The persistent vegetative state: Evidence that the lower brain survives because its neurons intrinsically resist ischemia

Abstract

Global ischemia caused by heart attack, pulmonary failure, near- drowning or traumatic brain injury often damages the higher brain but not the brainstem, leading to a ‘persistent vegetative state’ where the patient is awake but not aware. Approximately 30,000 US patients are held captive in this condition but not a single research study has addressed how the lower brain is preferentially protected in these people. In the higher brain, ischemia elicits a profound anoxic depolarization (AD) causing neuronal dysfunction and vasoconstriction within minutes. Might brainstem nuclei generate less damaging AD and so be more resilient? Here we compared neuronal resistance to acute injury induced by simulated ischemia in ‘higher’ brain (neocortex, hippocampus, striatum, thalamus and cerebellar cortex) versus ‘lower’ brain (hypothalamus and brainstem) in live slices from rat and mouse. Light transmittance (LT) imaging in response to 10 min of oxygen/glucose deprivation (OGD) revealed immediate and acutely damaging AD propagating through gray matter of higher regions. In adjacent lower brain nuclei, OGD-evoked AD caused little tissue injury. Whole-cell patch recordings from higher neurons under OGD revealed an immediate and irreversible loss of membrane potential (strong AD) that did not recover. In contrast lower neurons only slowly depolarized (weak AD) and then repolarized post- OGD. Two-photon microscopy confi rmed non- recoverable swelling of cortical pyramidal neurons during OGD, while lower neurons appeared uninjured. All of the above responses were mimicked by bath exposure to 100 µM ouabain which inhibits the Na+ K+ pump or to 1-10 nM palytoxin which converts the pump into an open cationic channel. Our working hypothesis is that the Na+/K+ pump isoforms expressed in lower brain neurons confer resilience during ischemic stress and that higher brain ‘shutdown’ has evolutionary advantages.