Spreading Depolarizations

Spreading depolarizations (SDs) are recurrent waves of intense neuronal and glial depolarization that develop in apparently spontaneous fashion in ischemic stroke, intracranial hemorrhage, and trauma. Although Leão first described spreading depression, an SD wave in normal (i.e., uninjured) brain, in 1944, it was not until the late 1970s that periinfarct spreading depression-like waves were detected in experimental focal cerebral ischemia . Today we know that SDs occur after most types of injury in human brain, and worsen both tissue and functional neurological outcome .

Basic Characteristics

The electrophysiological events underlying SDs have been reviewed in detail . SDs are associated with massive transmembrane K ⁺ , Ca ²⁺ , Na ⁺ , and water shifts, as well as cell swelling. The depolarization and ion fluxes create a characteristic 20- to 30-mV extracellular negative slow potential shift ( Fig. 30.1 ). In otherwise normal brain, all transmembrane ion and water balances are restored within less than a minute, which is even more metabolically costly than seizures. Once triggered, SDs slowly propagate within the gray matter at a rate of ∼3–6 mm/min by way of contiguity. When SDs occur in or propagate into otherwise normal tissue, complete neuronal membrane depolarization precludes all spontaneous and evoked activity resulting in electrocorticogram (ECoG) depression. Because Leão discovered and described the basic features of SD in normal brain by using ECoG recordings with high-pass filtering, he only detected ECoG depression rather than the massive pan-depolarization, and termed the phenomenon spreading depression. But since the ECoG is already depressed in injured tissue (e.g., ischemic penumbra), SD events can not cause further ECoG depression in these regions. Therefore, SD (spreading depolarization ) is a more accurate and inclusive term that has replaced spreading depression . Nevertheless, the term spreading depression has historical significance, and is well recognized and widely used by the scientific and clinical community, especially in the migraine field where SD occurs in normal brain to create the perception of aura.

Impact on Injury Outcome

SDs in injured brain often last longer than in healthy brain because blood flow-, O ₂ -, and glucose-dependent restoration of transmembrane ion gradients is often delayed, and because, in contrast to the large hyperemic response they evoke in normal brain, SDs cause vasoconstriction and further reduce tissue perfusion and oxygenation in injured brain ( Fig. 30.2 ) . Understandably, the vasoconstrictive effect, combined with the tremendous metabolic burden they impose on the tissue, severely worsens supply–demand mismatch, and is highly detrimental to the survival of already metabolically compromised brain tissue. As a result, SDs expand the injury (e.g., ischemic core), and contribute to neurological worsening. Additional mechanisms by which SDs can be detrimental in injured brain are (1) disruption of the blood–brain barrier, potentially leading to malignant cerebral edema, mass effect, and herniation, and (2) triggering of epileptic seizures. Confirming the pathophysiological importance of SDs, pharmacological SD inhibitors (e.g., NMDA receptor blockers) reduce infarct volumes and improve neurological outcomes in experimental models of ischemic stroke . As a cautionary note, however, SDs may also have beneficial effects particularly at later stages of injury maturation and recovery when supply–demand mismatch is no longer a critical factor in tissue outcome. They have been shown to stimulate neurogenesis, and may even promote angiogenesis.