Bregt Van Nieuwenhuyse

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.

Real-time detection of epileptic seizures in animal models using reservoir computing.

In recent years, an increasing number of studies have investigated the effects of closed-loop anti-epileptic treatments. Most of the current research still is very labour intensive: real-time treatment is manually triggered and conclusions can only be drawn after multiple days of manual review and annotation of the electroencephalogram (EEG). In this paper we propose a technique based on reservoir computing (RC) to automatically and in real-time detect epileptic seizures in the intra-cranial EEG (iEEG) of epileptic rats in order to immediately trigger seizure treatment. The performance of the system is evaluated in two different seizure types: absence seizures from genetic absence epilepsy rats from Strasbourg (GAERS) and limbic seizures from post status epilepticus (PSE) rats. The dataset consists of 452 hours iEEG from 23 GAERS and 2083 hours iEEG from 22 PSE rats. In the default set-up the system detects 0.09 and 0.13 false positives per seizure and misses 0.07 and 0.005 events per seizure for GAERS and PSE rats respectively. It achieves an average detection delay below 1s in GAERS and less than 10s in the PSE data. This detection delay and the number of missed seizures can be further decreased when a higher false positive rate is allowed. Our method outperforms state-of-the-art detection techniques and only a few parameters require optimization on a limited training set. It is therefore suited for automatic seizure detection based on iEEG and may serve as a useful tool for epilepsy researchers. The technique avoids the time-consuming manual review and annotation of EEG and can be incorporated in a closed-loop treatment strategy.

Modulation of Hippocampal Activity by Vagus Nerve Stimulation in Freely Moving Rats.

BACKGROUND Vagus Nerve Stimulation (VNS) has seizure-suppressing effects but the underlying mechanism is not fully understood. To further elucidate the mechanisms underlying VNS-induced seizure suppression at a neurophysiological level, the present study examined effects of VNS on hippocampal excitability using dentate gyrus evoked potentials (EPs) and hippocampal electroencephalography (EEG). METHODS Male Sprague-Dawley rats were implanted with a VNS electrode around the left vagus nerve. A bipolar stimulation electrode was implanted in the left perforant path and a bipolar recording electrode was implanted in the left dentate gyrus for EEG and dentate field EP recording. Following recovery, VNS was applied in freely moving animals, using a duty cycle of 7 s on/18 s off, 30 Hz frequency, 250 µs pulse width, and an intensity of either 0 (SHAM), 25 µA or 1000 µA, while continuously monitoring EEG and dentate field EPs. RESULTS VNS at 1000 µA modulated dentate field EPs by decreasing the field excitatory post-synaptic potential (fEPSP) slope and increasing the latency and amplitude of the population spike. It additionally influenced hippocampal EEG by slowing theta rhythm from 7 Hz to 5 Hz and reducing theta peak and gamma band power. No effects were observed in the SHAM or 25 µA VNS conditions. CONCLUSION VNS modulated hippocampal excitability of freely moving rats in a complex way. It decreased synaptic efficacy, reflected by decreased fEPSP slope and EEG power, but it simultaneously facilitated dentate granule cell discharge indicating depolarization of dentate granule cells.

Hippocampal Deep Brain Stimulation Reduces Glucose Utilization in the Healthy Rat Brain

PurposeThe effects of deep brain stimulation (DBS) have been studied primarily by cellular studies, which lack the ability to elucidate DBS-related responses on a whole-brain scale. 2-Deoxy-2-[18F]fluoro-d-glucose positron emission tomography ([18F]FDG-PET) reflects changes in neural activity throughout the entire brain volume. The aim of this study was to investigate the whole-brain effect of DBS on the glucose utilization in healthy rats.ProceduresSeven rats were implanted with a DBS electrode in the right hippocampus and injected with [18F]FDG to measure the glucose metabolism during DBS.ResultsAnalysis reveals significant DBS-induced decreases in the glucose metabolism in the bilateral hippocampus and other limbic structures.ConclusionsThis study demonstrates that DBS exhibits not only a local effect around the electrode tip but also in other limbic regions. [18F]FDG-PET studies have the potential to provide better insight into the mechanism of action of DBS by simultaneously observing activity at multiple sites in the brain.

Unilateral vs. bilateral hippocampal DBS in a rat model for temporal lobe epilepsy

Molecular Imaging of Inflammation Reveals Differences Between Drug-Resistant and Drug-Sensitive Animals in a Chronic Model of Temporal Lobe Epilepsy