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

Terminal spreading depolarization and electrical silence in death of human cerebral cortex

Objective: Restoring the circulation is the primary goal in emergency treatment of cerebral ischemia. However, better understanding of how the brain responds to energy depletion could help predict the time available for resuscitation until irreversible damage and advance development of interventions that prolong this span. Experimentally, injury to central neurons begins only with anoxic depolarization. This potentially reversible, spreading wave typically starts 2 to 5 minutes after the onset of severe ischemia, marking the onset of a toxic intraneuronal change that eventually results in irreversible injury. Methods: To investigate this in the human brain, we performed recordings with either subdural electrode strips (n = 4) or intraparenchymal electrode arrays (n = 5) in patients with devastating brain injury that resulted in activation of a Do Not Resuscitate–Comfort Care order followed by terminal extubation. Results: Withdrawal of life‐sustaining therapies produced a decline in brain tissue partial pressure of oxygen (ptiO2) and circulatory arrest. Silencing of spontaneous electrical activity developed simultaneously across regional electrode arrays in 8 patients. This silencing, termed “nonspreading depression,” developed during the steep falling phase of ptiO2 (intraparenchymal sensor, n = 6) at 11 (interquartile range [IQR] = 7–14) mmHg. Terminal spreading depolarizations started to propagate between electrodes 3.9 (IQR = 2.6–6.3) minutes after onset of the final drop in perfusion and 13 to 266 seconds after nonspreading depression. In 1 patient, terminal spreading depolarization induced the initial electrocerebral silence in a spreading depression pattern; circulatory arrest developed thereafter. Interpretation: These results provide fundamental insight into the neurobiology of dying and have important implications for survivable cerebral ischemic insults. Ann Neurol 2018;83:295–31

Neurobiological Mechanisms of Metacognitive Therapy – An Experimental Paradigm

IntroductionThe neurobiological mechanisms underlying the clinical effects of psychotherapy are scarcely understood. In particular, the modifying effects of psychotherapy on neuronal activity are largely unknown. We here present data from an innovative experimental paradigm using the example of a patient with treatment resistant obsessive-compulsive disorder (trOCD) who underwent implantation of bilateral electrodes for deep brain stimulation (DBS). The aim of the paradigm was to examine the short term effect of metacognitive therapy (MCT) on neuronal local field potentials (LFP) before and after 5 MCT sessions.MethodsDBS electrodes were implanted bilaterally with stereotactic guidance in the bed nucleus of the stria terminalis/ internal capsule (BNST/IC). The period between implantation of the electrodes and the pacemaker was used for the experimental paradigm. DBS electrodes were externalized via extension cables, yielding the opportunity to record LFP directly from the BNST/IC. The experimental paradigm was designed as follows: (a) baseline recording of LFP from the BNST/IC, (b) application of 5 MCT sessions over 3 days, (c) post-MCT recording from the BNST/IC. The Obsessive-Compulsive Disorder- scale (OCD-S) was used to evaluate OCD symptoms.ResultsOCD symptoms decreased after MCT. These reductions were accompanied by a decrease of the relative power of theta band activity, while alpha, beta, and gamma band activity was significantly increased after MCT. Further, analysis of BNST/IC LFP and frontal cortex EEG coherence showed that MCT decreased theta frequency band synchronization.DiscussionImplantation of DBS electrodes for treating psychiatric disorders offers the opportunity to gather data from neuronal circuits, and to compare effects of therapeutic interventions. Here, we demonstrate direct effects of MCT on neuronal oscillatory behavior, which may give possible cues for the neurobiological changes associated with psychotherapy

Simulation der Spreading Depolarization Trajektorien in der Hirnrinde: Korrelation zwischen der Geschwindigkeit und der Anfälligkeit bei den Patienten mit aneurysmaler Subarachnoidalblutung

Cortical spreading depolarization (SD) is fundamental mechanism observed in neuronal tissue which is provoked by critically low substrate influx. SD is characterized by the near-complete breakdown of transcellular ion gradients measurable as a pronounced drop in the membrane potential in neuronal tissue during many pathological states. So called slow potential change (SPC) propagates at the velocities between 2 and 9 mm/min. Typically the SD velocities correlate with the SD susceptibility in many animal models. For patients in neurocritical care, the Co-Operative Studies on Brain Injury Depolarization (COSBID) recommends several variables to quantify the SD occurrence and susceptibility, without providing the method for measurement of SD velocity. Therefore we developed an algorithm to estimate the SD velocities. The model is based on the semi-lunar arc representing the SD-wavefront which propagates across geometrically discretized brain surface. The surface was reconstructed from MRI scans to provide the spatial input. Temporal component is given by the differences between the SPC hit-times measured on the single electrodes of subdural six-channel electrode strip. After the onset of aneurysmatic subarachnoid hemorrhage (aSAH) the patients were admitted to intensive care unit and were subjected to electrocorticographic (ECoG) monitoring over the period of fifteen days. From the total of 70 available patients the analysis was technically feasible on 12 of them. The results contained great number of fitted trajectories. The output parameter, the SD-velocity (median 3.6(2.8 4.8) mm/min), was calculated from the velocities of every single trajectory of the corresponding event. Estimated SD-velocity was correlated against the independent clinical variables related to the SD susceptibility. Statistically significant correlations supported the validity of here proposed method. Not a single trajectory was found when electrode strip was placed on a lesion. Significantly frequent inability to render trajectories was present in the sub-group with the duration of isoelectric SDs >4min compared against the sub-group with the duration <4min, without significant difference in velocity between the two. It seems the SD velocity depends on local conditions of the tissue, in contrast to the propagation complexity which depends on the SD frequency and duration. Low rate of success in reconstructing the brains with pronounced anatomical changes as well as the inability of algorithm to exploit the SD-events with less than three active electrodes, are the limitations of this method.Spreading Depolarization (SD) ist der grundlegende Mechanismus, des beinahe kompletten Zusammenbruchs der transzellulären Ionengradienten mit resultierenden drastischen Abfall des Membranpotentials, der im neuronalen Gewebe bei einer Vielzahl neurologischer Erkrankungen auftritt. Die SD breitet sich in der Hirnrinde mit einer Geschwindigkeit zwischen 2 und 9 mm/min aus und wird als sogennante langsame Potentialänderung (englisch = slow potential change (SPC)) gemessen. Typischerweise korrelieren die Geschwindigkeit und die Suszeptibilität des Gewebes gegenüber der SD bei vielen Tiermodellen. Für das Monitoring von Patienten empfiehlt Co-Operative Studies on Brain Injury Depolarizations (COSBID) mehrere Variablen für die Quantifizierung des SD-Vorkommens und der SD-Suszeptibilität, nur fehlte bis jetzt eine zuverlässige Methode zur Geschwindigkeitsmessung. Deshalb haben wir einen Algorithmus für die Einschätzung der SD-Geschwindigkeit entwickelt. Das verwendete Modell basiert auf der Ausbreitung der semilunaren Wellenfront der SD auf der geometrisch diskreten Hirnoberfläche. Diese wurde aus den MRT-Aufnahmen rekonstruiert und dient als räumliche Eingangskomponente. Als zeitliche Eingangskomponente dienten die Differenzen zwischen den Ankunftszeiten der SD auf einzelnen Kontakten des sechskanaligen Elektrodenstreifens. Die Daten wurden bei Patienten die an einer aneurysmatischer Arachnoidalblutung littten und in Rahmen von COSBID untersucht wurden, erhoben. Von den 70 gemessenen Patienten war die Analyse nur bei 12 durchführbar. Die Ergebnisse enthielten eine große Anzahl der modellierten Trajektorien, außer bei Fällen in denen der Elektrodenstreifen auf einer Läsion platziert wurde. Das Ausgangsparameter, die SD-Geschwindigkeit (median 3,6 (2,8 4,8) mm/min), wurde aus den einzelnen Trajektoriengeschwindigkeiten berechnet. Dieses wurde gegen unabhängige suszeptibilitätsbezogene klinische Variablen mit hoher Signifikanz validiert. Oberhalb der Dauerg von 4 min war das Modelfitting von isoelektrischen SDs signifikant oft erfolglos, wobei sich die Geschwindigkeiten zwischen den beiden Untergruppen nicht unterscheiden. Es scheint dass die SD-Geschwindigkeit durch lokale Gewebeparameter und die Ausbreitungskomplexität durch die SD-Häufigkeit sowie die SD-Dauer beeinflusst wird. Niedrige Erfolgsrate bei der Diskretisierung der Hirnoberfläche aufgrund der durch die Erkrankung veränderten Anatomie und algorithmusbedingte Mindestanzahl von drei aktiven Elektroden sind die Schwächen dieser Methode

Influence of fMRI smoothing procedures on replicability of fine scale motor localization

Recent publications analyzing the influence of spatial smoothing on fMRI brain activation results demonstrated that smoothing may artificially combine activations from adjacent though functionally and anatomically distinct brain regions and that activation from large draining vessels may be smoothed into neighboring neuronal tissue. To investigate whether functional localizations may be artificially shifted by the smoothing procedure we performed replicability measurements. Localization centers of motor hand activations achieved during different conditions (isolated hand movements and simultaneous hand and chin movements) were compared with respect to smoothing effects. The voxel with the highest probability to represent a true positive activation was localized with a non-smoothed and a standard 4 × 4 × 6 mm smoothed correlational data analysis technique. Results show an increase of motor center aberrations between measurements by about 100% due to data smoothing indicating a statistically significant decrease in localization replicability

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

Experimental and preliminary clinical evidence of an ischemic zone with prolonged negative DC shifts surrounded by a normally perfused tissue belt with persistent electrocorticographic depression

In human cortex it has been suggested that the tissue at risk is indicated by clusters of spreading depolarizations (SDs) with persistent depression of high-frequency electrocorticographic (ECoG) activity. We here characterized this zone in the ET-1 model in rats using direct current (DC)-ECoG recordings. Topical application of the vasoconstrictor endothelin-1 (ET-1) induces focal ischemia in a concentration-dependent manner restricted to a region exposed by a cranial window, while a healthy cortex can be studied at a second naïve window. SDs originate in the ET-1-exposed cortex and invade the surrounding tissue. Necrosis is restricted to the ET-1-exposed cortex. In this study, we discovered that persistent depression occurred in both ET-1-exposed and surrounding cortex during SD clusters. However, the ET-1-exposed cortex showed longer-lasting negative DC shifts and limited high-frequency ECoG recovery after the cluster. DC-ECoG recordings of SD clusters with persistent depression from patients with aneurysmal subarachnoid hemorrhage were then analyzed for comparison. Limited ECoG recovery was associated with significantly longer-lasting negative DC shifts in a similar manner to the experimental model. These preliminary results suggest that the ischemic zone in rat and human cortex is surrounded by a normally perfused belt with persistently reduced synaptic activity during the acute injury phase

Spreading depolarizations in ischaemia after subarachnoid haemorrhage, a diagnostic phase III study

Focal brain damage after aneurysmal subarachnoid haemorrhage predominantly results from intracerebral haemorrhage, and early and delayed cerebral ischaemia. The prospective, observational, multicentre, cohort, diagnostic phase III trial, DISCHARGE-1, primarily investigated whether the peak total spreading depolarization-induced depression duration of a recording day during delayed neuromonitoring (delayed depression duration) indicates delayed ipsilateral infarction. Consecutive patients (n = 205) who required neurosurgery were enrolled in six university hospitals from September 2009 to April 2018. Subdural electrodes for electrocorticography were implanted. Participants were excluded on the basis of exclusion criteria, technical problems in data quality, missing neuroimages or patient withdrawal (n = 25). Evaluators were blinded to other measures. Longitudinal MRI, and CT studies if clinically indicated, revealed that 162/180 patients developed focal brain damage during the first 2 weeks. During 4.5 years of cumulative recording, 6777 spreading depolarizations occurred in 161/180 patients and 238 electrographic seizures in 14/180. Ten patients died early; 90/170 developed delayed infarction ipsilateral to the electrodes. Primary objective was to investigate whether a 60-min delayed depression duration cut-off in a 24-h window predicts delayed infarction with >0.60 sensitivity and >0.80 specificity, and to estimate a new cut-off. The 60-min cut-off was too short. Sensitivity was sufficient [= 0.76 (95% confidence interval: 0.65-0.84), P = 0.0014] but specificity was 0.59 (0.47-0.70), i.e. 0.60 sensitivity and >0.80 specificity. Although spontaneous resolution of the neurological deficit is still possible, we recommend initiating rescue treatment at the 60-min rather than the 180-min cut-off if progression of injury to infarction is to be prevented. Focal damage after subarachnoid haemorrhage results from intracerebral haemorrhage and cerebral ischaemia. In a prospective, observational, multicentre, diagnostic phase III trial, DISCHARGE-1, Dreier et al. examine whether monitoring cortical spreading depolarizations can predict delayed infarction-and thus poor outcomes

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