The Persistent Vegetative State: Evidence That the Lower Brain Survives Because Its Neurons Intrinsically Resist Ischemia

Andrew, R. David

doi:10.1007/978-3-319-21425-2_10

Cited by 5 publications

(16 citation statements)

References 70 publications

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“…We suggest that SD has evolved distant in our vertebrate past. Because occlusive stroke and cardiac arrest have only become prevalent recently as the human lifespan has increased, 19,20 sudden loss of blood flow in these non-traumatic cases will elicit SD and vasoconstriction (inverse neurovascular coupling) as though the brain region is hemorrhaging from TBI. 26 This may explain why SD during ischemia is robust in higher brain regions that are most exposed to impact.…”

Section: Discussionmentioning

confidence: 99%

“…In line with the findings here, hypothalamus and brainstem gray show only weak and recoverable AD in response to OGD. 19,20,35,37…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13][14] Several studies indicate that more rostral brain regions are more susceptible to ischemia 15,16 and generate stronger AD. [17][18][19][20] In this article, we examine whether this is also true regarding SD Kt and if there are regional differences in the ability to inhibit SD Kt in the presence of the glutamate receptor antagonist kynurenate. Live brain slices allow study of the intrinsic propensity of neurons to generate AD because potential variability in blood flow among brain regions is not a factor.…”

Section: Introductionmentioning

confidence: 99%

“…Along similar lines, we have proposed that mammalian SD promotes a ''lie-low'' survival strategy by promoting sudden loss of consciousness following TBI whereby the chances of epileptiform activity and brain hemorrhage are reduced and metabolism is lowered. 19,28 Immediately upon head trauma from a predator, from warfare or from falling out of a tree, shut-down is a good default behavior. It is better to be quiescent when injured than to be moving in a slow or epileptiform fashion which advertises injury.…”

Section: Introductionmentioning

confidence: 99%

“…9,10 Here we examine the regional susceptibility of the brain to generate SD Kt and whether that susceptibility emulates the propensity of higher brain neurons to generate strong AD in comparison with lower brain gray matter. 19,20 If SD Kt is a weaker or residual version of SD, it follows that lower brain regions being more protected from TBI by bone and higher brain (even early in vertebrate evolution) should be less susceptible to SD Kt .…”

Section: Introductionmentioning

confidence: 99%

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Spreading depolarization triggered by elevated potassium is weak or absent in the rodent lower brain

Andrew

Hsieh

Brisson

2016

J Cereb Blood Flow Metab

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We examined in live coronal slices from rat and mouse which brain regions generate potassium-triggered spreading depolarization (SD). This technique simulates cortical spreading depression, which underlies migraine aura in the intact brain. An SD episode was evoked by increasing bath [K] and recorded as a propagating front of elevated light transmittance representing transient neuronal swelling in gray matter of neocortex, hippocampus, striatum, and thalamus. In contrast, SD was not imaged in hypothalamic nuclei or brainstem with exception of those nuclei near the dorsal brainstem surface. In rat slices, single neurons were whole-cell current clamped during SD. "Higher" neurons depolarized to near zero millivolts indicating SD generation. In contrast, seven types of neurons in hypothalamus and brainstem only slowly depolarized without generating SD, supporting our imaging findings. Therefore, SD is not a default of CNS neurons but rather displays a region-specific susceptibility, similar to anoxic depolarization, which we have proposed is correlated with a region's vulnerability to traumatic brain injury. In the higher brain, SD may be a vestigial spreading depolarization that originally evolved to shut down and vasoconstrict gray matter regions more exposed to impact and contusion.

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Section: Discussionmentioning

confidence: 99%

“…In line with the findings here, hypothalamus and brainstem gray show only weak and recoverable AD in response to OGD. 19,20,35,37…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Spreading depolarization triggered by elevated potassium is weak or absent in the rodent lower brain

Andrew

Hsieh

Brisson

2016

J Cereb Blood Flow Metab

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The Critical Role of Spreading Depolarizations in Early Brain Injury: Consensus and Contention

et al. 2022

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Background When a patient arrives in the emergency department following a stroke, a traumatic brain injury, or sudden cardiac arrest, there is no therapeutic drug available to help protect their jeopardized neurons. One crucial reason is that we have not identified the molecular mechanisms leading to electrical failure, neuronal swelling, and blood vessel constriction in newly injured gray matter. All three result from a process termed spreading depolarization (SD). Because we only partially understand SD, we lack molecular targets and biomarkers to help neurons survive after losing their blood flow and then undergoing recurrent SD. Methods In this review, we introduce SD as a single or recurring event, generated in gray matter following lost blood flow, which compromises the Na+/K+ pump. Electrical recovery from each SD event requires so much energy that neurons often die over minutes and hours following initial injury, independent of extracellular glutamate. Results We discuss how SD has been investigated with various pitfalls in numerous experimental preparations, how overtaxing the Na+/K+ ATPase elicits SD. Elevated K+ or glutamate are unlikely natural activators of SD. We then turn to the properties of SD itself, focusing on its initiation and propagation as well as on computer modeling. Conclusions Finally, we summarize points of consensus and contention among the authors as well as where SD research may be heading. In an accompanying review, we critique the role of the glutamate excitotoxicity theory, how it has shaped SD research, and its questionable importance to the study of early brain injury as compared with SD theory.

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Multiscale computer modeling of spreading depolarization in brain slices

Kelley

Newton

Hrabětová

et al. 2022

Preprint

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Spreading depolarization (SD) is a slow-moving wave of neuronal depolarization accompanied by a breakdown of ion concentration homeostasis, followed by long periods of neuronal silence (spreading depression), and associated with several neurological conditions. We developed multiscale (ions to tissue slice) computer models of SD in brain slices using the NEURON simulator: 36,000 neurons (2 voltage-gated ion channels; 3 leak channels; 3 ion exchangers/pumps) in the extracellular space (ECS) of a slice (1 mm sides, varying thickness) with ion (K+ , Cl-, Na+) and O2 diffusion and equilibration with a surrounding bath. Glia and neurons cleared K+ from the ECS via Na+/K+ pumps. SD propagated through the slices at realistic speeds of 2-5 mm/min, which was augmented by 25-30% in models incorporating the effects of hypoxia or of propionate. In both cases, the speedup was mediated principally by ECS shrinkage. Our model allows us to make the following testable predictions: 1. SD can be inhibited by enlarging ECS volume; 2. SD velocity will be greater in areas with greater neuronal density, total neuronal volume, or larger/more dendrites; 3. SD is all-or-none: initiating K+ bolus properties have little impact on SD speed; 4. Slice thickness influences SD due to relative hypoxia in the slice core, exacerbated by SD in a pathological cycle; 5. Higher neuronal spike rates and faster spread will be observed in the core than the periphery of perfused slice during SD.

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The Persistent Vegetative State: Evidence That the Lower Brain Survives Because Its Neurons Intrinsically Resist Ischemia

Cited by 5 publications

References 70 publications

Spreading depolarization triggered by elevated potassium is weak or absent in the rodent lower brain

Spreading depolarization triggered by elevated potassium is weak or absent in the rodent lower brain

The Critical Role of Spreading Depolarizations in Early Brain Injury: Consensus and Contention

Multiscale computer modeling of spreading depolarization in brain slices

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