Tine Wyckhuys

Increased hippocampal noradrenaline is a biomarker for efficacy of vagus nerve stimulation in a limbic seizure model

J. Neurochem. (2011) 117, 461–469.

Electrical stimulation for the treatment of epilepsy.

SummaryDespite 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.

High Frequency Deep Brain Stimulation in the Hippocampus Modifies Seizure Characteristics in Kindled Rats

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.

Seizures in the intrahippocampal kainic acid epilepsy model: characterization using long-term video-EEG monitoring in the rat.

Objective –  Intrahippocampal injection of kainic acid (KA) in rats evokes a status epilepticus (SE) and leads to spontaneous seizures. However to date, precise electroencephalographic (EEG) and clinical characterization of spontaneous seizures in this epilepsy model using long‐term video‐EEG monitoring has not been performed.

Comparison of hippocampal Deep Brain Stimulation with high (130 Hz) and low frequency (5 Hz) on afterdischarges in kindled rats

Hippocampal Deep Brain Stimulation (DBS) is proposed as an experimental treatment for refractory epilepsy, but the optimal stimulation parameters are undetermined. High frequency hippocampal DBS at 130Hz is effective in both animals and patients with epilepsy. Low frequency stimulation (approximately 5Hz) is assumed to have anti-epileptic properties but the efficacy is highly debated. This animal study compares the effects of both stimulation modalities in kindled rats. Sprague Dawley rats (n=20) were fully kindled according to the Alternate Day Rapid Kindling-protocol. After a baseline kindling period, rats were divided into a high frequency group (HFS, 130Hz, n=11) and a low frequency group (LFS, 5Hz, n=9), both receiving 10 days of continuous DBS. During and after DBS, the seizure susceptibility of all rats was tested and the characteristics of the afterdischarges (ADs) were compared between both treatments. During HFS, AD threshold was higher (p<0.05) and at the stimulated site, AD latency was longer (p<0.01) than during baseline period. During LFS, a similar but smaller change was observed, but did not reach significance. The duration of the AD was not affected by either HFS or LFS. After termination of HFS, the effects on AD latency and AD threshold recovered to baseline. In conclusion, high frequency stimulation at 130Hz is more effective than LFS (5Hz) in affecting excitability in epileptic rats. This is reflected in a higher AD threshold and longer AD latency during application of stimulation.

Suppression of hippocampal epileptic seizures in the kainate rat by Poisson distributed stimulation

Purpose:  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.

Hippocampal deep brain stimulation induces decreased rCBF in the hippocampal formation of the rat

Deep brain stimulation (DBS) is a promising experimental approach to treat various neurological disorders. However, the optimal stimulation paradigm and the precise mechanism of action of DBS are unknown. Neuro-imaging by means of Single Photon Emission Computed Tomography (SPECT) is a non-invasive manner of evaluating regional cerebral blood flow (rCBF) changes, which are assumed to reflect changes in neural activity. In this study, rCBF changes induced by hippocampal DBS are evaluated by subtraction analysis of stimulation on/off using small animal microSPECT of the rat brain. Rats (n=13) were implanted with a multi-contact DBS electrode in the right hippocampus and injected with 10 mCi of HMPAO-Tc99(m) during application of various hippocampal DBS paradigms and amplitudes and during sham stimulation. Subtraction analysis revealed that hippocampal DBS caused a significant decrease in relative rCBF, both in the ipsi- (the side of the implanted electrode) and contralateral hippocampus. Hypoperfusion spread contralaterally with increasing stimulation amplitude. A clear distinction in spatial extent and intensity of hypoperfusion was observed between stimulation paradigms: bipolar Poisson Distributed Stimulation induced significant hypoperfusion ipsi- and contralaterally (p<0.01), while during other stimulation paradigms, rCBF-changes were less prominent. In conclusion, small animal microSPECT allows us to draw conclusions on the location, spatial extent and intensity of the hypoperfusion observed in the ipsi- and contralateral hippocampus, induced by hippocampal DBS. Our study demonstrates an innovative approach to visualize the effects of DBS and can be a useful tool in evaluating the effect of various stimulation paradigms and target areas for DBS.

Increased rat serum corticosterone suggests immunomodulation by stimulation of the vagal nerve

The role of the vagal nerve within the immune system has not been fully elucidated. Vagal afferents connect to several central nervous system structures, including the hypothalamus. We investigated the effect of vagal nerve stimulation (VNS) on serum corticosterone levels in rats. Corticosterone levels were measured following 1 h of high frequency (30 Hz) or low frequency (1 Hz) VNS in awake animals. There was a significant increase (p < 0.05) in serum corticosterone levels following 30 Hz VNS compared to 1 Hz VNS or sham stimulation. These results suggest an immediate effect of VNS on the hypothalamic pituitary-adrenal (HPA) axis and support the role of the vagal nerve in immunomodulation.

N-Acetylcysteine– and MK-801–Induced Changes in Glutamate Levels Do Not Affect In Vivo Binding of Metabotropic Glutamate 5 Receptor Radioligand 11C-ABP688 in Rat Brain

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 11C-ABP688, a PET ligand that binds to an allosteric site of the metabotropic glutamate 5 receptor, in rats by using small-animal PET and β-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 11C-ABP688 were performed to validate our study setup: first, metabolite analyses during workup (n = 3) and after a selected treatment (n = 3); second, a test–retest (n = 12) small-animal PET experiment (1 h scan; 27.75 MBq of 11C-ABP688 administered intravenously; <3 nmol/kg); and third, a small-animal PET and β-microprobe cold blocking study (n = 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 11C-ABP688 (n = 12) or β-microprobe measurements (n = 10/condition) of 11C-ABP688. Time–activity curves were extracted, and the nondisplaceable binding potential (BPND) was calculated by use of the simplified reference tissue model with the cerebellum as a reference region. Results: 11C-ABP688 BPND measurements were highly reproducible (test–retest), and both small-animal PET and β-microprobes were able to discriminate changes in 11C-ABP688 binding (cold blocking). The average small-animal PET BPND 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 BPND 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 β-microprobes were used, the average BPND 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 11C-ABP688 BPND in the rat brain. These data suggest that the in vivo affinity of 11C-ABP688 for binding to an allosteric site of the metabotropic glutamate 5 receptor is not modulated by changes in glutamate levels and that 11C-ABP688 is not capable of measuring acute fluctuations in endogenous levels of glutamate in vivo in the rat brain.

Automatic detection of epileptic seizures on the intra-cranial electroencephalogram of rats using reservoir computing

INTRODUCTION In this paper we propose a technique based on reservoir computing (RC) to mark epileptic seizures on the intra-cranial electroencephalogram (EEG) of rats. RC is a recurrent neural networks training technique which has been shown to possess good generalization properties with limited training. MATERIALS The system is evaluated on data containing two different seizure types: absence seizures from genetic absence epilepsy rats from Strasbourg (GAERS) and tonic-clonic seizures from kainate-induced temporal-lobe epilepsy rats. The dataset consists of 452hours from 23 GAERS and 982hours from 15 kainate-induced temporal-lobe epilepsy rats. METHODS During the preprocessing stage, several features are extracted from the EEG. A feature selection algorithm selects the best features, which are then presented as input to the RC-based classification algorithm. To classify the output of this algorithm a two-threshold technique is used. This technique is compared with other state-of-the-art techniques. RESULTS A balanced error rate (BER) of 3.7% and 3.5% was achieved on the data from GAERS and kainate rats, respectively. This resulted in a sensitivity of 96% and 94% and a specificity of 96% and 99% respectively. The state-of-the-art technique for GAERS achieved a BER of 4%, whereas the best technique to detect tonic-clonic seizures achieved a BER of 16%. CONCLUSION Our method outperforms up-to-date techniques and only a few parameters need to be optimized on a limited training set. It is therefore suited as an automatic aid for epilepsy researchers and is able to eliminate the tedious manual review and annotation of EEG.