Migraine is a prevalent neurological disorder, particularly among individuals aged 20–50 years, with significant social and economic impacts. Despite its high prevalence, the pathogenesis of migraine remains unclear. In this review, we provide a comprehensive overview of cortical spreading depolarization/depression (CSD) and its close association with migraine aura, focusing on its role in understanding migraine pathogenesis and therapeutic interventions. We discuss historical studies that have demonstrated the role of CSD in the visual phenomenon of migraine aura, along with modern imaging techniques confirming its propagation across the occipital cortex. Animal studies are examined to indicate that CSD is not exclusive to migraines; it also occurs in other neurological conditions. At the cellular level, we review how CSD is characterized by ionic changes and excitotoxicity, leading to neuronal and glial responses. We explore how CSD activates the trigeminal nervous system and upregulates the expression of calcitonin gene-related peptides (CGRP), thereby contributing to migraine pain. Factors such as genetics, obesity, and environmental conditions that influence the CSD threshold are discussed, suggesting potential therapeutic targets. Current treatments for migraine, including prophylactic agents and CGRP-targeting drugs, are evaluated in the context of their expected effects on suppressing CSD activity. Additionally, we highlight emerging therapies such as intranasal insulin-like growth factor 1 and vagus nerve stimulation, which have shown promise in reducing CSD susceptibility and frequency. By elucidating the molecular and cellular mechanisms of CSD, this review aims to enhance the understanding of migraine pathogenesis and support the development of targeted therapeutic strategies.

Background: Obesity is a risk factor for episodic migraine to develop into chronic migraine; hence, it is speculated that obesity and hyperleptinemia are associated with migraine. We hypothesized that leptin is involved in the mechanisms of cortical spreading depression (CSD). Therefore, we examined whether leptin affected a rat model of CSD to clarify the relationship between leptin and migraine. Methods: We evaluated the effect of intracerebroventricular (ICV) administration of leptin on a rat CSD model. We then examined whether once-a-day intraperitoneal administration of leptin for seven days (as a chronic hyperleptinemia model) affected rat CSD models. Finally, we induced CSD in Zucker fatty (ZF) rats, which is a well-known model of obesity. Results: In the parietal cortex, the percent change in cerebral blood flow and direct current (DC) potential decreased after ICV administration of leptin. A similar decrease in DC potential was observed in rats treated with intraperitoneal leptin. The number of CSDs increased significantly in rats given intraperitoneal leptin and in ZF rats. Conclusions: The present study suggests that leptin is involved in the mechanisms of CSD.

Alcohol has been recognized as the main trigger for a cluster headache attack, but clinical features to distinguish between cluster headache in drinkers and nondrinkers are unclear. Thus, the present study aimed to investigate the differences in clinical features of cluster headache between drinkers and nondrinkers. This retrospective, observational study compared the clinical features of cluster headache between drinkers and nondrinkers among patients who were diagnosed with cluster headache between November 2004 and April 2018 at the Japanese Red Cross Shizuoka Hospital. Demographic and clinical data were collected from medical records and/or by patient interview. Of 131 patients, 98 (75%) were drinkers, and 33 (25%) were nondrinkers. Compared with nondrinkers, drinkers had significantly more frequent conjunctival injection (43% vs. 21%, p = 0.037) but significantly less frequent nasal congestion (31% vs. 52%, p = 0.0037), vomiting (11% vs. 30%, p = 0.014), and photophobia (29% vs. 45%, p = 0.008). Among individuals with cluster headache, the frequencies of conjunctival injection, nasal congestion, vomiting, and photophobia were different between drinkers and nondrinkers. These results suggested that drinking might influence the responses of the cranial autonomic reflex with respect to conjunctival injection or nasal congestion.

Autoimmune encephalitis (AE) is an immune-mediated encephalitis characterized by the subacute onset of memory deficits, altered mental status, or psychiatric symptoms. Limbic encephalitis associated with rheumatoid arthritis (RA) has not been reported yet. A 57-year-old man presented with the subacute onset of headache, depression, and anorexia 7 months before the onset of RA. Brain magnetic resonance imaging showed symmetric parenchymal lesions involving the medial temporal lobes. He was diagnosed with RA and AE, but no autoantibodies to neuronal intracellular or cell-surface antigens were identified in either the serum or cerebrospinal fluid. His symptoms improved with immunotherapy. AE can develop as an extra-articular manifestation of RA.