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.

Jens P Dreier,Sebastian Major,Viktor Horst,Clemens Reiffurth,Johannes Woitzik,Coline L Lemale,Nils Hecht,Janos Lückl

doi:10.3389/fncel.2022.837650

Abstract

Neuronal cytotoxic edema is the morphological correlate of the near-complete neuronal battery breakdown called spreading depolarization, or conversely, spreading depolarization is the electrophysiological correlate of the initial, still reversible phase of neuronal cytotoxic edema. Cytotoxic edema and spreading depolarization are thus different modalities of the same process, which represents a metastable universal reference state in the gray matter of the brain close to Gibbs–Donnan equilibrium. Different but merging sections of the spreading-depolarization continuum from short duration waves to intermediate duration waves to terminal waves occur in a plethora of clinical conditions, including migraine aura, ischemic stroke, traumatic brain injury, aneurysmal subarachnoid hemorrhage (aSAH) and delayed cerebral ischemia (DCI), spontaneous intracerebral hemorrhage, subdural hematoma, development of brain death, and the dying process during cardio circulatory arrest. Thus, spreading depolarization represents a prime and simultaneously the most neglected pathophysiological process in acute neurology. Aristides Leão postulated as early as the 1940s that the pathophysiological process in neurons underlying migraine aura is of the same nature as the pathophysiological process in neurons that occurs in response to cerebral circulatory arrest, because he assumed that spreading depolarization occurs in both conditions. With this in mind, it is not surprising that patients with migraine with aura have about a twofold increased risk of stroke, as some spreading depolarizations leading to the patient percept of migraine aura could be caused by cerebral ischemia. However, it is in the nature of spreading depolarization that it can have different etiologies and not all spreading depolarizations arise because of ischemia. Spreading depolarization is observed as a negative direct current (DC) shift and associated with different changes in spontaneous brain activity in the alternating current (AC) band of the electrocorticogram. These are non-spreading depression and spreading activity depression and epileptiform activity. The same spreading depolarization wave may be associated with different activity changes in adjacent brain regions. Here, we review the basal mechanism underlying spreading depolarization and the associated activity changes. Using original recordings in animals and patients, we illustrate that the associated changes in spontaneous activity are by no means trivial, but pose unsolved mechanistic puzzles and require proper scientific analysis.

Highlights

The brain is the most complex structure known in the universe
Spreading depressions and non-spreading depressions of spontaneous activity may have occurred in the context of spreading depolarizations in these studies, because it is assumed that the large number of recorded migraine auras in these studies resulted from the procedure of catheterizing and injecting the carotid artery, which provoked visual migraine aura in more than 50% of the patients (Lassen and Friberg, 1991)
reactive oxygen species (ROS) production in response to an ischemic event in vivo increases to the pathological range only when (i) tissue is reperfused, (ii) neurons recover from the ischemia-induced spreading depolarization and (iii) extracellular glutamate concentration decreases again, which is the opposite of what is observed in cell culture upon glutamate application (Dirnagl et al, 1995; Dreier et al, 1998; Peters et al, 1998)

Summary

INTRODUCTION

The brain is the most complex structure known in the universe. In this electrochemical organ, consciousness arises in a hitherto unknown way, which can perceive, feel, think and react, and which is periodically switched off and on again. It is important to understand that the membrane potential changes dramatically for a millisecond during an action potential, as some Na+ and K+ ions cross the membrane, the transmembrane concentration gradients between the bulk solutions of the intracellular and extracellular space remain virtually unchanged, implying that the cell remains in the physiological double Gibbs–Donnan steady state. This means that the energy store loses almost no energy during one action potential. This is especially relevant when the experiments are used to correlate electrophysiology and behavior

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DISCUSSION

CONCLUSION