Stimulation induced recurrent epileptiform discharges block cortical and subcortical spreading depression in rats

Blockade of the spread depression [SD] in chemically or electrically stimulated areas of the cerebral cortex was analyzed in a series of experiments performed in 40 curarized, locally anaesthetised rats. Longlasting stimulation of the cerebral cortex (0.5 to 1.7 mA, 6 Hz, 0.1 ms) elicited recurrent episodes of enhanced evoked potentials propagating to remote cortical areas [Co], the caudate nucleus [Cd], the hippocampus [Hi] and the thalamus [Th] and was accompanied by marked slow potential shifts (4-6 mV amplitude, 2-3 min duration, at 2-5 min intervals]. The projected discharge interfered with SD initiation and propagation in all the examined structures. The SD blockade was most pronounced during the episodes and almost absent in the intervals between them. The block was manifested by reduced amplitude and duration of the slow potential of SD. Pentobarbital [20 mg/kg] suppressed the recurrent discharges and eliminated the corresponding SD blockade. Recurrent excitability changes induced by Cd and Th stimulation elicited similar effects but the threshold was higher in Cd and Th than in Co. SD was less effectively blocked by the projected discharge than by stimulation of the same structure, particularly in the vicinity of the recording electrodes, where the blockade could be observed even under pentobarbital. The SD blockade outlasted stimulation by a considerably longer period of time in Th (about 10 min) than in the Cd (about 3 min). The onset of stimulation and the projected episodes sometimes elicited SD waves but SD blockade prevailed with continued stimulation. The present findings support the hypothesis that excessive neural activity increases the potassium clearance and thus prevents the autoregenerative accumulation of potassium ions, mediating SD propagation.     

Cortical afterdischarges during Leao's cortical spreading depression.

Cortical spreading depression (CSD) has been employed in unanesthetized curarized rats, in order to analyse the role of the cerebral cortex in the generation of epileptic self-sustained parozysms produced by direct cortical electrical stimulation. CSD was preferred because it is reversible and may be repeated several times in the same animal. CSD evoked in the hemisphere contralateral to the stimulated cortex decreased the duration of the afterdischarge by 40% and modified its form and amplitude both at the cortical and reticular levels. The possible role of cortical and subcortical structures in the development of after-discharges is discussed.     

Cortical spreading depression modifies components of the inflammatory cascade

As more information becomes available regarding the role of inflammation following stroke, it is apparent that some inflammatory mediators are detrimental and others are beneficial to the progression of ischemic injury. Cortical spreading depression (CSD) is known to impart some degree of ischemic tolerance to the brain and to influence the expression of many genes. Many of the genes whose expression is altered by CSD are associated with inflammation, and it appears likely that modulation of the inflammatory response to ischemia by CSD contributes to ischemic tolerance. Understanding which inflammatory processes are influenced by CSD may lead to the identification of novel targets in the effort to develop an acute treatment for stroke.     

Cortical spreading depression confounds concentration-dependent pial arteriolar dilation during N-methyl-D-aspartate superfusion

Pial arterioles do not express N-methyl-D-aspartate (NMDA) receptors but dilate in response to topical NMDA application. We explored the mechanism underlying NMDA-mediated responses in murine pial arterioles (11-31 microm), using a closed cranial window preparation, and found that arteriolar dilation was not concentration dependent. Pial arteriolar diameter abruptly increased within 3 min of superfusing 50 or 100 microM NMDA. Dilation reached a peak within 1 min (46 +/- 14%) and then declined to a plateau (28 +/- 13%) for the duration of superfusion. Whereas a higher concentration (200 microM) did not produce further dilation, lower concentrations (1-10 microM) did not dilate the arterioles at all. MK-801 (10 microM) abrogated the dilation response, whereas Nomega-nitro-L-arginine (1 mM) attenuated the peak and abolished the sustained dilation during NMDA superfusion. We determined that NMDA-induced pial arteriolar responses were evoked by cortical spreading depression, because abrupt vasodilation during 50 or 100 microM NMDA superfusion was associated with a large negative slow potential shift and electrocorticogram suppression that spread from the superfusion window to distant cortical areas. Our data suggest that the responses of pial arterioles to NMDA are caused in part by neurovascular coupling due to cortical spreading depression.     

Functional hemidecortication by spreading depression or by focal epileptic discharge disrupts spatial memory in rats

The importance of neocortex for the acquisition and retrieval of the water tank navigation task has been examined in 110 hooded rats. The animals were trained to swim to a small (10 cm in diameter) submersed platform 1 cm below the surface of a large pool (120 cm in diameter) of opaque water. In Experiment 1, naive rats with unilateral cortical spreading depression (SD) elicited by application of a filter paper soaked with 25% KC1 on one hemicortex were unable to find the platform during 1 min in about 50% of the 12 acquisition trials. The performance of functionally hemidecorticated rats did not improve after a single trial with the intact brain, but escape latencies were significantly shortened in rats given 2,6 or 60 pretraining trials with intact brain. Even in the overtrained rats escape latencies under unilateral SD were significantly longer (14 sec) than in intact rats after 12 acquisition trials (5 sec). In Experiment 2, development of an epileptic focus established by local penicillin application onto the exposed cortical surface was electrophysiologically monitored. Regular interictal discharge (0.2 to 0.5 Hz) disrupted acquisition of the navigation task and interfered to a lesser degree with performance in rats given 12 and 36 pretraining trials with the intact brain. The occipital foci were more disruptive than the frontoparietal ones. Performance recovered with cessation of the epileptic discharge. It is concluded that spatial memory mediating navigation in the water tank task requires coordinated activity of both cerebral hemispheres.     

Changes in extracellular space volume and geometry induced by cortical spreading depression in immature and adult rats

Changes in extracellular space (ECS) diffusion parameters, DC potentials and extracellular potassium concentration were studied during single and repeated cortical spreading depressions (SD) in 13-15 (P13-15), 21 (P21) and 90-day-old (adult) Wistar rats. The real-time iontophoretic method using tetramethylammonium (TMA+)-selective microelectrodes was employed to measure three ECS parameters in the somatosensory cortex: the ECS volume fraction alpha (alpha = ECS volume/total tissue volume), ECS tortuosity lambda (increase in diffusion path length) and the nonspecific TMA+ uptake k'. SD was elicited by needle prick. SD was significantly longer at P13-15 than at P21 and in adults. During SD, alpha in all age groups decreased from 0.21-0.23 to 0.05-0.09; lambda increased from 1.55-1.65 to 1.95-2.07. Ten minutes after SD, alpha (in adults) and lambda (all age groups) increased compared to controls. This increase persisted even 1 hour after SD. When SD was repeated at 1 hour intervals, both alpha and lambda showed a gradual cumulative increase with SD repetition. Our study also shows that cortical SD is, as early as P13, accompanied by severe ECS shrinkage and increased diffusion path length (tortuosity) with values similar to adults, followed by a long-lasting increase in ECS volume and tortuosity when compared to pre-SD values.     

The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease

The term spreading depolarization describes a wave in the gray matter of the central nervous system characterized by swelling of neurons, distortion of dendritic spines, a large change of the slow electrical potential and silencing of brain electrical activity (spreading depression). In the clinic, unequivocal electrophysiological evidence now exists that spreading depolarizations occur abundantly in individuals with aneurismal subarachnoid hemorrhage, delayed ischemic stroke after subarachnoid hemorrhage, malignant hemispheric stroke, spontaneous intracerebral hemorrhage or traumatic brain injury. Spreading depolarization is induced experimentally by various noxious conditions including chemicals such as potassium, glutamate, inhibitors of the sodium pump, status epilepticus, hypoxia, hypoglycemia and ischemia, but it can can also invade healthy, naive tissue. Resistance vessels respond to it with tone alterations, causing either transient hyperperfusion (physiological hemodynamic response) in healthy tissue or severe hypoperfusion (inverse hemodynamic response, or spreading ischemia) in tissue at risk for progressive damage, which contributes to lesion progression. Therapies that target spreading depolarization or the inverse hemodynamic response may potentially treat these neurological conditions.     

Pulmonary vein isolation by high intensity focused ultrasound

Pulmonary vein isolation (PVI) using radiofrequency current (RFC) ablation is a potentially curative treatment option for patients with atrial fibrillation (AF). The shortcomings of the RFC technology (technically challenging, long procedure times, complications) steadily kindle the interest in new energy sources and catheter designs. High intensity focused ultrasound (HIFU) has the ability to precisely focus ultrasound waves in a defined area with a high energy density. HIFU balloon catheters (BC) positioned at the PV ostia appear to be an ideal tool to transmit the ablation energy in a circumferential manner to the PV ostia and may therefore bear substantial advantage over conventional ablation catheters in PVI procedures. In clinical trials the HIFU BC has shown promising success rates similar to RFC catheter ablation for PVI in patients with AF. However, procedure times are still long and serious complications have been observed. Therefore, it may be a valuable alternative to the conventional techniques in selected patients but further clinical trials have to be initiated.