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.

Abstract P717: Central Midbrain Strokes Are More Liable for Respiratory Failure Then Other Brain Stem Strokes

Background: Respiratory centers are known to be present in the central medulla oblongata and pons. There are multiple complex respiratory networks involving these centers. The midbrain periaqueductal grey is believed to act as a regulator of the respiratory function. The effect of brain-stem strokes on respiration remains understudied. There is a lack of clear understanding of the anatomical influence of such strokes on respiration. We attempted to identify brain-stem locations with the highest liability for respiratory failure in case of stroke. Methods: We included all ischemic and hemorrhagic brain-stem strokes from our stroke-registry between 2016 and 2018 then performed univariate/multivariate regression-analyses on variables that might predict respiratory failure and the need for intubation. The brain stem was divided into nine locations (right lateral, central, left lateral in each of the midbrain, pons, and medulla oblongata). Results: Out of 128 brain-stem strokes of different sizes and etiologies, central midbrain strokes were the only significant and independent affected location associated with respiratory failure and endotracheal intubation (coefficient= 0.1256, 95%-CI= 0.0175, 0.2338, p= 0.023). R-squared was equal to 15% when only central midbrain strokes stayed in the model. Conclusions: While one might assume that central medullary and pontine strokes have the most impact on respiration; our results show that central midbrain is the most impactful, accounting for about 15% of respiratory instability associated with brain-stem strokes. This can be explained by the adaptive nature of respiratory circuits within the medulla and pons. Central periaqueductal grey within the midbrain controls the rate and depth of respiration and might not have the same flexibility present elsewhere.

Cerebellum regulates the timing of periaqueductal grey neural encoding of fear memory and the expression of fear conditioned behaviours

The pivotal role of the periaqueductal grey (PAG) in fear learning is reinforced by the identification of neurons in rat ventral (vPAG) that encode fear memory through signalling the onset and offset of an auditory conditioned stimulus during retrieval. Within this framework, understanding of cerebellar contributions to survival circuits is advanced by the discovery that: (i) reversible inactivation of the medial cerebellar nucleus (MCN) during fear consolidation (a) reduces the temporal precision of vPAG offset, but not onset responses and (b) increases rearing behaviour during retrieval, and (ii) chemogenetic inhibition of the MCN-vPAG projection during fear acquisition (a) reduces the emission of fear-related ultrasonic vocalisations and (b) slows the extinction rate of fear-related freezing. These findings show that the cerebellum regulates fear memory processes at multiple timescales and in multiple ways. The current findings indicate that dysfunctional interactions in the cerebellar-survival network may underlie fear-related disorders and comorbidities.Impact StatementCerebellar-periaqueductal grey interactions contribute to fear conditioned processes and, as such, provide a novel target for treating psychological conditions including post-traumatic stress disorder.

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.

MicroRNA profiling of the pig periaqueductal grey (PAG) region reveals candidates potentially related to sex-dependent differences

Background MicroRNAs indirectly orchestrate myriads of essential biological processes. A wide diversity of miRNAs of the neurodevelopmental importance characterizes the brain tissue, which, however, exhibits region-specific miRNA profile differences. One of the most conservative regions of the brain is periaqueductal grey (PAG) playing vital roles in significant functions of this organ, also those observed to be sex-influenced. The domestic pig is an important livestock species but is also believed to be an excellent human model. This is of particular importance for neurological research because of the similarity of pig and human brains as well as difficult access to human samples. However, the pig PAG profile has not been characterized so far. Moreover, molecular bases of sex differences connected with brain functioning, including miRNA expression profiles, have not been fully deciphered yet. Methods Thus, in this study, we applied next-generation sequencing to characterize pig PAG expressed microRNAs. Furthermore, we performed differential expression analysis between females and males to identify changes of the miRNA profile and reveal candidates underlying sex-related differences. Results As a result, known brain-enriched, and new miRNAs which will expand the available profile, were identified. The downstream analysis revealed 38 miRNAs being differentially expressed (DE) between female and male samples. Subsequent pathway analysis showed that they enrich processes vital for neuron growth and functioning, such as long-term depression and axon guidance. Among the identified sex-influenced miRNAs were also those associated with the PAG physiology and diseases related to this region. Conclusions The obtained results broaden the knowledge on the porcine PAG miRNAome, along with its dynamism reflected in different isomiR signatures. Moreover, they indicate possible mechanisms associated with sex-influenced differences mediated via miRNAs in the PAG functioning. They also provide candidate miRNAs for further research concerning, i.e., sex-related bases of physiological and pathological processes occurring in the nervous system. Graphical abstract