Periaqueductal gray matter dysfunction in migraine and chronic daily headache may be due to free radical damage

Abstract

The periaqueductal gray matter (PAG) is at the center of a powerful descending antinociceptive neuronal network. We studied iron homeostasis in the PAG in episodic migraine patients between attacks and in chronic daily headache patients during headache using highresolution magnetic resonance imaging (MRI) techniques 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. We hypothesized that repeated hyperoxia of brainstem structures observed during migraine may generate free radical damage over time, resulting in iron deposition in vulnerable tissue. Seventeen patients diagnosed with episodic migraine with and without aura (EM), 17 with chronic daily headache (CDH) and medication overuse, and 17 normal adults (N) were imaged with a 3 tesla MRI system. In the PAG, there was a significant increase in mean R2’ and R2* values in both the EM and CDH groups (p<0.05) compared to normal, but no significant difference in these values between the EM and CDH groups, or between 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. Duration of the episodic migraine stage in the CDH group did not correlate significantly with R2’, although the total duration of the episodic migraine plus daily headache stages of the CDH group strongly correlated with R2’. No effect of age was noted on R2’. Decrease in mean R2’ and R2* values also was observed in the RN and SN of the CDH compared to N and EM groups (p<0.05), explained best by flow activation due to head pain. Iron homeostasis in the PAG was selectively, persistently and progressively impaired in the EM and CDH groups, possibly caused by free radicals generated during repeated migraine attacks. These results support and emphasize the role of the PAG in migraine, potentially by dysfunctional control of the trigeminovascular nociceptive system. Development of CDH out of EM may be associated with a critical threshold of iron deposition and drug withdrawal excitation of the dysfunctional PAG.