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Recurrent spontaneous spreading depolarizations facilitate acute dendritic injury in the ischemic penumbra.

ABSTRACT: Spontaneous spreading depolarizations (SDs) occur in the penumbra surrounding ischemic core. These SDs, often referred to as peri-infarct depolarizations, cause vasoconstriction and recruitment of the penumbra into the ischemic core in the critical first hours after focal ischemic stroke; however, the real-time spatiotemporal dynamics of SD-induced injury to synaptic circuitry in the penumbra remain unknown. A modified cortical photothrombosis model was used to produce a square-shaped lesion surrounding a penumbra-like "area at risk" in middle cerebral artery territory of mouse somatosensory cortex. Lesioning resulted in recurrent spontaneous SDs. In vivo two-photon microscopy of green fluorescent protein-expressing neurons in this penumbra-like area at risk revealed that SDs were temporally correlated with rapid (<6 s) dendritic beading. Dendrites quickly (<3 min) recovered between SDs to near-control morphology until the occurrence of SD-induced terminal dendritic injury, signifying acute synaptic damage. SDs are characterized by a breakdown of ion homeostasis that can be recovered by ion pumps if the energy supply is adequate. Indeed, the likelihood of rapid dendritic recovery between SDs was correlated with the presence of nearby flowing blood vessels, but the presence of such vessels was not always sufficient for rapid dendritic recovery, suggesting that energy needs for recovery exceeded energy supply of compromised blood flow. We propose that metabolic stress resulting from recurring SDs facilitates acute injury at the level of dendrites and dendritic spines in metabolically compromised tissue, expediting penumbral recruitment into the ischemic core.

SUBMITTER: Risher WC

PROVIDER: S-EPMC2918261 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Recurrent spontaneous spreading depolarizations facilitate acute dendritic injury in the ischemic penumbra.

Risher W Christopher WC Ard Deborah D Yuan Jianghe J Kirov Sergei A SA

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100701 29

Spontaneous spreading depolarizations (SDs) occur in the penumbra surrounding ischemic core. These SDs, often referred to as peri-infarct depolarizations, cause vasoconstriction and recruitment of the penumbra into the ischemic core in the critical first hours after focal ischemic stroke; however, the real-time spatiotemporal dynamics of SD-induced injury to synaptic circuitry in the penumbra remain unknown. A modified cortical photothrombosis model was used to produce a square-shaped lesion sur ...[more]

PMID: 20660268

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Project description:BackgroundSpreading depolarizations that occur in patients with malignant stroke, subarachnoid/intracranial hemorrhage, and traumatic brain injury are known to facilitate neuronal damage in metabolically compromised brain tissue. The dramatic failure of brain ion homeostasis caused by propagating spreading depolarizations results in neuronal and astroglial swelling. In essence, swelling is the initial response and a sign of the acute neuronal injury that follows if energy deprivation is maintained. Choosing spreading depolarizations as a target for therapeutic intervention, we have used human brain slices and in vivo real-time two-photon laser scanning microscopy in the mouse neocortex to study potentially useful therapeutics against spreading depolarization-induced injury.Methodology/principal findingsWe have shown that anoxic or terminal depolarization, a spreading depolarization wave ignited in the ischemic core where neurons cannot repolarize, can be evoked in human slices from pediatric brains during simulated ischemia induced by oxygen/glucose deprivation or by exposure to ouabain. Changes in light transmittance (LT) tracked terminal depolarization in time and space. Though spreading depolarizations are notoriously difficult to block, terminal depolarization onset was delayed by dibucaine, a local amide anesthetic and sodium channel blocker. Remarkably, the occurrence of ouabain-induced terminal depolarization was delayed at a concentration of 1 µM that preserves synaptic function. Moreover, in vivo two-photon imaging in the penumbra revealed that, though spreading depolarizations did still occur, spreading depolarization-induced dendritic injury was inhibited by dibucaine administered intravenously at 2.5 mg/kg in a mouse stroke model.Conclusions/significanceDibucaine mitigated the effects of spreading depolarization at a concentration that could be well-tolerated therapeutically. Hence, dibucaine is a promising candidate to protect the brain from ischemic injury with an approach that does not rely on the complete abolishment of spreading depolarizations.

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.

Project description:Importance:Advances in treatment of traumatic brain injury are hindered by the inability to monitor pathological mechanisms in individual patients for targeted neuroprotective treatment. Spreading depolarizations, a mechanism of lesion development in animal models, are a novel candidate for clinical monitoring in patients with brain trauma who need surgery. Objective:To test the null hypothesis that spreading depolarizations are not associated with worse neurologic outcomes. Design, Setting, and Participants:This prospective, observational, multicenter cohort study was conducted from February 2009 to August 2013 in 5 level 1 trauma centers. Consecutive patients who required neurological surgery for treatment of acute brain trauma and for whom research consent could be obtained were enrolled; participants were excluded because of technical problems in data quality, patient withdrawal, or loss to follow-up. Primary statistical analysis took place from April to December 2018. Evaluators of outcome assessments were blinded to other measures. Interventions:A 6-contact electrode strip was placed on the brain surface during surgery for continuous electrocorticography during intensive care. Main Outcomes and Measures:Electrocorticography was scored for depolarizations, following international consensus procedures. Six-month outcomes were assessed by the Glasgow Outcome Scale-Extended score. Results:A total of 157 patients were initially enrolled; 19 were subsequently excluded. The 138 remaining patients (104 men [75%]; median [interquartile range] age, 45 [29-64] years) underwent a median (interquartile range) of 75.5 (42.2-117.1) hours of electrocorticography. A total of 2837 spreading depolarizations occurred in 83 of 138 patients (60.1% incidence) who, compared with patients who did not have spreading depolarizations, had lower prehospital systolic blood pressure levels (mean [SD], 133 [31] mm Hg vs 146 [33] mm Hg; P?=?.03), more traumatic subarachnoid hemorrhage (depolarization incidences of 17 of 37 [46%], 18 of 32 [56%], 22 of 33 [67%], and 23 of 30 patients [77%] for Morris-Marshall Grades 0, 1, 2, and 3/4, respectively; P?=?.047), and worse radiographic pathology (in 38 of 73 patients [52%] and 42 of 60 patients [70%] for Rotterdam Scores 2-4 vs 5-6, respectively; P?=?.04). Of patients with depolarizations, 32 of 83 (39%) had only sporadic events that induced cortical spreading depression of spontaneous electrical activity, whereas 51 of 83 patients (61%) exhibited temporal clusters of depolarizations (?3 in a 2-hour span). Nearly half of those with clusters (23 of 51 [45%]) also had depolarizations in an electrically silent area of the cortex (isoelectric spreading depolarization). Patients with clusters did not improve in motor neurologic examinations from presurgery to postelectrocorticography, while other patients did improve. In multivariate ordinal regression adjusting for baseline prognostic variables, the occurrence of depolarization clusters had an odds ratio of 2.29 (95% CI, 1.13-4.65; P?=?.02) for worse outcomes. Conclusions and Relevance:In this cohort study of patients with acute brain trauma, spreading depolarizations were predominant but heterogeneous and independently associated with poor neurologic recovery. Monitoring the occurrence of spreading depolarizations may identify patients most likely to benefit from targeted management strategies.

Project description:ImportanceWhether endovascular thrombectomy (EVT) efficacy for patients with acute ischemic stroke and large cores varies depending on the extent of ischemic injury is uncertain.ObjectiveTo describe the relationship between imaging estimates of irreversibly injured brain (core) and at-risk regions (mismatch) and clinical outcomes and EVT treatment effect.Design, setting, and participantsAn exploratory analysis of the SELECT2 trial, which randomized 352 adults (18-85 years) with acute ischemic stroke due to occlusion of the internal carotid or middle cerebral artery (M1 segment) and large ischemic core to EVT vs medical management (MM), across 31 global centers between October 2019 and September 2022.InterventionEVT vs MM.Main outcomes and measuresPrimary outcome was functional outcome-90-day mRS score (0, no symptoms, to 6, death) assessed by adjusted generalized OR (aGenOR; values >1 represent more favorable outcomes). Benefit of EVT vs MM was assessed across levels of ischemic injury defined by noncontrast CT using ASPECTS score and by the volume of brain with severely reduced blood flow on CT perfusion or restricted diffusion on MRI.ResultsAmong 352 patients randomized, 336 were analyzed (median age, 67 years; 139 [41.4%] female); of these, 168 (50%) were randomized to EVT, and 2 additional crossover MM patients received EVT. In an ordinal analysis of mRS at 90 days, EVT improved functional outcomes compared with MM within ASPECTS categories of 3 (aGenOR, 1.71 [95% CI, 1.04-2.81]), 4 (aGenOR, 2.01 [95% CI, 1.19-3.40]), and 5 (aGenOR, 1.85 [95% CI, 1.22-2.79]). Across strata for CT perfusion/MRI ischemic core volumes, aGenOR for EVT vs MM was 1.63 (95% CI, 1.23-2.16) for volumes ≥70 mL, 1.41 (95% CI, 0.99-2.02) for ≥100 mL, and 1.47 (95% CI, 0.84-2.56) for ≥150 mL. In the EVT group, outcomes worsened as ASPECTS decreased (aGenOR, 0.91 [95% CI, 0.82-1.00] per 1-point decrease) and as CT perfusion/MRI ischemic core volume increased (aGenOR, 0.92 [95% CI, 0.89-0.95] per 10-mL increase). No heterogeneity of EVT treatment effect was observed with or without mismatch, although few patients without mismatch were enrolled.Conclusion and relevanceIn this exploratory analysis of a randomized clinical trial of patients with extensive ischemic stroke, EVT improved clinical outcomes across a wide spectrum of infarct volumes, although enrollment of patients with minimal penumbra volume was low. In EVT-treated patients, clinical outcomes worsened as presenting ischemic injury estimates increased.Trial registrationClinicalTrials.gov Identifier: NCT03876457.

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Recurrent spontaneous spreading depolarizations facilitate acute dendritic injury in the ischemic penumbra.

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Recurrent spontaneous spreading depolarizations facilitate acute dendritic injury in the ischemic penumbra.

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