Acute-Phase Recording of the Spreading Depolarization Continuum in Aged Nonhuman Primates During Focal Ischemic Stroke

BACKGROUND: Decades of experimental and clinical data revealed that spreading depolarizations (SDs) play a central causal role in the development of cortical lesions after acute brain injury. However, clinical documentation of events at the onset of focal ischemic stroke and during the initial phase of cortical injury development is lacking because electroencephalography monitoring of SD typically starts hours or days later. Here, we used nonhuman primates to map electrophysiological pathology through focal ischemic stroke’s onset and acute stage. METHODS: Craniotomies were performed over both hemispheres on 4 male and 1 female nemestrina and rhesus macaques aged 23 years to 32 years. Subdural electrode arrays were placed bilaterally over the middle cerebral artery territory, recording from 24 electrodes 1 cm apart on the left cortex and 7 on the right. After 30 minutes of baseline monitoring, the left middle cerebral artery and, in some cases, also the left internal carotid or anterior cerebral arteries were permanently occluded with aneurysmal clips. RESULTS: Repetitive SDs occurred during the next 3 hours, followed by terminal SD during euthanasia. No epileptiform activity was observed in any of the 5 animals. Nonspreading electrical silence developed in the ischemic core within seconds of ischemic onset, followed by terminal SD and SD-initiated negative ultraslow potential after several minutes. These events defined the ischemic core and led to histologically confirmed cell damage. Initial and subsequent transient SDs caused spreading depression of spontaneous activity in the normally perfused surrounding cortex without any signs of histological damage. Cardiocirculatory arrest at the end of experiments first induced nonspreading depression of activity followed by SD and, eventually, the SD-initiated negative ultraslow potential, which indicated brain death. CONCLUSIONS: Results in gyrencephalic nonhuman primates hold significant implications for understanding the role of SD in acute brain injury development and for the clinical translation and diagnosis of pathologies manifested in the SD continuum.