Cortical spreading depolarization (CSD) is a phenomenon of depressed electrical activity in the brain that has been clinically associated with a variety of acute brain injuries, including 100% of patients with malignant hemispheric ischemic stroke. In addition to being a real-time marker of brain damage, CSDs are also believed to be a mechanism of secondary injury in the compromised tissue of acute brain injuries. Accumulating evidence proves that the expansion of ischemic territory is closely coupled to the occurrence of CSDs, due to the increased metabolic demand of repolarization (oxygen depletion associated with vasoconstriction). Thus, recent studies have focused on the use of various drugs to create complete cessation of CSDs in the injured brain as a method of preventing further tissue loss. However, these pharmacological approaches are systemic and typically have significant side effects. Therefore, new strategies are needed to selectively reduce the deleterious consequences of CSDs. Whether or not injury occurs after CSDs depends greatly on the capacity of tissues to re-establish ionic gradients in the aftermath of CSDs. This capacity is influenced mainly by the availability of ATP and the ability of a brain region to profoundly increase cerebral blood flow (CBF) to match the energy demands. The trigeminal nerve is the largest cranial nerve forming an extensive network throughout the central nervous system (CNS), and is unique because of its intimate connection with the cerebral and meningeal blood vessels, referred to as the trigemino-cerebrovascular system. It is also capable of activating the diving reflex, whose primary role is to conserve oxygen for sensitive brain and heart tissue. We have previously shown that electrical stimulation of the trigeminal nerve (TNS) not only increases CBF but also significantly increases brain oxygen tension in the brains of normal, traumatic brain injury, and hemorrhagic shock rats. Additionally, in our preliminary studies, TNS treatment in normal brains increased the threshold current required for eliciting CSD and slowed its propagation velocity. Furthermore, TNS treatment immediately before middle cerebral artery occlusion (MCAO) in rats decreased infarction volumes, and the numbers of CSDs. We therefore hypothesize that TNS can reduce the detrimental consequences of CSDs in the injured brain by initiating cerebral vasodilation and increasing energy substrate levels for quicker repolarization. In this proposal, we aim to: (1) Investigate the effects of TNS on the release of cerebral vasodilators and energy substrates in the normal brain; (2) Explore the effects of TNS in obtaining the ideal amount of cerebral vasodilators and energy substrates to reduce injury development after CSDs. The proposed study would be the first ever research to reduce deleterious consequences of CSDs on the basis of precision medicine for the injured brain. The information obtained from these studies will lead us to a better understanding of the therapeutic potential of TNS in the injured brain, and its mechanism of action on CSDs across the spectrum of mild, moderate and severe ischemic regions using validated animal models.

Public Health Relevance

Cortical spreading depolarization (CSD) is both a real-time marker and mechanism of acute lesion development in the injured brain, and thus a candidate for targeted therapy. Recently, we have shown that trigeminal nerve stimulation (TNS) can preserve energy substrates and induce cerebral vasodilation in the injured brain ? which boosts recovery from CSDs to minimize injury development. Using the concept of precision medicine, the goal of this proposal is to selectively reduce the incidence and detrimental consequences of CSDs in the injured brain - by the use of TNS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Koenig, James I
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Feinstein Institute for Medical Research
United States
Zip Code