Sex Differences of Periaqueductal Grey Matter Functional Connectivity in Migraine

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.

Neglected woman with hyperemesis gravidarum leading to Wernicke encephalopathy

A teenage primigravida at 13 weeks of gestation presented with hyperemesis gravidarum of 45 days and a history of giddiness and inability to walk due to involuntary movements of limbs and eyes since 2 days. She was treated with intravenous fluids, thiamine and antiemetics. MRI brain showed hyperintensities in bilateral dorsomedial thalami, periaqueductal grey matter in T2-weighted and FLAIR images. A diagnosis of Wernicke encephalopathy was made and she was managed in intensive care unit and received injection thiamine as per the guidelines and her weakness and ataxia improved over 3 weeks and she was discharged at 17 weeks of pregnancy in good state of health.

The effects of morphine on the CNS

The 1973 paper by Jacquet and Lajtha, was a pivotal report in understanding the effects of opioids on nociception, as it investigated the effects of morphine on different brain structures. To do this, the authors used a microinjection technique that allowed them to specifically target subcortical sites. The animals used in this study were rats, and evaluation of the nociceptive threshold was based on the behavioural reaction to electrical shock. Two reactions were evaluated: flinch or jump responses. The main result was that, depending on the dose and the site of injection, morphine produced either an increase in nociceptive threshold (analgesia), or a decrease in the nociceptive threshold (hyperalgesia). The authors also reported severe effects characterized by hyper-reactivity and violent uncontrolled jumping in stereotyped circular leaps when morphine was administered in the periaqueductal grey matter.