Our findings report an unbiased quantitative whole brain assessment of morphological abnormalities in migraine. This might help to identify indicators for migraine as a possibly progressive brain disease. In order to reveal the causes and consequences of brain damage in migraine, further neuroimaging studies have to investigate quantitative brain changes in a longitudinal design.

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Objective: To evaluate the presence, localization, and specificity of structural hypothalamic and whole brain changes in cluster headache and chronic paroxysmal hemicrania (CPH). Methods: We compared T1-weighted magnetic resonance images of subjects with cluster headache (episodic n ¼ 24; chronic n ¼ 23; probable n ¼ 14), CPH (n ¼ 9), migraine (with aura n ¼ 14; without aura n ¼ 19), and no headache (n ¼ 48). We applied whole brain voxel-based morphometry (VBM) using two complementary methods to analyze structural changes in the hypothalamus: region-of-interest analyses in whole brain VBM, and manual segmentation of the hypothalamus to calculate volumes. We used both conservative VBM thresholds, correcting for multiple comparisons, and less conservative thresholds for exploratory purposes. Results: Using region-of-interest VBM analyses mirrored to the headache side, we found enlargement (p < 0.05, small volume correction) in the anterior hypothalamic gray matter in subjects with chronic cluster headache compared to controls, and in all participants with episodic or chronic cluster headache taken together compared to migraineurs. After manual segmentation, hypothalamic volume (meanAESD) was larger (p < 0.05) both in subjects with episodic (1.89 AE 0.18 ml) and chronic (1.87 AE 0.21 ml) cluster headache compared to controls (1.72 AE 0.15 ml) and migraineurs (1.68 AE 0.19 ml). Similar but non-significant trends were observed for participants with probable cluster headache (1.82 AE 0.19 ml; p ¼ 0.07) and CPH (1.79 AE 0.20 ml; p ¼ 0.15). Increased hypothalamic volume was primarily explained by bilateral enlargement of the anterior hypothalamus. Exploratory whole brain VBM analyses showed widespread changes in pain-modulating areas in all subjects with headache. Interpretation: The anterior hypothalamus is enlarged in episodic and chronic cluster headache and possibly also in probable cluster headache or CPH, but not in migraine.