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.

Keywords: epilepsy; ischemia; migraine; spreading depolarization; spreading depression; subarachnoid hemorrhage; sudden unexpected death in epilepsy.

Figure 1

Full-band (DC-coupled) recordings of spreading depression. Two events propagate across the full electrode strip from electrodes 6 to 1, as shown by negative DC shifts and 0.5–50 Hz depressions of spontaneous activity. Analysis focused on electrode 3 in monopolar mode (electrode 3 versus reference, gold). Adapted from Ref. (14).

Figure 2

Schematic diagram summarizing the complex mechanisms underlying the spreading depression (SD) phenomenon at the tripartite synapse. High extracellular K⁺ concentration causes an increase of neuronal excitability and a high level of extracellular Glu. Increased electrical activity leads to release of vasodilator factors with a consequent increase in blood flow. ATPase activity is insufficient to maintain ion homeostasis and leads to high level of adenosine which, in turn, prevents vesicular release of Glu at presynaptic level. A change in dendritic structures and the loss of dendritic spines occur («beading»). The astrocyte-mediated buffering of K⁺ and Glu is inadequate to quickly restore the electrochemical homeostasis, and thus sustains the SD mechanism.