Vagus nerve stimulation (VNS) is an adjunctive treatment for refractory epilepsy in patients who are unsuitable candidates for epilepsy surgery (Ben-Menachem 2002). Worldwide, more than 50 000 epilepsy patients have been treated with VNS. Several studies, including two large double-blind randomized clinical trials (Ben-Menachem et al. 1994;DeGiorgio et al. 2000), have confirmed the efficacy of VNS in different types of epilepsy. Seizure reduction as a result of VNS ranges from 25% to 55%, and varies considerably from patient to patient. In responders, VNS causes either a rapid or a delayed reduction in seizure frequency. However, a significant fraction (approximately one third) of patients do not respond to VNS. Because the mechanism of action of VNS in epilepsy is currently unknown, it is not clear which factors determine the patient's response to the treatment, nor what the most optimal stimulation parameters are.The vagus nerve is a mixed nerve consisting of 20% efferent (motor) and 80% afferent (sensory) fibers. The nucleus of the solitary tract receives the largest number of vagal afferents. The nucleus of the solitary tract in turn Received July 5, 2010; revised manuscript received January 18, 2011; accepted February 8, 2011.Address correspondence and reprint requests to Robrecht Raedt, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. E-mail: robrecht.raedt@ugent.be 1 These authors contributed equally to this work.

Summary: Despite the advent of new pharmacological treatments and the high success rate of many surgical treatments for epilepsy, a substantial number of patients either do not become seizure-free or they experience major adverse events (or both). Neurostimulation-based treatments have gained considerable interest in the last decade. Vagus nerve stimulation (VNS) is an alternative treatment for patients with medically refractory epilepsy, who are unsuitable candidates for conventional epilepsy surgery, or who have had such surgery without optimal outcome. Although responder identification studies are lacking, long-term VNS studies show response rates between 40% and 50% and long-term seizure freedom in 5% to 10% of patients. Surgical complications and perioperative morbidity are low. Research into the mechanism of action of VNS has revealed a crucial role for the thalamus and cortical areas that are important in the epileptogenic process. Acute deep brain stimulation (DBS) in various thalamic nuclei and medial temporal lobe structures has recently been shown to be efficacious in small pilot studies. There is little evidence-based information on rational targets and stimulation parameters. Amygdalohippocampal DBS has yielded a significant decrease of seizure counts and interictal EEG abnormalities during long-term follow-up. Data from pilot studies suggest that chronic DBS for epilepsy may be a feasible, effective, and safe procedure. Further trials with larger patient populations and with controlled, randomized, and closed-loop designs should now be initiated. Further progress in understanding the mechanism of action of DBS for epilepsy is a necessary step to making this therapy more efficacious and established.

This study shows that the characteristics of spontaneous seizures in the intrahippocampal KA model display many similarities to other SE models and human temporal lobe epilepsy.

SUMMARYPurpose: Hippocampal deep brain stimulation (DBS) is an experimental therapy for patients with pharmacoresistant temporal lobe epilepsy (TLE). Despite the successful clinical application of DBS, the optimal stimulation parameters are undetermined. We evaluate the efficacy of a new form of DBS, using continuous stimuli with Poisson distributed intervals (Poisson distributed stimulation, PDS) in the kainate (KA) rat model, a validated model for human TLE. Methods: Status epilepticus was elicited by injection of KA (i.p.). After development of spontaneous seizures, rats were implanted with hippocampal DBS-and depth electroencephalography (EEG) electrodes. After baseline EEG monitoring, one group of rats (n = 13) was treated with PDS and a second (n = 11) received regular high frequency stimulation (HFS) at 130 Hz. Stimulation intensity was 100 lA below the threshold for induction of epileptiform EEG activity.Results: Stimulation intensity was significantly lower for PDS (156 ± 20 lA) than HFS (207 ± 23 lA; p < 0.02). Seven (54%) of 13 rats treated with PDS and 5 (45%) of 11 rats treated with HFS experienced a significant reduction in seizure frequency. In PDS-improved rats, seizure frequency was reduced to 33% (p < 0.01) of baseline value and in HFS-improved rats to 50% (p < 0.01). After termination of PDS, seizure rate returned to baseline value. Discussion: Continuous hippocampal PDS significantly reduces the number of spontaneous seizures. Compared to regular HFS, there is a slightly larger number of improved rats and a larger efficacy at a considerably lower stimulus intensity. The first two observations leave room for optimization, whereas a lower intensity is beneficial for battery life.

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Summary:Purpose: This experimental animal study evaluates the effect of high frequency deep brain stimulation (HFS DBS) on seizures in the Alternate Day Rapid Kindling model for temporal lobe epilepsy (TLE). The target for HFS is the hippocampus, as this structure is often presumed to be the seizure focus in human TLE.Methods: Rats (n = 12) were fully kindled in the hippocampus according to the Alternate Day Rapid Kindling protocol. Characteristics of the evoked afterdischarges (AD) were determined in the baseline period using AD threshold, AD latency, and AD duration as parameters. Rats were divided into a treated group (n = 7) that received 130 Hz HFS for 1 week, and a control group (n = 5) that did not receive HFS. Rats were retested in the following week. After 1 additional week of rest, the HFS group was continuously stimulated again for 1 week, during which AD evoked by kindling stimuli were characterized again.Results: HFS had a direct effect on evoked AD: during HFS, it increased AD threshold to 203 ± 13% of controls (p < 0.01) and increased AD latency to 191 ± 19% (p < 0.05). It decreased AD duration to 71 ± 9% (p < 0.05) of controls. The effect outlasted the HFS stimulation as in the week following HFS similar differences, but smaller in size, could still be established.Conclusion: Continuous HFS (130 Hz) in the hippocampus of epileptic rats modulates the characteristics of evoked AD in a way that reflects a reduction in excitability of the target region.

Abnormal glutamate transmission is involved in various neurologic disorders, such as epilepsy, schizophrenia, and Parkinson disease. At present, no imaging techniques are capable of measuring acute fluctuations in endogenous glutamate levels in vivo. We evaluated the potential of 11 C-ABP688, a PET ligand that binds to an allosteric site of the metabotropic glutamate 5 receptor, in rats by using small-animal PET and b-microprobes after pharmacologic challenges with N-acetylcysteine (NAc) and MK-801. Both compounds are known to induce increases in endogenous glutamate levels. Methods: Three experiments with 11 C-ABP688 were performed to validate our study setup: first, metabolite analyses during workup (n 5 3) and after a selected treatment (n 5 3); second, a test-retest (n 5 12) small-animal PET experiment (1 h scan; 27.75 MBq of 11 C-ABP688 administered intravenously; ,3 nmol/kg); and third, a small-animal PET and b-microprobe cold blocking study (n 5 6/ condition) with unlabeled ABP688. After this experimental validation, rats were pretreated with either NAc (intravenous infusion of 50 mg/kg/h) or MK-801 (0.16 mg/kg; given intraperitoneally); this step was followed by small-animal PET with 11 C-ABP688 (n 5 12) or b-microprobe measurements (n 5 10/condition) of 11 C-ABP688. Time-activity curves were extracted, and the nondisplaceable binding potential (BP ND ) was calculated by use of the simplified reference tissue model with the cerebellum as a reference region. Results: 11 C-ABP688 BP ND measurements were highly reproducible (test-retest), and both small-animal PET and b-microprobes were able to discriminate changes in 11 C-ABP688 binding (cold blocking). The average small-animal PET BP ND measurements in the test experiment for the caudate putamen, frontal cortex, cerebral cortex, hippocampus, and thalamus were 2.58, 1.40, 1.60, 1.86, and 1.09, respectively. However, no significant differences in BP ND measurements were observed with small-animal PET in the test and retest conditions on the one hand and the NAc and MK-801 conditions on the other hand for any of these regions. When b-microprobes were used, the average BP ND in the caudate putamen was 0.94, and no significant changes in the test and MK-801 conditions were observed. Conclusion: Pharmacologic challenges with NAc and MK-801 did not affect the 11 C-ABP688 BP ND in the rat brain. These data suggest that the in vivo affinity of 11 C-ABP688 for binding to an allosteric site of the metabotropic glutamate 5 receptor is not modulated by changes in glutamate levels and that 11 C-ABP688 is not capable of measuring acute fluctuations in endogenous levels of glutamate in vivo in the rat brain.

SUMMARYPurpose: Despite different treatment options for patients with refractory epilepsy such as epilepsy surgery and neurostimulation, many patients still have seizures and/or drug-related cerebral and systemic side effects. Local intracerebral delivery of antiepileptic compounds may represent a novel strategy with specific advantages such as the option of higher local doses and reduced side effects. In this study we evaluate the antiepileptic effect of local delivery of adenosine in the kainic acid rat model, a validated model for temporal lobe epilepsy. Methods: Fifteen rats, in which intraperitoneal kainic acid injection had induced spontaneous seizures, were implanted with a combination of depth electrodes and a cannula in both hippocampi. Cannulas were connected to osmotic minipumps to allow continuous hippocampal delivery. Rats were freely moving and permanently monitored by video-EEG (electroencephalography). Seizures were scored during 2 weeks of local hippocampal delivery of saline (baseline), followed by 2 weeks of local adenosine (6 mg/ml) (n = 10) or saline (n = 5) delivery (0.23 ll/h) (treatment). In 7 of 10 adenosine-treated rats, saline was also delivered during a washout period. Results: During the treatment period a mean daily seizure frequency reduction of 33% compared to the baseline rate was found in adenosine-treated rats (p < 0.01). Four rats had a seizure frequency reduction of at least 50%. Both nonconvulsive and convulsive seizures significantly decreased during the treatment period. In the saline-control group, mean daily seizure frequency increased with 35% during the treatment period. Conclusions: This study demonstrates the antiseizure effect of continuous adenosine delivery in the hippocampi in rats with spontaneous seizures.