Svetlana Lublinsky

Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group

Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches.

Quantitative imaging assessment of blood-brain barrier permeability in humans

The blood–brain barrier (BBB) is a functional and structural barrier separating the intravascular and neuropil compartments of the brain. It characterizes the vascular bed and is essential for normal brain functions. Dysfunction in the BBB properties have been described in most common neurological disorders, such as stroke, traumatic injuries, intracerebral hemorrhage, tumors, epilepsy and neurodegenerative disorders. It is now obvious that the BBB plays an important role in normal brain activity, stressing the need for applicable imaging and assessment methods. Recent advancements in imaging techniques now make it possible to establish sensitive and quantitative methods for the assessment of BBB permeability. However, most of the existing techniques require complicated and demanding dynamic scanning protocols that are impractical and cannot be fulfilled in some cases. We review existing methods for the evaluation of BBB permeability, focusing on quantitative magnetic resonance-based approaches and discuss their drawbacks and limitations. In light of those limitations we propose two new approaches for BBB assessment with less demanding imaging sequences: the “post-pre” and the “linear dynamic” methods, both allow semi-quantitative permeability assessment and localization of dysfunctional BBB with simple/partial dynamic imaging protocols and easy-to-apply analysis algorithms. We present preliminary results and show an example which compares these new methods with the existing standard assessment method. We strongly believe that the establishment of such “easy to use” and reliable imaging methods is essential before BBB assessment can become a routine clinical tool. Large clinical trials are awaited to fully understand the significance of BBB permeability as a biomarker and target for treatment in neurological disorders.

Impaired neurovascular coupling to ictal epileptic activity and spreading depolarization in a patient with subarachnoid hemorrhage: Possible link to blood–brain barrier dysfunction

Spreading depolarization describes a sustained neuronal and astroglial depolarization with abrupt ion translocation between intraneuronal and extracellular space leading to a cytotoxic edema and silencing of spontaneous activity. Spreading depolarizations occur abundantly in acutely injured human brain and are assumed to facilitate neuronal death through toxic effects, increased metabolic demand, and inverse neurovascular coupling. Inverse coupling describes severe hypoperfusion in response to spreading depolarization. Ictal epileptic events are less frequent than spreading depolarizations in acutely injured human brain but may also contribute to lesion progression through increased metabolic demand. Whether abnormal neurovascular coupling can occur with ictal epileptic events is unknown. Herein we describe a patient with aneurysmal subarachnoid hemorrhage in whom spreading depolarizations and ictal epileptic events were measured using subdural opto‐electrodes for direct current electrocorticography and regional cerebral blood flow recordings with laser‐Doppler flowmetry. Simultaneously, changes in tissue partial pressure of oxygen were recorded with an intraparenchymal oxygen sensor. Isolated spreading depolarizations and clusters of recurrent spreading depolarizations with persistent depression of spontaneous activity were recorded over several days followed by a status epilepticus. Both spreading depolarizations and ictal epileptic events where accompanied by hyperemic blood flow responses at one optode but mildly hypoemic blood flow responses at another. Of note, quantitative analysis of Gadolinium‐diethylene‐triamine‐pentaacetic acid (DTPA)–enhanced magnetic resonance imaging detected impaired blood–brain barrier integrity in the region where the optode had recorded the mildly hypoemic flow responses. The data suggest that abnormal flow responses to spreading depolarizations and ictal epileptic events, respectively, may be associated with blood–brain barrier dysfunction.

Imaging blood–brain barrier dysfunction as a biomarker for epileptogenesis

A biomarker that will enable the identification of patients at high-risk for developing post-injury epilepsy is critically required. Microvascular pathology and related blood-brain barrier dysfunction and neuroinflammation were shown to be associated with epileptogenesis after injury. Here we used prospective, longitudinal magnetic resonance imaging to quantitatively follow blood-brain barrier pathology in rats following status epilepticus, late electrocorticography to identify epileptic animals and post-mortem immunohistochemistry to confirm blood-brain barrier dysfunction and neuroinflammation. Finally, to test the pharmacodynamic relevance of the proposed biomarker, two anti-epileptogenic interventions were used; isoflurane anaesthesia and losartan. Our results show that early blood-brain barrier pathology in the piriform network is a sensitive and specific predictor (area under the curve of 0.96, P < 0.0001) for epilepsy, while diffused pathology is associated with a lower risk. Early treatments with either isoflurane anaesthesia or losartan prevented early microvascular damage and late epilepsy. We suggest quantitative assessment of blood-brain barrier pathology as a clinically relevant predictive, diagnostic and pharmaco!dynamics biomarker for acquired epilepsy.

Epileptiform activity and spreading depolarization in the blood-brain barrier-disrupted peri-infarct hippocampus are associated with impaired GABAergic inhibition and synaptic plasticity.

Peri-infarct opening of the blood–brain barrier may be associated with spreading depolarizations, seizures, and epileptogenesis as well as cognitive dysfunction. We aimed to investigate the mechanisms underlying neural network pathophysiology in the blood–brain barrier-dysfunctional hippocampus. Photothrombotic stroke within the rat neocortex was associated with increased intracranial pressure, vasogenic edema, and peri-ischemic blood–brain barrier dysfunction that included the ipsilateral hippocampus. Intrahippocampal recordings revealed electrographic seizures within the first week in two-thirds of animals, accompanied by a reduction in gamma and increase in theta frequency bands. Synaptic interactions were studied in parasagittal hippocampal slices at 24 h and seven days post-stroke. Field potential recordings in CA1 and CA3 uncovered multiple population spikes, epileptiform episodes, and spreading depolarizations at 24 h. Input–output analysis revealed that fEPSP-spike coupling was significantly enhanced at seven days. In addition, CA1 feedback and feedforward inhibition were diminished. Slices generating epileptiform activity at seven days revealed impaired bidirectional long-term plasticity following high and low-frequency stimulation protocols. Microarray and PCR data confirmed changes in expression of astrocyte-related genes and suggested downregulation in expression of GABAA-receptor subunits. We conclude that blood-brain barrier dysfunction in the peri-infarct hippocampus is associated with early disinhibition, hyperexcitability, and abnormal synaptic plasticity.

Automated Cross-Sectional Measurement Method of Intracranial Dural Venous Sinuses

BACKGROUND AND PURPOSE: MRV is an important blood vessel imaging and diagnostic tool for the evaluation of stenosis, occlusions, or aneurysms. However, an accurate image-processing tool for vessel comparison is unavailable. The purpose of this study was to develop and test an automated technique for vessel cross-sectional analysis. MATERIALS AND METHODS: An algorithm for vessel cross-sectional analysis was developed that included 7 main steps: 1) image registration, 2) masking, 3) segmentation, 4) skeletonization, 5) cross-sectional planes, 6) clustering, and 7) cross-sectional analysis. Phantom models were used to validate the technique. The method was also tested on a control subject and a patient with idiopathic intracranial hypertension (4 large sinuses tested: right and left transverse sinuses, superior sagittal sinus, and straight sinus). The cross-sectional area and shape measurements were evaluated before and after lumbar puncture in patients with idiopathic intracranial hypertension. RESULTS: The vessel-analysis algorithm had a high degree of stability with <3% of cross-sections manually corrected. All investigated principal cranial blood sinuses had a significant cross-sectional area increase after lumbar puncture (P ≤ .05). The average triangularity of the transverse sinuses was increased, and the mean circularity of the sinuses was decreased by 6% ± 12% after lumbar puncture. Comparison of phantom and real data showed that all computed errors were <1 voxel unit, which confirmed that the method provided a very accurate solution. CONCLUSIONS: In this article, we present a novel automated imaging method for cross-sectional vessels analysis. The method can provide an efficient quantitative detection of abnormalities in the dural sinuses.

Creating normograms of dural sinuses in healthy persons using computer-assisted detection for analysis and comparison of cross-section dural sinuses in the brain

Dural sinuses vary in size and shape in many pathological conditions with abnormal intracranial pressure. Size and shape normograms of dural brain sinuses are not available. The creation of such normograms may enable computer-assisted comparison to pathologic exams and facilitate diagnoses. The purpose of this study was to quantitatively evaluate normal magnetic resonance venography (MRV) studies in order to create normograms of dural sinuses using a computerized algorithm for vessel cross-sectional analysis. This was a retrospective analysis of MRV studies of 30 healthy persons. Data were analyzed using a specially developed Matlab algorithm for vessel cross-sectional analysis. The cross-sectional area and shape measurements were evaluated to create normograms. Mean cross-sectional size was 53.27±13.31 for the right transverse sinus (TS), 46.87+12.57 for the left TS (p=0.089) and 36.65+12.38 for the superior sagittal sinus. Normograms were created. The distribution of cross-sectional areas along the vessels showed distinct patterns and a parallel course for the median, 25th, 50th and 75th percentiles. In conclusion, using a novel computerized method for vessel cross-sectional analysis we were able to quantitatively characterize dural sinuses of healthy persons and create normograms.

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-fronts 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 algorithms 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.

Quantitative imaging biomarkers for dural sinus patterns in idiopathic intracranial hypertension

To quantitatively characterize transverse dural sinuses (TS) on magnetic resonance venography (MRV) in patients with idiopathic intracranial hypertension (IIH), compared to healthy controls, using a computer assisted detection (CAD) method.

Quantifying response to intracranial pressure normalization in idiopathic intracranial hypertension via dynamic neuroimaging

Idiopathic intracranial hypertension (IIH) is characterized by elevated intracranial pressure without a clear cause.