It is quite likely that changes in neuronal activity during the premonitory phase reflect the actual anatomical origin of a migraine attack and might thus represent a possible therapeutic target,” explains Laura Schulte, MD. “Acute migraine medication works best when taken very early in the course of a migraine attack. Thus, identifying biomarkers of the premonitory phase might enable identification of migraine onset hours before pain occurs and might thus render optimal treatment outcomes.” The research team followed more than 27,000 women with migraine (history of migraine without aura or migraine with aura) or headache for a median of 22.7 years. The team evaluated reported incidence of death and used medical records to determine if the deaths were caused by cardiovascular disease, any cancer, or female-specific cancer causes. For a small study published in Annals of Neurology, Dr. Schulte and colleagues aimed at identifying neuronal changes in pain processing occurring before the onset of migraine pain. “We invited patients with migraine to undergo functional MRI of trigeminal nociception daily for 1 month, thus including days with migraine pain and days before headache onset,” says Dr. Schulte. “Using this paradigm, we were able to investigate neuronal changes within the 24 hours before headache onset.” Based on cumulative data of 27 spontaneous migraine attacks, including scans before, during, and after migraine pain, as well as interictal scans, the researchers found that, as a response to painful trigeminal stimulation, the hypothalamus is activated within the last 48 hours before headache onset but not earlier. “This is important as hypothalamic activity might account for many premonitory symptoms of migraine, such as food craving and sleep disturbances, and is thus a neuronal correlate of the premonitory phase of migraine,” notes Dr. Schulte. “This provides evidence that the premonitory phase of migraine might not last longer than 48 hours and points toward the hypothalamus as a key player in the premonitory phase of migraine and a possible role of this brain area in migraine attack generation.” Looking forward, Dr. Schulte suggests the need to understand the processes leading up to the predominant hypothalamic activation in the premonitory phase. “The hypothalamus is not an isolated area of the brain but rather a hub of integration between homeostatic networks and higher areas of the brain,” she adds. “We need to understand the whole neuronal network and the interactions of its nodes to get the big picture of migraine attack generation.”