Sex Differences of Periaqueductal Grey Matter Functional Connectivity in Migraine

Kinga Gecse; Daniel Baksa; Dóra Dobos; Csaba Sandor Aranyi; Attila Galambos; Natália Kocsel; Edina Szabó; Gyöngyi Kökönyei; Miklós Emri; Gyorgy Bagdy; Gabriella Juhasz

doi:10.3389/fpain.2021.767162

Sex Differences of Periaqueductal Grey Matter Functional Connectivity in Migraine

Front Pain Res (Lausanne). 2021 Nov 30:2:767162. doi: 10.3389/fpain.2021.767162. eCollection 2021.

Authors

Kinga Gecse^{1

2}, Daniel Baksa^{1

2}, Dóra Dobos^{1

2}, Csaba Sandor Aranyi³, Attila Galambos^{2

4}, Natália Kocsel^{2

4}, Edina Szabó^{2

4

5}, Gyöngyi Kökönyei^{1

2

4}, Miklós Emri³, Gyorgy Bagdy^{1

6

7}, Gabriella Juhasz^{1

2}

Affiliations

¹ Department of Pharmacodynamics, Faculty of Pharmacy, Semmelweis University, Budapest, Hungary.
² SE-NAP2 Genetic Brain Imaging Migraine Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary.
³ Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
⁴ Institute of Psychology, ELTE Eötvös Loránd University, Budapest, Hungary.
⁵ Center for Pain and the Brain (PAIN Research Group), Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States.
⁶ NAP-2-SE New Antidepressant Target Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary.
⁷ MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary.

Abstract

The existence of "sex phenotype" in migraine is a long-standing scientific question. Fluctuations of female sex hormones contribute to migraine attacks, and women also have enhanced brain activity during emotional processing and their functional brain networks seem to be more vulnerable to migraine-induced disruption compared to men. Periaqueductal grey matter (PAG) is a core region of pain processing and modulation networks with possible sex-related implications in migraine. In our study, sex differences of PAG functional resting-state connectivity were investigated in the interictal state in 32 episodic migraines without aura patients (16 women and 16 men). A significant main effect of sex was detected in PAG connectivity with postcentral, precentral, and inferior parietal gyri, and further differences were found between right PAG and visual areas (superior occipital gyrus, calcarine, and cuneus), supplementary motor area, and mid-cingulum connectivity. In all cases, PAG functional connectivity was stronger in female migraineurs compared to males. However, higher average pain intensity of migraine attacks correlated with stronger connectivity of PAG and middle temporal, superior occipital, and parietal gyri in male migraineurs compared to females. Migraine-related disability is also associated with PAG connectivity but without sex differences. Our results indicate that sex differences in PAG connectivity with brain regions involved in sensory and emotional aspects of pain might contribute to the "sex-phenotype" in migraine. The stronger functional connectivity between PAG and pain processing areas may be a sign of increased excitability of pain pathways even in resting-state in females compared to male migraineurs, which could contribute to female vulnerability for migraine. However, pain intensity experienced by male migraineurs correlated with increased connectivity between PAG and regions involved in the subjective experience of pain and pain-related unpleasantness. The demonstrated sex differences of PAG functional connectivity may support the notion that the female and male brain is differently affected by migraine.

Keywords: disability; female; headache; male; pain intensity; periaqueductal grey (PAG).