Cortical Spreading Depolarization After Severe Traumatic Brain Injury

The goal of this study is to improve our understanding of cortical spreading depolarizations (CSDs) as a mechanism of secondary injury in severe traumatic brain injury (TBI). The primary obstacles to advancing treatment of TBI are its heterogeneity in terms of cause, severity, pathophysiology and the paucity of therapeutic targets. At the current time, there is no intervention to reverse or restore the function of brain tissue damaged or lost during the initial traumatic insult; therefore the therapeutic focus is centered on minimizing secondary insults that result in expansion of the initial brain injury.

The past several years have witnessed significant advancement in the understanding of potential mechanisms of secondary injury after severe TBI. This is important work as secondary injury after severe TBI is thought to significantly increase the severity of the initial injury and this type of injury is thought to be open to interventions to attenuate the subsequent injury severity. Among the putative mechanisms of secondary injury after severe TBI, it was recently demonstrated that there is a relationship between CSD events and worse outcomes after severe TBI. Therefore, a more thorough understanding of the factors that influence the initiation and frequency of CSDs after TBI is warranted in order to develop therapeutic strategies to reduce or block these events from occurring.

In young people, TBI is the leading cause of morbidity and mortality in developed countries. TBI is a frequent sequelae of accidental injury in the USA with approximately 2.5 million people affected per year, approximately 10% of whom requiring extended hospitalization, often in an intensive care unit. Around 275,000 (15.1%) of hospital admissions and 52,000 deaths in the USA each year are due to TBI. Those that survive the initial insult invariably face prolonged stays in a neurologic intensive care unit (ICU), possible neurosurgical intervention, and prolonged period of post-acute supportive care. In the US, it is estimated that 5.3 million individuals are living with long-term disability as a result of TBI.

Given the complexity and duration of medical care that accompanies severe TBI, it follows that the cost of care associated with TBI are immense. It is estimated that total hospital charges for TBI-related admissions in 2010 were $21.4 billion. Beyond hospital charges, it is estimated that TBI costs the US economy $76.5 billion annually with the costs for disability and lost productivity outweighing those of acute medical care and rehabilitation.

Since their first description in 1944, spreading depolarizations (SDs) were subsequently demonstrated in numerous animal studies as a mechanism of secondary brain injury after ischemic stroke, subarachnoid hemorrhage (SAH), and traumatic brain injury. SDs have also been demonstrated to occur in the cerebral grey matter of the human brain in patients after acute brain injuries such as TBI, SAH, and ischemic stroke. To date, electrocorticography (ECoG) monitoring of over 500 patients after TBI has shown that SDs occur in 55-90% of individuals for days to weeks after the initial injury. These studies have demonstrated an initial peak in SD frequency at 1-2 days post-TBI and a second peak at 6-7 days. Furthermore, SDs are associated with worse outcomes after TBI.