Altered functional magnetic resonance imaging resting-state connectivity in periaqueductal gray networks in migraine

Abstract

Objective: The periaqueductal gray matter (PAG), a known modulator of somatic pain transmission, shows evidence of interictal functional and structural abnormalities in migraineurs, which may contribute to hyperexcitability along spinal and trigeminal nociceptive pathways, and lead to the migraine attack. The aim of this study was to examine functional connectivity of the PAG in migraine.

Methods: Using resting-state functional MRI, we compared functional connectivity between PAG and a subset of brain areas involved in nociceptive/somatosensory processing and pain modulation in 17 subjects with migraine, during a pain-free state, versus 17 gender- and age-matched controls. We also assessed the relation between intrinsic resting-state correlations within PAG networks and the average monthly frequency of migraine attacks, as well as allodynia.

Results: Our findings show stronger connectivity between the PAG and several brain areas within nociceptive and somatosensory processing pathways in migraineurs versus controls. In addition, as the monthly frequency of migraine attacks worsens, the strength of the connectivity in some areas within these pathways increases, whereas a significant decrease in functional resting-state connectivity between the PAG and brain regions with a predominant role in pain modulation (prefrontal cortex, anterior cingulate, amygdala) can be evidenced. Finally, migraineurs with a history of allodynia exhibit significantly reduced connectivity between PAG, prefrontal regions, and anterior cingulate compared to migraineurs without allodynia.

Interpretation: These data reveal interictal dysfunctional dynamics within pain pathways in migraine manifested as an impairment of the descending pain modulatory circuits, likely leading to loss of pain inhibition, and hyperexcitability primarily in nociceptive areas.

Figure 1

Sagittal sections of the MNI brain illustrating representative brain regions that show positive functional resting state connectivity with the periaqueductal gray in (A) 17 healthy subjects and in (B) 17 age- and gender-matched patients with migraine, interictally. Statistical threshold corresponds to Z>5.0

Figure 2

Sagittal sections of the MNI brain showing in 17 patients with migraine, interictally, A) brain areas where increased functional resting-state connectivity with the periaqueductal gray (PAG) positively correlates with the frequency of migraine attacks; B) brain regions where decreased functional connectivity with the PAG is associated with an increased frequency of migraine attacks. Statistical threshold corresponds to Z>2.3 and a corrected cluster significance of p=0.05, including clusters with at least 20 contiguous voxels.

Figure 3

Coronal views of the MNI showing brain areas (Z>2.3 and a corrected cluster significance of p=0.05 corresponding to at least 20 contiguous voxels) of reduced functional resting-state connectivity with the periaqueductal gray in five migraineurs with a history of allodynia compared to five age- and gendermatched migraineurs without any history of allodynia development during the migraine attack. R= right.