Understanding Spreading Depression from Headache to Sudden Unexpected Death

Abstract

Spreading depression (SD) is a neurophysiological phenomenon characterized by abrupt changes in intracellular ion gradients and sustained depolarization of neurons. It leads to loss of electrical activity, changes in the synaptic architecture, and an altered vascular response. Although SD is often described as a unique phenomenon with homogeneous characteristics, it may be strongly affected by the particular triggering event and by genetic background. Furthermore, SD may contribute differently to the pathogenesis of widely heterogeneous clinical conditions. Indeed, clinical disorders related to SD vary in their presentation and severity, ranging from benign headache conditions (migraine syndromes) to severely disabling events, such as cerebral ischemia, or even death in people with epilepsy. Although the characteristics and mechanisms of SD have been dissected using a variety of approaches, ranging from cells to human models, this phenomenon remains only partially understood because of its complexity and the difficulty of obtaining direct experimental data. Currently, clinical monitoring of SD is limited to patients who require neurosurgical interventions and the placement of subdural electrode strips. Significantly, SD events recorded in humans display electrophysiological features that are essentially the same as those observed in animal models. Further research using existing and new experimental models of SD may allow a better understanding of its core mechanisms, and of their differences in different clinical conditions, fostering opportunities to identify and develop targeted therapies for SD-related disorders and their worst consequences.

Effect of Nortriptyline on Spreading Depolarization

“…The primary aim of this study was to clarify some molecular aspects of spreading depolarization, as an important mechanism in the pathophysiology of some neurological diseases like stroke, epilepsy, migraine, and traumatic brain injury (3)(4)(5). The shape of SD in an extracellular recording is typically triphasic.…”

“…Since the description of very slowly propagating waves of "cortical spreading depression" in old studies of Leao in 1944 (1) and the following studies by Grafstein (2) describing the depolarizing nature of the waves, spreading depolarization (SD) has become more and more important in the pathophysiology of some neurological diseases such as epilepsy, stroke, traumatic brain injury and migraine with aura (3)(4)(5). The depolarization waves in SD propagate as concentric circles starting from a focus in the brain and affect many neurons and glial cells through the spreading way.…”

Scurrying to Understand Sudden Expected Death in Epilepsy: Insights From Animal Models

“…63 These findings indicate a causal relationship between spreading depolarization and SUDEP. 75 An interesting way to explore effects of mutation on cellular function is to use induced pluripotent stem cells (iPSCs) from patients with epilepsy. Forebrain-like pyramidal-and bipolarshaped neurons derived from patients with Dravet syndrome show increased sodium currents, spontaneous firing, and other signs of hyperexcitability compared to neurons derived from healthy controls.…”

Using NEURON for Reaction-Diffusion Modeling of Extracellular Dynamics

“…These simulations focused on the wave of cell depolarization and omitted the silencing of electrical activity that follows—looking at the spreading depolarization rather than at the specifics of the spreading depression itself (Dreier, 2011 ). This second phase of neuronal inactivity may be related to depolarization blockade, as well as to synaptic plasticity and the accumulation of extracellular adenosine (Frenguelli and Wall, 2016 ; Cozzolino et al, 2018 ).…”