Previous studies have shown diffuse gray matter (GM) abnormalities in regions involved in pain and visual processing in migraine patients. A longitudinal study found GM atrophy of sensory-discriminative brain regions in these patients after one year.To explore longitudinal GM changes over a four-year follow up in migraine patients and their association with patients’ clinical characteristics and disease activity.Using a 3.0 Tesla scanner, brain dual-echo and 3D T1-weighted scans were acquired from 25 patients with migraine and 25 healthy controls at baseline and after 4 years (range of follow-up years: controls 1.7-6.6, patients: 2.9-5.6 years). Tensor-based morphometry (1) and SPM12 were used to assess longitudinal changes of GM volumes in migraine patients after 4 years and according to the disease duration and attack frequency and their changes. Pairwise longitudinal registration (2) was used to align the first and second scan of each subject: the method is based on pairwise inverse-consistent registration and incorporates a bias field correction. The rate of volume change was quantified by saving the map of divergence of the velocity field, where positive values indicate expansion and negative values contraction. The mid-point average template image was also saved and used for groupwise alignment (3) to the final customized template and then to the standard space (MNI atlas).Eight patients (32%) reported an increased number of migraine attacks at follow up. At baseline, compared to controls, migraine patients showed cerebellar GM atrophy and higher volume of regions of the right fronto-temporo-parietal lobes. At follow up, compared to controls, migraine patients had an increased volume of fronto-parietal regions (Figure 1), which was related to a higher number of migraine attacks at baseline (r=0.58, p<0.001) and was more prominent in those patients with increasing number of attacks during the study. At follow up, compared to controls, migraine patients developed GM atrophy of the right thalamus and occipital areas (Figure 2). Thalamic atrophy was more pronounced in patients with a longer disease duration.The migraine brain changes dynamically over time. Various pathophysiological mechanisms might affect different brain regions in migraineurs after 4 years. GM volume increase of fronto-parietal areas involved in nociception might represent a compensatory response to high migraine attack frequency. GM atrophy of the thalamus, which plays a fundamental role in migraine pathophysiology, might be influenced by disease progression.