What is it? First reported over half a century ago by the Brazilian Physiologist Aristides Leão the phenomenon of spreading depression (SD) was so named because it was observed as a slowly moving depression of electrical activity in the cerebral cortex as measured with the electroencephalogram (EEG). It has since been discovered that spreading depression consists of a wave of membrane depolarization (a "DC voltage shift") and ionic concentration changes which can last for up to two minutes at any given point and typically travels at a speed between three to twelve millimeters per minute. Wave passage is typically accompanied by a period of increased blood flow and is followed by a prolonged period of vasodilation. Spreading depression is widely believed to be the electrophysiological process that causes migraine headaches, and has been observed to accompany cerebral ischemia, hypoxia, and concussion. There is some evidence for ischemic infarct tolerance in tissue that has been previously exposed to spreading depression. Furthermore, an approaching wave of spreading depression is usually preceded by seemingly random bursts of electrical activity. These electrical bursts, referred to as prodromal spikes, or AC voltage shifts, resemble epileptic discharges. Thus spreading depression has also been used as an animal model of epilepsy.
Theories of Spreading Depression. There is no generally accepted theory explaining spreading depression. Previously published models do not provide a mechanism to explain why gap junction poisons prevent spreading depression. It had been previously suggested that neuroglia, which are widely connected by gap junctions, might provide a substrate for SD wave propagation. However, it has also been demonstrated that the application of glial poisons do not prevent spreading depression. Hence it is unlikely that the required gap junctions are glial. Furthermore, the previous models do not explain the inconsistent effects of Ca++ removal and/or calcium channel antagonists. Finally, no previous model has described the nearly 50% reduction in interstitial volume which occurs during spreading depression.
A New Mathematical Model of Spreading Depression. A novel model of spreading depression has been developed. This model differs from previous ones in that it incorporates the effects of (a) gap junctions, (b) intracellular voltage gradients, and (b) osmotically induced volume changes. The earlier biophysical models have all been based on the assumption that spreading depression propagates as a diffusional potassium wave through extracellular space. Because intracellular space was believed to be compartmentalized into separate neurons concentration changes within the individual cells were treated as purely local phenomena in these models. Information was propagated only through membrane currents and extracellular diffusion. A different approach is taken in the new model. It is assumed that neurons are interconnected by gap junctions. Ions are allowed to propagate through an intracellular continuum formed by the resulting neuronal syncytium.
Because of the large ionic movements that occur during spreading depression, neither the cable equation nor standard compartmental models can be used to describe ionic concentration changes. Both of these approaches are derived based on the assumption that the all concentration changes are small. Furthermore, a simple system of reaction-diffusion equations coupled by membrane currents is also insufficient. This is because voltage gradients develop along the length of dendritic processes during SD. To alleviate this difficulty electric fields as described by the Nernst-Planck equation are incorporated directly into the derivation of the diffusion equation. The resulting electrodiffusion equation is similar in form to standard reaction-diffusion equations but has an extra term which takes the voltage gradients into account. The electro-diffusive approach has been previously shown to be equivalent to the cable-approach in the limit of small ionic variations. Ions move between the neuronal syncytium and interstitial space via the standard array of ion channels and pumps. Cytoplasmic ionic movements are also caused by the extra electro-diffusive term. These ionic movements, coupled with large membrane fluxes of sodium and chloride, lead to an osmotic imbalance. This imbalance is countered by the flow of water into or out of cells, causing the cells to expand or contract. These cellular volume changes are spatially limited by the surrounding parenchyma (expansion) and intracellular organelles (contraction).
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