Cortical spreading depression

Cortical Spreading Depression/Depolarization (CSD) is a depolarization wave in the cerebral grey matter, which in its mild form causes migraine, and in its severe forms may induce permanent damage of brain tissue. It is a remarkably complex event that involves dramatic changes in neural and vascular function.

CSD is an important mechanism for the expansion of ischemic or traumatic brain injury. Novel clinical studies have demonstrated numerous CSD episodes in up to 60 % of patients in the first week after traumatic brain injury, and in almost all patients with subarachnoid haemorrhage and malignant stroke. These discoveries indicate that CSD in cortical grey matter trigger prolonged hypoxia.  CSD come in any forms like earthquakes on the Richter scale.  The mild forms are associated with migraine while the severe forms are linked to the acutely injured human brain cortex where they kill brain cells by inducing increasingly big gaps between energy supply and use.  The primary event, e.g. the stroke or the TBI kills the cell in the centre of the lesion but the brain creates so to speak further deterioration of brain tissue by single, repeated or even clustered depolarization waves that constrict blood vessels and use all the energy available. In the end the cells cannot repolarize and cells in the peri-ischemic region and cells die because of energy loss.

During and following CSD there are reports of a dramatic slowing of capillary red blood cell flow, flow arrest and even transient disappearance of red blood cells from capillary segments lasting as long as a minute. However, the studies carried out so far have been unable to document focal or diffuse capillary narrowing, compression or occlusion. The flow reduction in parenchymal arterioles and capillaries may precede vasoconstriction in larger pial arteries, but the principle site at which the cerebrovascular resistance increases is unclear. This is of critical relevance for an understanding of the role of CSD in the pathophysiology of stroke and other brain injury states.

Two-photon image of mouse cortex in which a red fluorescent indicator is expressed in smooth muscle cells (large blood vessel) and in capillary pericytes (single cells on smaller vessels).

In our ongoing project we use mice with genetically expressed fluorescent indicators in vivo, to investigate the impact of CSD on the neurovascular unit and in particular the communication between cells at different levels of branching. We also use genetic mouse models of migraine with aura, Familial Hemiplegic Migraine type 1 (FHM1) and type 2 (FHM2) and a mouse model of stroke in which we evaluate the role of CSDs in the peri-ischemic region.

Recent publications from the group: