Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group
Charité1, University of Copenhagen2, Harvard University3, Heidelberg University4, University of New Mexico5, University of Cologne6, Max Planck Society7, Innsbruck Medical University8, Yamaguchi University9, University of Cincinnati10, University of Antwerp11, University of Bonn12, King's College London13, French Institute of Health and Medical Research14, Claude Bernard University Lyon 115, Goethe University Frankfurt16, Columbia University17, Ben-Gurion University of the Negev18, Dalhousie University19, Georgia Regents University20, Queen's University21, University of Szeged22, University of Utah23, Autonomous University of Barcelona24, Humboldt University of Berlin25, University of Jena26, Cajal Institute27, Imperial College London28, University of Pittsburgh29, University of Miami30, University of Tübingen31, Leiden University32, Utrecht University33, University of British Columbia34
01 May 2017-Journal of Cerebral Blood Flow and Metabolism (Nature Publishing Group)-Vol. 37, Iss: 5, pp 1595-1625
TL;DR: Consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions are provided, which offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches.
Abstract: 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.
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TL;DR: The InTBIR Participants and Investigators have provided informed consent for the study to take place in Poland.
Abstract: Additional co-authors: Endre Czeiter, Marek Czosnyka, Ramon Diaz-Arrastia, Jens P Dreier, Ann-Christine Duhaime, Ari Ercole, Thomas A van Essen, Valery L Feigin, Guoyi Gao, Joseph Giacino, Laura E Gonzalez-Lara, Russell L Gruen, Deepak Gupta, Jed A Hartings, Sean Hill, Ji-yao Jiang, Naomi Ketharanathan, Erwin J O Kompanje, Linda Lanyon, Steven Laureys, Fiona Lecky, Harvey Levin, Hester F Lingsma, Marc Maegele, Marek Majdan, Geoffrey Manley, Jill Marsteller, Luciana Mascia, Charles McFadyen, Stefania Mondello, Virginia Newcombe, Aarno Palotie, Paul M Parizel, Wilco Peul, James Piercy, Suzanne Polinder, Louis Puybasset, Todd E Rasmussen, Rolf Rossaint, Peter Smielewski, Jeannette Soderberg, Simon J Stanworth, Murray B Stein, Nicole von Steinbuchel, William Stewart, Ewout W Steyerberg, Nino Stocchetti, Anneliese Synnot, Braden Te Ao, Olli Tenovuo, Alice Theadom, Dick Tibboel, Walter Videtta, Kevin K W Wang, W Huw Williams, Kristine Yaffe for the InTBIR Participants and Investigators
1,354 citations
TL;DR: Increasing evidence from epidemiological, clinical and experimental studies indicate that age-related cerebromicrovascular dysfunction and microcirculatory damage play critical roles in the pathoge as discussed by the authors.
Abstract: Increasing evidence from epidemiological, clinical and experimental studies indicate that age-related cerebromicrovascular dysfunction and microcirculatory damage play critical roles in the pathoge
287 citations
University of Cincinnati Academic Health Center1, University of New Mexico2, Georgia Regents University3, Harvard University4, Queen's University5, Imperial College London6, University of Utah7, Humboldt University of Berlin8, Charité9, University of Cologne10, University of Szeged11, Max Planck Society12, Innsbruck Medical University13, University of Copenhagen14, University Hospital Heidelberg15, King's College London16
TL;DR: The spreading depolarization continuum further applies to other models of acute cortical lesions, suggesting that it is a universal principle of cortical lesion development.
Abstract: A modern understanding of how cerebral cortical lesions develop after acute brain injury is based on Aristides Leao's historic discoveries of spreading depression and asphyxial/anoxic depolarization. Treated as separate entities for decades, we now appreciate that these events define a continuum of spreading mass depolarizations, a concept that is central to understanding their pathologic effects. Within minutes of acute severe ischemia, the onset of persistent depolarization triggers the breakdown of ion homeostasis and development of cytotoxic edema. These persistent changes are diagnosed as diffusion restriction in magnetic resonance imaging and define the ischemic core. In delayed lesion growth, transient spreading depolarizations arise spontaneously in the ischemic penumbra and induce further persistent depolarization and excitotoxic damage, progressively expanding the ischemic core. The causal role of these waves in lesion development has been proven by real-time monitoring of electrophysiology, blood flow, and cytotoxic edema. The spreading depolarization continuum further applies to other models of acute cortical lesions, suggesting that it is a universal principle of cortical lesion development. These pathophysiologic concepts establish a working hypothesis for translation to human disease, where complex patterns of depolarizations are observed in acute brain injury and appear to mediate and signal ongoing secondary damage.
279 citations
Cites background from "Recording, analysis, and interpreta..."
...During repetitive SDs, the failure of subsets of neurons to repolarize may underlie the shallow negative ultraslow potential (NUP) that is sometimes observed.(10,151) Third, in comparison to the initial depolarization of ischemia, neuronal injury from secondary SDs may be more dependent on excess accumulation of extracellular glutamate and NMDA receptormediated Ca2þ loading....
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Emory University1, University of Amsterdam2, Aix-Marseille University3, University of Erlangen-Nuremberg4, Anschutz Medical Campus5, Boston Children's Hospital6, University of Colorado Denver7, University of California, Los Angeles8, Georgetown University9, Yale University10, UCB11, University of California, San Francisco12, University of Eastern Finland13, University of California, Davis14, Turku University Hospital15, Morehouse School of Medicine16, University of Bonn17, Mario Negri Institute for Pharmacological Research18, UCL Institute of Neurology19, University of Veterinary Medicine Vienna20
TL;DR: The identification of impending epilepsy biomarkers to allow better patient selection, together with better alignment with multisite preclinical trials in animal models, should guide the clinical testing of new hypotheses for epileptogenesis and its prevention.
Abstract: The most common forms of acquired epilepsies arise following acute brain insults such as traumatic brain injury, stroke, or central nervous system infections. Treatment is effective for only 60%-70% of patients and remains symptomatic despite decades of effort to develop epilepsy prevention therapies. Recent preclinical efforts are focused on likely primary drivers of epileptogenesis, namely inflammation, neuron loss, plasticity, and circuit reorganization. This review suggests a path to identify neuronal and molecular targets for clinical testing of specific hypotheses about epileptogenesis and its prevention or modification. Acquired human epilepsies with different etiologies share some features with animal models. We identify these commonalities and discuss their relevance to the development of successful epilepsy prevention or disease modification strategies. Risk factors for developing epilepsy that appear common to multiple acute injury etiologies include intracranial bleeding, disruption of the blood-brain barrier, more severe injury, and early seizures within 1 week of injury. In diverse human epilepsies and animal models, seizures appear to propagate within a limbic or thalamocortical/corticocortical network. Common histopathologic features of epilepsy of diverse and mostly focal origin are microglial activation and astrogliosis, heterotopic neurons in the white matter, loss of neurons, and the presence of inflammatory cellular infiltrates. Astrocytes exhibit smaller K+ conductances and lose gap junction coupling in many animal models as well as in sclerotic hippocampi from temporal lobe epilepsy patients. There is increasing evidence that epilepsy can be prevented or aborted in preclinical animal models of acquired epilepsy by interfering with processes that appear common to multiple acute injury etiologies, for example, in post-status epilepticus models of focal epilepsy by transient treatment with a trkB/PLCγ1 inhibitor, isoflurane, or HMGB1 antibodies and by topical administration of adenosine, in the cortical fluid percussion injury model by focal cooling, and in the albumin posttraumatic epilepsy model by losartan. Preclinical studies further highlight the roles of mTOR1 pathways, JAK-STAT3, IL-1R/TLR4 signaling, and other inflammatory pathways in the genesis or modulation of epilepsy after brain injury. The wealth of commonalities, diversity of molecular targets identified preclinically, and likely multidimensional nature of epileptogenesis argue for a combinatorial strategy in prevention therapy. Going forward, the identification of impending epilepsy biomarkers to allow better patient selection, together with better alignment with multisite preclinical trials in animal models, should guide the clinical testing of new hypotheses for epileptogenesis and its prevention.
190 citations
Cites background from "Recording, analysis, and interpreta..."
...Similarly, spreading depolarizations (a form of peri-injury spreading depression seen on intracranial EEG) are common in a variety of acute brain injuries, including subarachnoid hemorrhage, TBI, spontaneous intraparenchymal hemorrhage, and malignant ischemic stroke.(14) Acute Key Points...
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TL;DR: It is summarized that spreading depolarization is the electrophysiological correlate of the cytotoxic edema in various gray matter structures of the brain and vasogenic edema is the other major type of cerebral edema with relevance to ischemic stroke.
133 citations
References
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Stanford University1, HCL Technologies2, Universidad Mayor3, UCL Institute of Child Health4, University of Bonn5, University of California, Los Angeles6, Umeå University7, New York University8, Columbia University9, Yonsei University10, Albert Einstein College of Medicine11, University of Pavia12, University of Melbourne13, Karolinska Institutet14, University of Calgary15
TL;DR: A revised definition of epilepsy brings the term in concordance with common use for individuals who either had an age‐dependent epilepsy syndrome but are now past the applicable age or who have remained seizure‐free for the last 10 years and off antiseizure medicines for at least the last 5 years.
Abstract: Epilepsy was defined conceptually in 2005 as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. This definition is usually practically applied as having two unprovoked seizures >24 h apart. The International League Against Epilepsy (ILAE) accepted recommendations of a task force altering the practical definition for special circumstances that do not meet the two unprovoked seizures criteria. The task force proposed that epilepsy be considered to be a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for individuals who either had an age-dependent epilepsy syndrome but are now past the applicable age or who have remained seizure-free for the last 10 years and off antiseizure medicines for at least the last 5 years. "Resolved" is not necessarily identical to the conventional view of "remission or "cure." Different practical definitions may be formed and used for various specific purposes. This revised definition of epilepsy brings the term in concordance with common use. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
3,491 citations
TL;DR: In this article, an interesting response elicited by electrical stimulation was noticed in the cortex of rabbits, and the distinctive feature of this response was a marked, enduring reduction of the "spontaneous" electrical activity of the cortex.
Abstract: THIS STUDY originated in an attempt to secure more data for the understanding of the cortical electrogram which occurs in “experimental epilepsy,” and of the conditions in which it is brought forth by electrical stimulation. Early in the development of the study an interesting response, elicited by electrical stimulation, was noticed in the cortex of rabbits. The distinctive feature of this response was a marked, enduring reduction of the “spontaneous” electrical activity of the cortex. We have endeavored to define experimentally some of the characteristics of this response.
2,485 citations
"Recording, analysis, and interpreta..." refers background in this paper
...If epileptiform field potentials arise on the tailing end of the DC shift this should be documented as ‘‘spreading convulsion’’ which is a historical term based on van Harreveld and Stamm (Figure 3(d)).(58,109,121) If a spreading convulsion occurs in isoelectric tissue it may also be documented as ‘‘isoelectric SD’’ depending on the scope of the study....
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...(d) A spreading convulsion is an SD in which epileptic field potentials arise on the tailing end of the DC shift.(58,109,121) Dreier et al....
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TL;DR: It is suggested that the limited survival of the penumbra is due to periinfarct depolarizations, which result in repeated episodes of tissue hypoxia, because the increased metabolic workload is not coupled to an adequate increase of collateral blood supply.
Abstract: The classic concept of the viability thresholds of ischemia differentiates between two critical flow rates, the threshold of electrical failure and the threshold of membrane failure. These thresholds mark the upper and lower flow limits of the ischemic penumbra which is thought ot suffer only functional but not structural injury. Recent studies of the functional and metabolic disturbances suggest a more complex pattern of thresholds. At declining flow rates, protein synthesis is inhibited at first (at a threshold of about 0.55 ml/gm/min), followed by a stimulation of anaerobic glycolysis (at 0.35 ml/gm/min), the release of neurotransmitters and the beginning disturbance of energy metabolism (at about 0.20 ml/min), and finally the anoxic depolariztion (<0.15 ml/gm/min). The penumbra, as defined by the classic flow thresholds, does not remain viable for extended periods. Since viability of the tissue requires maintenance of energy-dependent metabolic processes, penumbra is redefined as a region of constrained blood supply in which the energy metabolism is preserved. Imaging of the penumbra by combining autoradiographic cerebral blood flow measurements with bioluminescent images of adenosine triphosphate (ATP) demonstrates a gradual expansion of the infarct core (in which ATP is depleted) into the penumbra until, after a few hours, the penumbra has disappeared. It is suggested that the limited survival of the penumbra is due to periinfarct depolarizations, which result in repeated episodes of tissue hypoxia, because the increased metabolic workload is not coupled to an adequate increase of collateral blood supply. This explains pharmacological suppression of periinfarct depolarizations lowering the threshold of metabolic disturbances and reducing the volume of the ischemic infarct.
1,367 citations
"Recording, analysis, and interpreta..." refers background in this paper
...Typically, the first SD starts in the ischemic core at one or more points in the tissue 2–5min after the onset of ischemia.(107,108,156,160,166,167) Notably, SD does not mark the onset of cell death, but rather starts the clock on the countdown to cell death....
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...This indicates that rCBF must still have been above 15–23 mL/100 g/min at electrodes 5 and 6 when the SD invaded the underlying cortex.(107) Most likely, the SD triggered...
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...Spontaneous electrical activity can only be maintained in tissue if rCBF is above the range of 15–23mL/ 100 g/min.(107) An abrupt decrease of rCBF below this range inevitably causes arrest of spontaneous activity within several tens of seconds well before ischemia induces SD (left panel in Figure 8)....
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...by a perfusion level below 15 mL/100 g/min, the inner penumbra (ip) by a perfusion level below 20 mL/100 g/min and the outer penumbra (op) by a perfusion level below 55 mL/100 g/min (a).(107) The first electrophysiological change in response to ischemia is nonspreading depression of activity(15) which is complete in core and inner penumbra about 30–40 s after the onset of ischemia...
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TL;DR: High-field functional MRI with near-continuous recording during visual aura in three subjects observed blood oxygenation level-dependent signal changes that strongly suggest that an electrophysiological event such as CSD generates the aura in human visual cortex.
Abstract: Cortical spreading depression (CSD) has been suggested to underlie migraine visual aura. However, it has been challenging to test this hypothesis in human cerebral cortex. Using high-field functional MRI with near-continuous recording during visual aura in three subjects, we observed blood oxygenation level-dependent (BOLD) signal changes that demonstrated at least eight characteristics of CSD, time-locked to percept/onset of the aura. Initially, a focal increase in BOLD signal (possibly reflecting vasodilation), developed within extrastriate cortex (area V3A). This BOLD change progressed contiguously and slowly (3.5 ± 1.1 mm/min) over occipital cortex, congruent with the retinotopy of the visual percept. Following the same retinotopic progression, the BOLD signal then diminished (possibly reflecting vasoconstriction after the initial vasodilation), as did the BOLD response to visual activation. During periods with no visual stimulation, but while the subject was experiencing scintillations, BOLD signal followed the retinotopic progression of the visual percept. These data strongly suggest that an electrophysiological event such as CSD generates the aura in human visual cortex.
1,335 citations
TL;DR: The combined experimental and clinical studies point to fruitful areas in which to look for migraine treatments of the future and provide a framework within which important aspects of the migraine attack can be modelled.
Abstract: The characteristic form and development of sensory disturbances during migraine auras suggests that the underlying mechanism is a disturbance of the cerebral cortex, probably the cortical spreading depression (CSD) of Leao. The demonstration of unique changes of brain blood flow during attacks of migraine with aura, which have been replicated in animal experiments during CSD, constitutes another important line of support for the 'spreading depression' theory, which may be a key to an understanding of the migraine attack. Cortical spreading depression is a short-lasting depolarization wave that moves across the cortex at a rate of 3-5 mm/min. A brief phase of excitation heralds the reaction which is immediately followed by prolonged nerve cell depression synchronously with a dramatic failure of brain ion homeostasis, efflux of excitatory amino acids from nerve cells and enhanced energy metabolism. Recent experimental work has shown that CSD in the neocortex of a variety of species including man is dependent on activation of a single receptor, the N-methyl-D-aspartate receptor, one of the three subtypes of glutamate receptors. The combined experimental and clinical studies point to fruitful areas in which to look for migraine treatments of the future and provide a framework within which important aspects of the migraine attack can be modelled.
1,089 citations
"Recording, analysis, and interpreta..." refers background in this paper
...Spreading convulsion is a peculiar hybrid phenomenon between IEE and SD, characterized by epileptiform field potentials on the tailing end of the DC shift instead of the usually triggered spreading depression (Figure 3(d)).(40,57,58) Similar to SDs, IEEs often occur in patients with severe cerebral injuries in both the acute and subacute period....
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