Pathophysiological Insights into Spreading Depolarization in Severe Traumatic Brain Injury

Excerpt

Cortical spreading depolarization (SD) was first identified over 70 years ago by the Brazilian neurophysiologist Leão [1], and has emerged as a plausible mechanism to account for time-dependent expansion of cerebral dysfunction and injury [2]. SD is defined as a transient wave of cellular depolarization involving both neurons and astrocytes, which propagates within gray matter at a velocity of 1–9 mm/min³. It has been described in patients with ischemic stroke, aneurysmal subarachnoid hemorrhage (SAH), post-SAH delayed cerebral injury, intracerebral hemorrhage, and severe traumatic brain injury (TBI), and it is believed to play a role in the aura preceding migraine headaches [3]. SD has been successfully modeled in murine and large animal brain injury paradigms [4‐6]. The depolarization of cell membranes is associated with cytotoxic edema, influx of Na⁺, Cl⁻, and Ca²⁺ ions, efflux of K⁺ ions, and an extracellular accumulation of neurotransmitters. An ensuing loss of spontaneous electrical activity is defined as spreading depression. The duration of depolarization in individual cells may last from seconds to minutes and is influenced by the level of perfusion. In the absence of ischemia (e.g., in migraine), repolarization typically occurs without permanent injury to neurons, whereas with cerebral blood flow less than 10 ml/min/100 g, adenosine triphosphate (ATP) generation is insufficient to restore transmembrane electrochemical gradients and cells remain permanently depolarized and eventually die. Intermediate levels of perfusion usually result in delayed repolarization, but recurrent waves of depolarization emanating from more ischemic regions overwhelm the cellular machinery required to restore transmembrane gradients and to defend against excitotoxic injury, leading to delayed cell death. A causal role for SDs in the expansion of infarction is supported by studies in which experimentally induced waves of SD produced larger infarctions [7, 8]. …