The Complex Relationship between Estrogen and Migraines: A Scoping Review

Background:Migraine headaches are a chronic and complex medical issue for millions of patients worldwide. Despite how common migraines are, there is much to be unveiled regarding their pathogenesis due to the numerous factors implicated in the pathophysiology of migraines. Migraines are significantly more common in women and many female migrainers notice menstrual associations of their headaches. Because of this, migraines have popularly been hypothesized to be largely hormonally mediated. Estrogen has been commonly implicated in migraine pathogenesis yet its exact role in the pathophysiology of migraines has yet to be fully understood. Methods: We conducted a scoping review of the literature regarding estrogen’s role in migraine pathogenesis and included 11 studies out of an initial 199 in the final review. Results: The estrogen withdrawal hypothesis is the most discussed theory about estrogen’s role in migraine physiology and describes the association of migraine onset with natural declines in estrogen levels. Estrogen is also implicated in biochemical pain pathways, and specifically effects pain processing, trigeminal nociception, and neural inflammatory peptides. Human studies have been conducted in female populations such as pregnant women and postmenopausal women, and these studies have supported the estrogen withdrawal hypothesis.Conclusions: Hormone replacement therapy remains to treat migraines is promising, yet still lacks definitive evidence in its efficacy. More primary research into estrogen’s mechanisms in migraine pathogenesis is needed, as its specific roles are still unclear. While human-based, clinical trials on the subject are rare, they would provide great insight into migraines and would allow clinicians to better treat patients. Systematic Review registrations: none

Partial Similarity Reveals Dynamics in Brainstem-Midbrain Networks during Trigeminal Nociception

Imaging studies help us understand the important role of brainstem and midbrain regions in human trigeminal pain processing without solving the question of how these regions actually interact. In the current study, we describe this connectivity and its dynamics during nociception with a novel analytical approach called Partial Similarity (PS). We developed PS specifically to estimate the communication between individual hubs of the network in contrast to the overall communication within that network. Partial Similarity works on trial-to-trial variance of neuronal activity acquired with functional magnetic resonance imaging. It discovers direct communication between two hubs considering the remainder of the network as confounds. A similar method to PS is Representational Similarity, which works with ordinary correlations and does not consider any external influence on the communication between two hubs. Particularly the combination of Representational Similarity and Partial Similarity analysis unravels brainstem dynamics involved in trigeminal pain using the spinal trigeminal nucleus (STN)—the first relay station of peripheral trigeminal input—as a seed region. The combination of both methods can be valuable tools in discovering the network dynamics in fMRI and an important instrument for future insight into the nature of various neurological diseases like primary headaches.

The role of the meningeal lymphatic system in local inflammation and trigeminal nociception implicated in migraine pain

BackgroundA system of lymphatic vessels has been recently characterized in the meninges, with a postulated role in ‘cleaning’ the brain via cerebral fluid drainage. As meninges are the origin site of migraine pain, we hypothesized that malfunctioning of the lymphatic system should affect the local trigeminal nociception. To test this hypothesis, we studied nociceptive and inflammatory mechanisms in the meninges of K14-VEGFR3-Ig mice lacking the meningeal lymphatic system.MethodsWe recorded the spiking activity of meningeal afferents and estimated the local mast cells infiltration, calcitonin gene-related peptide (CGRP) and cytokine levels (basal and stimulated), as well as the dural trigeminal innervation in freshly-isolated hemiskull preparations from K14-VEGFR3-Ig (K14) or wild type C57BL/6 mice (WT).ResultsWe found that the meningeal level of CGRP and of the pro-inflammatory cytokines IL12-p70 and TNFα (implicated in migraine) were reduced in the meninges of K14 mice. On the contrary, in the meninges of K14 mice, we found an increased level of the mast cell activator MCP-1 and, consistently, a larger number of dural mast cells. The other migraine-related pro-inflammatory cytokines did not differ between the two genotypes. The patterns of trigeminal innervation in meninges remained unchanged and we did not observe alterations in basal or ATP-induced nociceptive firing in the meningeal afferents.ConclusionsIn summary, the lack of meningeal lymphatic system does not induce migraine-like nociceptive state per se, but leads to a new balance between pro- and antiinflammatory factors implicated in migraine mechanisms.

Altered activity in the nucleus raphe magnus underlies cortical hyperexcitability and facilitates trigeminal nociception in a rat model of medication overuse headache

Background The pathogenesis of medication overuse headache (MOH) involves hyperexcitability of cortical and trigeminal neurons. Derangement of the brainstem modulating system, especially raphe nuclei may contribute to this hyperexcitability. The present study aimed to investigate the involvement of the nucleus raphe magnus (NRM) in the development of cortical and trigeminal hyperexcitability in a rat model of MOH. Results Chronic treatment with acetaminophen increased the frequency of cortical spreading depression (CSD) and the number of c-Fos-immunoreactive (Fos-IR) neurons in the trigeminal nucleus caudalis (TNC). In the control group, muscimol microinjected into the NRM increased significantly the frequency of CSD-evoked direct current shift and Fos-IR neurons in the TNC. This facilitating effect was not found in rats with chronic acetaminophen exposure. In a model of migraine induced by intravenous systemic infusion of nitroglycerin (NTG), rats with chronic exposure to acetaminophen exhibited significantly more frequent neuronal firing in the TNC and greater Fos-IR than those without the acetaminophen treatment. Muscimol microinjection increased neuronal firing in the TNC in control rats, but not in acetaminophen-treated rats. The number of Fos-IR cells in TNC was not changed significantly. Conclusion Chronic exposure to acetaminophen alters the function of the NRM contributing to cortical hyperexcitability and facilitating trigeminal nociception.