Is Spreading Depolarization Characterized by an Abrupt, Massive Release of Gibbs Free Energy from the Human Brain Cortex?

Abstract

In the evolution of the cerebral cortex, the sophisticated organization in a steady state far away from thermodynamic equilibrium has produced the side effect of two fundamental pathological network events: ictal epileptic activity and spreading depolarization. Ictal epileptic activity describes the partial disruption, and spreading depolarization describes the near-complete disruption of the physiological double Gibbs–Donnan steady state. The occurrence of ictal epileptic activity in patients has been known for decades. Recently, unequivocal electrophysiological evidence has been found in patients that spreading depolarizations occur abundantly in stroke and brain trauma. The authors propose that the ion changes can be taken to estimate relative changes in Gibbs free energy from state to state. The calculations suggest that in transitions from the physiological state to ictal epileptic activity to spreading depolarization to death, the cortex releases Gibbs free energy in a stepwise fashion. Spreading depolarization thus appears as a twilight state close to death. Consistently, electrocorticographic recordings in the core of focal ischemia or after cardiac arrest display a smooth transition from the initial spreading depolarization component to the later ultraslow negative potential, which is assumed to reflect processes in cellular death.

A Biophysical Model for Cytotoxic Cell Swelling

“…The depolarized, pathological equilibrium corresponds to a Gibbs-Donnan-like state in which the potential energy that is normally stored in the electrochemical ion gradients has largely dissipated (Dreier et al, 2013) and is therefore also known as a state of free energy-starvation (Hübel et al, 2014). This equilibrium state appeared to be stable up to a pump strength of ϳ185% of the default value, such that the model is bistable for a wide range of Na ϩ /K ϩ pump rates (Fig.…”

“…In each cycle, the Na ϩ / K ϩ -ATPase exchanges three intracellular sodium ions for two extracellular potassium ions, and therefore generates a net transmembrane current I Pump . The net pump current was modeled after the experimental data of Hamada et al (2003) as a function of the intracellular sodium concentration, as follows:…”

Chloride Cotransporters as a Molecular Mechanism underlying Spreading Depolarization-Induced Dendritic Beading

“…Founders of the GFP-M colony were kindly provided by Dr. J. Sanes (Harvard University, Boston, MA). This strain of mice expresses the enhanced green fluorescent protein (EGFP) in sparse subsets of neocortical and hippocampal pyramidal neurons (Feng et al, 2000). The founding mice of the CX3CR1-EGFP colony were purchased from The Jackson Laboratory.…”

“…Two-dimensional (2D) maps of cerebral blood flow with high spatiotemporal resolution were acquired by laser speckle imaging as described previously (Dunn et al, 2001;Sigler et al, 2008;Risher et al, 2010). Briefly, the cortical surface was illuminated through ananamorphicbeamexpander(EdmundOptics)bya785nmStockerYale laser (ProPhotonix) at an angle of ϳ30°and imaged with a 4ϫ/0.075 NA objective (Zeiss).…”

“…The extracellular negative slow potential change between Ϫ5 and Ϫ30 mV serves as a robust measure of SD because it directly reflects the depolarization of a large population of cortical neurons (Canals et al, 2005). The full spectrum from short-lasting to very long-lasting SD waves has been observed in association with cerebral pathologies, such as migraine aura, stroke, and traumatic brain injury, not only in experimental animals but also in patients (Hadjikhani et al, 2001;Oliveira-Ferreira et al, 2010;Hartings et al, 2011a;Dreier and Reiffurth, 2015). Moreover, multiple or prolonged SDs may instigate secondary neuronal damage in patients experiencing acute cerebral injuries (Dreier et al, 2006;Hartings et al, 2011b;Lauritzen et al, 2011).…”