Migraines are not the only culprits when it comes to extraordinary head pain. Cluster headaches have long puzzled researchers, too, although studies are slowly revealing the parts of the brain involved when those punctuated bursts of pain occur.

The excruciating headaches tend to turn up in bouts lasting six to eight weeks. During these cycles, afflicted individuals—more often men—experience intense daily headaches on one side of the head, each lasting an hour or two, explains headache expert Peter Goadsby, a neurologist at the University of California, San Francisco.

In the late 1990s Goadsby and his colleagues linked cluster headaches to heightened synaptic activity falling in or near the hypothalamus, a brain region that mediates hunger, thirst, sleep, sex drive and more. Yet researchers are still trying to understand how activity in this hypothalamus-adjacent area could conjure the condition—and to determine what other glitches in brain structure, metabolism or interactions contribute to sufferers' throbbing noggins.

At least one study suggests that in cluster headache sufferers this hypothalamus-adjoining region may differ not only in its electrical activity but also in its interactions with other parts of the brain. In PLOS ONE in February, a Beijing-based team imaged the brains of a dozen men in the midst of cluster headache bouts. The researchers traced blood flow—and, with it, functional connections—between the hypothalamus and other parts of the brain. Compared with unaffected men, the cluster headache sufferers did have unusual hypothalamic connections. When headaches hit, these altered interactions often involved parts of the brain associated with pain processing. But hypothalamic connections were off-kilter between headaches, too, pointing to more persistent brain differences in those prone to cluster headaches.