Occurrence Of Spreading Depolarization Research Articles

253 Tissue Partial Pressure of Oxygen During Spreading Depolarization in Malignant Stroke is Associated With Outcome

INTRODUCTION: Spreading depolarization (SD) describes a propagating neuronal mass depolarization within the cerebral cortex that likely represents a relevant mechanism of secondary lesion progression. METHODS: This prospective observational study included 25 patients with MHS that underwent decompressive hemicraniectomy (DC) followed by subdural placement of an electrocorticography (ECoG) strip electrode and cortical implantation of a PtiO2 probe within in the periinfarct tissue. Continuous ECoG and PtiO2 recordings were obtained at bedside for five days and analyzed for the occurrence of SD and SD-associated PtiO2 changes, as well as their association with clinical outcome at 6 months. RESULTS: The overall simultaneous ECoG and PtiO2 recording time was 2603 hours, during which 796 SDs were detected. The overall SD duration and SD frequency did not correlate with outcome. During the observation period, the overall PtiO2baseline changed significantly with an almost linear increase that reached a peak around 100 hours (*p=0.0055), followed by a PtiO2 drop until the end of the monitoring period (*p = 0.0048). Accordingly, low baseline PtiO2 (<15 mmHg) was mainly noted during the first 24 hours but did not correlate with outcome (p = 0.916). Conversely, 20 out of 25 patients showed SD-associated PtiO2 changes in 363 out of 796 SDs (45.6%), which were categorized as biphasic (222), hypoxic (119) and hyperoxic (22). Among these SD-associated PtiO2 responses, a high occurrence rate, biphasic response pattern and high amplitude correlated significantly with favorable outcome (mRS 1-3) at 6 months. CONCLUSIONS: SD-associated PtiO2 coupling in patients suffering hemispheric stroke appears to be associated with clinical outcome and could reflect the presence of viable and metabolically less impaired peri-infarct tissue.

Astrocytes as critical players of the fine balance between inhibition and excitation in the brain: spreading depolarization as a mechanism to curb epileptic activity.

Spreading depolarizations (SD) are slow waves of complete depolarization of brain tissue followed by neuronal silencing that may play a role in seizure termination. Even though SD was first discovered in the context of epilepsy research, the link between SD and epileptic activity remains understudied. Both seizures and SD share fundamental pathophysiological features, and recent evidence highlights the frequent occurrence of SD in experimental seizure models. Human data on co-occurring seizures and SD are limited but suggestive. This mini-review addresses possible roles of SD during epileptiform activity, shedding light on SD as a potential mechanism for terminating epileptiform activity. A common denominator for many forms of epilepsy is reactive astrogliosis, a process characterized by morphological and functional changes to astrocytes. Data suggest that SD mechanisms are potentially perturbed in reactive astrogliosis and we propose that this may affect seizure pathophysiology.

Spreading depolarization causes reperfusion failure after cerebral ischemia

Despite successful recanalization, reperfusion failure associated with poor neurological outcomes develops in half of treated stroke patients. We explore here whether spreading depolarization (SD) is a predictor of reperfusion failure. Global forebrain ischemia/reperfusion was induced in male and female C57BL/6 mice (n = 57). SD and cerebral blood flow (CBF) changes were visualized with transcranial intrinsic optical signal and laser speckle contrast imaging. To block SD, MK801 was applied (n = 26). Neurological deficit, circle of Willis (CoW) anatomy and neuronal injury were evaluated 24 hours later. SD emerged after ischemia onset in one or both hemispheres under a perfusion threshold (CBF drop to 21.1 ± 4.6 vs. 33.6 ± 4.4%, SD vs. no SD). The failure of later reperfusion (44.4 ± 12.5%) was invariably linked to previous SD. In contrast, reperfusion was adequate (98.9 ± 7.4%) in hemispheres devoid of SD. Absence of the P1 segment of the posterior cerebral artery in the CoW favored SD occurrence and reperfusion failure. SD occurrence and reperfusion failure were associated with poor neurologic function, and neuronal necrosis 24 hours after ischemia. The inhibition of SD significantly improved reperfusion. SD occurrence during ischemia impairs later reperfusion, prognosticating poor neurological outcomes. The increased likelihood of SD occurrence is predicted by inadequate collaterals.

Close association between spreading depolarization and development of infarction under experimental ischemia in anesthetized male mice

Clinical and experimental evidence suggests that spreading depolarizations (SD) usually occur in patients with ischemic or hemorrhagic stroke when the gray matter of the brain is affected. In this study, we evaluated spatiotemporal changes of cerebral blood flow (CBF) during middle cerebral artery (MCA) occlusion and examined the relationship between SD occurrence and cerebral infarct development. In male isoflurane-anesthetized C57BL/6J mice, CBF changes over the ipsilateral parietal bone were recorded by laser speckle flowgraphy during and after transient (45 min, n = 22) or permanent occlusion (n = 22) of the distal MCA. Infarct volume was evaluated 24 hr after the operation. Upon MCA occlusion, CBF decreased by −55.6 ± 8.5 % in the lowest CBF and linearly recovered with increasing distance from the region. At 1–10 min after onset of occlusion, SD occurred and concentrically propagated from the core region, showing a decrease of CBF in the whole observed area along with a transient hyperemia and oligemia in the normal region. SD spontaneously re-occurred and propagated around the ischemic area in 37 % of mice, accompanied with a marked decrease of CBF in the core or a marked increase of CBF in the normal region. The CBF response to SDs gradually changed from the core to the normal area, depending upon the distance from the core region. Infarction was not observed in transiently (n = 2) or permanently (n = 4) occluded mice without SD. The infarct area tended to be larger with increasing number of SDs in transiently occluded mice. In conclusion, our findings suggest that the occurrence of SD during ischemia might elicit infarct formation and/or influence infarct development.

Numerical Simulation of Concussive-Generated Cortical Spreading Depolarization to Optimize DC-EEG Electrode Spacing for Noninvasive Visual Detection.

Cortical spreading depolarization (SD) is a propagating depolarization wave of neurons and glial cells in the cerebral gray matter. SD occurs in all forms of severe acute brain injury, as documented by using invasive detection methods. Based on many experimental studies of mechanical brain deformation and concussion, the occurrence of SDs in human concussion has often been hypothesized. However, this hypothesis cannot be confirmed in humans, as SDs can only be detected with invasive detection methods that would require either a craniotomy or a burr hole to be performed on athletes. Typical electroencephalography electrodes, placed on the scalp, can help detect the possible presence of SD but have not been able to accurately and reliably identify SDs. To explore the possibility of a noninvasive method to resolve this hurdle, we developed a finite element numerical model that simulates scalp voltage changes that are induced by a brain surface SD. We then compared our simulation results with retrospectively evaluated data in patients with aneurysmal subarachnoid hemorrhage from Drenckhahn et al. (Brain 135:853, 2012). The ratio of peak scalp to simulated peak cortical voltage, Vscalp/Vcortex, was 0.0735, whereas the ratio from the retrospectively evaluated data was 0.0316 (0.0221, 0.0527) (median [1st quartile, 3rd quartile], n = 161, p < 0.001, one sample Wilcoxon signed-rank test). These differing values provide validation because their differences can be attributed to differences in shape between concussive SDs and aneurysmal subarachnoid hemorrhage SDs, as well as the inherent limitations in human study voltage measurements. This simulated scalp surface potential was used to design a virtual scalp detection array. Error analysis and visual reconstruction showed that 1cm is the optimal electrode spacing to visually identify the propagating scalp voltage from a cortical SD. Electrode spacings of 2cm and above produce distorted images and high errors in the reconstructed image. Our analysis suggests that concussive (and other) SDs can be detected from the scalp, which could confirm SD occurrence in human concussion, provide concussion diagnosis on the basis of an underlying physiological mechanism, and lead to noninvasive SD detection in the setting of severe acute brain injury.

Cerebral Autoregulation Correlation With Outcomes and Spreading Depolarization in Aneurysmal Subarachnoid Hemorrhage.

Delayed cerebral ischemia remains one of the principal therapeutic targets after aneurysmal subarachnoid hemorrhage. While large vessel vasospasm may contribute to ischemia, increasing evidence suggests that physiological impairment through disrupted impaired cerebral autoregulation (CA) and spreading depolarizations (SDs) also contribute to delayed cerebral ischemia and poor neurological outcome. This study seeks to explore the intermeasure correlation of different measures of CA, as well as correlation with SD and neurological outcome. Simultaneous measurement of 7 continuous indices of CA was calculated in 19 subjects entered in a prospective study of SD in aneurysmal subarachnoid hemorrhage undergoing surgical aneurysm clipping. Intermeasure agreement was assessed, and the association of each index with modified Rankin Scale score at 90 days and occurrence of SD was assessed. There were 4102 hours of total monitoring time across the 19 subjects. In time-resolved assessment, no CA measures demonstrated significant correlation; however, most demonstrate significant correlation averaged over 1 hour. Pressure reactivity (PRx), oxygen reactivity, and oxygen saturation reactivity were significantly correlated with modified Rankin Scale score at 90 days. PRx and oxygen reactivity also were correlated with the occurrence of SD events. Across multiple CA measure reactivity indices, a threshold between 0.3 and 0.5 was most associated with intervals containing SD. Different continuous CA indices do not correlate well with each other on a highly time-resolved basis, so should not be viewed as interchangeable. PRx and oxygen reactivity are the most reliable indices in identifying risk of worse outcome in patients with aneurysmal subarachnoid hemorrhage undergoing surgical treatment. SD occurrence is correlated with impaired CA across multiple CA measurement techniques and may represent the pathological mechanism of delayed cerebral ischemia in patients with impaired CA. Optimization of CA in patients with aneurysmal subarachnoid hemorrhage may lead to decreased incidence of SD and improved neurological outcomes. Future studies are needed to evaluate these hypotheses and approaches.

Cortical Spreading Depolarizations and Clinically Measured Scalp EEG Activity After Aneurysmal Subarachnoid Hemorrhage and Traumatic Brain Injury.

Spreading depolarizations (SDs) are associated with worse outcome following subarachnoid hemorrhage (SAH) and traumatic brain injury (TBI), but gold standard detection requires electrocorticography with a subdural strip electrode. Electroencephalography (EEG) ictal-interictal continuum abnormalities are associated with poor outcomes after TBI and with both delayed cerebral ischemia (DCI) and poor outcomes after SAH. We examined rates of SD detection in patients with SAH and TBI with intraparenchymal and subdural strip electrodes and assessed which continuous EEG (cEEG) measures were associated with intracranially quantified SDs. In this single-center cohort, we included patients with SAH and TBI undergoing ≥ 24h of interpretable intracranial monitoring via eight-contact intraparenchymal or six-contact subdural strip platinum electrodes or both. SDs were rated according to established consensus criteria and compared with cEEG findings rated according to the American Clinical Neurophysiology Society critical care EEG monitoring consensus criteria: lateralized rhythmic delta activity, generalized rhythmic delta activity, lateralized periodic discharges, generalized periodic discharges, any ictal-interictal continuum, or a composite scalp EEG tool for seizure risk estimation: the 2HELPS2B score. Among patients with SAH, cEEG was assessed for validated DCI biomarkers: new or worsening epileptiform abnormalities and new background deterioration. Over 6years, SDs were recorded in 5 (18%) of 28 patients recorded with intraparenchymal electrodes and 4 (40%) of 10 patients recorded with subdural strip electrodes. There was no significant association between occurrence of SDs and day 1 cEEG findings (American Clinical Neurophysiology Society main terms lateralized periodic discharges, generalized periodic discharges, lateralized rhythmic delta activity, or seizures, individually or in combination). After SAH, established cEEG DCI predictors were not associated with SDs. Intraparenchymal recordings yielded low rates of SD, and documented SDs were not associated with ictal-interictal continuum abnormalities or other cEEG DCI predictors. Identifying scalp EEG correlates of SD may require training computational EEG analytics and use of gold standard subdural strip electrocorticography recordings.

Transient Hypoperfusion to Ischemic/Anoxic Spreading Depolarization is Related to Autoregulatory Failure in the Rat Cerebral Cortex

BackgroundIn ischemic stroke, cerebral autoregulation and neurovascular coupling may become impaired. The cerebral blood flow (CBF) response to spreading depolarization (SD) is governed by neurovascular coupling. SDs recur in the ischemic penumbra and reduce neuronal viability by the insufficiency of the CBF response. Autoregulatory failure and SD may coexist in acute brain injury. Here, we set out to explore the interplay between the impairment of cerebrovascular autoregulation, SD occurrence, and the evolution of the SD-coupled CBF response.MethodsIncomplete global forebrain ischemia was created by bilateral common carotid artery occlusion in isoflurane-anesthetized rats, which induced ischemic SD (iSD). A subsequent SD was initiated 20–40 min later by transient anoxia SD (aSD), achieved by the withdrawal of oxygen from the anesthetic gas mixture for 4–5 min. SD occurrence was confirmed by the recording of direct current potential together with extracellular K+ concentration by intracortical microelectrodes. Changes in local CBF were acquired with laser Doppler flowmetry. Mean arterial blood pressure (MABP) was continuously measured via a catheter inserted into the left femoral artery. CBF and MABP were used to calculate an index of cerebrovascular autoregulation (rCBFx). In a representative imaging experiment, variation in transmembrane potential was visualized with a voltage-sensitive dye in the exposed parietal cortex, and CBF maps were generated with laser speckle contrast analysis.ResultsIschemia induction and anoxia onset gave rise to iSD and aSD, respectively, albeit aSD occurred at a longer latency, and was superimposed on a gradual elevation of K+ concentration. iSD and aSD were accompanied by a transient drop of CBF (down to 11.9 ± 2.9 and 7.4 ± 3.6%, iSD and aSD), but distinctive features set the hypoperfusion transients apart. During iSD, rCBFx indicated intact autoregulation (rCBFx < 0.3). In contrast, aSD was superimposed on autoregulatory failure (rCBFx > 0.3) because CBF followed the decreasing MABP. CBF dropped 15–20 s after iSD, but the onset of hypoperfusion preceded aSD by almost 3 min. Taken together, the CBF response to iSD displayed typical features of spreading ischemia, whereas the transient CBF reduction with aSD appeared to be a passive decrease of CBF following the anoxia-related hypotension, leading to aSD.ConclusionsWe propose that the dysfunction of cerebrovascular autoregulation that occurs simultaneously with hypotension transients poses a substantial risk of SD occurrence and is not a consequence of SD. Under such circumstances, the evolving SD is not accompanied by any recognizable CBF response, which indicates a severely damaged neurovascular coupling.

Rapid hematoma growth triggers spreading depolarizations in experimental intracortical hemorrhage

Recurrent waves of spreading depolarization (SD) occur in brain injury and are thought to affect outcomes. What triggers SD in intracerebral hemorrhage is poorly understood. We employed intrinsic optical signaling, laser speckle flowmetry, and electrocorticography to elucidate the mechanisms triggering SD in a collagenase model of intracortical hemorrhage in mice. Hematoma growth, SD occurrence, and cortical blood flow changes were tracked. During early hemorrhage (0–4 h), 17 out of 38 mice developed SDs, which always originated from the hematoma. No SD was detected at late time points (8–52 h). Neither hematoma size, nor peri-hematoma perfusion were associated with SD occurrence. Further, arguing against ischemia as a trigger factor, normobaric hyperoxia did not inhibit SD occurrence. Instead, SDs always occurred during periods of rapid hematoma growth, which was two-fold faster immediately preceding an SD compared with the peak growth rates in animals that did not develop any SDs. Induced hypertension accelerated hematoma growth and resulted in a four-fold increase in SD occurrence compared with normotensive animals. Altogether, our data suggest that spontaneous SDs in this intracortical hemorrhage model are triggered by the mechanical distortion of tissue by rapidly growing hematomas.

Rapid Neuronal Ultrastructure Disruption and Recovery during Spreading Depolarization-Induced Cytotoxic Edema.

Two major pathogenic events that cause acute brain damage during neurologic emergencies of stroke, head trauma, and cardiac arrest are spreading depolarizing waves and the associated brain edema that course across the cortex injuring brain cells. Virtually nothing is known about how spreading depolarization (SD)-induced cytotoxic edema evolves at the ultrastructural level immediately after insult and during recovery. In vivo 2-photon imaging followed by quantitative serial section electron microscopy was used to assess synaptic circuit integrity in the neocortex of urethane-anesthetized male and female mice during and after SD evoked by transient bilateral common carotid artery occlusion. SD triggered a rapid fragmentation of dendritic mitochondria. A large increase in the density of synapses on swollen dendritic shafts implies that some dendritic spines were overwhelmed by swelling or merely retracted. The overall synaptic density was unchanged. The postsynaptic dendritic membranes remained attached to axonal boutons, providing a structural basis for the recovery of synaptic circuits. Upon immediate reperfusion, cytotoxic edema mainly subsides as affirmed by a recovery of dendritic ultrastructure. Dendritic recuperation from swelling and reversibility of mitochondrial fragmentation suggests that neurointensive care to improve tissue perfusion should be paralleled by treatments targeting mitochondrial recovery and minimizing the occurrence of SDs.

Neural shutdown under stress: an evolutionary perspective on spreading depolarization.

Neural function depends on maintaining cellular membrane potentials as the basis for electrical signaling. Yet, in mammals and insects, neuronal and glial membrane potentials can reversibly depolarize to zero, shutting down neural function by the process of spreading depolarization (SD) that collapses the ion gradients across membranes. SD is not evident in all metazoan taxa with centralized nervous systems. We consider the occurrence and similarities of SD in different animals and suggest that it is an emergent property of nervous systems that have evolved to control complex behaviors requiring energetically expensive, rapid information processing in a tightly regulated extracellular environment. Whether SD is beneficial or not in mammals remains an open question. However, in insects, it is associated with the response to harsh environments and may provide an energetic advantage that improves the chances of survival. The remarkable similarity of SD in diverse taxa supports a model systems approach to understanding the mechanistic underpinning of human neuropathology associated with migraine, stroke, and traumatic brain injury.

Spreading Depolarization during the Acute Stage of Experimental Subarachnoid Hemorrhage in Mice.

Spreading depolarization (SD) has been suggested as a pathomechanism for delayed cerebral ischemia after subarachnoid hemorrhage (SAH). However, the role of SD during the acute phase of SAH is still unclear. The objective of this study was to investigate (a) the occurrence of SD with intrinsic optical signal (IOS) imaging, (b) the effect of ketamine on SD, and (c) the resulting brain edema (brain water content (BWC)) during the acute stage of experimental SAH in mice. SAH was elicited by the endovascular filament perforation method. After SAH or sham operation, ketamine or saline, 30mg/kg, was given every half hour. Changes in tissue light reflectance were recorded with IOS. BWC was measured during the acute stage. Overall, 199 SDs occurred in SAH groups and 33 SDs appeared in sham groups. These SDs displayed distinct originating and spreading patterns. Compared with saline, ketamine decreased SD spread and influenced the amplitude, duration, and speed of SD. However, the occurrence of SD was not prevented by ketamine. Moreover, ketamine did not reduce BWC after SAH. These results demonstrate that SD occurs with a high incidence during the acute stage of SAH. SDs are heterogeneous in incidence, origination, and propagation. It remains unclear whether ketamine effects on SD may be viewed as therapeutically beneficial after SAH.

Spreading depolarizations in the rat endothelin-1 model of focal cerebellar ischemia

Focal brain ischemia is best studied in neocortex and striatum. Both show highly vulnerable neurons and high susceptibility to spreading depolarization (SD). Therefore, it has been hypothesized that these two variables generally correlate. However, this hypothesis is contradicted by findings in cerebellar cortex, which contains highly vulnerable neurons to ischemia, the Purkinje cells, but is said to be less susceptible to SD. Here, we found in the rat cerebellar cortex that elevated K+ induced a long-lasting depolarizing event superimposed with SDs. Cerebellar SDs resembled those in neocortex, but negative direct current (DC) shifts and regional blood flow responses were usually smaller. The K+ threshold for SD was higher in cerebellum than in previous studies in neocortex. We then topically applied endothelin-1 (ET-1) to the cerebellum, which is assumed to cause SD via vasoconstriction-induced focal ischemia. Although the blood flow decrease was similar to that in previous studies in neocortex, the ET-1 threshold for SD was higher. Quantitative cell counting found that the proportion of necrotic Purkinje cells was significantly higher in ET-1-treated rats than sham controls even if ET-1 had not caused SDs. Our results suggest that ischemic death of Purkinje cells does not require the occurrence of SD.

Neurostereologic Lesion Volumes and Spreading Depolarizations in Severe Traumatic Brain Injury Patients: A Pilot Study.

Spreading depolarizations (SDs) occur in 50-60% of patients after surgical treatment of severe traumatic brain injury (TBI) and are independently associated with unfavorable outcomes. Here we performed a pilot study to examine the relationship between SDs and various types of intracranial lesions, progression of parenchymal damage, and outcomes. In a multicenter study, fifty patients (76% male; median age 40) were monitored for SD by continuous electrocorticography (ECoG; median duration 79h) following surgical treatment of severe TBI. Volumes of hemorrhage and parenchymal damage were estimated using unbiased stereologic assessment of preoperative, postoperative, and post-ECoG serial computed tomography (CT) studies. Neurologic outcomes were assessed at 6months by the Glasgow Outcome Scale-Extended. Preoperative volumes of subdural and subarachnoid hemorrhage, but not parenchymal damage, were significantly associated with the occurrence of SDs (P's < 0.05). Parenchymal damage increased significantly (median 34ml [Interquartile range (IQR) - 2, 74]) over 7 (5, 8) days from preoperative to post-ECoG CT studies. Patients with and without SDs did not differ in extent of parenchymal damage increase [47ml (3, 101) vs. 30ml (- 2, 50), P = 0.27], but those exhibiting the isoelectric subtype of SDs had greater initial parenchymal damage and greater increases than other patients (P's < 0.05). Patients with temporal clusters of SDs (≥ 3 in 2h; n = 10 patients), which included those with isoelectric SDs, had worse outcomes than those without clusters (P = 0.03), and parenchymal damage expansion also correlated with worse outcomes (P = 0.01). In multivariate regression with imputation, both clusters and lesion expansion were significant outcome predictors. These results suggest that subarachnoid and subdural blood are important primary injury factors in provoking SDs and that clustered SDs and parenchymal lesion expansion contribute independently to worse patient outcomes. These results warrant future prospective studies using detailed quantification of TBI lesion types to better understand the relationship between anatomic and physiologic measures of secondary injury.

Na+/K+-ATPase α isoform deficiency results in distinct spreading depolarization phenotypes

Compromised Na+/K+-ATPase function is associated with the occurrence of spreading depolarization (SD). Mutations in ATP1A2, the gene encoding the α2 isoform of the Na+/K+-ATPase, were identified in patients with familial hemiplegic migraine type 2 (FHM2), a Mendelian model disease for SD. This suggests a distinct role for the α2 isoform in modulating SD susceptibility and raises questions about underlying mechanisms including the roles of other Na+/K+-ATPase α isoforms. Here, we investigated the effects of genetic ablation and pharmacological inhibition of α1, α2, and α3 on SD using heterozygous knock-out mice. We found that only α2 heterozygous mice displayed higher SD susceptibility when challenged with prolonged extracellular high potassium concentration ([K+]o), a pronounced post SD oligemia and higher SD speed in-vivo. By contrast, under physiological [K+]o, α2 heterozygous mice showed similar SD susceptibility compared to wild-type littermates. Deficiency of α3 resulted in increased resistance against electrically induced SD in-vivo, whereas α1 deficiency did not affect SD. The results support important roles of the α2 isoform in SD. Moreover, they suggest that specific experimental conditions can be necessary to reveal an inherent SD phenotype by driving a (meta-) stable system into decompensation, reminiscent of the episodic nature of SDs in various diseases.

Cilostazol decreases duration of spreading depolarization and spreading ischemia after aneurysmal subarachnoid hemorrhage.

Traditionally, angiographic vasospasm (aVS) has been thought to cause delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). However, successful treatment of aVS alone does not result in improved neurological outcome. Therefore, there may be other potential causes of poor neurological outcome, including spreading depolarization (SD). A recent study showed beneficial effects of cilostazol on DCI and neurological outcome. The present prospective clinical trial and experimental study focused on effects of cilostazol on SDs. Fifty aSAH patients were treated with clip ligation and randomly assigned to a cilostazol (n = 23) or control group (n = 27). Effects of cilostazol on DCI, aVS, and SDs, measured with subdural electrodes, were examined. The effect of cilostazol on SD-induced perfusion deficits (spreading ischemia) was assessed in an aSAH-mimicking model. There was a trend for less DCI in the cilostazol group, but it did not reach our threshold for statistical significance (13.0% vs 40.0%, odds ratio = 0.266, 95% confidence interval [CI] = 0.059-1.192, p = 0.084). However, the total SD-induced depression duration per recording day (22.2 vs 30.2 minutes, β = -251.905, 95% CI = -488.458 to -15.356, p = 0.043) and the occurrence of isoelectric SDs (0 vs 4 patients, β = -0.916, 95% CI = -1.746 to -0.085, p = 0.037) were significantly lower in the cilostazol group. In rats, cilostazol significantly shortened SD-induced spreading ischemia compared to vehicle (Student t test, difference = 30.2, 95% CI = 5.3-55.1, p = 0.020). Repair of the neurovascular response to SDs by cilostazol, as demonstrated in the aSAH-mimicking model, may be a promising therapy to control DCI. Ann Neurol 2018;84:873-885.

Spreading depolarization in acute brain injury inhibited by ketamine: a prospective, randomized, multiple crossover trial.

OBJECTIVERetrospective clinical data and case studies support a therapeutic effect of ketamine in suppression of spreading depolarization (SD) following brain injury. Preclinical data strongly support efficacy in terms of frequency of SD as well as recovery from electrocorticography (ECoG) depression. The authors present the results of the first prospective controlled clinical trial testing the role of ketamine used for clinical sedation on occurrence of SD.METHODSTen patients with severe traumatic brain injury (TBI) or aneurysmal subarachnoid hemorrhage (SAH) were recruited for this pilot trial. A standard ECoG strip was placed at the time of craniotomy, and the patients were then placed on an alternating every-6-hour schedule of ketamine or other sedation agent. The order of treatment was randomized. The ketamine dose was adjusted to clinical effect or maintained at a subanesthetic basal dose (0.1 mg/kg/hr) if no sedation was required. SD was scored using standard criteria, blinded to ketamine dosing. Occurrence of SD was compared with the hourly dose of ketamine to determine the effect of ketamine on SD occurrence.RESULTSSuccessful ECoG recordings were obtained in all 10 patients: 8 with SAH and 2 with TBI. There were a total of 1642 hours of observations with adequate ECoG: 833 hours off ketamine and 809 hours on ketamine. Analysis revealed a strong dose-dependent effect such that hours off ketamine or on doses of less than 1.15 mg/kg/hr were associated with an increased risk of SD compared with hours on doses of 1.15 mg/kg/hr or more (OR 13.838, 95% CI 1.99-1000). This odds ratio decreased with lower doses of 1.0 mg/kg/hr (OR 4.924, 95% CI 1.337-43.516), 0.85 mg/kg/hr (OR 3.323, 95% CI 1.139-16.074), and 0.70 mg/kg/hr (OR 2.725, 95% CI 1.068-9.898) to a threshold of no effect at 0.55 mg/kg/hr (OR 1.043, 95% CI 0.565-2.135). When all ketamine data were pooled (i.e., on ketamine at any dose vs off ketamine), a nonsignificant overall trend toward less SD during hours on ketamine (χ2 = 3.86, p = 0.42) was observed.CONCLUSIONSKetamine effectively inhibits SD over a wide range of doses commonly used for sedation, even in nonintubated patients. These data also provide the first prospective evidence that the occurrence of SD can be influenced by clinical intervention and does not simply represent an unavoidable epiphenomenon after injury. These data provide the basis for future studies assessing clinical improvement with SD-directed therapy.Clinical trial registration no.: NCT02501941 (clinicaltrials.gov).

Near-infrared diffuse reflectance signals for monitoring spreading depolarizations and progression of the lesion in a male rat focal cerebral ischemia model.

In ischemic stroke research, a better understanding of the pathophysiology and development of neuroprotection methods are crucial, for which in vivo imaging to monitor spreading depolarizations (SDs) and evolution of tissue damage is desired. Since these events are accompanied by cellular morphological changes, light-scattering signals, which are sensitive to cellular and subcellular morphology, can be used for monitoring them. In this study, we performed transcranial imaging of near-infrared (NIR) diffuse reflectance at ∼800 nm, which sensitively reflects light-scattering change, and examined how NIR reflectance is correlated with simultaneously measured cerebral blood flow (CBF) for a rat middle cerebral artery occlusion (MCAO) model. After MCAO, wavelike NIR reflectance changes indicating occurrence of SDs were generated and propagated around the ischemic core for ∼90 min, during which time NIR reflectance increased not only within the ischemic core but also in the peripheral region. The area with increased reflectance expanded with increase in the number of SD occurrences, the correlation coefficient being 0.7686 (n = 5). The area with increased reflectance had become infarcted at 24 hr after MCAO. The infarct region was found to be associated with hypoperfusion or no-flow response to SD, but hyperemia or hypoperfusion followed by hyperemia response to SD was also observed, and the regional heterogeneity seemed to be connected with the rat cerebrovasculature and hence existence/absence of collateral flow. The results suggest that NIR reflectance signals depicted early evolution of tissue damage, which was not seen by CBF changes, and enabled lesion progression monitoring in the present stroke model.

Brain temperature but not core temperature increases during spreading depolarizations in patients with spontaneous intracerebral hemorrhage

Spreading depolarizations (SDs) are highly active metabolic events, commonly occur in patients with intracerebral hemorrhage (ICH) and may be triggered by fever. We investigated the dynamics of brain-temperature (Tbrain) and core-temperature (Tcore) relative to the occurrence of SDs. Twenty consecutive comatose ICH patients with multimodal electrocorticograpy (ECoG) and Tbrain monitoring of the perihematomal area were prospectively enrolled. Clusters of SDs were defined as ≥2 SDs/h. Generalized estimating equations were used for statistical calculations. Data are presented as median and interquartile range. During 3097 h (173 h [81–223]/patient) of ECoG monitoring, 342 SDs were analyzed of which 51 (15%) occurred in clusters. Baseline Tcore and Tbrain was 37.3℃ (36.9–37.8) and 37.4℃ (36.7–37.9), respectively. Tbrain but not Tcore significantly increased 25 min preceding the onset of SDs by 0.2℃ (0.1–0.2; p < 0.001) and returned to baseline 35 min following SDs. During clusters, Tbrain increased to a higher level (+0.4℃ [0.1–0.4]; p = 0.006) when compared to single SDs. A higher probability (OR = 36.9; CI = 36.8–37.1; p < 0.001) of developing SDs was observed during episodes of Tbrain ≥ 38.0℃ (23% probability), than during Tbrain ≤ 36.6℃ (9% probability). Spreading depolarizations – and in particular clusters of SDs – may increase brain temperature following ICH.

Simulation of spreading depolarization trajectories in cerebral cortex: Correlation of velocity and susceptibility in patients with aneurysmal subarachnoid hemorrhage.

In many cerebral grey matter structures including the neocortex, spreading depolarization (SD) is the principal mechanism of the near-complete breakdown of the transcellular ion gradients with abrupt water influx into neurons. Accordingly, SDs are abundantly recorded in patients with traumatic brain injury, spontaneous intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage (aSAH) and malignant hemispheric stroke using subdural electrode strips. SD is observed as a large slow potential change, spreading in the cortex at velocities between 2 and 9 mm/min. Velocity and SD susceptibility typically correlate positively in various animal models. In patients monitored in neurocritical care, the Co-Operative Studies on Brain Injury Depolarizations (COSBID) recommends several variables to quantify SD occurrence and susceptibility, although accurate measures of SD velocity have not been possible. Therefore, we developed an algorithm to estimate SD velocities based on reconstructing SD trajectories of the wave-front's curvature center from magnetic resonance imaging scans and time-of-SD-arrival-differences between subdural electrode pairs. We then correlated variables indicating SD susceptibility with algorithm-estimated SD velocities in twelve aSAH patients. Highly significant correlations supported the algorithm's validity. The trajectory search failed significantly more often for SDs recorded directly over emerging focal brain lesions suggesting in humans similar to animals that the complexity of SD propagation paths increase in tissue undergoing injury.