Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature

Abstract

Spreading depression (SD) is a transient wave of near-complete neuronal and glial depolarization associated with massive transmembrane ionic and water shifts. It is evolutionarily conserved in the central nervous systems of a wide variety of species from locust to human. The depolarization spreads slowly at a rate of only millimeters per minute by way of grey matter contiguity, irrespective of functional or vascular divisions, and lasts up to a minute in otherwise normal tissue. As such, SD is a radically different breed of electrophysiological activity compared with everyday neural activity, such as action potentials and synaptic transmission. Seventy years after its discovery by Leão, the mechanisms of SD and its profound metabolic and hemodynamic effects are still debated. What we did learn of consequence, however, is that SD plays a central role in the pathophysiology of a number of diseases including migraine, ischemic stroke, intracranial hemorrhage, and traumatic brain injury. An intriguing overlap among them is that they are all neurovascular disorders. Therefore, the interplay between neurons and vascular elements is critical for our understanding of the impact of this homeostatic breakdown in patients. The challenges of translating experimental data into human pathophysiology notwithstanding, this review provides a detailed account of bidirectional interactions between brain parenchyma and the cerebral vasculature during SD and puts this in the context of neurovascular diseases.

The impact of aging on spreading depolarization in the intact and ischemic rat brain

“…As the name implies, SD propagates over the nervous tissue, at a rate of 3-6 millimeters per minute, developing radially from a central point of origin in the cerebral grey matter. A sufficiently strong stimulus that is able to depolarize a critical volume of brain cells estimated to be ~1 mm 3 in the rat neocortex triggers SD 15 . The negative shift of the direct current (DC) potential is the hallmark of SD, which evolves parallel with ionic movements between the intra-and extracellular compartments: SD is accompanied by an increase of extracellular K + from 3-4 to 30-60 mM, and the concomitant decrease of the extracellular concentration of Na + from 140-150 to 50-70 mM and of Ca 2+ from 1-1.5 to 0.2-0.8 mM 16 .…”

“…This need is met by increased local CBF. The hemodynamic response to SD consists of at least for sequential elements, which are achieved by a finely regulated balance between vasoconstriction and vasodilation 15 . In the intact brain, a short-lasting, initial vasoconstriction temporally coincides with the depolarization (i.e.…”

“…3B)., The different phases of the SD-related CBF response are assumed to be the result of a sequence and combination of extracellular ionic, neurotransmitter, and metabolic changes. It has been postulated that, similar to somatosensory activation, neurovascular coupling drives the hyperemic element of the SD-coupled CBF response 15 .…”

“…As presented in the Introduction, the SD-coupled CBF response in the physiologically intact rat cortex consists of at least 4 distinct elements: an initial transient vasoconstriction, a marked hyperemia, a slight late hyperemia and a long-lasting oligemic phase 15 . Ischemia shifts this balance toward the domination of the initial vasoconstrictive (hypoemic) element of the pattern, possibly as a function of decreasing perfusion pressure 28,65 .…”

“…11). If these observations represent more than a coincidence, it would appear that the coupling during SD must have a metabovascular component, even though the prevalence of neurovascular over metabolic coupling with SD has been promoted 15 . Our data further indicate, that if such a coupling exists, it is severely impaired in the aged brain (Fig.…”