migraine patients had also a connectivity decrease in the thalamus and higher cortical areas, suggesting a less inhibitory involvement of migraine cerebellum on trigeminal nociception. The frontal cortex is the area associated with cerebral abnormalities in migraine patients [18-19]. Previous studies suggested that the medial prefrontal cortex could be involved in mediating the attenuation of pain perception by a cognitive control mechanisms [20-21], associated with pain modulation [22-23]. Schmitz et al.  reported that migraine patients had a less gray matter density in the medial prefrontal cortex correlated signiﬁcantly with a slower response time to the set-shifting task.
In coherence with previous VBM ﬁndings, [12-13,19] our results corroborate with the study of Kim et al. , that found a less volume of insula bilaterally, motor/premotor, prefrontal and cingulate cortex, right posterior parietal cortex, and orbitofrontal cortex. Moreover, Jin et al.  showed a less GMV in several brain regions involved in pain processing, such as left medial prefrontal cortex, cingulate, right occipital lobe, cerebellum, and brainstem. The results obtained affirm that migraine patients have a less GMV in the precentral gyrus as well as in the post-central gyrus and temporal lobe.
In literature, the possible mechanisms underlying the reduction of grey matter in migraine are currently unknown. The observed decrease in grey matter may reflect tissue shrinkage (changes in extracellular space and microvascular volume) as well as more complex processes as neurodegeneration. Therefore, there are several possible explanations for the observed abnormalities in our patients. Variations in gray matter may result from repeated ischaemia caused by blood flow both during migraine attacks and in the interictal phase. In contrast, the reduction of gray matter may be a consequence of migraine specific neurotoxic mechanisms. It has been hypothesized that migraine is associated with a state of neuronal hyperexcitability, involving over-activity of the aminoacid exciters glutamate and aspartate. VBM analysis shown that migraineurs present a significant reduction in the gray matter of different brain areas involving to the pain activation network .