Periaqueductal Gray Matter Dysfunction in Migraine: Cause or the Burden of Illness?

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Abstract
Objective.—The periaqueductal gray matter (PAG) is at the center of a powerful descending antinociceptive neuronal network. We studied iron homeostasis in the PAG as an indicator of function in patients with episodic migraine (EM) between attacks and patients with chronic daily headache (CDH) during headache. High‐resolution magnetic resonance techniques were used to map the transverse relaxation rates R2, R2*, and R2′ in the PAG, red nucleus (RN), and substantia nigra (SN). R2′ is a measure of non‐heme iron in tissues.Methods.—Seventeen patients diagnosed with EM with and without aura, 17 patients diagnosed with CDH and medication overuse, and 17 normal adults (N) were imaged with a 3.0‐tesla magnetic resonance imaging system. For each subject, mean values of the relaxation rates, R2 (1/T2), R2* (1/T2*), and R2′ (R2* − R2) were obtained for the PAG, RN, and SN. R2, R2*, and R2′ values of the EM, CDH, and N groups were compared using analysis of variance, Student t test, and correlation analysis.Results.—In the PAG, there was a significant increase in mean R2′ and R2* values in both the EM and CDH groups (P<.05) compared with the N group, but no significant difference in these values was demonstrated between the EM and CDH groups, or between those with migraine with or without aura in the EM group. Positive correlations were found for duration of illness with R2′ in the EM and CDH groups. A decrease in mean R2′ and R2* values also was observed in the RN and SN of the CDH group compared with the N and EM groups (P<.05), explained best by flow activation due to head pain.Conclusions.—Iron homeostasis in the PAG was selectively, persistently, and progressively impaired in the EM and CDH groups, possibly caused by repeated migraine attacks. These results support and emphasize the role of the PAG as a possible “generator” of migraine attacks, potentially by dysfunctional control of the trigeminovascular nociceptive system.