The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão’s legacy

Abstract

A modern understanding of how cerebral cortical lesions develop after acute brain injury is based on Aristides Leão's historic discoveries of spreading depression and asphyxial/anoxic depolarization. Treated as separate entities for decades, we now appreciate that these events define a continuum of spreading mass depolarizations, a concept that is central to understanding their pathologic effects. Within minutes of acute severe ischemia, the onset of persistent depolarization triggers the breakdown of ion homeostasis and development of cytotoxic edema. These persistent changes are diagnosed as diffusion restriction in magnetic resonance imaging and define the ischemic core. In delayed lesion growth, transient spreading depolarizations arise spontaneously in the ischemic penumbra and induce further persistent depolarization and excitotoxic damage, progressively expanding the ischemic core. The causal role of these waves in lesion development has been proven by real-time monitoring of electrophysiology, blood flow, and cytotoxic edema. The spreading depolarization continuum further applies to other models of acute cortical lesions, suggesting that it is a universal principle of cortical lesion development. These pathophysiologic concepts establish a working hypothesis for translation to human disease, where complex patterns of depolarizations are observed in acute brain injury and appear to mediate and signal ongoing secondary damage.

Enhancing Continuous Online Microdialysis Using Dexamethasone: Measurement of Dynamic Neurometabolic Changes during Spreading Depolarization

“…This seems characteristic of an extreme variant of SD called spreading ischemia, although without direct measurement of blood flow this cannot be confirmed. 42 Anecdotally, this event illustrates the potential of intracranial microdialysis to provide an alarm signal in near real time of a severe, in this case lethal, metabolic crisis. It remains to be seen, of course, whether such an alarm signal would be valuable in a clinical setting.…”

Reversible Disruption of Neuronal Mitochondria by Ischemic and Traumatic Injury Revealed by Quantitative Two-Photon Imaging in the Neocortex of Anesthetized Mice

“…Previously, the role of mitochondrial dysfunction has been addressed in vivo using endpoint measures of histological and biochemical markers (Matsumoto et al, 1999;Schinzel et al, 2005) or classic ultrastructural studies (Garcia et al, 1978;Solenski et al, 2002). Employment of in vitro preparations, such as primary cultured neurons, acute and organotypic brain slices have provided a mechanistic concept of mitochondria alteration during traumatic and ischemic injury-like events.…”

“…Recent advances in optical techniques, such as two-photon laser scanning microscopy (Svoboda et al, 1997;Peron et al, 2015) and genetic animal models (Feng et al, 2000;Misgeld et al, 2007), allow repetitive real-time visualization of subcellular structures. Previously, we have developed an automatic approach, based on supervised statistical computer learning, for quantifying the degree of mitochondrial fragmentation in cortical neurons, and validated it using the irreversible global ischemia paradigm (Lihavainen et al, 2015).…”

Unraveling the complexities of invasive multimodality neuromonitoring

“…21 Spreading depolarizations are waves of intense depolarization that emanate from foci of cortical injury to produce widespread metabolic distress, cytotoxic edema, and impaired neurovascular coupling. 15,21,32 Spreading depolarizations are strong predictors of poor outcome after TBI, ischemic stroke, intracerebral hemorrhage, and SAH.…”

“…21 Spreading depolarizations are waves of intense depolarization that emanate from foci of cortical injury to produce widespread metabolic distress, cytotoxic edema, and impaired neurovascular coupling. 15,21,32 Spreading depolarizations are strong predictors of poor outcome after TBI, ischemic stroke, intracerebral hemorrhage, and SAH. 15,20,21,32 Given that ketamine impedes the occurrence and propagation of spreading depolarizations, monitoring for these deleterious physiological stressors could positively impact patient outcome.…”