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Background: Spreading depolarizations (SDs) can be viewed at a cellular level using calcium imaging (CI), but this approach is limited to laboratory applications and animal experiments. Optical intrinsic signal imaging (OISI), on the other hand, is amenable to clinical use and allows viewing of large cortical areas without contrast agents. A better understanding of the behavior of OISI-observed SDs under different brain conditions is needed. Methods: We performed simultaneous calcium and OISI of SDs in GCaMP6f mice. SDs propagate through the cortex as a pathological wave and trigger a neurovascular response that can be imaged with both techniques. We imaged both mechanically stimulated SDs (sSDs) in healthy brains and terminal SDs (tSDs) induced by system hypoxia and cardiopulmonary failure. Results: We observed a lag in the detection of SDs in the OISI channels compared with CI. sSDs had a faster velocity than tSDs, and tSDs had a greater initial velocity for the first 400 µm when observed with CI compared with OISI. However, both imaging methods revealed similar characteristics, including a decrease in the sSD (but not tSD) velocities as the wave moved away from the site of initial detection. CI and OISI also showed similar spatial propagation of the SD throughout the image field. Importantly, only OISI allowed regional ischemia to be detected before tSDs occurred. Conclusions: Altogether, data indicate that monitoring either neural activity or intrinsic signals with high-resolution optical imaging can be useful to assess SDs, but OISI may be a clinically applicable way to predict, and therefore possibly mitigate, hypoxic-ischemic tSDs. [ABSTRACT FROM AUTHOR]

Background: Spreading 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). Methods: A 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. Results: A 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. Conclusions: Neuromonitoring 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. [ABSTRACT FROM AUTHOR]

Spreading depolarizations (SDs) are profound disruptions of cellular homeostasis that slowly propagate through gray matter and present an extraordinary metabolic challenge to brain tissue. Recent work has shown that SDs occur commonly in human patients in the neurointensive care setting and have established a compelling case for their importance in the pathophysiology of acute brain injury. The International Conference on Spreading Depolarizations (iCSD) held in Boca Raton, Florida, in September of 2018 included a discussion session focused on the question of "Which SDs are deleterious to brain tissue?" iCSD is attended by investigators studying various animal species including invertebrates, in vivo and in vitro preparations, diseases of acute brain injury and migraine, computational modeling, and clinical brain injury, among other topics. The discussion included general agreement on many key issues, but also revealed divergent views on some topics that are relevant to the design of clinical interventions targeting SDs. A draft summary of viewpoints offered was then written by a multidisciplinary writing group of iCSD members, based on a transcript of the session. Feedback of all discussants was then formally collated, reviewed and incorporated into the final document. It is hoped that this report will stimulate collection of data that are needed to develop a more nuanced understanding of SD in different pathophysiological states, as the field continues to move toward effective clinical interventions.

Background: How widely spreading depolarizations (SDs) propagate through the gyrencephalic brain, including sulci and deeper cortical areas, remains an important clinical question. Here, we investigated SDs that occur spontaneously after subarachnoid placement of autologous blood clots in sulci of the juvenile swine brain. Methods: To investigate the three-dimensional spread of waves, animals underwent continuous diffusion-weighted magnetic resonance imaging (DW-MRI) for up to 6 h following clot placement. SD is the mechanism of the cytotoxic edema of developing infarction that is diagnosed by DW-MRI, and DW-MRI also captures transient diffusion restriction caused by SD in less injured or healthy brains. Here, images (b = 0, 375, and 750) were acquired across five coronal slices with 1.25 × 1.25-mm in-plane resolution and 5-mm slice thickness, and the protocol was repeated every 6.83–9.15 s. Spatial drift correction, temporal smoothing, and signal intensity normalization were applied to generate videos of diffusion signal intensity changes for each coronal slice. Results: Review of video data from five animals revealed ten discrete events consisting of focal diffusion restriction that propagated through cerebral cortex. All events originated in the cortex surrounding the sulcal clot, either in the gyrus (n = 4) or in the sulcal depth (n = 6). In six cases, two to three independent waves spread simultaneously in medial, lateral, and antero–posterior directions. Waves traveled within sulcal walls, traversed the depths of sulci to re-emerge on the adjacent gyrus, and, in three cases, spread fully around the dorsolateral convexity. One event spread deep to olfactory regions along midline cortex, and no events were observed contralateral to the subarachnoid clot. Conclusions: Together, these results suggest that SDs in the injured gyrencephalic brain originate near the injury focus and can spread extensively through the cortex to wide and deep uninjured regions. These findings have implications for transient neurologic deficits in the neurocritically ill patient and relevance to patient monitoring and therapeutics. [ABSTRACT FROM AUTHOR]

Background: In 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. Methods: Incomplete 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. Results: Ischemia 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. Conclusions: We 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. [ABSTRACT FROM AUTHOR]

Background: Spreading depolarization (SD) and the initial, still reversible phase of neuronal cytotoxic edema in the cerebral gray matter are two modalities of the same process. SD may thus serve as a real-time mechanistic biomarker for impending parenchyma damage in patients during neurocritical care. Using subdural platinum/iridium (Pt/Ir) electrodes, SD is observed as a large negative direct current (DC) shift. Besides SD, there are other causes of DC shifts that are not to be confused with SD. Here, we systematically analyzed DC artifacts in ventilated patients by observing changes in the fraction of inspired oxygen. For the same change in blood oxygenation, we found that negative and positive DC shifts can simultaneously occur at adjacent Pt/Ir electrodes. Methods: Nurses and intensivists typically increase blood oxygenation by increasing the fraction of inspired oxygen at the ventilator before performing manipulations on the patient. We retrospectively identified 20 such episodes in six patients via tissue partial pressure of oxygen (ptiO2) measurements with an intracortical O2 sensor and analyzed the associated DC shifts. In vitro, we compared Pt/Ir with silver/silver chloride (Ag/AgCl) to assess DC responses to changes in pO2, pH, or 5-min square voltage pulses and investigated the effect of electrode polarization on pO2-induced DC artifacts. Results: Hyperoxygenation episodes started from a ptiO2 of 37 (30–40) mmHg (median and interquartile range) reaching 71 (50–97) mmHg. During a total of 20 episodes on each of six subdural Pt/Ir electrodes in six patients, we observed 95 predominantly negative responses in six patients, 25 predominantly positive responses in four patients, and no brain activity changes. Adjacent electrodes could show positive and negative responses simultaneously. In vitro, Pt/Ir in contrast with Ag/AgCl responded to changes in either pO2 or pH with large DC shifts. In response to square voltage pulses, Pt/Ir falsely showed smaller DC shifts than Ag/AgCl, with the worst performance under anoxia. In response to pO2 increase, Pt/Ir showed DC positivity when positively polarized and DC negativity when negatively polarized. Conclusions: The magnitude of pO2-induced subdural DC shifts by approximately 6 mV was similar to that of SDs, but they did not show a sequential onset at adjacent recording sites, could be either predominantly negative or positive in contrast with the always negative DC shifts of SD, and were not accompanied by brain activity depression. Opposing polarities of pO2-induced DC artifacts may result from differences in baseline electrode polarization or subdural ptiO2 inhomogeneities relative to subdermal ptiO2 at the quasi-reference. [ABSTRACT FROM AUTHOR]

Background: Chronic subdural hematoma (cSDH) is a common neurosurgical condition responsible for excess morbidity, particularly in the geriatric population. Recovery after evacuation is complicated by fluctuating neurological deficits in a high proportion of patients. We previously demonstrated that spreading depolarizations (SDs) may be responsible for some of these events. In this study, we aim to determine candidate risk factors for probable SD and assess the influence of probable SD on outcome. Methods: We used two cohorts who underwent surgery for cSDH. The first cohort (n = 40) had electrocorticographic monitoring to detect SD. In the second cohort (n = 345), we retrospectively identified subjects with suspected SD based on the presence of transient neurological symptoms not explained by structural etiology or ictal activity on electroencephalography. We extracted standard demographic and outcome variables for comparisons and modeling. Results: Of 345 subjects, 80 (23%) were identified in the retrospective cohort as having probable SD. Potential risk factors included history of hypertension, worse clinical presentation on the Glasgow Coma Scale, and lower Hounsfield unit density and volume of the preoperative subdural hematoma. Probable SD was associated with multiple worse-outcome measures, including length of stay and clinical outcomes, but not increased mortality. On a multivariable analysis, probable SD was independently associated with worse outcome, determined by the Glasgow Outcome Scale score at the first clinic follow-up (odds ratio 1.793, 95% confidence interval 1.022–3.146) and longer hospital length of stay (odds ratio 7.952, 95% confidence interval 4.062–15.563). Conclusions: Unexplained neurological deficits after surgery for cSDH occur in nearly a quarter of patients and may be explained by SD. We identified several potential candidate risk factors. Patients with probable SD have worse outcomes, independent of other baseline risk factors. Further data with gold standard monitoring are needed to evaluate for possible predictors of SD to target therapies to a high-risk population. [ABSTRACT FROM AUTHOR]

An acute reduction in plasma osmolality causes rapid uptake of water by astrocytes but not by neurons, whereas both cell types swell as a consequence of lost blood flow (ischemia). Either hypoosmolality or ischemia can displace the brain downwards, potentially causing death. However, these disorders are fundamentally different at the cellular level. Astrocytes osmotically swell or shrink because they express functional water channels (aquaporins), whereas neurons lack functional aquaporins and thus maintain their volume. Yet both neurons and astrocytes immediately swell when blood flow to the brain is compromised (cytotoxic edema) as following stroke onset, sudden cardiac arrest, or traumatic brain injury. In each situation, neuronal swelling is the direct result of spreading depolarization (SD) generated when the ATP-dependent sodium/potassium ATPase (the Na+/K+ pump) is compromised. The simple, and incorrect, textbook explanation for neuronal swelling is that increased Na+ influx passively draws Cl− into the cell, with water following by osmosis via some unknown conduit. We first review the strong evidence that mammalian neurons resist volume change during acute osmotic stress. We then contrast this with their dramatic swelling during ischemia. Counter-intuitively, recent research argues that ischemic swelling of neurons is non-osmotic, involving ion/water cotransporters as well as at least one known amino acid water pump. While incompletely understood, these mechanisms argue against the dogma that neuronal swelling involves water uptake driven by an osmotic gradient with aquaporins as the conduit. Promoting clinical recovery from neuronal cytotoxic edema evoked by spreading depolarizations requires a far better understanding of molecular water pumps and ion/water cotransporters that act to rebalance water shifts during brain ischemia. [ABSTRACT FROM AUTHOR]

Background: Recurrent spreading depolarizations (SDs) occur in patients after aneurysmal subarachnoid hemorrhage (aSAH), resulting in metabolic stress to brain. These events are closely associated with delayed cerebral ischemia. Preclinical data suggest that the beneficial effect of nimodipine demonstrated in clinical trials may be related to inhibition of SD rather than limitation of large artery vasospasm. Methods: Subjects enrolled in a phase 3 trial of intraventricularly delivered, sustained-release nimodipine (EG-1962) versus standard of care oral nimodipine (NEWTON 2) who required surgical clipping had subdural strip electrodes implanted for monitoring of SD. SD was then scored blinded to NEWTON 2 allocation. Results: Five subjects underwent electrocorticography monitoring of SD. Three of five patients had SD. There were fewer SDs, a lower rate of SD, and shorter depression durations in subjects treated with EG-1962 compared to standard of care. Outcomes were worse in the standard of care group, though there were baseline imbalances. Conclusions: These results are consistent with a beneficial effect of locally delivered nimodipine (EG-1962) on SD after aSAH in more severely injured patients who are at risk of delayed cerebral ischemia related to SD. Larger studies are warranted to test this effect. [ABSTRACT FROM AUTHOR]

Background: Electrocorticography (ECoG) in brain-injured patients allows to detect spreading depolarization, a potential mechanism of secondary ischemia. Here, we describe the relationship of spreading depolarization with changes in cerebral hemodynamics using a brain tissue probe applying near infrared spectroscopy (NIRS). Methods: Simultaneous ECoG and NIRS monitoring was performed in a patient with severe aneurysmal subarachnoid hemorrhage. Changes in cerebral blood oxygenation and regional cerebral blood volume were studied before and after the occurrence of spreading depolarization. Cerebral blood flow measurements were performed daily using an indocyanine green dye dilution mode. Results: Single events of spreading depolarizations demonstrated with transient hyperoxic responses and increase in cerebral blood volume. On the other hand, temporal clusters of recurrent spreading depolarizations were associated with prolonged hypoxic responses and decrease in cerebral blood volume. Cerebral blood flow measurements showed higher values before compared to after onset of spreading depolarization (33.7 ± 8.4 vs. 24.2 ± 4.5 ml/100 g/min). Conclusions: The findings suggest that NIRS monitoring in the cerebral white matter might reflect the hemodynamic signature of spreading depolarization detected by ECoG recordings. This is of potential interest for the further development of both neuromonitoring methods. [ABSTRACT FROM AUTHOR]