Possible Cortical Spreading Depression Recorded Intraoperatively Following a Generalized Seizure: Illustrative Case

Background: We present a compelling case fitting the phenomenon of cortical spreading depression detected by intraoperative neurophysiological monitoring (IONM) following an intraoperative seizure during a craniotomy for revascularization. Cortical spreading depression (CSD, also called cortical spreading depolarization) is a pathophysiological phenomenon whereby a wave of depolarization is thought to propagate across the cerebral cortex, creating a brief period of relative neuronal inactivity. The relationship between CSD and seizures is unclear, although some literature has made a correlation between seizures and a cortical environment conducive to CSD. Methods: Intraoperative somatosensory evoked potentials (SSEPs) and electroencephalography (EEG) were monitored continuously during the craniotomy procedure utilizing standard montages. Electrophysiological data from pre-ictal, ictal, and post-ictal periods were recorded. Results: During the procedure, intraoperative EEG captured a generalized seizure followed by a stepwise decrease in somatosensory evoked potential cortical amplitudes, compelling for the phenomenon of CSD. The subsequent partial recovery of neuronal function was also captured electrophysiologically. Discussion: While CSD is considered controversial in some aspects, intraoperative neurophysiological monitoring allowed for the unique analysis of a case demonstrating a CSD-like phenomenon. To our knowledge, this is the first published example of this phenomenon in which intraoperative neurophysiological monitoring captured a seizure, along with a stepwise subsequent reduction in SSEP cortical amplitudes not explained by other variables.

Cortical spreading depression-induced preconditioning in the brain

Cortical spreading depression is a technique used to depolarize neurons. During focal or global ischemia, cortical spreading depression-induced preconditioning can enhance tolerance of further injury. However, the underlying mechanism for this phenomenon remains relatively unclear. To date, numerous issues exist regarding the experimental model used to precondition the brain with cortical spreading depression, such as the administration route, concentration of potassium chloride, induction time, duration of the protection provided by the treatment, the regional distribution of the protective effect, and the types of neurons responsible for the greater tolerance. In this review, we focus on the mechanisms underlying cor- tical spreading depression-induced tolerance in the brain, considering excitatory neurotransmission and metabolism, nitric oxide, genomic reprogramming, inflammation, neurotropic factors, and cellular stress response. Specifically, we clarify the procedures and detailed information regarding cortical spreading depression-induced preconditioning and build a foundation for more comprehensive investigations in the field of neural regeneration and clinical application in the future.

Spreading depression and focal venous cerebral ischemia enhance cortical neurogenesis

Endogenous neurogenesis can arise from a variety of physiological stimuli including exercise, learning, or ＂enriched environment＂ as well as pathological conditions such as ischemia, epilepsy or cortical spreading depression. Whether all these conditions use a common trigger to set off endogenous neurogenesis is yet unclear. We hypothesized that cortical spreading depression（CSD） induces neurogenesis in the cerebral cortex and dentate gyrus after cerebral venous ischemia. Forty-two Wistar rats alternatively underwent sham operation（Sham）, induction of ten CSDs or venous ischemia provoked via occlusion of two adjacent superficial cortical vein followed by ten induced CSDs（CSD ＋ 2-VO）. As an additional control, 15 na？ve rats received no intervention except 5-bromo-2′-deoxyuridine（Brd U） treatment for 7 days. Sagittal brain slices（40 μm thick） were co-stained for Brd U and doublecortin（DCX; new immature neuronal cells） on day 9 or Neu N（new mature neuronal cells） on day 28. On day 9 after sham operation, cell proliferation and neurogenesis occurred in the cortex in rats. The sole induction of CSD had no effect. But on days 9 and 28, more proliferating cells and newly formed neurons in the ipsilateral cortex were observed in rats subjected to CSD ＋ 2VO than in rats subjected to sham operation. On days 9 and 28, cell proliferation and neurogenesis in the ipsilateral dentate gyrus was increased in sham-operated rats than in na？ve rats. Our data supports the hypothesis that induced cortical neurogenesis after CSD ＋ 2-VO is a direct effect of ischemia, rather than of CSD alone.

EFFECTS OF NAAG AND MPEP ON RAT CORTICAL SPREADING DEPRESSION

Cortical spreading depression(CSD)is a pathophysiological phenomenon.There are sufficient evidences to prove that CSD plays an important role in some neurological disorders.However,exact mechanisms of its initiation and propagation are still unclear.Previous studies showed that glutamate receptors could be concerned with CSD,but those studies were mostly performed oriented to ionotropic glutamate receptors(iGluRs).There is relatively little report about effects of metabotropic glutamate receptors(mGluRs)on CSD.Here,we applied optical intrinsic signal imaging(OISI)combined with direct current(DC)potential recording to examine influences of some mGluRs antagonist(or agonist)on CSD propagation in rat’s brain,to indirectly validate actions of some mGluRs on CSD.We found that N-acetyl-l-aspartyl-l-glutamate(NAAG,an agonist at mGluR3)inhibited the propagation of CSD,and the inhibition was gradually developed with time.However,6-methyl-2-phenylethynyl-pyridine(MPEP,an antagonist of mGluR5)did not produce any significant alterations with the CSD propagation.Our findings suggest that mGluR3 could play an important role in the CSD propagation,but the activity of mGluR5 was comparatively weak.These findings can help to understand the propagation mechanism of CSD,and consider the therapy of some neurological diseases involved with CSD.

ACCURATELY DETERMINING PROPAGATION VELOCITY OF CORTICAL SPREADING DEPRESSION IN RATS BY OPTICAL INTRINSIC SIGNAL IMAGING

Cortical spreading depression(CSD)is a wave of neuronal and glial depolarization that propagates across the cortex at a rate of 2–5mm/min accompanied by reversible electroencephalogram(EEG)suppression,a negative shift of direct current(DC)potential,and change of optical intrinsic signals(OIS).Propagation velocity of CSD is an important parameter used to study this phenomenon.It is commonly determined in an electrophysiological way that measures the time required for a CSD wave to pass along two electrodes.Since the electrophysiology technique fails to reveal the spreading pattern of CSD,velocity calculated in this manner might be inaccurate.In this study,we combined the electrophysiological recording and OIS imaging(OISI)for detecting changes in DC potential and OIS during CSD simultaneously.An optical method based on OISI to determine the CSD velocity,which is measured by generating a series of regions of interest(ROI)perpendicular to the advancing wavefront along propagation direction of CSD at different time points and then dividing by the distance between ROIs over time,is presented.Comparison of the accuracy of the two approaches in determining the CSD velocity is made as well.The average rate of 33 CSDs is 3.52±0.87mm/min by use of the optical method and 4.36±1.65mm/min by use of the electrophysiological method.Because of the information about spreading pattern of CSD provided optically,the velocity determined by OISI is of smaller deviation and higher accuracy.

TWO-DIMENSIONAL VISUALIZATION OF THE PROPAGATION SPEED OF CORTICAL SPREADING DEPRESSION IN RAT CORTEX

Cortical spreading depression(CSD),which is a significant pathological phenomenon that correlates with migraines and cerebral ischemia,has been characterized by a wave of depolarization among neuronal cells and propagates across the cortex at a rate of 2–5mm/min.Although the propagation pattern of CSD was well-investigated using high-resolution optical imaging technique,the variation of propagation speed of CSD across different regions of cortex was not well-concerned,partially because of the lack of ideal approach to visualize two-dimensional distribution of propagation speed of CSD over the whole imaged cortex.Here,we have presented a method to compute automatically the propagation speed of CSD throughout every spots in the imaged cortex.In this method,temporal clustering analysis(TCA)and least square estimation(LSE)were first used to detect origin site where CSD was induced.Taking the origin site of CSD as the origin of coordinates,the data matrix of each image was transformed into the corresponding points based on the polar-coordinate representation.Then,two fixed-distance regions of interest(ROIs)are sliding along with the radial coordinate at each polar angle within the image for calculating the time lag with correlating algorithm.Finally,we could draw a twodimensional image,in which the value of each pixel represented the velocity of CSD when it spread through the corresponding area of the imaged cortex.The results demonstrated that the method can reveal the heterogeneity of propagation speed of CSD in the imaged cortex with high fidelity and intuition.

The Spreading Depression Propagation: How Electrochemical Patterns Distort or Create Perception

At the transition from quiescence to propagating waves recorded in isolated retinas, a circular electric current closes in the extracellular matrix;this circular current creates a magnetic torus flow that, when entering quiescent tissue in front of the wave, recruits elements and when leaving behind, helps to build the absolute refractory state. The waving magnetic torus is the consequence of the vortex effect and explains the energy boost that drives propagation. Methods: We interpret experimental results from intrinsic and extrinsic fluorescence dyes, voltage, calcium and pH sensitive, optical signals from isolated retinas, and time series recordings using ion exchange resins: Ca, K, pH, Na, Cl recorded extracellularly at retinas, cerebellums and cortices coupled to spreading depression waves. Finally, we checked the ECoG activity, also a time series, at the transition from after discharges to spreading depression in rat hippocampus. Results: The integrated assessment of the diversified measurements led to the realization that the magnetic flow at the wavefront is a major contributor to the wave propagation mechanisms. This flow couples mass and charge flows as a swirling torus from excited to quiescent tissue. Conclusions: An alternative model of the brain is possible, apart from the classical HH and molecular biology model. Physical chemistry of charged gels and its flows explains the results. The conceptual framework uses far from equilibrium thermodynamics.

Role of cortical spreading depression in the pathophysiology of migraine

A migraine is a recurring neurological disorder characterized by unilateral, intense, and pulsatile headaches. In one-third of migraine patients, the attacks are preceded by a visual aura, such as a slowly-propagating scintillating scotoma. Migraine aura is thought to be a result of the neurovascular phenomenon of cortical spreading depression （SD）, a self-propagating wave of depolarization that spreads across the cerebral cortex. Several animal experiments have demonstrated that cortical SD causes intracranial neurogenic inflammation around the meningeal blood vessels, such as plasma protein extravasation and pro-inflammatory peptide release. Cortical SD has also been reported to activate both peripheral and central trigeminal nociceptive pathways. Although several issues remain to be resolved, recent evidence suggests that cortical SD could be the initial trigger of intracranial neurogenic inflammation, which then contributes to migraine headaches via subsequent activation of trigeminal afferents.

ASimplified Neuronal Model for the Instigation and Propagation of Cortical Spreading Depression

In this paper,we construct a simplified neuronal model that is capable of simulating the instigation of cortical spreading depression(CSD)and propagation of a CSD wave.Our model is a simplification and extension of a single neuron model proposed in the literature for studying the instigation of CSD.Using the simplified neuronal model,we construct a network of these simplified neurons.This network model shows that the propagation of a CSD wave occurs naturally after it is instigated electrically or chemically.Although the model is simple,the speed of the CSD wave predicted by our model is consistent with experimentally observed values.Finally,our model allows us to investigate the effects of specific ion channels on the spread of a CSD wave.

Variation of repetitive cortical spreading depression waves is related with relative refractory period： a computational study

Cortical spreading depression （CSD） is an important experimental model for diseases such as stroke, epilepsy and migraine. Previous observations indicated that the amplitude and velocity of the typical direct current potential shift during repetitive CSD waves were varying. The recovery state of the tissue was found related with the variation of successive CSD waves. A computational model in this paper aimed to investigate the role of relative refractory period of CSD. This model simulated that continuous injection of KCI solution induced repetitive CSD waves. The first CSD wave often had a larger amplitude and faster velocity than those of the succeeding secondary waves. The relative refractory period lasted much longer than the recovery of ions turbulence. If the induction interval was long enough for recovery, a series of CSD waves would have the same profile asthe first one. In the relative refractory period, an early stimulation might lead to a late initiation of CSD, i.e., ＂haste makes waste＂. The amplitude and velocity of CSD waves were found increasing with the initiation interval and asymptotic to those of the first CSD wave. This study verified that the propagation dynamics of CSD waves is modulated by the relative refractory period. It suggested that the refractory period is critical for preventing undesirable CSD waves.

Gene expression microarray analysis of the spinal trigeminal nucleus in a rat model of migraine with aura

Cortical spreading depression can trigger migraine with aura and activate the trigeminal vascular system. To examine gene expression profiles in the spinal trigeminal nucleus in rats following cortical spreading depression-induced migraine with aura, a rat model was established by injection of 1 M potassium chloride, which induced cortical spreading depression. DNA microarray analysis revealed that, compared with the control group, the cortical spreading depression group showed seven upregulated genes-myosin heavy chain 1/2, myosin light chain 1, myosin light chain （phosphorylatable, fast skeletal muscle）, actin alpha 1, homeobox B8, carbonic anhydrase 3 and an unknown gene. Two genes were downregulated-RGD1563441 and an unknown gene. Real-time quantitative reverse transcription-PCR and bioinformatics analysis indicated that these genes are involved in motility, cell migration, CO2/nitric oxide homeostasis and signal transduction.