Sounding out migraine-related interactions between the brainstem and cortex.

The clinical features of a migraine attack include symptoms generated by both the brainstem and the cortex. Significant changes in the activity of both brain regions during migraine have been clearly demonstrated with functional imaging techniques (1,2). How these brain regions interact before, during, and after a migraine attack remains much less clear. Cortical spreading depression (CSD), the slowly propagated wave of cortical activity that is believed to be the physiological substrate of migraine aura, can activate brainstem nociceptive pathways in animal models (3–6). It is well known that different types of brain injury can trigger CSD (7), but the trigger(s) for CSD in the setting of migraine are unknown. The paper by Vinogradova in this issue of Cephalalgia uses a novel approach, the audiogenic seizure model in rats, to show that CSD can be triggered by sound-evoked brainstem activity. These findings raise important questions about the potential role of the brainstem as a driver of changes in cortical activity during migraine. Audiogenic seizures are brainstem seizures evoked by loud sound (8). Theyoccur primarily in rodents and there are certain strains of rodents, somewith identified genetic alterations (9), that have amarked propensity to develop this type of seizure. Audiogenic seizures are characterized by ‘‘wild running’’ behavior followed in some cases by tonic or tonic-clonic motor behavior. They are believed to be triggered by activity in the inferior colliculus, and they have been reported to be associated with electrographic seizure activity in the midbrain in periaqueductal gray and substantia nigra, as well as in the medulla, and lateral geniculate bodies (8). The study by Vinogradova shows that repetitive but not single audiogenic seizures in rat, identified based on characteristic running behavior, are followed by unilateral CSD as measured by implanted electrodes. With further stimulation at higher amplitude, cortical seizures may also occur following the spreading depression event, and the CSD events may be bilateral. These findings are interesting on multiple levels. First, they suggest that there may be mechanisms by which activity in the brainstem could trigger CSD. Second, they represent an example of migraine-related changes in cortical activity triggered by a sensory stimulus. Finally, they may provide some new insights into the overlapping mechanisms of migraine and seizures. A number of studies using immunohistochemical and electrophysiological techniques in rodents have shown that CSD can activate second-order trigeminal neurons via the trigeminal nerve (3,4). Others have provided strong evidence that CSD can modulate the activity of second-order trigeminal neurons directly by descending central pathways that are distinct from the trigeminal nerve (5,6). It has been postulated that these peripheral and central descending pathways mediate the activation of nociceptive pathways by CSD, thereby linking CSD (and aura) to migraine headache. The results presented byVinogradova raise the possibility that there could also be ascending pathways from the brainstem to the cortex that are involved in the initiation of CSD. In addition to direct ascending neural pathways, another possibility is that CSD could be evoked by vascular responses to audiogenic seizures. Goadsby and colleagues found that brainstem stimulation, specifically stimulation of the locus coeruleus, can produce substantial cortical vasoconstriction in multiple animal models (10,11). Prolonged sound exposure in rats may also be associated with decreased cortical blood flow, in addition to substantial increases in brain capillary permeability as well as epidural and ventricular hemorrhages (8).