Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction.
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ABSTRACT:
SUBMITTER: Hartings JA
PROVIDER: S-EPMC5841026 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundCortical spreading depolarizations (CSDs) are associated with worse outcomes in patients with aneurysmal subarachnoid hemorrhage (SAH). Animal models are required to assess whether CSDs can worsen outcomes or are an epiphenomenon; however, little is known about the presence of CSDs in existing animal models. Therefore, we designed a study to determine whether CSDs occur in a mouse model of SAH.MethodsA total of 36 mice were included in the study. We used the anterior prechiasmatic injection model of SAH under isoflurane anesthesia. A needle was inserted through the mouse olfactory bulb with the point terminating at the base of the skull, and arterial blood or saline (100 µl) was injected over 10 s. Changes in cerebral blood volume over the entire dorsal cortical surface were assessed with optical intrinsic signal imaging for 5 min following needle insertion.ResultsCSDs occurred in 100% of mice in the hemisphere ipsilateral to olfactory bulb needle insertion (CSD1). Saline-injected mice had 100% survival (n = 10). Blood-injected mice had 88% survival (n = 23 of 26). A second, delayed, CSD ipsilateral to CSD1 occurred in 31% of blood-injected mice. An increase in the time interval between CSD1 and blood injection was associated with the occurrence of a second CSD in blood-injected mice (mean intervals 26.4 vs. 72.7 s, p < 0.0001, n = 18 and 8). We observed one blood-injected animal with a second CSD in the contralateral hemisphere and observed terminal CSDs in mice that died following SAH injection.ConclusionsThe prechiasmatic injection model of SAH includes CSDs that occur at the time of needle insertion. The occurrence of subsequent CSDs depends on the timing between CSD1 and blood injection. The mouse prechiasmatic injection model could be considered an SAH plus CSD model of the disease. Further work is needed to determine the effect of multiple CSDs on outcomes following SAH.
| S-EPMC9250554 | biostudies-literature
Project description:Cortical spreading depolarizations (SD) are strongly associated with worse tissue injury and clinical outcomes in the setting of aneurysmal subarachnoid hemorrhage (SAH). Animal studies have suggested a causal relationship, and new therapies to target SDs are starting to be tested in clinical studies. A recent set of single-center randomized trials assessed the effect of the phosphodiesterase inhibitor cilostazol in patients with SAH. Cilostazol led to improved functional outcomes and SD-related metrics in treated patients through a putative mechanism of improved cerebral blood flow. Another promising therapeutic approach includes attempts to block SDs with, for example, the NMDA receptor antagonist ketamine. SDs have emerged not only as a therapeutic target but also as a potentially useful biomarker for brain injury following SAH. Additional clinical and preclinical experimental work is greatly needed to assess the generalizability of existing therapeutic trials and to better delineate the relationship between SDs, SAH, and functional outcome.
| S-EPMC7283429 | biostudies-literature
Project description:Cortical spreading depolarization (SD) is the electrophysiological event underlying migraine aura, and a critical contributor to secondary damage after brain injury. Experimental models of SD have been used for decades in migraine and brain injury research; however, they are highly invasive and often cause primary tissue injury, diminishing their translational value. Here we present a non-invasive method to trigger SDs using light-induced depolarization in transgenic mice expressing channelrhodopsin-2 in neurons (Thy1-ChR2-YFP). Focal illumination (470 nm, 1-10 mW) through intact skull using an optical fiber evokes power-dependent steady extracellular potential shifts and local elevations of extracellular [K+] that culminate in an SD when power exceeds a threshold. Using the model, we show that homozygous mice are significantly more susceptible to SD (i.e., lower light thresholds) than heterozygous ChR2 mice. Moreover, we show SD susceptibility differs significantly among cortical divisions (motor, whisker barrel, sensory, visual, in decreasing order of susceptibility), which correlates with relative channelrhodopsin-2 expression. Furthermore, the NMDA receptor antagonist MK-801 blocks the transition to SD without diminishing extracellular potential shifts. Altogether, our data show that the optogenetic SD model is highly suitable for examining physiological or pharmacological modulation of SD in acute and longitudinal studies.
| S-EPMC6373833 | biostudies-literature
Project description:Spreading depolarizations (SDs) are classically thought to be associated with spreading depression of cortical activity. Here, we found that SDs in patients with subarachnoid hemorrhage produce variable, ranging from depression to booming, changes in electrocorticographic activity, especially in the delta frequency band. In rats, depression of activity was characteristic of high-potassium-induced full SDs, whereas partial superficial SDs caused either little change or a boom of activity at the cortical vertex, supported by volume conduction of signals from spared delta generators in the deep cortical layers. Partial SDs also caused moderate neuronal depolarization and sustained excitation, organized in gamma oscillations in a narrow sub-SD zone. Thus, our study challenges the concept of homology between spreading depolarization and spreading depression by showing that SDs produce variable, from depression to booming, changes in activity at the cortical surface and in different cortical layers depending on the depth of SD penetration.
| S-EPMC10676372 | biostudies-literature
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.
| S-EPMC2883076 | biostudies-literature
Project description:Cortical spreading depolarizations (CSDs) are increasingly suspected to play an exacerbating role in a range of acute brain injuries, including stroke, possibly through their interactions with cortical blood flow. We use simultaneous wide-field imaging of neural activity and hemodynamics in Thy1-GCaMP6f mice to explore the neurovascular dynamics of CSDs during and following Rose Bengal-mediated photothrombosis. CSDs are observed in all mice as slow-moving waves of GCaMP fluorescence extending far beyond the photothrombotic area. Initial CSDs are accompanied by profound vasoconstriction and leave residual oligemia and ischemia in their wake. Later, CSDs evoke variable responses, from constriction to biphasic to vasodilation. However, CSD-evoked vasoconstriction is found to be more likely during rapid, high-amplitude CSDs in regions with stronger oligemia and ischemia, which, in turn, worsens after each repeated CSD. This feedback loop may explain the variable but potentially devastating effects of CSDs in the context of acute brain injury.
| S-EPMC8590206 | biostudies-literature
Project description:BackgroundSpreading depolarization (SD) has been linked to the impairment of neurovascular coupling. However, the association between SD occurrence and cerebrovascular pressure reactivity as a surrogate of cerebral autoregulation (CA) remains unclear. Therefore, we analyzed CA using the long-pressure reactivity index (L-PRx) during SDs in patients with aneurysmal subarachnoid hemorrhage (aSAH).MethodsA retrospective study of patients with aSAH who were recruited at two centers, Heidelberg (HD) and Berlin (BE), was performed. Continuous monitoring of mean arterial pressure (MAP) and intracranial pressure (ICP) was recorded. ICP was measured using an intraparenchymal probe in HD patients and was measure in BE patients through external ventricular drainage. Electrocorticographic (ECoG) activity was continuously recorded between 3 and 13 days after hemorrhage. Autoregulation according to L-PRx was calculated as a moving linear Pearson's correlation of 20-min averages of MAP and ICP. For every identified SD, 60-min intervals of L-PRx were averaged, plotted, and analyzed depending on SD occurrence. Random L-PRx recording periods without SDs served as the control.ResultsA total of 19 patients (HD n = 14, BE n = 5, mean age 50.4 years, 9 female patients) were monitored for a mean duration of 230.4 h (range 96-360, STD ± 69.6 h), during which ECoG recordings revealed a total number of 277 SDs. Of these, 184 represented a single SD, and 93 SDs presented in clusters. In HD patients, mean L-PRx values were 0.12 (95% confidence interval [CI] 0.11-0.13) during SDs and 0.07 (95% CI 0.06-0.08) during control periods (p < 0.001). Similarly, in BE patients, a higher L-PRx value of 0.11 (95% CI 0.11-0.12) was detected during SDs than that during control periods (0.08, 95% CI 0.07-0.09; p < 0.001). In a more detailed analysis, CA changes registered through an intraparenchymal probe (HD patients) revealed that clustered SD periods were characterized by signs of more severely impaired CA (L-PRx during SD in clusters: 0.23 [95% CI 0.20-0.25]; single SD: 0.09 [95% CI 0.08-0.10]; control periods: 0.07 [95% CI 0.06-0.08]; p < 0.001). This group also showed significant increases in ICP during SDs in clusters compared with single SD and control periods.ConclusionsNeuromonitoring for simultaneous assessment of cerebrovascular pressure reactivity using 20-min averages of MAP and ICP measured by L-PRx during SD events is feasible. SD occurrence was associated with significant increases in L-PRx values indicative of CA disturbances. An impaired CA was found during SD in clusters when using an intraparenchymal probe. This preliminary study validates the use of cerebrovascular reactivity indices to evaluate CA disturbances during SDs. Our results warrant further investigation in larger prospective patient cohorts.
| S-EPMC10499750 | biostudies-literature
Project description:Multimodal neuromonitoring in neurocritical care increasingly includes electrocorticography to measure epileptic events and spreading depolarizations. Spreading depolarization causes spreading depression of activity (=isoelectricity) in electrically active tissue. If the depression is long-lasting, further spreading depolarizations occur in still isoelectric tissue where no activity can be suppressed. Such spreading depolarizations are termed isoelectric and are assumed to indicate energy compromise. However, experimental and clinical recordings suggest that long-lasting spreading depolarization-induced depression and isoelectric spreading depolarizations are often recorded outside of the actual ischemic zones, allowing the remote diagnosis of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Here, we analyzed simultaneous electrocorticography and tissue partial pressure of oxygen recording in 33 aneurysmal subarachnoid hemorrhage patients. Multiple regression showed that both peak total depression duration per recording day and mean baseline tissue partial pressure of oxygen were independent predictors of outcome. Moreover, tissue partial pressure of oxygen preceding spreading depolarization was similar and differences in tissue partial pressure of oxygen responses to spreading depolarization were only subtle between isoelectric spreading depolarizations and spreading depressions. This further supports that, similar to clustering of spreading depolarizations, long spreading depolarization-induced periods of isoelectricity are useful to detect energy compromise remotely, which is valuable because the exact location of future developing pathology is unknown at the time when the neurosurgeon implants recording devices.
| S-EPMC5435278 | biostudies-literature
Project description:BackgroundCortical spreading depolarization (CSD) is a phenomenon classically associated with migraine aura. CSDs have also been implicated in secondary injury following ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and traumatic brain injury; however, most investigations involving these disease processes do not account for the occurrence of CSDs. A major barrier to detection of CSDs in experimental models is that currently validated methods are invasive and require specialized equipment and a high level of expertise to implement.New methodWe present a low-cost, easy-to-implement approach to the detection of CSDs in the mouse through full-thickness intact skull. Our method uses the optical intrinsic signal from white light illumination (OIS-WL) and allows for real-time in vivo detection of CSDs using readily available USB cameras.ResultsOIS-WL detected 100% of CSDs that were seen with simultaneous electrode recording (69 CSDs in 28 mice), laser Doppler flowmetry (82 CSDs in 10 mice), laser speckle flowmetry (68 CSDs in 25 mice), or combined electrode recording plus laser speckle flowmetry (29 CSDs in 20 mice). OIS-WL detected 1 additional CSD that was missed by laser Doppler flowmetry.Comparison with existing methodsOIS-WL is less invasive than electrophysiological recordings and easier to implement than laser speckle flowmetry. Moreover, it provides excellent spatial and temporal resolution for dynamic imaging of CSDs in the setting of brain injury.ConclusionsDetection of CSDs with an inexpensive USB camera and white light source provides a reliable method for the in vivo and non-invasive detection of CSDs through unaltered mouse skull.
| S-EPMC6214472 | biostudies-literature
Project description:Spreading depolarizations are highly prevalent and spatiotemporally punctuated events worsening the outcome of brain injury. Trigger factors are poorly understood but may be linked to sudden worsening in supply-demand mismatch in compromised tissue. Sustained or transient elevations in intracranial pressure are also prevalent in the injured brain. Here, using a mouse model of large hemispheric ischaemic stroke, we show that mild and brief intracranial pressure elevations (20 or 30 mmHg for just 3 min) potently trigger spreading depolarizations in ischaemic penumbra (4-fold increase in spreading depolarization occurrence). We also show that 30 mmHg intracranial pressure spikes as brief as 30 s are equally effective. In contrast, sustained intracranial pressure elevations to the same level for 30 min do not significantly increase the spreading depolarization rate, suggesting that an abrupt disturbance in the steady state equilibrium is required to trigger a spreading depolarization. Laser speckle flowmetry consistently showed a reduction in tissue perfusion, and two-photon pO2 microscopy revealed a drop in venous pO2 during the intracranial pressure spikes suggesting increased oxygen extraction fraction, and therefore, worsening supply-demand mismatch. These haemodynamic changes during intracranial pressure spikes were associated with highly reproducible increases in extracellular potassium levels in penumbra. Consistent with the experimental data, a higher rate of intracranial pressure spikes was associated with spreading depolarization clusters in a retrospective series of patients with aneurysmal subarachnoid haemorrhage with strong temporal correspondence. Altogether, our data show that intracranial pressure spikes, even when mild and brief, are capable of triggering spreading depolarizations. Aggressive prevention of intracranial pressure spikes may help reduce spreading depolarization occurrence and improve outcomes after brain injury.
| S-EPMC9126007 | biostudies-literature