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 … [↵][1]1To whom correspondence should be addressed. Email: jens.dreier{at}charite.de. [1]: #xref-corresp-1-1