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SUMMARYPurpose: Focal brain cooling is effective for suppression of epileptic seizures, but it is unclear if seizures can be suppressed without a substantial influence on normal neurologic function. To address the issue, a thermoelectrically driven cooling system was developed and applied in freemoving rat models of focal seizure and epilepsy. Methods: Focal seizures limited to the unilateral forelimb were induced by local application of a penicillin G solution or cobalt powder to the unilateral sensorimotor cortex. A proportional integration and differentiation (PID)-controlled, thermoelectrically driven cooling device (weight of 11 g) and bipolar electrodes were chronically implanted on the eloquent area (on the epileptic focus) and the effects of cooling (20, 15, and 10°C) on electrocorticography, seizure frequency, and neurologic changes were investigated. Key Findings: Cooling was associated with a distinct reduction of the epileptic discharges. In both models, cooling of epileptic foci significantly improved both seizure frequency and neurologic functions from 20°C down to 15°C. Cooling to 10°C also suppressed seizures, but with no further improvement in neurologic function. Subsequent investigation of sensorimotor function revealed significant deterioration in foot-fault tests and the receptive field size at 15°C. Significance: Despite the beneficial effects in ictal rats, sensorimotor functions deteriorated at 15°C, thereby suggesting a lower limit for the therapeutic temperature. These results provide important evidence of a therapeutic effect of temperatures from 20 to 15°C using an implantable, hypothermal device for focal epilepsy.

SUMMARYObjective: Recently, focal brain cooling (FBC) was proposed as a method for treating refractory epilepsy. However, the precise influence of cooling on the molecular basis of epilepsy has not been elucidated. Thus the aim of this study was to assess the effect of FBC on glutamate (Glu) concentration, cerebral blood flow (CBF), and glucose metabolism in patients with intractable epilepsy. Methods: Nine patients underwent FBC at 15°C for 30 min prior to cortical resection (n = 6) or hippocampectomy (n = 3). Measurement of metabolites and CBF, as well as electrocorticography (ECoG), was performed. Results: Epileptic discharge (ED), as observed by ECoG, disappeared in the cooling period and reappeared in the rewarming period. Glu concentrations were high during the precooling period and were reduced to 51.2% during the cooling period (p = 0.025). Glycerol levels showed a similar decrease (p = 0.028). Lactate concentration was high during the precooling period and was reduced during the cooling period (21.3% decrease; p = 0.005). Glucose and pyruvate levels were maintained throughout the procedure. Changes in CBF were parallel to those observed by ECoG. Significance: FBC reduced EDs and concentrations of Glu and glycerol. This demonstrates the neuroprotective effect of FBC. Our findings confirm that FBC is a reasonable and optimal treatment option for patients with intractable epilepsy.

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BackgroundInflammation and apoptosis caused by intracerebral hemorrhage (ICH) are two important factors that affect patient prognosis and survival. Toll-like receptor 4 (TLR4) triggers activation of the inflammatory pathway, causing synthesis and release of inflammatory factors. The inflammatory environment also causes neuronal apoptosis. However, no studies have reported the role of TLR4 in inflammation and apoptosis.MethodsWe performed survival curve analysis and behavioral scores on TLR4 knockout mice and wild-type mice after inducing ICH. We used TLR4 knockout mice and wild-type mice to make ICH models with type VII collagenase and explored the link between TLR4 in inflammation and apoptosis. We used Western blot to detect the expression of apoptosis-related proteins, inflammatory factors, and their receptors at different time points after ICH induction. The effects of TLR4 on apoptosis were observed by TUNEL, Hoechst, and HE staining techniques. The association with TLR4 in inflammation and apoptosis was explored using IL-1β and TNF-α antagonists. Data conforming to a normal distribution are expressed as mean ± standard deviation. Grade and quantitative data were compared with rank sum test and t test between two groups. P < 0.05 was considered statistically significant.ResultsTLR4 knockout significantly increased the survival rate of ICH mice. The scores of TLR4 knockout mice were significantly lower than those of wild-type mice. We found that TLR4 knockout mice significantly inhibited apoptosis and the expression of inflammatory factors after the induction of ICH. The apoptosis of ICH-induced mice was significantly improved after injecting IL-1β and TNF-α antagonists. Moreover, the anti-apoptotic effect of the antagonist in wild-type mice is more pronounced. A single injection of the antagonist failed to improve apoptosis in TLR4 knockout mice.ConclusionsWe conclude that TLR4-induced inflammation after ICH promotes neuronal apoptosis. IL-1β and TNF-α antagonists attenuate this apoptotic effect. Therefore, targeting TLR4 in patients with clinical ICH may attenuate inflammatory response, thereby attenuating apoptosis and improving prognosis.