Much debate exists about how the brain transitions into an epileptic seizure. One source of confusion is that there are likely to be critical differences between experimental seizure models. To address this, we have compared the evolving activity patterns in two widely used in vitro models of epileptic discharges. Brain slices from young adult mice were prepared in the same way and bathed either in 0 Mg2+ or 100 µmol/L 4AP artificial cerebrospinal fluid. We have found that while local field potential recordings of epileptiform discharges in the two models appear broadly similar, patch‐clamp analysis reveals an important difference in the relative degree of glutamatergic involvement. 4AP affects parvalbumin‐expressing interneurons more than other cortical populations, destabilizing their resting state and inducing spontaneous bursting behavior. Consequently, the most prominent pattern of transient discharge (“interictal event”) in this model is almost purely GABAergic, although the transition to seizure‐like events (SLEs) involves pyramidal recruitment. In contrast, interictal discharges in 0 Mg2+ are only maintained by a very large glutamatergic component that also involves transient discharges of the interneurons. Seizure‐like events in 0 Mg2+ have significantly higher power in the high gamma frequency band (60–120Hz) than these events do in 4AP, and are greatly delayed in onset by diazepam, unlike 4AP events. We, therefore, conclude that the 0 Mg2+ and 4AP models display fundamentally different levels of glutamatergic drive, demonstrating how ostensibly similar pathological discharges can arise from different sources. We contend that similar interpretative issues will also be relevant to clinical practice.

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ACCIDENTAL ligation of the hcpatic artery is fortunately rare. Twenty-seven cases have been reported in the literature up to datc. The rarity of the lesion and the complete investigation carried out prompts the presentation of this report. CASE REPORT.W. W., male, age 49, was admitted to Dr. R. R . Graham's service of the Toronto General Hospital on Kov. 5 , 1930, with a right inguinal hernia, haemorrhoids, and a slight prolapse of the rectum. During the course of routine history and physical examination, a pyloric carcinoma was diagnosed and confirnicd by radiological examination. Accordingly on Nov. 12, 1930, following the usual pre-operative preparation, a partial gastrectomy was done.A moderately extensive pyloric carcinoma was found, with enlarged lymphglands extending upward into the gastro-hepatic omentum and along the lesser curvature of the stomach, almost t o the msophagus ; glandular enlargement in the gastrocolic omcntuni was not extensive. There was marked inflammatory reaction and induration of the gastro-hepatic ornentum which extended along the anterior border of the foramen of Winslow. The pylorus was freed after division of the gastrocolic omentum. The vessels along the superior border of the pylorus were isolated, divided, and ligated. During this procedure a large vessel which was enmeshed in inflammatory adhesions was divided and tied. It was immediately thought that the hepat,ic artery had been severed. Subsequently more careful examination following the closrire of the duodenal stump confirmed this belief. Approximately one inch of thc hepatic artery had been removed a t a point about one and a quarter inches from its origin in the coeliac axis. The operation was completed in the usual manner, a posterior end-to-side retrocolic gastrojejunal anastomosis being done. No changes were noted in the liver during the operation. The abdomen was closed in layers without drainage, and the patient returned t,o the ward in good condition. Post-operatively continuous intravenous saline was given by the drop method, supplemented with the usual sedatives. Blood-sugar (F~ig. 343) and non-protein nitrogen estimation (Fig. 344) were done hourly for the first four hours and at greater intervals thereafter. These showed no marked variation from the normal. The Van den Bergh reactions were negative throughout, and small quantities of urobilin were detected in the urine only the day preceding death.Clinically the patient progressed favourably for the first three days. The evening of the fourth day his temperature rose to 10.7" F. with a simultaneous elevation in pulse and respirations. Bilateral bronchopneumonia was diagnosed. He became rapidly worse and died on the seventh day of pneumonia, cardiac failure, and terminal pulmonary edema.Post-mortem examination revealrd extensive bilateral bronchopneumonia of * From tlir Ikpartment of Surgery and rkpartment of l'ntliology, I'nivrrsity of Toronto.

Brain state transitions are readily apparent from changes in brain rhythms1, but are difficult to predict, suggestive that the underlying cause is latent to passive recording methods. Among the most important transitions, clinically, are the starts of seizures. We here show that an “active probing” approach may have several important benefits for epileptic management, including by helping predict these transitions. We used mice expressing the optogenetic actuator, channelrhodopsin, in pyramidal cells, allowing this population to be stimulated in isolation. Intermittent stimulation at frequencies as low as 0.033 Hz (period = 30 s) delayed the onset of seizure-like events in an acute brain slice model of ictogenesis, but the effect was lost if stimulation was delivered at even lower frequencies (1/min). Notably, active probing additionally provides advance indication of when seizure-like activity is imminent, revealed by monitoring the postsynaptic response to stimulation. The postsynaptic response, recorded extracellularly, showed an all-or-nothing change in both amplitude and duration, a few hundred seconds before seizure-like activity began – a sufficient length of time to provide a helpful warning of an impending seizure. The change in the post-synaptic response then persisted for the remainder of the recording, indicative of a state change from a pre-epileptic to a pro-epileptic network. This occurred in parallel with a large increase in the stimulation-triggered Ca2+ entry into pyramidal dendrites, and a step increase in the number of postsynaptic somatic action potentials, both consistent with a reduction in the threshold for dendritic action potentials. In 0 Mg2+ bathing media, the reduced threshold was not associated with changes in glutamatergic synaptic function, nor of GABAergic release from either parvalbumin or somatostatin interneurons, but simulations indicate that the step change in the optogenetic response can instead arise from incremental increases in intracellular [Cl-]. The change in the response to stimulation was replicated by artificially raising intracellular [Cl-], using the optogenetic chloride-pump, Halorhodopsin. By contrast, increases in extracellular [K+] cannot account for the firing patterns in the response to stimulation, although this, and other cellular changes, may contribute to ictal initiation in other circumstances. We describe how these various cellular changes form a synergistic network of positive feedback mechanisms, which may explain the precipitous nature of seizure onset. This model of seizure initiation draws together several major lines of epilepsy research and as well as providing an important proof-of-principle regarding the utility of open-loop brain stimulation for clinical management of the condition.

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