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Terminal spreading depolarization and electrical silence in death of human cerebral cortex.

ABSTRACT: OBJECTIVE:Restoring the circulation is the primary goal in emergency treatment of cerebral ischemia. However, better understanding of how the brain responds to energy depletion could help predict the time available for resuscitation until irreversible damage and advance development of interventions that prolong this span. Experimentally, injury to central neurons begins only with anoxic depolarization. This potentially reversible, spreading wave typically starts 2 to 5 minutes after the onset of severe ischemia, marking the onset of a toxic intraneuronal change that eventually results in irreversible injury. METHODS:To investigate this in the human brain, we performed recordings with either subdural electrode strips (n?=?4) or intraparenchymal electrode arrays (n?=?5) in patients with devastating brain injury that resulted in activation of a Do Not Resuscitate-Comfort Care order followed by terminal extubation. RESULTS:Withdrawal of life-sustaining therapies produced a decline in brain tissue partial pressure of oxygen (pti O2 ) and circulatory arrest. Silencing of spontaneous electrical activity developed simultaneously across regional electrode arrays in 8 patients. This silencing, termed "nonspreading depression," developed during the steep falling phase of pti O2 (intraparenchymal sensor, n?=?6) at 11 (interquartile range [IQR]?=?7-14) mmHg. Terminal spreading depolarizations started to propagate between electrodes 3.9 (IQR?=?2.6-6.3) minutes after onset of the final drop in perfusion and 13 to 266 seconds after nonspreading depression. In 1 patient, terminal spreading depolarization induced the initial electrocerebral silence in a spreading depression pattern; circulatory arrest developed thereafter. INTERPRETATION:These results provide fundamental insight into the neurobiology of dying and have important implications for survivable cerebral ischemic insults. Ann Neurol 2018;83:295-310.

SUBMITTER: Dreier JP

PROVIDER: S-EPMC5901399 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Terminal spreading depolarization and electrical silence in death of human cerebral cortex.

Dreier Jens P JP Major Sebastian S Foreman Brandon B Winkler Maren K L MKL Kang Eun-Jeung EJ Milakara Denny D Lemale Coline L CL DiNapoli Vince V Hinzman Jason M JM Woitzik Johannes J Andaluz Norberto N Carlson Andrew A Hartings Jed A JA

Annals of neurology 20180215 2

<h4>Objective</h4>Restoring the circulation is the primary goal in emergency treatment of cerebral ischemia. However, better understanding of how the brain responds to energy depletion could help predict the time available for resuscitation until irreversible damage and advance development of interventions that prolong this span. Experimentally, injury to central neurons begins only with anoxic depolarization. This potentially reversible, spreading wave typically starts 2 to 5 minutes after the ...[more]

PMID: 29331091

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Project description:OBJECTIVE: Delayed ischemic neurological deficit (DIND) contributes to poor outcome in subarachnoid hemorrhage (SAH) patients. Because there is continuing uncertainty as to whether proximal cerebral artery vasospasm is the only cause of DIND, other processes should be considered. A potential candidate is cortical spreading depolarization (CSD)-induced hypoxia. We hypothesized that recurrent CSDs influence cortical oxygen availability. METHODS: Centers in the Cooperative Study of Brain Injury Depolarizations (COSBID) recruited 9 patients with severe SAH, who underwent open neurosurgery. We used simultaneous, colocalized recordings of electrocorticography and tissue oxygen pressure (p(ti)O(2)) in human cerebral cortex. We screened for delayed cortical infarcts by using sequential brain imaging and investigated cerebral vasospasm by angiography or time-of-flight magnetic resonance imaging. RESULTS: In a total recording time of 850 hours, 120 CSDs were found in 8 of 9 patients. Fifty-five CSDs ( approximately 46%) were found in only 2 of 9 patients, who later developed DIND. Eighty-nine ( approximately 75%) of all CSDs occurred between the 5th and 7th day after SAH, and 96 (80%) arose within temporal clusters of recurrent CSD. Clusters of CSD occurred simultaneously, with mainly biphasic CSD-associated p(ti)O(2) responses comprising a primary hypoxic and a secondary hyperoxic phase. The frequency of CSD correlated positively with the duration of the hypoxic phase and negatively with that of the hyperoxic phase. Hypoxic phases significantly increased stepwise within CSD clusters; particularly in DIND patients, biphasic p(ti)O(2) responses changed to monophasic p(ti)O(2) decreases within these clusters. Monophasic hypoxic p(ti)O(2) responses to CSD were found predominantly in DIND patients. INTERPRETATION: We attribute these clinical p(ti)O(2) findings mainly to changes in local blood flow in the cortical microcirculation but also to augmented metabolism. Besides classical contributors like proximal cerebral vasospasm, CSD clusters may reduce O(2) supply and increase O(2) consumption, and thereby promote DIND.

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Terminal spreading depolarization and electrical silence in death of human cerebral cortex.

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Terminal spreading depolarization and electrical silence in death of human cerebral cortex.

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