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

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.

Increased Direct Current-Electroencephalography Shifts During Induction of Anesthesia in Elderly Patients Developing Postoperative Delirium

“…During SD, regional depolarizations in individual neurons establish longitudinal gradients of depolarization and transmembrane current loops that sum in the extracellular space to build the negative DC signal ( Dreier et al, 2013 ). This is accompanied by an almost complete breakdown of transmembrane ion gradients and neuronal cytotoxic edema ( Lemale et al, 2022 ). Extracellular DC shifts during epileptic seizures, like SD, are also characterized by a highly zonal laminar profile, but they are associated with much smaller ion shifts than SD ( Lemale et al, 2022 ).…”

“…This is accompanied by an almost complete breakdown of transmembrane ion gradients and neuronal cytotoxic edema ( Lemale et al, 2022 ). Extracellular DC shifts during epileptic seizures, like SD, are also characterized by a highly zonal laminar profile, but they are associated with much smaller ion shifts than SD ( Lemale et al, 2022 ). In addition, current source density analyses showed clear differences in the laminar profiles of DC shifts between SDs and seizures which underlines that these are two very different classes of phenomena ( Wadman et al, 1992 ; Makarova et al, 2010 ).…”

Stroke-prone salt-sensitive spontaneously hypertensive rats show higher susceptibility to spreading depolarization (SD) and altered hemodynamic responses to SD

“…79,80 However, the findings are also interesting for the association between migraine with aura and stroke. [81][82][83][84][85][86][87] The vascular risk factor hypertension, which is significantly more common in migraine patients, [88][89][90][91] has been suggested as one of the possible mediators for this association. However, it may not be mediation in the strict sense, but the basic mechanisms underlying the development of (1) salt-sensitive hypertension, (2) cerebrovascular dysfunction, and (3) SD, respectively, may overlap.…”

Multiscale Computer Modeling of Spreading Depolarization in Brain Slices

“…This may reflect biophysical mechanisms absent from the model or a lack of appropriate volume changes in ECS and intraneuronal spaces. In particular, we did not model large, intracellular, negatively charged macromolecules that produce Gibbs-Donnan effects which contribute to SD [Lemale et al, 2022].…”