Small-animal repetitive transcranial magnetic stimulation combined with [¹8F]-FDG microPET to quantify the neuromodulation effect in the rat brain.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neurostimulation technique for the treatment of various neurological and psychiatric disorders. To investigate the working mechanism of this treatment approach, we designed a small-animal coil for dedicated use in rats and we combined this neurostimulation method with small-animal positron emission tomography (microPET or µPET) to quantify regional 2-deoxy-2-((18)F)fluoro-d-glucose ([(18)F]-FDG) uptake in the rat brain, elicited by a low- (1 Hz) and a high- (50 Hz) frequency paradigm. Rats (n=6) were injected with 1 mCi of [(18)F]-FDG 10 min after the start of 30 min of stimulation (1 Hz, 50 Hz or sham), followed by a 20-min µPET image acquisition. Voxel-based statistical parametric mapping (SPM) image analysis of 1-Hz and 50-Hz versus sham stimulation was performed. For both the 1-Hz and 50-Hz paradigms we found a large [(18)F]-FDG hypermetabolic cluster (2.208 mm(3) and 2.616 mm(3), resp.) (analysis of variance (ANOVA), p<0.05) located in the dentate gyrus complemented with an additional [(18)F]-FDG hypermetabolic cluster (ANOVA, p<0.05) located in the entorhinal cortex (2.216 mm(3)) for the 50-Hz stimulation. The effect on [(18)F]-FDG metabolism was 2.9 ± 0.8% at 1 Hz and 2.5 ± 0.8% at 50 Hz for the dentate gyrus clusters and 3.3 ± 0.5% for the additional cluster in the entorhinal cortex at 50 Hz. The maximal (4.19 vs. 2.58) and averaged (2.87 vs. 2.21) T-values are higher for 50 Hz versus 1 Hz. This experimental study demonstrates the feasibility to combine µPET imaging in rats stimulated with rTMS using a custom-made small-animal magnetic stimulation setup to quantify changes in the cerebral [(18)F]-FDG uptake as a measure for neuronal activity.

Modulation of seizure threshold by vagus nerve stimulation in an animal model for motor seizures.

OBJECTIVE: The precise mechanism of action of vagus nerve stimulation (VNS) in suppressing epileptic seizures remains to be elucidated. This study investigates whether VNS modulates cortical excitability by determining the threshold for provoking focal motor seizures by cortical electrical stimulation before and after VNS. MATERIAL AND METHODS: Male Wistar rats (n = 8) were implanted with a cuff-electrode around the left vagus nerve and with stimulation electrodes placed bilaterally on the rat motor cortex. Motor seizure threshold (MST) was assessed for each rat before and immediately after 1 h of VNS with standard stimulation parameters, during two to three sessions on different days. RESULTS: An overall significant increase of the MST was observed following 1 h of VNS compared to the baseline value (1420 microA and 1072 microA, respectively; P < 0.01). The effect was reproducible over time with an increase in MST in each experimental session. CONCLUSIONS: VNS significantly increases the MST in a cortical stimulation model for motor seizures. These data indicate that VNS is capable of modulating cortical excitability.

Deep brain stimulation for epilepsy: knowledge gained from experimental animal models.

Since the development of Deep Brain Stimulation (DBS) for Parkinson's Disease, DBS has been suggested as a treatment option for various other neurological disorders. Stimulation of deep brain structures for refractory epilepsy appears to be a safe treatment option with promising results. As research on the evaluation and optimization of DBS for refractory epilepsy may be difficult and unethical in patients, studies on animal models of epilepsy are indispensable. Various brain structures and specific nuclei such as the basal ganglia, the cerebellum, the locus coeruleus and temporal lobe structures have been investigated as target areas for DBS. Additionally, a wide variety of stimulation parameters are available, with a range of stimulation frequencies, pulse widths and stimulation intensities. This review provides an overview of the relevant literature on experimental animal studies of DBS for epilepsy. Knowledge gained from animal studies can be used to answer questions regarding the optimal brain targets and stimulation parameters in human applications.

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.

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. MATERIALS AND METHODS: Rats were implanted with bipolar hippocampal depth electrodes and a cannula for the injection of KA (0.4 lg /0.2 ll) in the right hippocampus. Video-EEG monitoring was used to determine habitual parameters of spontaneous seizures such as seizure frequency, severity, progression and day-night rhythms. RESULTS: Spontaneous seizures were detected in all rats with 13 out of 15 animals displaying seizures during the first eight weeks after SE. A considerable fraction (35%) of the spontaneous seizures did not generalize secondarily. Seizure frequency was quite variable and the majority of the KA treated animals had less than one seizure per day. A circadian rhythm was observed in all rats that showed sufficient seizures per day. CONCLUSIONS: 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.

Serial day rapid kindling is an effective tool in screening the anti-epileptic properties of topiramate.

INTRODUCTION: In this study, a serial day rapid kindling protocol was used to fully kindle rats in a matter of days. Subsequently, the anticonvulsant profile of a relatively new anti-epileptic drug, topiramate, was evaluated in a cross-over design to further validate this rapid kindling model. METHODS: Rats were kindled during three consecutive days, according to the serial day rapid kindling protocol. Topiramate was tested at a dose of 100mg/kg, i.p., over the next 2 days using a cross-over design. The stability of the kindled state was evaluated in all rats during two retest paradigms. During the drug-testing procedure, rats received a single i.p. injection of either topiramate or verhicle. Starting 1 h later the rats received additional kindling stimulations during which their response was measured. RESULTS: Serial day rapid kindling induced a long lasting and stable fully kindled state that allowed for the anti-epileptic drug screening procedure. Topiramate reduced both the afterdischarge duration and ameliorated seizure semiology in the kindled rats. DISCUSSION: Serial day rapid kindling provided a tool to rapidly kindle rats in 3 days. Using a cross-over design, clear indications on anti-epileptic activity of a given drug can be determined using few laboratory animals.