Cortical spreading depression: An enigma

Abstract

The brain is a complex organ with active components composed largely of neurons, glial cells, and blood vessels. There exists an enormous experimental and theoretical literature on the mechanisms involved in the functioning of the brain, but we still do not have a good understanding of how it works on a gross mechanistic level. In general, the brain maintains a homeostatic state with relatively small ion concentration changes, the major ions being sodium, potassium, and chloride. Calcium ions are present in smaller quantities but still play an important role in many phenomena. Cortical spreading depression (CSD for short) was discovered over 60 years ago by A.A.P. Leao, a Brazilian physiologist doing his doctoral research on epilepsy at Harvard University, “Spreading depression of activity in the cerebral cortex," J. Neurophysiol., 7 (1944), pp. 359-390. Cortical spreading depression is characterized by massive changes in ionic concentrations and slow nonlinear chemical waves, with speeds on the order of mm/min, in the cortex of different brain structures in various experimental animals. In humans, CSD is associated with migraine with aura, where a light scintillation in the visual field propagates, then disappears, and is followed by a sustained headache. To date, CSD remains an enigma, and further detailed experimental and theoretical investigations are needed to develop a comprehensive picture of the diverse mechanisms involved in producing CSD. A number of mechanisms have been hypothesized to be important for CSD wave propagation. In this paper, we briefly describe several characteristics of CSD wave propagation, and examine some of the mechanisms that are believed to be important, including ion diffusion, membrane ionic currents, osmotic effects, spatial buffering, neurotransmitter substances, gap junctions, metabolic pumps, and synaptic connections. Continuum models of CSD, consisting of coupled nonlinear diffusion equations for the ion concentrations, and a discrete lattice-Boltzmann method approach will be described. Also, we will describe some open problems and remaining challenges.