Periaqueductal Gray Matter: A Potential Biomarker of Chronic Migraine

Human brain. Coloured sagittal magnetic resonance imaging (MRI) scan through the midline of a normal human brain, passing through the cerebral cortex, the cerebellum (lower right), the corpus callosum (centre), the thalamus, the mid-brain, the pons, the medulla oblongata and the spinal cord (lower centre). The brain membranes (meninges) are shown in blue. The front of the brain is at left.
There is an increased iron accumulation in basal ganglia nuclei, especially the red nucleus, and in periaqueductal gray matter in patients with chronic migraine.

Compared with patients with episodic migraine and healthy controls, patients with chronic migraine have higher iron deposition in the red nucleus (RN) and periaqueductal gray matter (PAG), according to case-control study findings published in Neurology. In addition, iron grounds volume in PAG correctly identified chronic migraine and was associated with elevated biomarkers of endothelial dysfunction and blood-brain barrier (BBB) disruption.

Patients with episodic migraine (n=57) and chronic migraine (n=55) from the outpatient Headache Clinic of the department of neurology at the Hospital Clinico Universitario de Santiago de Compostela, Spain, were enrolled in the study. In addition, headache-free controls (n=25) were recruited for comparison. In all patients, iron deposition was measured with 3T magnetic resonance imaging (MRI) and ImageJ, a National Institutes of Health software.

Serum levels of inflammation, endothelial dysfunction, and BBB disruption were also measured using enzyme-linked immunosorbent assay (ELISA) during interictal periods.

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Individuals with chronic migraine had larger iron grounds volume in the RN vs participants with episodic migraine (70.2±6.8 vs 25.5±7.3 mL, respectively; P <.001) and controls (70.2±6.8 vs 15.1±10.8 mL, respectively; P <.001). Participants with chronic migraine also had larger iron deposits in PAG vs participants with episodic migraine (360.3±6.5 vs 249.7±6.9 μL, respectively; P <.001) and headache-free controls (360.3±6.5 vs 168.6±10.3 μL, respectively; P <.001).

The optimal threshold for iron volume in RN and PAG was 15 μL (80% sensitivity, 71% specificity) and 240 μL (93% sensitivity, 97% specificity), respectively.

Associations were found between iron grounds volume in PAG with higher soluble tumor necrosis factor-like WEAK (r=0.395; P =.005) and cellular fibronectin (r=0.294; P =.040) plasma levels.

Study limitations included the age variation of patients, the small number of participants in each group, and the recruitment of patients from only 1 center.

“It is necessary to establish whether these lesions (iron deposits in RN and PAG) are chronic and irreversible (in which case they could be associated with the irreversibility of the migraine process and could be considered a biomarker of [chronic migraine]) or reversible,” concluded the researchers.


Domínguez C, López A, Ramos-Cabrer P, et al. Iron deposition in periaqueductal gray matter as a potential biomarker for chronic migraine. Neurology. 2019;92(10):e1076-e1085.