Spreading Depolarization Research Articles

Palytoxin Evokes Reversible Spreading Depolarization in the Locust CNS.

Spreading depolarization (SD) describes the near-complete depolarization of CNS neural cells as a consequence of chemical, electrical, and metabolic perturbations. It is well-established as the central mechanism underlying insect coma and various mammalian neurological dysfunctions. Despite significant progress in our understanding, the question remains: which cation channel, if any, generates SD in the CNS? Previously, we speculated that the sodium-potassium ATPase (NKA) might function as a large-conductance ion channel to initiate SD in insects, potentially mediated by a palytoxin (PLTX)-like endogenous activator. In the current study, we evaluate the effectiveness and properties of PLTX as an SD initiator in L. migratoria. Whereas bath-applied PLTX failed to ignite SD, direct injection into the neuropil triggered SD in 57% of the preparations. Notably, PLTX-induced SD onset was significantly more rapid compared to ouabain injection and azide controls, though their electrophysiological features remained similar. Furthermore, PLTX-induced SD was recoverable and resulted in a greater frequency of repetitive SD events compared to ouabain. Surprisingly, prior PLTX treatment disrupted the onset and recovery of subsequent SD evoked by other means. PLTX injection could attenuate the amplitude and even completely inhibit the onset of azide-induced SD at higher doses. These results show that PLTX can trigger repetitive and reversible SD-like events in locusts and simultaneously interfere with anoxic SD occurrence. We suggest that the well-documented NKA pump conversion into an open non-selective cationic channel is a plausible mechanism of SD activation in the locust CNS, warranting additional investigations.

Metabolic Pathophysiology of Cortical Spreading Depression: A Review.

Cortical spreading depression (CSD) is an electrophysiologic pathological state in which a wave of depolarization in the cerebral cortex is followed by the suppression of spontaneous neuronal activity. This transient spread of neuronal depolarization on the surface of the cortex is the hallmark of CSD. Numerous investigations have demonstrated that transmembrane ion transport, astrocytic ion clearing and fatigue, glucose metabolism, the presence of certain genetic markers, point mutations, and the expression of the enzyme responsible for the production of various arachidonic acid derivatives that participate in the inflammatory response, namely, cyclooxygenase (COX), all influence CSD. Here, we explore the associations between CSD occurrence in the cortex and various factors, including how CSD is related to migraines, how the glucose state affects CSD, the effect of TBI and its relationship with CSD and glucose metabolism, how different markers can be measured to determine the severity of CSD, and possible connections to oligemia, orexin, and leptin.

Reduced neurovascular coupling of the visual network in migraine patients with aura as revealed with arterial spin labeling MRI: is there a demand-supply mismatch behind the scenes?

BackgroundAlthough neuroimaging investigations have consistently demonstrated that “hyperresponsive” and “hyperconnected” visual cortices may represent the functional substrate of cortical spreading depolarization in patients with migraine with aura, the mechanisms which underpin the brain “tendency” to ignite the cortical spreading depolarization and, consequently, aura phenomenon are still matter of debate. Considering that triggers able to induce aura phenomenon constrain brain to increase global (such as physical activity, stressors and sleep abnormalities) or local (such as bright light visual stimulations) energy demand, a vascular supply unable to satisfy the increased energy requirement could be hypothesized in these patients.MethodsTwenty-three patients with migraine with aura, 25 patients with migraine without aura and 20 healthy controls underwent a 3-Tesla MRI study. Cerebral blood flow and local functional connectivity (regional homogeneity) maps were obtained and registered to the MNI space where 100 cortical regions were derived using a functional local-global normative parcellation. A surrogate estimate of the regional neurovascular coupling for each subject was obtained at each parcel from the correlation coefficient between the z-scored ReHo map and the z-scored cerebral blood flow maps.ResultsA significantly higher regional cerebral blood flow across the visual cortex of both hemispheres (i.e. fusiform and lingual gyri) was detected in migraine with aura patients when compared to patients with migraine without aura (p < 0.05, corrected for multiple comparisons). Concomitantly, a significantly reduced neurovascular coupling (p < 0.05, false discovery rate corrected) in the primary visual cortex parcel (VIS-4) of the large-scale visual network was observed in the left hemisphere of patients with migraine with aura (0.23±0.03), compared to both patients with migraine without aura (0.32±0.05) and healthy controls (0.29±0.05).ConclusionsVisual cortex neurovascular “decoupling” might represent the “link” between the exposure to trigger factors and aura phenomenon ignition. While physiological vascular oversupply may compensate neurovascular demand-supply at rest, it becomes inadequate in case of increased energy demand (e.g. when patients face with trigger factors) paving the way to the aura phenomenon ignition in patients with migraine with aura. Whether preventive treatments may exert their therapeutic activity on migraine with aura restoring the energy demands and cerebral blood flow trade-off within the visual network should be further investigated.

Persistent Na + current couples spreading depolarization to seizures in Scn8a gain of function mice.

Spreading depolarization (SD) is a slowly propagating wave of massive cellular depolarization that transiently impairs the function of affected brain regions. While SD typically arises as an isolated hemispheric event, we previously reported that reducing M-type potassium current (I KM ) by ablation of Kcnq2 in forebrain excitatory neurons results in tightly coupled spontaneous bilateral seizure-SD complexes in the awake mouse cortex. Here we find that enhanced persistent Na + current due to gain-of-function (GOF) mutations in Scn8a (N1768D/+, hereafter D/+) produces a similar compound cortical excitability phenotype. Chronic DC-band EEG recording detected spontaneous bilateral seizure-SD complexes accompanied by seizures with a profound tonic component, which occurs predominantly during the light phase and were detected in the mutant mice across ages between P40-100. Laser speckle contrast imaging of cerebral blood flow dynamics resolved SD as bilateral wave of hypoperfusion and subsequent hour-lasting hypoperfusion in Scn8a D/+ cortex in awake head-restrained mice subjected to a subconvulsive PTZ. Subcortical recordings in freely moving mice revealed that approximately half of the spontaneous cortical seizure-SD complexes arose with concurrent SD-like depolarization in the thalamus and delayed depolarization in the striatum. In contrast, SD-like DC potential shifts were rarely detected in the hippocampus or upper pons. Consistent with the high spontaneous incidence in vivo , cortical slices from Scn8a D/+ mice showed a raised SD susceptibility, and pharmacological inhibition of persistent Na + current (I NaP ), which is enhanced in Scn8a D/+ neurons, inhibited SD generation in cortical slices ex vivo , indicating that I NaP contributes to SD susceptibility. Ex vivo Ca 2+ imaging studies using acute brain slices expressing genetic Ca 2+ sensor (Thy1-GCAMP6s) demonstrated that pharmacological activation of I KM suppressed Ca 2+ spikes and SD, whereas I KM inhibitor drastically increased the frequency of Ca 2+ spikes in the hippocampus of Scn8a D/+ mice, but not in WT, suggesting that I KM restrains the hyperexcitability resulting from Scn8a GOF mutation. Together, our study identifies a cortical SD phenotype in Scn8a GOF mice shared with the Kcnq2 - cKO model of developmental epileptic encephalopathy and reveals that an imbalance of non-inactivating inward and outward membrane currents bidirectionally modulates spatiotemporal SD susceptibility.

Transient destabilization of interhemispheric functional connectivity induced by spreading depolarization

ABSTRACT Cortical spreading depolarization (CSD), a slowly propagating wave of transient cellular depolarization, is a reliable cortical response to various brain insults (stroke, trauma, seizures) and underlying mechanism of migraine aura. Little is known about CSD effects on brain network activity. Using undirected (mutual information, MI) and directed (transfer entropy, TE) measures, we studied the dynamics of cross-hemispheric connectivity associated with the development of unilateral CSD in freely behaving rats and the involvement of inhibitory transmission in mechanisms of the coupling changes. We show that the development of CSD in the cortex of one hemisphere is followed by the transient loss of undirected functional connectivity (MI) between ipsilateral and contralateral cortical regions. The post-CSD functional disconnection of the hemispheres was accompanied by an increase in driving force from an unaffected contralateral cortex to an affected one (TE). Mild cortical disinhibition produced by pretreatment with an inhibitory receptor blocking agent (penthylenetetrazole) did not affect CSD but attenuated (MI) or eliminated (TE) the CSD-induced connectivity changes. The effects of CSD on functional connectivity in awake rodents were similar at the individual and group levels, suggesting that the described connectivity response may be a promising network biomarker of CSD occurrence in patients.

Combining Imaging and Electrophysiology to Visualize and Record Spreading Depolarizations in Mice.

Spreading Depolarizations (SDs) are massive events in the brain that often go undetected due to their slow propagation through gray matter. Because SD detection can be elusive, it is optimally confirmed using multiple methods. This protocol describes methods for combining imaging and electrophysiology to detect SDs in a manner that most laboratories can reliably and easily adopt. SDs occur following traumatic brain injuries, stroke, subarachnoid hemorrhages, ischemia, and migraine aura. Historically, SDs have been recorded using DC amplifiers, which can resolve the slow extracellular shift and the depression in high-frequency activity. However, DC amplifiers are nearly impossible to use for chronic in vivo recordings. This protocol employs a common AC amplifier for in vivo electrophysiology recordings to confirm high-frequency depression, along with non-invasive imaging necessary to detect the propagating wave of SD. These methods can be reliably adopted and/or modified for most experimental approaches to confirm the presence or absence of SDs following brain injury.

Effects of passive smoking on cortical spreading depolarization in male and female mice

BackgroundPatients with migraine are typically advised to avoid passive smoking because it may aggravate headaches and other health conditions. However, there is insufficient high-quality evidence on the association between passive smoking and migraine, which warrants further investigation using animal models. Therefore, using a mouse model, we examined the effect of passive smoking on susceptibility to cortical spreading depolarization (CSD), the biological basis of migraine with aura.FindingsFifty C57BL/6 mice (25 males and 25 females) were exposed for one hour to cigarette smoke or room air. Subsequently, potassium chloride (KCl) was administered under isoflurane anesthesia to induce CSD, and the CSD threshold, frequency of induction, and propagation velocity were determined. The threshold to induce CSD (median [interquartile range (IQR)]) was significantly lower in female mice (adjusted p = 0.01) in the smoking group (0.05 [0.05, 0.088]) than in the sham group (0.125 [0.1, 0.15]); however, there was no significant difference in the male mice (adjusted p = 0.77). CSD frequency or propagation velocity did not differ significantly between the two groups for either sex.ConclusionsFemale mice in the smoking group showed lower CSD threshold compared to the sham group, suggesting a potential sex-specific difference in the effect of smoking on the pathogenesis of CSD and migraine with aura. This finding may contribute to the understanding of migraine pathophysiology in association with passive smoking and sex difference.

Spontaneous spreading depolarizations originate subcortically in a novel mouse model of familial hemiplegic migraine type 2

The mechanisms of initiation of spreading depolarization (SD) are understudied due to a paucity of disease models with spontaneously occurring events. We here present a novel mouse model of familial hemiplegic migraine type 2 (FHM2), expressing the missense T345A-mutated α2 subunit of the Na+/K+ adenosine triphosphatase pump (Atp1a2T345A). Homozygous Atp1a2T345A mice showed regular spontaneous SDs that exhibit a diurnal rhythm and typically originate from the hippocampus. Heterozygous Atp1a2T345A mice rarely exhibited spontaneous SDs and, for electrically induced SDs, only showed an increased propagation speed, whereas homozygotes showed both increased propagation and decreased threshold. Remarkably, despite hippocampal hyperexcitability, spontaneous SDs in Atp1a2T345A mice were only rarely associated with epileptic behavior, and seizure expression during kindling was decreased. Spontaneous SDs could be prevented by modulation of persistent sodium currents. Hippocampal SDs occurred in the presence of an NMDA-receptor antagonist, but these events did not reach the cortex, suggesting that initiation and propagation of SD depend on different mechanisms in this model.

Collateral is brain: Low perfusion triggers spreading depolarization and futile reperfusion after acute ischemic stroke

Futile reperfusion is a phenomenon of inadequate perfusion despite successful recanalization after acute ischemic stroke (AIS). It is associated with poor patient outcomes and has received increasing interest due to its clinical diagnosis becoming more common. However, the underlying mechanisms remain elusive, and experimental studies are focused on the pathological background of futile reperfusion. Our recent study has confirmed that poor primary collateralization plays a crucial role in the insufficiency of reperfusion after AIS in mice. Specifically, the absence of primary collaterals in the circle of Willis (CoW) promoted the development of spreading depolarizations (SDs) during AIS. In our experimental stroke model, the occurrence of SDs during ischemia always predicted futile reperfusion. Conversely, in mice with a complete CoW, no SDs were observed, and reperfusion was complete. Importantly, the human CoW displays variation in the primary collaterals in approximately 50% of the population. Therefore, futile reperfusion may result from SD evolution in AIS patients. Our purpose here is to emphasize the crucial role of SD in the development of futile reperfusion. We propose that adequate collateral recruitment can prevent SD occurrence, leading to improved reperfusion and AIS outcomes.

Novel and reappraised wide-band EEG findings in migraineurs: its correlation with several clinical variables

ObjectiveCortical spreading depolarization is one possible pathogenesis of migraine, of which slow neurophysiological change is barely recorded in conventional EEG settings. Using wide-band EEG conditions, we reappraised the features of EEG in migraineurs, including subdelta-band EEG changes. MethodsThis retrospective study included 144 patients with migraine. We delineated EEG of focal delta slow (FDS) (1-4 Hz) by time constant (TC) 0.3 s and focal subdelta slow (FSDS) (< 1 Hz) by TC 2 s. Relationships between clinical variables and EEG findings were evaluated. ResultsOf 144 patients, 39 had aura and 105 did not. FSDS and FDS were observed in 38 and 58 patients, respectively. No EEG was recorded during the aura. In multivariate analysis with the phase of migraine, family history, age, and percentage of sleep during EEG recording, the phase of migraine was related to the occurrence of FSDS (postdrome vs interictal, prodrome, and headache respectively (OR = 49.00 [95% CI = 3.89-616.66], 46.28 [2.99-715.78], 32.79 [2.23-481.96], p = 0.0026, 0.0061, 0.011). FDS was clinically unremarkable for differential evaluation. ConclusionsWide-band EEG abnormality in migraineurs, i.e., FSDS, can be affected by migraine phase. SignificanceWide-band EEG finding could be a biomarker related to clinical variables in migraines.

Organellular imaging in vivo reveals a depletion of endoplasmic reticular calcium during post-ictal cortical spreading depolarization.

During cortical spreading depolarization (CSD), neurons exhibit a dramatic increase in cytosolic calcium, which may be integral to CSD-mediated seizure termination. This calcium increase greatly exceeds that during seizures, suggesting the calcium source may not be solely extracellular. Thus, we sought to determine if the endoplasmic reticulum (ER), the largest intracellular calcium store, is involved. We developed a two-photon calcium imaging paradigm to simultaneously record the cytosol and ER during seizures in awake mice. Paired with direct current recording, we reveal that CSD can manifest as a slow post-ictal cytosolic calcium wave with a concomitant depletion of ER calcium that is spatiotemporally consistent with a calcium-induced calcium release. Importantly, we observed both naturally occurring and electrically induced CSD suppressed post-ictal epileptiform activity. Collectively, this work links ER dynamics to CSD, which serves as an innate process for seizure suppression and a potential mechanism underlying therapeutic electrical stimulation for epilepsy.

Oxytocin shortens spreading depolarization-induced periorbital allodynia

BackgroundMigraine is among the most prevalent and burdensome neurological disorders in the United States based on disability-adjusted life years. Cortical spreading depolarization (SD) is the most likely electrophysiological cause of migraine aura and may be linked to trigeminal nociception. We previously demonstrated, using a minimally invasive optogenetic approach of SD induction (opto-SD), that opto-SD triggers acute periorbital mechanical allodynia that is reversed by 5HT1B/1D receptor agonists, supporting SD-induced activation of migraine-relevant trigeminal pain pathways in mice. Recent data highlight hypothalamic neural circuits in migraine, and SD may activate hypothalamic neurons. Furthermore, neuroanatomical, electrophysiological, and behavioral data suggest a homeostatic analgesic function of hypothalamic neuropeptide hormone, oxytocin. We, therefore, examined the role of hypothalamic paraventricular nucleus (PVN) and oxytocinergic (OXT) signaling in opto-SD-induced trigeminal pain behavior.MethodsWe induced a single opto-SD in adult male and female Thy1-ChR2-YFP transgenic mice and quantified fos immunolabeling in the PVN and supraoptic nucleus (SON) compared with sham controls. Oxytocin expression was also measured in fos-positive neurons in the PVN. Periorbital mechanical allodynia was tested after treatment with selective OXT receptor antagonist L-368,899 (5 to 25 mg/kg i.p.) or vehicle at 1, 2, and 4 h after opto-SD or sham stimulation using von Frey monofilaments.ResultsOpto-SD significantly increased the number of fos immunoreactive cells in the PVN and SON as compared to sham stimulation (p < 0.001, p = 0.018, respectively). A subpopulation of fos-positive neurons also stained positive for oxytocin. Opto-SD evoked periorbital mechanical allodynia 1 h after SD (p = 0.001 vs. sham), which recovered quickly within 2 h (p = 0.638). OXT receptor antagonist L-368,899 dose-dependently prolonged SD-induced periorbital allodynia (p < 0.001). L-368,899 did not affect mechanical thresholds in the absence of opto-SD.ConclusionsThese data support an SD-induced activation of PVN neurons and a role for endogenous OXT in alleviating acute SD-induced trigeminal allodynia by shortening its duration.

The Impact of Sedative Choice in the Management of Aneurysmal Subarachnoid Hemorrhage: A Scoping Review.

Aneurysmal subarachnoid hemorrhage (aSAH) is characterized by high mortality and morbidity. This scoping review assesses the current evidence regarding the use of sedatives and analgesics in the acute intensive care unit management of aSAH. We conducted a systematic search of Ovid MEDLINE, Ovid Embase, Ovid EmCare, APA PsycInfo, CINAHL, and the Cochrane Database of Systematic Reviews from inception to June 2023. Studies were included if they enrolled intensive care unit patients aged 18 or older with a significant proportion (> 20%) who had aSAH and evaluated the impact of one or more commonly used analgosedatives on physiological parameters in the management of aSAH. The methodological quality of the studies was assessed using the Methodological Index for Nonrandomized Studies score. Of 2,583 articles, 11 met the inclusion criteria. The median sample size was 47 (interquartile range 10-127), and the median Methodological Index for Nonrandomized Studies score was 9.5 (interquartile range 8-11). The studies' publication years ranged from 1980 to 2023. Dexmedetomidine and ketamine showed potential benefits in reducing the incidence of cortical spreading depolarization and delayed cerebral ischemia. Propofol and opioids appeared safe but lacked robust evidence for efficacy. Benzodiazepines were associated with increased delayed cerebral ischemia-related cerebral infarctions and cortical spreading depolarization events. The evidence available to guide the use of analgosedative medications in aSAH is critically inadequate. Dexmedetomidine and ketamine warrant further exploration in large-scale prospective studies because of their potential benefits. Improved study designs with consistent definitions and a focus on patient-centered outcomes are necessary to inform clinical practice.

Spreading Depolarization After Aneurysmal Subarachnoid Hemorrhage

Aneurysmal subarachnoid hemorrhage(aSAH) is a critical condition that often results in severe neurological deficits. Recent studies have highlighted the role of spreading depolarization(SD) in post-aSAH secondary brain injury. SD comprises rapid and sequential changes in neuronal and glial membrane potentials that disrupt energy metabolism and induce neuronal dysfunction. Implicated in both early brain injury(EBI) and delayed cerebral ischemia(DCI), SD worsens clinical outcomes. This review explores the SD-associated mechanisms in aSAH, ascertains the contribution of SD to EBI and DCI, and identifies potential SD-targeted therapeutic strategies to improve the prognosis of aSAH.

Oxygen-Based Autoregulation Indices Associated with Clinical Outcomes and Spreading Depolarization in Aneurysmal Subarachnoid Hemorrhage.

Impairment in cerebral autoregulation has been proposed as a potentially targetable factor in patients with aneurysmal subarachnoid hemorrhage (aSAH); however, there are different continuous measures that can be used to calculate the state of autoregulation. In addition, it has previously been proposed that there may be an association of impaired autoregulation with the occurrence of spreading depolarization (SD) events. Study participants with invasive multimodal monitoring and aSAH were enrolled in an observational study. Autoregulation indices were prospectively calculated from this database as a 10s moving correlation coefficient between various cerebral blood flow (CBF) surrogates and mean arterial pressure (MAP). In study participants with subdural electrocorticography (ECoG) monitoring, SD was also scored. Associations between clinical outcomes using the modified Rankin scale and occurrence of either isolated or clustered SD were assessed. A total of 320 study participants were included, 47 of whom also had ECoG SD monitoring. As expected, baseline severity factors, such as modified Fisher scale score and World Federation of Neurosurgical Societies scale grade, were strongly associated with the clinical outcome. SD probability was related to blood pressure in a triphasic pattern, with a linear increase in probability below MAP of ~ 100 mm Hg. Multiple autoregulation indices were available for review based on moving correlations between mean arterial pressure (MAP) and various surrogates of cerebral blood flow (CBF). We calculated the pressure reactivity (PRx) using two different sources for intracranial pressure (ICP). We calculated the oxygen reactivity (ORx) using the partial pressure of brain tissue oxygen (PbtO2) from the Licox probe. We calculated the cerebral blood flow reactivity (CBFRx) using perfusion measurements from the Bowman perfusion probe. Finally, we calculated the cerebral oxygen saturation reactivity (OSRx) using regional cerebral oxygen saturation measured by near-infrared spectroscopy from the INVOS sensors. Only worse ORx and OSRx were associated with worse clinical outcomes. Both ORx and OSRx also were found to increase in the hour prior to SD for both sporadic and clustered SD. Impairment in autoregulation in aSAH is associated with worse clinical outcomes and occurrence of SD when using ORx and OSRx. Impaired autoregulation precedes SD occurrence. Targeting the optimal MAP or cerebral perfusion pressure in patients with aSAH should use ORx and/or OSRx as the input function rather than intracranial pressure.

The Na+/K+-ATPase generically enables deterministic bursting in class I neurons by shearing the spike-onset bifurcation structure.

Slow brain rhythms, for example during slow-wave sleep or pathological conditions like seizures and spreading depolarization, can be accompanied by oscillations in extracellular potassium concentration. Such slow brain rhythms typically have a lower frequency than tonic action-potential firing. They are assumed to arise from network-level mechanisms, involving synaptic interactions and delays, or from intrinsically bursting neurons. Neuronal burst generation is commonly attributed to ion channels with slow kinetics. Here, we explore an alternative mechanism generically available to all neurons with class I excitability. It is based on the interplay of fast-spiking voltage dynamics with a one-dimensional slow dynamics of the extracellular potassium concentration, mediated by the activity of the Na+/K+-ATPase. We use bifurcation analysis of the complete system as well as the slow-fast method to reveal that this coupling suffices to generate a hysteresis loop organized around a bistable region that emerges from a saddle-node loop bifurcation-a common feature of class I excitable neurons. Depending on the strength of the Na+/K+-ATPase, bursts are generated from pump-induced shearing the bifurcation structure, spiking is tonic, or cells are silenced via depolarization block. We suggest that transitions between these dynamics can result from disturbances in extracellular potassium regulation, such as glial malfunction or hypoxia affecting the Na+/K+-ATPase activity. The identified minimal mechanistic model outlining the sodium-potassium pump's generic contribution to burst dynamics can, therefore, contribute to a better mechanistic understanding of pathologies such as epilepsy syndromes and, potentially, inform therapeutic strategies.

Ketamine for Critically Ill Patients with Severe Acute Brain Injury: A Systematic Review with Meta-analysis and Trial Sequential Analysis of Randomized Clinical Trials.

Patients with severe acute brain injury have a high risk of a poor clinical outcome due to primary and secondary brain injury. Ketamine reportedly inhibits cortical spreading depolarization, an electrophysiological phenomenon that has been associated with secondary brain injury, making ketamine potentially attractive for patients with severe acute brain injury. The aim of this systematic review is to explore the current literature regarding ketamine for patients with severe acute brain injury. We systematically searched international databases for randomized clinical trials comparing ketamine by any regimen versus placebo, no intervention, or any control drug for patients with severe acute brain injury. Two authors independently reviewed and selected trials for inclusion, extracted data, assessed risk of bias, and performed analysis using Review Manager and Trial Sequential Analysis. Evidence certainty was assessed using Grading of Recommendations Assessment, Development and Evaluation. The primary outcomes were the proportion of participants with an unfavorable functional outcome, the proportion of participants with one or more serious adverse events, and quality of life. We identified five randomized trials comparing ketamine versus sufentanil, fentanyl, other sedatives, or saline (total N = 149 participants). All outcomes were at overall high risk of bias. The proportions of participants with one or more serious adverse events did not differ between ketamine and sufentanil or fentanyl (relative risk 1.45, 95% confidence interval 0.81-2.58; very low certainty). Trial sequential analysis showed that further trials are needed. The level of evidence regarding the effects of ketamine on functional outcome and serious adverse events in patients with severe acute brain injury is very low. Ketamine may markedly, modestly, or not at all affect these outcomes. Large randomized clinical trials at low risk of bias are needed.

Spreading depolarization causes reversible neuronal mitochondria fragmentation and swelling in healthy, normally perfused neocortex.

Mitochondrial function is tightly linked to morphology, and fragmentation of dendritic mitochondria during noxious conditions suggests loss of function. In the normoxic cortex, spreading depolarization (SD) is a phenomenon underlying migraine aura. It is unknown whether mitochondria structure is affected by normoxic SD. In vivo two-photon imaging followed by quantitative serial section electron microscopy (ssEM) was used to monitor dendritic mitochondria in the normoxic cortex of urethane-anesthetized mature male and female mice during and after SD initiated by focal KCl microinjection. Structural dynamics of dendrites and their mitochondria were visualized by transfecting excitatory, glutamatergic neurons of the somatosensory cortex with bicistronic AAV, which induced tdTomoto labeling in neuronal cytoplasm and mitochondria labeling with roGFP. Normoxic SD triggered rapidly reversible fragmentation of dendritic mitochondria alongside dendritic beading; however, mitochondria took significantly longer to recover. Several rounds of SD resulted in transient mitochondrial fragmentation and dendritic beading without accumulating injury, as both recovered. SsEM corroborated normoxic SD-elicited dendritic and mitochondrial swelling and transformation of the filamentous mitochondrial network into shorter, swollen tubular, and globular structures. Our results revealed normoxic SD-induced disruption of the dendritic mitochondrial structure that might impact mitochondrial bioenergetics during migraine with aura.

Inflammatory response of leptomeninges to a single cortical spreading depolarization

BackgroundNeurogenic meningeal inflammation is regarded as a key driver of migraine headache. Multiple evidence show importance of inflammatory processes in the dura mater for pain generation but contribution of the leptomeninges is less clear. We assessed effects of cortical spreading depolarization (CSD), the pathophysiological mechanism of migraine aura, on expression of inflammatory mediators in the leptomeninges.MethodsA single CSD event was produced by a focal unilateral microdamage of the cortex in freely behaving rats. Three hours later intact cortical leptomeninges and parenchyma of ipsi-lesional (invaded by CSD) and sham-treated contra-lesional (unaffected by CSD) hemispheres were collected and mRNA levels of genes associated with inflammation (Il1b, Tnf, Ccl2; Cx3cl1, Zc3h12a) and endocannabinoid CB2 receptors (Cnr2) were measured using qPCR.ResultsThree hours after a single unilateral CSD, most inflammatory factors changed their expression levels in the leptomeninges, mainly on the side of CSD. The meninges overlying affected cortex increased mRNA expression of all proinflammatory cytokines (Il1b, Tnf, Ccl2) and anti-inflammatory factors Zc3h12a and Cx3cl1. Upregulation of proinflammatory cytokines was found in both meninges and parenchyma while anti-inflammatory markers increased only meningeal expression.ConclusionA single CSD is sufficient to produce pronounced leptomeningeal inflammation that lasts for at least three hours and involves mostly meninges overlying the cortex affected by CSD. The prolonged post-CSD inflammation of the leptomeninges can contribute to mechanisms of headache generation following aura phase of migraine attack.

Neurosurgical Management of Traumatic Brain Injury

The neurosurgical management of traumatic brain injury (TBI) plays a critical role in ensuring acute survival and mitigating secondary brain damage, which significantly impacts patients' quality of life. TBI is defined as an external force impacting the skull, leading to brain injuries and subsequent functional impairments. It is a leading cause of mortality and morbidity, particularly among young individuals. The initial clinical examination is crucial, with external signs like scalp injuries, hematomas, nasal fluid leakage, skull deformities, and neurological deficits providing important clues to injury patterns. Pupil examination is particularly critical, as mydriasis coupled with reduced consciousness may indicate an acute life-threatening increase in intracranial pressure (ICP), necessitating immediate neurosurgical intervention. TBI assessment often utilizes the Glasgow Coma Scale (GCS), classifying injuries as mild (GCS 13-15), moderate (GCS 9-12), or severe (GCS <9). Even mild TBI can lead to long-term complications. TBI should be viewed as a disease process rather than a singular event. Primary brain damage results from shearing forces on the parenchyma, manifesting as contusions, hematomas, or diffuse axonal injury. Secondary brain damage is driven by mechanisms such as inflammation and spreading depolarizations. Treatment aims not only to secure immediate survival but also to reduce secondary injuries, with ICP management being crucial. Neurosurgical interventions are guided by cranial pathologies, with options including ICP monitoring, burr hole trepanation, craniotomy. In severe TBI cases with refractory ICP elevation, decompressive craniectomy may be performed as a last resort, significantly reducing mortality but often resulting in high morbidity and vegetative states, necessitating careful consideration of indications.