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

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 Ј in the PAG, red nucleus (RN), and substantia nigra (SN). R2 Ј 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 Ј (R2* Ϫ R2) were obtained for the PAG, RN, and SN. R2, R2*, and R2 Ј 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 Ј and R2* values in both the EM and CDH groups ( P Ͻ .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 Ј in the EM and CDH groups. A decrease in mean R2 Ј and R2* values also was observed in the RN and SN of the CDH group compared with the N and EM groups ( P Ͻ .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. Key words: periaqueductal gray matter, iron, transverse relaxation rates Abbreviations: PAG periaqueductal gray matter, MWOA migraine without aura, DRN dorsal raphe nucleus, LC locus ceruleus, R2, R2*, R2 Ј transverse relaxation rates, RN red nucleus, SN substantia nigra, EM episodic migraine, CDH chronic daily headache, MWA migraine with aura, N healthy normal adults, GESFIDE gradient-echo sampling of free induction delay and echo, RF radiofrequency, ISODATA Iterative Self-organizing Data Analysis Technique ( Headache 2001;41:629-637) The midbrain periaqueductal gray matter (PAG) is an anatomically heterogeneous, functionally diverse region of densely layered neurons surrounding the aqueduct of Sylvius.1 Receiving input from the frontal cortex and hypothalamus and projecting to the rostral ventromedial medulla and from there to the medullary and spinal dorsal horn, the PAG is the center of a powerful descending antinociceptive neuronal network.2 Further, the PAG can be consideredFrom the

Diagnosis, pathophysiology and management of chronic migraine: a proposal of the Belgian Headache Society

“…It is generally accepted that the common forms of migraine with or without aura (Table 2): abnormal thickness, connectivity and/or activation of certain cortical and subcortical areas [24][25][26][27], increased transmitter [28] or iron content [29][30][31], decreased ATP content [32,33] and an abnormal pattern of sensory processing [34,35]. The latter is characterized by low amplitude of initial responses and hyperresponsivity with lack of habituation of late responses during repeated sensory stimuli [36], and has been attributed to a thalamocortical dysrhythmia caused by deficient monoaminergic control by brain stem nuclei (review in [37]).…”

“…cortical sensitivity and % responsivity to sensory stimuli [35,36] % fractional anisotropy thalamus (MR-DTI) [43] ! cortical thickness and activation S1, temporal lobe [26] % cortical thickness and/or activation insula, cingulate, visual areas [24,26] % rs connectivity amygdala-insula [27] % iron content PAG and globus pallidus [29][30][31] % rs connectivity PAG-precuneus, visual [25] % tissue density in PAG [129] ! olfaction-induced trigeminal nucleus activation % pre-ictally [130] % subclinical posterior circulation infarcts [30] Chronic migraine % cortical sensitivity and !…”

“…insula, cingulate [26] % rs connectivity limbic areas (Am, Ins, ACC)-thalamus, PAG, midtemporal, entorhinal, S1 [131] ! rs connectivity caudate-insula; % putamen-insula [132] % activation dorsolateral pons [47] %% iron content PAG and globus pallidus (T2) [29,31] ! central pain modulation [133,134] no % of posterior circulation infarcts [104] Medication overuse headache !…”

Preventing chronicity of migraine

“…Neuroimaging studies showed that brain white matter lesions increased with episode frequency, possibly demonstrating progression of the disease [6]. In addition, repetitive attacks may lead to chronic headache through a progressive impairment of the central antinociceptive system in the periaqueductal grey matter that controls activity of the trigeminovascular system [7]. In this context, prophylactic medication that acts to reduce the number of migraine attacks, more likely than abortive agents, might have a long-term effect on the natural evolutive history of migraine.…”

Observations of the “carry–over effect” following successful termination of chronic migraine in the adolescent with short–term dihydroergotamine, dexamethasone and hydroxyzine: a pilot study

“…Although this is a very small study, which requires confirmation by a larger controlled study, our data suggest a significant carryover effect in the young migraineur by administering short-term parenteral dihydroergotamine, dexamethasone and hydroxyzine. of the brainstem, may be operative in chronic headache syndromes [1,2]. Chronic central sensitisation caused by repetitive uncontrolled severe migraine attacks in a young person might lower the threshold for future attacks ultimately leading to an intractable, treatment-resistant malignant disease course in adult life.…”