Suppression Of Epileptic Seizures Research Articles

Charge-Mode Neural Stimulator With a Capacitor-Reuse Residual Charge Detector and Active Charge Balancing for Epileptic Seizure Suppression.

This study proposes a charge-mode neural stimulator for electrical stimulation systems that utilizes a capacitor-reuse technique with a residual charge detector and achieves active charge balancing simultaneously. The design is mainly used for epilepsy suppression systems to achieve real-time symptom relief during seizures. A charge-mode stimulator is adopted in consideration of the complexity of circuit design, the high voltage tolerance of transistors, and system integration requirements in the future. The residual charge detector allows users to understand the current stimulus situation, enabling them to make optimal adjustments to the stimulation parameters. On the basis of the information on actual stimulation charge, active charge balancing can effectively prevent the accumulation of mismatched charges on electrode impedance. The capacitor- and phase-reuse techniques help realize high integration of the overall stimulator circuit in consideration of the commonality of the use of a capacitor and charging/discharging phase in the stimulation circuit and charge detector. The proposed charge-mode neural stimulator is implemented in a TSMC 0.18 µm 1P6M CMOS process with a core area of 0.2127 mm2. Measurement results demonstrate the accuracy of the stimulation's functionality and the programmable stimulus parameters. The effectiveness of the proposed charge-mode neural stimulator for epileptic seizure suppression is verified through animal experiments.

A stimuli-responsive nanocarrier for diagnosis of seizures and inhibition of glutaminase in epilepsy

Epilepsy is marked by unpredictable and recurrent episodes of seizures. It is characterized by glutamate excitotoxicity and changes in stimuli such as pH, temperature and oxidative environment. This study aimed to formulate novel nanoparticulate theranostic nanocarrier for combined effects of diagnosis and treatment of epilepsy by: i) in-situ detection of epileptic conditions through characteristic changes in pH through the synthesis of pH-responsive polymer (CS-g-PD) and ii) ‘on-demand’ therapeutic alleviation of epileptic seizures through an inhibitor of glutaminase, 6-diazo-5-oxo-norleucine (DON). The formulation of DON-CS-g-PD-SLNs possessed nanodimensions (∼197.56 ± 17.87) nm and zeta potential (4.19 ± 0.29), with entrapment efficiency of (80.29 ± 0.006%). The coating pH-responsive polymer showed good sensitivity for acidic conditions by releasing the drug in pH 6.4 and resisting release in higher pH 7.2. In-vivo studies in Wistar rats showed suppression of epileptic seizures, escalation in the duration latency and reduction in duration of convulsions and recovery period. Furthermore, it was also successful in reducing the levels of glutaminase (p < 0.0001) in the brain of PTZ-kindled rats, thereby leading to a decrease in glutamate levels (p < 0.01). Hence, the nanocarriers show promising potential as ‘on-demand’ theranostics in epilepsy by reducing both the incidence and severity of convulsions.

A wireless and battery-less implant for multimodal closed-loop neuromodulation in small animals.

Fully implantable wireless systems for the recording and modulation of neural circuits that do not require physical tethers or batteries allow for studies that demand the use of unconstrained and freely behaving animals in isolation or in social groups. Moreover, feedback-control algorithms that can be executed within such devices without the need for remote computing eliminate virtual tethers and any associated latencies. Here we report a wireless and battery-less technology of this type, implanted subdermally along the back of freely moving small animals, for the autonomous recording of electroencephalograms, electromyograms and body temperature, and for closed-loop neuromodulation via optogenetics and pharmacology. The device incorporates a system-on-a-chip with Bluetooth Low Energy for data transmission and a compressed deep-learning module for autonomous operation, that offers neurorecording capabilities matching those of gold-standard wired systems. We also show the use of the implant in studies of sleep-wake regulation and for the programmable closed-loop pharmacological suppression of epileptic seizures via feedback from electroencephalography. The technology can support a broader range of applications in neuroscience and in biomedical research with small animals.

Neural Sources of Vagus Nerve Stimulation–Induced Slow Cortical Potentials

ObjectivesThis study investigated neuronal sources of slow cortical potentials (SCPs) evoked during vagus nerve stimulation (VNS) in patients with epilepsy who underwent routine electroencephalography (EEG) after implantation of the device. Materials and MethodsWe analyzed routine clinical EEG from 24 patients. There were 5 to 26 trains of VNS during EEG. To extract SCPs from the EEG, a high-frequency filter of 0.2 Hz was applied. These EEG epochs were averaged and used for source analyses. The averaged waveforms for each patient and their grand average were subjected to multidipole analysis. Patients with at least 50% seizure frequency reduction were considered responders. Findings from EEG analysis dipole were compared with VNS responses. ResultsVNS-induced focal SCPs whose dipoles were estimated to be located in several cortical areas including the medial prefrontal cortex, postcentral gyrus, and insula, with a significantly higher frequency in patients with a good VNS response than in those with a poor response. ConclusionsThis study suggested that some VNS-induced SCPs originating from the so-called vagus afferent network are related to the suppression of epileptic seizures.

Intelligent Wireless EEG Measurement System With Electrical and Optogenetic Stimulation for Epileptic Seizure Detection and Suppression

A two-channel real-time intelligent electroencephalography (EEG) measurement system with electrical and optical stimulations is presented for seizure detection and suppression. Based on software control through a wireless interface, this system provides closed- and open-loop feedback control with programmable waveform for electrical and optical stimulations. Matlab graphical user interface is used to monitor the intracranial EEG, perform the algorithm for seizure detection, and adjust the required intensity, frequency, duty cycle, and duration of electrical and optical stimulations. The whole hardware device is embedded on a printed circuit board with the size of 27.3 mm $\times23.6$ mm. C57BL/6 mice with Thy1-ChR2-YFP gene transfer and drug-induced seizure are used to demonstrate epileptic seizure suppression according to electrical and optogenetic stimulation in the proposed wireless EEG measurement system.

Increased Seizure Susceptibility for Rats Subject to Early Life Hypoxia Might Be Associated with Brain Dysfunction of NRG1-ErbB4 Signaling in Parvalbumin Interneurons.

Neuregulin 1 (NRG1)-induced activation of ErbB4 in parvalbumin (PV) inhibitory interneurons is reported to serve as a critical endogenous negative-feedback mechanism to repress brain epileptogenesis. Here, we investigated the seizure susceptibility and the role of NRG1-ErbB4 signaling in PV interneurons in the suppression of epileptic seizures for rats subject to early life hypoxia. Neonatal postnatal day 5 (P5) rats were exposed to intermittent hypoxia (IH) or control (CON) room air for 10 days. In the prefrontal cortex (PFC) of P54 rats, we determined the impact of neonatal IH exposures on the expression of PV, NRG1, ErbB4, and phosphorylated ErbB4 (p-ErbB4) during the seizure induction. Seizure susceptibility tests with the common convulsant agent pentylenetetrazole (PEN) at P54 revealed that rats subject to neonatal hypoxia exposure developed faster and more serious epileptic seizures. Neonatal IH exposures (1) decreased the number of PV cells in the PFC of P54 rats; (2) interrupted the expression of NRG1 gene; and (3) altered the activity of NRG1 on PV interneurons in the PFC after the seizure induction. Intracerebroventricular delivery of exogenous NRG1 before seizure induction by PEN significantly reduced the seizure susceptibility for neonatal IH-exposed rats. The ErbB4 inhibitor AG1478 inhibited the exogenous NRG1's effects on seizure susceptibility. Environmental enrichment (EE) rescued the abovementioned pathophysiological alterations and significantly attenuated the epileptic seizures after the seizure induction for neonatal IH-exposed rats. Our study indicated early life hypoxia exposure might increase the seizure susceptibility for rats and contribute to pathophysiological dysfunction of NRG1-ErbB4 signaling in PV interneurons in the suppression of epileptic seizures. EE might attenuate the increased seizure susceptibility for neonatal IH-exposed rats through rescuing pathophysiological alterations of NRG1-ErbB4 signaling in PV interneurons.

Reliability Analysis of an Epileptic Seizure Detector Powered by an Energy Harvester

Due to a limited lifetime of a battery, energy harvesters have been studied as alternative energy sources for implantable biomedical devices such as an implantable stimulator for epileptic seizure suppression. However, energy harvesters have weakness in providing stable power. We designed a neural recording circuit powered solely by a piezoelectric energy harvester, and applied its output to a seizure detector to analyze the reliability of the recorded signal. Performance of the seizure detector was evaluated. We found that the average time differences between with and without voltage variances were about 0.05 s under regular vibrations and about 0.07 s under irregular vibrations, respectively. The ratio of average true positive alarm period varied within about 0.02% under regular vibrations and 0.029% under irregular vibrations, respectively. The ratio of average false positive alarm period varied within about 0.004% under regular vibrations and 0.014% under irregular vibrations, respectively. This paper presents a reliability analysis of an epileptic seizure detector with a neural signal recording circuit powered by a piezoelectric energy harvester. The results showed that a supply voltage variance within ±10% could be acceptable for reliable operation of a seizure detector.

Dietary Flavonoids Interaction with CREB-BDNF Pathway: An Unconventional Approach for Comprehensive Management of Epilepsy

cAMP response element binding protein (CREB) is a key transcriptional regulator that regulates the transcription of genes related with neuronal differentiation, synaptic plasticity, learning and memory. Brain derived neurotrophic factor (BDNF), is a CREB dependent gene which plays a pivotal role in the pathogenesis of epilepsy and central comorbid condi-tions associated with epilepsy. However, the beneficial or detrimental consequences of CREB-BDNF activation on the in-duction and/or progression of seizures depend specifically on the region of brain involved and the time of activation. The bi-oactive molecules that alter the activity of CREB in a way to have specialized effects in different brain regions and neural cir-cuits involved could potentially be utilized for therapeutic purposes. Flavonoids are the polyphenolic compounds which lead to phosphorylation of CREB in the hippocampus, followed by increase in extracellular signal regulated kinase (ERK) and BDNF. Several members of flavonoid family have also showed suppression of epileptic seizures via interaction with CREB/BDNF pathway. Moreover, epilepsy is often accompanied by a number of behavioural and psychological comorbid conditions that further gets aggravated by the use of conventional antiepileptic drug therapy. Multiple studies have also sup-ported the beneficial effects of flavonoids in cognitive and memory impairments by upregulation of CREB-BDNF pathway. The current review is an attempt to collate the available preclinical and clinical studies to establish the therapeutic potential of various dietary flavonoids in comprehensive management of epilepsy with relation to CREB-BDNF pathway.

Model-based robust suppression of epileptic seizures without sensory measurements.

Uncontrolled seizures may lead to irreversible damages in the brain and various limitations in the patient's life. There exist experimental studies to stabilize the patient seizures. However, the experimental setups have many sensory devices to measure the dynamics of the brain cortex. These equipments prevent to produce small portable stabilizers for patients in everyday life. Recently, a comprehensive cortex model is introduced to apply model-based observers and controllers. However, this cortex model can be uncertain and have time-varying parameters. Therefore, in this paper, a robust Takagi-Sugeno (TS) controller and observer are designed to suppress the epileptic seizures without sensory measurements. The unavailable sensory measurements are provided by the designed nonlinear observer. The exponential convergence of the observer and controller is satisfied by the feedback parameter design using linear matrix inequalities. In addition, TS fuzzy observer-controller design has been compared with the conventional PID method in terms of control performance and design problem. The numerical computations show that the epileptic seizures are more effectively suppressed by the TS fuzzy observer-based controller under uncertain membrane potential dynamics.

Chemogenetic suppression of spontaneous seizures in a rat model for temporal lobe epilepsy

Event Abstract Back to Event Chemogenetic suppression of spontaneous seizures in a rat model for temporal lobe epilepsy Marie-Gabrielle Goossens1*, Emma Christiaen2, Paul Boon1, Kristl Vonck1, Evelien Carrette1, Jana Desloovere1, Chris Van Den Haute3, Veerle Baekelandt3, Wytse J. Wadman1, Christian Vanhove2 and Robrecht Raedt1 1 Ghent University, Department of Head and Skin, Belgium 2 Medical Imaging and Signal Processing, Ghent University, Belgium 3 Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Belgium AIM The hippocampus is believed to play a crucial role in seizure generation in temporal lobe epilepsy (TLE), a common form of medication-resistant epilepsy. This preclinical study evaluated chemogenetics as a potential therapy for TLE. Using this approach, excitatory neurons of the epileptic hippocampus were selectively inhibited through ligand-based activation of an inhibitory Designer Receptor Exclusively Activated by Designer Drugs (DREADD). METHODS The intraperitoneal kainic acid rat model for TLE was used. Animals (n=6) were injected in right hippocampus with adeno-associated viral vector carrying CamKIIα-hM4Di-mCherry. Two weeks after injection, rats were bilaterally implanted with depth electrodes in the dentate gyrus and CA1 region of both hippocampi. Seizure frequency before and after activating DREADDs with subclinical doses of clozapine was determined using continuous video-EEG recordings. First, EEG was monitored during a baseline period of six days. Next, single injections of different clozapine doses (0.01, 0.1 or 1 mg/kg bodyweight/24h, s.c.) and vehicle were compared. For each dose, EEG was monitored during three days of treatment. Finally, one dose was selected to evaluate an improved dosing scheme in a randomized-blind trial. EEG was monitored during a baseline period of one days, followed by one day of treatment with clozapine (0.1mg/kg bodyweight/6h) or vehicle. In all experiments, seizure frequency during baseline recordings was used to normalize the data. RESULTS Clozapine-induced activation of DREADDs had a dose-dependent seizure suppressing effect. Clozapine doses of 0.01, 0.1 and 1 mg/kg resulted in a clear lag in average cumulative seizure frequency of about 2, 5 and 8 hours respectively. Repeated clozapine administration resulted in a strong suppression of epileptic seizures in all animals tested. During treatment, the average daily seizure frequency was reduced with 86%±7% (SEM). CONCLUSION Clozapine-mediated activation of hM4Di DREADDs in excitatory hippocampal neurons temporary suppresses spontaneous seizures in a rat model for TLE in a dose-dependent way. Repeated clozapine administration results in a sustained suppression of epileptic seizures. Keywords: Temporal Lobe Epilepsy, IPKA rat model, DREADD receptors, Clozapine, Chemogenetic manipulation, hM4Di receptors Conference: 13th National Congress of the Belgian Society for Neuroscience , Brussels, Belgium, 24 May - 24 May, 2019. Presentation Type: Poster presentation Topic: Behavioral/Systems Neuroscience Citation: Goossens M, Christiaen E, Boon P, Vonck K, Carrette E, Desloovere J, Van Den Haute C, Baekelandt V, Wadman WJ, Vanhove C and Raedt R (2019). Chemogenetic suppression of spontaneous seizures in a rat model for temporal lobe epilepsy. Front. Neurosci. Conference Abstract: 13th National Congress of the Belgian Society for Neuroscience . doi: 10.3389/conf.fnins.2019.96.00024 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 28 Apr 2019; Published Online: 27 Sep 2019. * Correspondence: Mx. Marie-Gabrielle Goossens, Ghent University, Department of Head and Skin, Ghent, Belgium, MarieGabrielle.Goossens@UGent.be Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Marie-Gabrielle Goossens Emma Christiaen Paul Boon Kristl Vonck Evelien Carrette Jana Desloovere Chris Van Den Haute Veerle Baekelandt Wytse J Wadman Christian Vanhove Robrecht Raedt Google Marie-Gabrielle Goossens Emma Christiaen Paul Boon Kristl Vonck Evelien Carrette Jana Desloovere Chris Van Den Haute Veerle Baekelandt Wytse J Wadman Christian Vanhove Robrecht Raedt Google Scholar Marie-Gabrielle Goossens Emma Christiaen Paul Boon Kristl Vonck Evelien Carrette Jana Desloovere Chris Van Den Haute Veerle Baekelandt Wytse J Wadman Christian Vanhove Robrecht Raedt PubMed Marie-Gabrielle Goossens Emma Christiaen Paul Boon Kristl Vonck Evelien Carrette Jana Desloovere Chris Van Den Haute Veerle Baekelandt Wytse J Wadman Christian Vanhove Robrecht Raedt Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. 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A Fully Integrated 16-Channel Closed-Loop Neural-Prosthetic CMOS SoC With Wireless Power and Bidirectional Data Telemetry for Real-Time Efficient Human Epileptic Seizure Control

A 16-channel closed-loop neuromodulation system-on-chip (SoC) for human epileptic seizure control is proposed and designed. In the proposed SoC, a 16-channel neural-signal acquisition unit (NSAU), a biosignal processor (BSP), a 16-channel high-voltage-tolerant stimulator (HVTS), and wireless power and bidirectional data telemetry are designed. In the NSAU, the input protection circuit is used to prevent MOSFET from overstressing by the high-voltage stimulations. Hence, NSAUs can share electrodes with stimulators. The auto-reset chopper-stabilized capacitive-coupled instrumentation amplifiers (AR-CSCCIAs) are designed with the chopper-stabilized technique with a new offset reduction loop. The measured input-referred noise is 2.09 $\mu \textrm {V}_{\mathrm {rms}}$ and the noise-efficiency factor (NEF) is 3.78. The entropy-and-spectrum seizure detection algorithm is implemented in the BSP with 0.76-s seizure detection latency and 97.8% detection accuracy. When the seizure onset is detected by the BSP, the HVTS with adaptive supply control delivers 0.5–3-mA biphasic current stimulation to suppress the seizure onset. The proposed SoC is powered wirelessly, and the bidirectional data telemetry is realized through the same pair of coils in 13.56 MHz. The downlink data rate is 211 Kb/s with the binary phase-shift keying (BPSK) modulation and a new BPSK demodulator. The uplink data rate is 106 Kb/s with the load-shift keying (LSK) modulation. The proposed SoC is fabricated in a 0.18- $\mu \text{m}$ CMOS technology and occupies 25 mm2. Electrical tests have been performed to characterize the SoC performance. In vivo animal experiments using mini-pigs have been performed to successfully verify the closed-loop neuromodulation functions on epileptic seizure suppression.

A 16-Channel CMOS Chopper-Stabilized Analog Front-End ECoG Acquisition Circuit for a Closed-Loop Epileptic Seizure Control System.

In this paper, a 16-channel analog front-end (AFE) electrocorticography signal acquisition circuit for a closed-loop seizure control system is presented. It is composed of 16 input protection circuits, 16 auto-reset chopper-stabilized capacitive-coupled instrumentation amplifiers (AR-CSCCIA) with bandpass filters, 16 programmable transconductance gain amplifiers, a multiplexer, a transimpedance amplifier, and a 128-kS/s 10-bit delta-modulated successive-approximation-register analog-to-digital converter (SAR ADC). In closed-loop seizure control system applications, the stimulator shares the same electrode with the AFE amplifier for effective suppression of epileptic seizures. To prevent from overstress in MOS devices caused by high stimulation voltage, an input protection circuit with a high-voltage-tolerant switch is proposed for the AFE amplifier. Moreover, low input-referred noise is achieved by using the chopper modulation technique in the AR-CSCCIA. To reduce the undesired effects of chopper modulation, an improved offset reduction loop is proposed to reduce the output offset generated by input chopper mismatches. The digital ripple reduction loop is also used to reduce the chopper ripple. The fabricated AFE amplifier has 49.1-/59.4-/67.9-dB programmable gain and 2.02-μVrms input referred noise in a bandwidth of 0.59-117 Hz. The measured power consumption of the AFE amplifier is 3.26 μW per channel, and the noise efficiency factor is 3.36. The in vivo animal test has been successfully performed to verify the functions. It is shown that the proposed AFE acquisition circuit is suitable for implantable closed-loop seizure control systems.

Crucial Roles of the Endocannabinoid 2-Arachidonoylglycerol in the Suppression of Epileptic Seizures

Endocannabinoid signaling is considered to suppress excessive excitability of neural circuits and to protect the brain from seizures. However, the precise mechanisms of this effect are poorly understood. Here, we report that 2-arachidonoylglycerol (2-AG), one of the two major endocannabinoids, is crucial for suppressing seizures. We found that kainate-induced seizures in mice lacking the 2-AG synthesizing enzyme, diacylglycerol lipase α, were much more severe compared with those in cannabinoid CB1 receptor knockout mice and were comparable to those in mice lacking both CB1- and CB2-receptor-mediated signaling. In the dentate gyrus, 2-AG suppressed excitatory input around the inner and middle molecular layers through CB1 and presumably CB2 receptors, respectively. This 2-AG-mediated suppression contributed to decreased granule cell excitability and the dampening of seizures. Furthermore, lack of 2-AG signaling enhanced kindling epileptogenesis and spontaneous seizures after kainate-induced status epilepticus. These results highlight critical roles of 2-AG signaling in the suppression of epileptic seizures.

뇌전증 경련 억제를 위한 실시간 폐루프 신경 자극 시스템 설계

뇌전증 경련 억제를 위한 실시간 폐루프 신경 자극 시스템 설계

NeuroBi: A Highly Configurable Neurostimulator for a Retinal Prosthesis and Other Applications.

To evaluate the efficacy of a suprachoroidal retinal prosthesis, a highly configurable external neurostimulator is required. In order to meet functional and safety specifications, it was necessary to develop a custom device. A system is presented which can deliver charge-balanced, constant-current biphasic pulses, with widely adjustable parameters, to arbitrary configurations of output electrodes. This system is shown to be effective in eliciting visual percepts in a patient with approximately 20 years of light perception vision only due to retinitis pigmentosa, using an electrode array implanted in the suprachoroidal space of the eye. The flexibility of the system also makes it suitable for use in a number of other emerging clinical neurostimulation applications, including epileptic seizure suppression and closed-loop deep brain stimulation. Clinical trial registration number NCT01603576 (www.clinicaltrials.gov).

Design of high-voltage-tolerant stimulus driver with adaptive loading consideration to suppress epileptic seizure in a 0.18-μm CMOS process

A novel design of high-voltage-tolerant stimulus driver for epileptic seizure suppression with low power design and adaptive loading consideration is proposed in this work. The proposed design can deliver the required stimulus current within a specific range of loading impedance. Besides, this design in 0.18-μm low-voltage CMOS process can be operated with high supply voltage (VCC) of 5–10 V without using the high-voltage transistors, and the process steps of high-voltage transistors can be reduced. The proposed design can be further integrated for an electronic epilepsy prosthetic system-on-chip.

Implantable Stimulator for Epileptic Seizure Suppression With Loading Impedance Adaptability

The implantable stimulator for epileptic seizure suppression with loading impedance adaptability was proposed in this work. The stimulator consisted of the high voltage generator, output driver, adaptor, and switches, can constantly provide the required 40-μA stimulus currents, as the loading impedance varied within 10 kΩ -300 kΩ. The performances of this design have been successfully verified in silicon chip fabricated by a 0.35- μm 3.3-V/24-V CMOS process. The power consumption of this work was only 1.1 mW-1.4 mW. The animal test results with the fabricated chip of proposed design have successfully verified in the Long-Evans rats with epileptic seizures.

SUPPRESSION OF EPILEPTIC ACTIVITY IN RABBITS THROUGH SEROTONIN-MODULATING ANTICONSOLIDATION PROTEIN

The article concerns molecular basis of epileptic seizures development and elaboration of novel ways of their suppression through upregulation of serotonergic system activity on subcellular level by administration of serotonin-modulating anticonsolidation protein (SMAP). This protein had been purified earlier from the rat brains, possesses with Mr 186 kDa and is being in linear relationship with serotonin. Epileptic seizures were formed in Shinshilla rabbits by microapplication of 300 units of sodium penicillin solution into the brain amygdala. The evoked potentials (EP) to light flashes were fixed in the visual cortex, colliculus superior and retina. The epileptic seizures reached their peak for 50 min and lasted for 3 h. During their development, strengthening of the EP in the form of increasing their positive components, advent of interictal spikes and visually myoclonical seizures was observed. Administration of SMAP (3.5 ml, 1.5 mg/ml, i.m.) to rabbits 30 min after induction of epileptic seizures led to their suppression and elimination of their all manifestations including interictal spikes. The conclusion is done that upregulation of SMAP leads to suppression of epileptic seizures.

Cooling of the epileptic focus suppresses seizures with minimal influence on neurologic functions

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 free-moving rat models of focal seizure and epilepsy. 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. 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. 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.

A Single Amino Acid Mutation in SNAP-25 Induces Anxiety-Related Behavior in Mouse

Synaptosomal-associated protein of 25 kDa (SNAP-25) is a presynaptic protein essential for neurotransmitter release. Previously, we demonstrate that protein kinase C (PKC) phosphorylates Ser187 of SNAP-25, and enhances neurotransmitter release by recruiting secretory vesicles near to the plasma membrane. As PKC is abundant in the brain and SNAP-25 is essential for synaptic transmission, SNAP-25 phosphorylation is likely to play a crucial role in the central nervous system. We therefore generated a mutant mouse, substituting Ser187 of SNAP-25 with Ala using “knock-in” technology. The most striking effect of the mutation was observed in their behavior. The homozygous mutant mice froze readily in response to environmental change, and showed strong anxiety-related behavior in general activity and light and dark preference tests. In addition, the mutant mice sometimes exhibited spontaneously occurring convulsive seizures. Microdialysis measurements revealed that serotonin and dopamine release were markedly reduced in amygdala. These results clearly indicate that PKC-dependent SNAP-25 phosphorylation plays a critical role in the regulation of emotional behavior as well as the suppression of epileptic seizures, and the lack of enhancement of monoamine release is one of the possible mechanisms underlying these defects.