Exploitation of the spreading depolarization-induced cytotoxic edema for high-resolution, 3D mapping of its heterogeneous propagation paths

Abstract

Spreading depolarization (SD) is among the most archaic pathological phenomena of the central nervous system and already occurs in comparably primitive animals, such as locusts and cockroaches (1). SD describes a regenerative, all-or-none type of depolarization wave in gray matter of the central nervous system characterized by the abrupt, near-complete breakdown of the transneuronal ion gradients. It is assumed that SD is perceived as migraine aura when it invades a perceptual and eloquent brain region, where it induces spreading depression of the normal brain activity. However, SD also occurs in various conditions other than migraine, including stroke and traumatic brain injury (TBI). Although there is unequivocal electrophysiological evidence that SD often induces spreading depression of activity in stroke and TBI, computational dysfunction before SD migration through the tissue usually precludes the patient percept of a migraine aura in these injurious conditions (2). Initiation, recovery, pharmacology, depression patterns, and toxicity may vary dramatically along the propagation path of a single SD wave, dependent on the local conditions of the tissue. However, all SDs-no matter whether they occur in well-nourished, traumatized, or severely ischemic tissue-share the same phenomenology, including the same magnitude of neuronal depolarization and the principal ion changes involved, a similar release of free energy (free-energy starving) and spread in the tissue. SDs also share influx of water into neurons driven by the ionic changes across the cellular membrane. In other words, SD is the principal mechanism of the cytotoxic edema in many gray matter structures of the brain. Using two-photon microscopy, the cytotoxic edema is observed as SD-induced dendritic beading (3). Beaded morphology allows a larger volume to be encompassed within an equivalent surface area. Beading-induced changes in cell membrane morphology are sufficient to significantly hinder intracellular water mobility (4). Using diffusion-weighted MRI (DW-MRI), this translates into a characteristic drop in the apparent diffusion coefficient when SD is moving in the tissue, no matter whether or not the tissue is ischemic (5) (Fig. 1). In PNAS, Cain et al. elegantly exploit this characteristic trait to trace SD's propagation path in the naïve mouse brain in a 3D, whole-brain perspective with high-temporal resolution Fig. 1. SD is associated with near-complete breakdown of the transcellular ion concentration gradients, which causes intracellular hyperosmolality. The resulting water influx into neurons leads to cytotoxic edema, which causes abrupt dendritic beading. Beaded morphology allows a larger volume to be encompassed within an equivalent surface area. In normal neurites, water mobility is highly restricted by the cell membrane perpendicular to the main axis, whereas water molecules diffusing along the main axis of the neurite encounter few barriers on the timescale of DW-MRI measurements. However, undulation of the cell membrane induced by neuri...

The negative ultraslow potential, electrophysiological correlate of infarction in the human cortex

“…SDs are characterized by abrupt, near-complete breakdown of the neuronal transmembrane ion gradients with marked loss of Gibbs free energy ( Kraig and Nicholson, 1978 ; Windmuller et al , 2005 ), including a toxic intraneuronal calcium and sodium surge ( Dietz et al , 2008 ), neuron swelling with dendritic beading and signal decrease on ADC maps (cytotoxic oedema) ( Takano et al , 1996 , 2007 ; Risher et al , 2010 ; Dreier and Reiffurth, 2017 ), depolarization of mitochondria ( Bahar et al , 2000 ; Zhou et al , 2010 ), marked glutamate release (excitotoxicity) ( Fabricius et al , 1993 ; Zhou et al , 2013 ; Hinzman et al , 2015 ) and depolarization of astrocytes secondary to the extracellular potassium surge ( Muller and Somjen, 2000 ; Chuquet et al , 2007 ). Notably, SD propagation rate is similar between severely ischaemic and normal tissue ( Aitken et al , 1998 ; Jarvis et al , 2001 ; Farkas et al , 2008 ; Bogdanov et al , 2016 ), but SD duration is significantly longer in ischaemic tissue ( Hartings et al , 2017 b ).…”

Migraine Aura, Transient Ischemic Attacks, Stroke, and Dying of the Brain Share the Same Key Pathophysiological Process in Neurons Driven by Gibbs–Donnan Forces, Namely Spreading Depolarization

“…Accordingly, the swelling of the neuronal somas and the so-called beading of the dendrites as a result of the water influx can be detected in two-photon laser scanning microscopy simultaneously with the negative shift of the DC potential ( Andrew et al, 2007 ; Takano et al, 2007 ; Murphy et al, 2008 ; Risher et al, 2010 , 2011 ; Steffensen et al, 2015 ). These facts are important for the understanding of water diffusion restrictions in the gray matter, which can be detected by magnetic resonance imaging (MRI) ( Dreier and Reiffurth, 2017 ). Thus, the beaded morphology during spreading depolarization allows the neurons to enclose a larger volume of water within a constant surface area ( Budde and Frank, 2010 ).…”

Early Detection of Cerebral Infarction After Focal Ischemia Using a New MRI Indicator

“…SD that spreads beyond the territory of ischemia is termed Bperi-infarct depolarization^(PID) [59,60]. SD shares influx of water into neurons driven by the ionic changes across the cellular membrane, which has been considered the principal mechanism of the cytotoxic edema [61]. The cytotoxic edema detected in the surviving zone can be generated not only by ischemic stress but also by ischemia-induced PID.…”