Real-time detection of lesion development in acute brain injury

In the golden era of anatomy and physiology, spreading depression, first discovered in 1944,^1,2 was one of the original hot topics in neuroscience and was considered fundamental in understanding brain function and disease. ³ However, it has since languished as a rather niche subject, never garnering mainstream interest. A comparison to brain seizures is instructive, since seizures were another early hot topic and both spreading depression and seizures occur as idiopathic conditions (migraine aura and epilepsy, respectively) and also after provocation by acute injury. A PubMed search of 2010–2015 (spreading depression OR peri-infarct depolarization OR anoxic depolarization) revealed only 106 publications per year on spreading depression, while a search of “seizure” returned 4970. Brain seizures are now the subject of at least nine specialized biomedical journals, while there has not been a single journal issue devoted to the topic of spreading depression—until now.

Through the decades, spreading depression and related phenomena—collectively, spreading depolarizations (see definitions here^4,5)—suffered from a lack of confirmed clinical relevance. This situation was only rectified in the new millenium with the publication of a landmark article that sparked renewed interest in the field, ⁶ and a dedicated research group, the Co-Operative Studies on Brain Injury Depolarizations (COSBID), was formed to accelerate clinical and basic science investigations. In this issue, Strong and Lauritzen ⁷ review this historic journey over some 70 years. Now, after more than a decade of clinical studies, it is clear that spreading depolarizations are a common, recurrent pathologic mechanism in patients with stroke and brain trauma, occurring with at least four-fold greater incidence than provoked seizures. ^{8 – 10} With the promise of this revitalized discipline, the editors of JCBFM have commissioned the first-ever full journal issue devoted to spreading depolarizations as part of their Clinical Issues series.

What are spreading depolarizations? In today’s era of molecular medicine, Leão’s curious “spreading depression of cortical activity” may appear to be a crude measure of brain health or an epiphenomenon of more relevant molecular signaling. It may even be considered archaic since, similar to seizures, it is highly conserved throughout phylogeny as a pathologic vulnerability of nervous tissue. ¹¹ Yet in his discoveries of the “spreading depression of cortical activity” and anoxic depolarization, Leão seeded a field of discovery that is now being harvested as a breakthrough in translational neuroscience. Collectively, Leão’s waves constitute a continuum of spreading depolarizations, a general term describing pathologic waves of rapidly developing, sustained depolarization of a large fraction of neurons and astrocytes en masse that propagate slowly through the brain’s gray matter.^4,5,12,13 Neurons undergo an abrupt, near-complete breakdown of the transmembrane ion gradients during spreading depolarization, in contrast to the slow breakdown that can be observed in other cells of the body before death. In the 1980s and 1990s, it became clear that the full continuum of spreading depolarizations features prominently in animal models of stroke, and here we review how the continuum explains early and delayed lesion development across a variety of experimental models. ⁴ The emerging picture is that spreading depolarizations are the tissue mechanism that precipitates the changes long recognized by both experimentalists and clinicians as hallmarks of lesion development in cerebral gray matter: loss of ion homeostasis, release of excitatory amino acids, cytotoxic edema, and even depressed cerebral blood flow. Rather than epiphenomena, experimental evidence suggests that spreading depolarizations are a requisite and causal factor in progressive development of acute gray matter lesions—the mechanism underlying the adage that “time is brain.”

This central hypothesis holds the potential to bridge the large chasm between clinical and experimental approaches to neuroprotection. Neuroprotection developed in the 1970s as the concept that neuronal structure and function could be preserved in disease by identification and interference with pathophysiologic processes. With the molecular biology revolution of the same era, the approach to neuroprotection in biomedical science has been inherently reductionistic, focused on individual molecules, receptors, signaling cascades, and other subcellular processes. Without the ability to investigate and confirm the clinical relevance of these mechanisms, however, dozens of clinical trials in acute brain injury have failed. These failures have highlighted the need to better understand and diagnose—in patients—the pathophysiologic processes relevant to progressive structural and functional deterioration. By contrast, the current practice of clinical neuroscience—particularly, the approach to treating acute brain injuries such as ischemic stroke, ruptured aneurysms, and traumatic brain injury—has been directed at the level of organs, organ systems, and their interaction at the organism (patient) level. Thus, patient management is based on evaluation and treatment of global variables such as intracranial pressure, oxygenation levels, and neurologic exams. Largely absent in this approach is consideration of perhaps the most obvious and important factor in neurologic impairment: lesions of the brain parenchyma. Infarcts and contusions are easily and routinely diagnosed in computed tomographic and magnetic resonance imaging, but clinical imaging is performed more to explain etiology of clinical status, after the damage is done.

What if lesion development rather could be tracked in real time as a basis and guide for neuroprotection intervention? The results of COSBID studies suggest that pathologic concepts of lesion development established in experimental models also translate to patients and could be applied to clinical care. Furthermore, the monitoring of hundreds of patients has revealed a tremendous heterogeneity of spreading depolarizations and suggests that real-time monitoring of progressive impairment, well suited for risk stratification, is imminently possible. For instance, in electrically active cortex, spreading depolarization causes spreading depression of the brain’s local spontaneous activity, and the depression duration can vary widely depending on local baseline energy status. At the extreme, spreading depolarization can even be observed in electrically silent (isoelectric) brain tissue where further depression cannot occur. Moreover, spreading depolarizations can occur as isolated events or repeat in continuous temporal clusters. The quantification of these variables thus takes advantage of the enormous heterogeneity of spreading depolarization waves in time and in space across brain tissue—the spreading depolarization continuum—to provide simple, empirical, and clinically useful characterization of disease progression. Marking an important milestone for this new clinical field, here for the first time, we establish consensus recommendations for the monitoring, analysis, and interpretation of these spreading depolarizations in neurointensive care. ⁵

In sum, the cumulative experimental and clinical evidence suggest, as a working hypothesis, that spreading depolarizations is a marker and mechanism of acute lesion development in brain parenchyma. As such, reliable and routine bedside monitoring of depolarizations could provide a breakthrough in approaches to clinical neuroprotection by placing a spotlight on the culprit and enabling personalized, targeted intervention before damage is permanent. In clinical trials, this implies a more selective and specific criterion for patient inclusion and would allow administration of therapies tailored to the individual based on monitoring of the targeted mechanism. However, much work remains for both experimentalists and clinicians to further investigate these concepts, refine and simplify monitoring techniques, and determine effective intervention strategies. This translational research should be conducted on a two-way street between clinic and lab, with efforts to replicate clinical observations in experimental models and vice versa. In the clinic, high priority should be placed on documentation of the clinical course and imaging together with neuromonitoring, in revival of the “anatomy and physiology” approach. It is our hope that this JCBFM Clinical Issue will inspire and accelerate this work, and we are grateful to the editors for this opportunity. We hope that the readership of JCBFM enjoys this issue.