Prolonged febrile seizures in the immature rat model enhance hippocampal excitability long term.

Febrile seizures (FSs) constitute the most prevalent seizure type during childhood. Whether prolonged FSs alter limbic excitability, leading to spontaneous seizures (temporal lobe epilepsy) during adulthood, has been controversial. Recent data indicate that, in the immature rat model, prolonged FSs induce transient structural changes of some hippocampal pyramidal neurons and long-term functional changes of hippocampal circuitry. However, whether these neuroanatomical and electrophysiological changes promote hippocampal excitability and lead to epilepsy has remained unknown. By using in vivo and in vitro approaches, we determined that prolonged hyperthermia-induced seizures in immature rats caused long-term enhanced susceptibility to limbic convulsants that lasted to adulthood. Thus, extensive hippocampal electroencephalographic and behavioral monitoring failed to demonstrate spontaneous seizures in adult rats that had experienced hyperthermic seizures during infancy. However, 100% of animals developed hippocampal seizures after systemic administration of a low dose of kainate, and most progressed to status epilepticus. Conversely, a minority of normothermic and hyperthermic controls had (brief) seizures, none developing status epilepticus. In vitro, spontaneous epileptiform discharges were not observed in hippocampal-entorhinal cortex slices derived from either control or experimental groups. However, Schaeffer collateral stimulation induced prolonged, self-sustaining, status epilepticus-like discharges exclusively in slices from experimental rats. These data indicate that hyperthermic seizures in the immature rat model of FSs do not cause spontaneous limbic seizures during adulthood. However, they reduce thresholds to chemical convulsants in vivo and electrical stimulation in vitro, indicating persistent enhancement of limbic excitability that may facilitate the development of epilepsy

Spatial and amplitude dynamics of neurostimulation: Insights from the acute intrahippocampal kainate seizure mouse model

OBJECTIVE: Neurostimulation is an emerging treatment for patients with drug-resistant epilepsy, which is used to suppress, prevent, and terminate seizure activity. Unfortunately, after implantation and despite best clinical practice, most patients continue to have persistent seizures even after years of empirical optimization. The objective of this study is to determine optimal spatial and amplitude properties of neurostimulation in inhibiting epileptiform activity in an acute hippocampal seizure model. METHODS: We performed high-throughput testing of high-frequency focal brain stimulation in the acute intrahippocampal kainic acid mouse model of status epilepticus. We evaluated combinations of six anatomic targets and three stimulus amplitudes. RESULTS: We found that the spike-suppressive effects of high-frequency neurostimulation are highly dependent on the stimulation amplitude and location, with higher amplitude stimulation being significantly more effective. Epileptiform spiking activity was significantly reduced with ipsilateral 250 μA stimulation of the CA1 and CA3 hippocampal regions with 21.5% and 22.2% reductions, respectively. In contrast, we found that spiking frequency and amplitude significantly increased with stimulation of the ventral hippocampal commissure. We further found spatial differences with broader effects from CA1 versus CA3 stimulation. SIGNIFICANCE: These findings demonstrate that the effects of therapeutic neurostimulation in an acute hippocampal seizure model are highly dependent on the location of stimulation and stimulus amplitude. We provide a platform to optimize the anti-seizure effects of neurostimulation, and demonstrate that an exploration of the large electrical parameter and location space can improve current modalities for treating epilepsy. PLAIN LANGUAGE SUMMARY: In this study, we tested how electrical pulses in the brain can help control seizures in mice. We found that the electrode\u27s placement and the stimulation amplitude had a large effect on outcomes. Some brain regions, notably nearby CA1 and CA3, responded positively with reduced seizure-like activities, while others showed increased activity. These findings emphasize that choosing the right spot for the electrode and adjusting the strength of electrical pulses are both crucial when considering neurostimulation treatments for epilepsy

Electrical Stimulation and Glutamate in the Hippocampus of Epilepsy Patients

Electrical brain stimulation has been proposed as a promising treatment option for patients with medically resistant epilepsy disorder. Glutamate levels in the epileptogenic human hippocampus are elevated interictally and increase with seizures. Fifty Hz stimulation is a candidate therapeutic stimulation that is also used for clinical cortical mapping. We examined the effects of 50 Hz stimulation on glutamate efflux in the hippocampus of patients with medically refractory epilepsy. Subjects (n = 10) underwent intracranial EEG (icEEG) evaluation for possible therapeutic resection. Electrical stimulation was delivered through implanted hippocampal electrodes (n = 11) and microdialysate samples were collected every 2 mins. Basal interictal glutamate was measured with the zero-flow microdialysis method. Stimulation of the epileptogenic hippocampus induced significant glutamate efflux at the time of stimulation (p = 0.005, n = 10) that was significantly related to the basal glutamate concentration (R2 = 0.81, p = 0.001). During stimulation, four patients experienced seizures and two had auras. No change in glutamate level was observed in the group of patients who experienced a seizure (p = 0.47, n = 4). Conversely, a significant increase in glutamate was observed in the patients that did not experience a seizure (p = 0.005, n = 7). Basal glutamate levels were significantly higher in the no seizure group (p = 0.04, n = 5) than in the stimulated seizure group (n = 4). Fifty Hz stimulation of the epileptogenic hippocampus can cause significant glutamate efflux and may produce seizures or auras. The degree of stimulated glutamate elevation is related to the basal glutamate concentration but not to the induction of seizures. Electrical stimulation at 50 Hz may exacerbate interictal glutamate dysregulation in the epileptiogenic hippocampus and may not be optimal for seizure control

Optogenetic dissection of ictal propagation in the hippocampal–entorhinal cortex structures

Temporal lobe epilepsy (TLE) is one of the most common drug-resistant forms of epilepsy in adults and usually originates in the hippocampal formations. However, both the network mechanisms that support the seizure spread and the exact directions of ictal propagation remain largely unknown. Here we report the dissection of ictal propagation in the hippocampal–entorhinal cortex (HP–EC) structures using optogenetic methods in multiple brain regions of a kainic acid-induced model of TLE in VGAT-ChR2 transgenic mice. We perform highly temporally precise cross-area analyses of epileptic neuronal networks and find a feed-forward propagation pathway of ictal discharges from the dentate gyrus/hilus (DGH) to the medial entorhinal cortex, instead of a re-entrant loop. We also demonstrate that activating DGH GABAergic interneurons can significantly inhibit the spread of ictal seizures and largely rescue behavioural deficits in kainate-exposed animals. These findings may shed light on future therapeutic treatments of TLE

Functional MRI during hippocampal deep brain stimulation in the healthy rat brain

Deep Brain Stimulation (DBS) is a promising treatment for neurological and psychiatric disorders. The mechanism of action and the effects of electrical fields administered to the brain by means of an electrode remain to be elucidated. The effects of DBS have been investigated primarily by electrophysiological and neurochemical studies, which lack the ability to investigate DBS-related responses on a whole-brain scale. Visualization of whole-brain effects of DBS requires functional imaging techniques such as functional Magnetic Resonance Imaging (fMRI), which reflects changes in blood oxygen level dependent (BOLD) responses throughout the entire brain volume. In order to visualize BOLD responses induced by DBS, we have developed an MRI-compatible electrode and an acquisition protocol to perform DBS during BOLD fMRI. In this study, we investigate whether DBS during fMRI is valuable to study local and whole-brain effects of hippocampal DBS and to investigate the changes induced by different stimulation intensities. Seven rats were stereotactically implanted with a custom-made MRI-compatible DBS-electrode in the right hippocampus. High frequency Poisson distributed stimulation was applied using a block-design paradigm. Data were processed by means of Independent Component Analysis. Clusters were considered significant when p-values were <0.05 after correction for multiple comparisons. Our data indicate that real-time hippocampal DBS evokes a bilateral BOLD response in hippocampal and other mesolimbic structures, depending on the applied stimulation intensity. We conclude that simultaneous DBS and fMRI can be used to detect local and whole-brain responses to circuit activation with different stimulation intensities, making this technique potentially powerful for exploration of cerebral changes in response to DBS for both preclinical and clinical DBS

Valproate and 4-methyloctanoic acid, an analogue of valproate, in animal models of epilepsy

Valproic acid (VPA) is a commonly used drug for the treatment of epilepsy, bipolar disorder and migraine, yet its mechanisms of action are unknown. The neuroprotective effect of VPA has been hypothesized to be secondary to inhibition of the cAMP/protein kinase A (PKA) pathway. Here, the result show that VPA (1mM) inhibited mossy fibre long-term potentiation induced (LTP) by application of high frequency stimulation in dentate gyrus. Furthermore, VPA (1mM) inhibited enhancement of mossy fibre responses induced by application of forskolin (50 μM), consistent with an effect on the PKA pathway. Using biochemical assays, it was further demonstrated that this was not due to a direct effect on PKA, but resulted from inhibition of adenylyl cyclase. The results further show using in vitro seizure models (Pentylenetetrazole model and low- Mg2+ model) that this mechanism cannot fully explain VPA’s anti-seizure effect, but rather, by modifying synaptic plasticity, it may be more important for VPA’s antiepileptogenic and neuroprotective action. VPA therefore has distinct mechanisms of action that contribute to its diverse biological activity. In hippocampi from epileptic rats (following pilocarpine-induced status epilepticus), but not in control tissue, VPA affects short-term plasticity, indicating that VPA may have specific effects in epileptic rather than control animals. Using in vitro seizure models (Pentylenetetrazole model and low-Mg2+ model) and an in vivo status epilepticus model (the perforant pathway stimulation model), 4- methyloctanoic acid is further established that it is a more potent antiepileptic drug than VPA and provides neuroprotective effects which are similar to VPA. Furthermore, 4- methyloctanoic acid (1mM) inhibited enhancement of mossy fibre responses induced by application of forskolin (50 μM), indicating that 4-methyloctanoic acid shares the same effect as VPA on modulation of PKA

MODELS OF EPILEPSY USED IN ANTIEPILEPTIC DRUG DISCOVERY: A REVIEW

This article describes various experimental models of seizure and epilepsy. Epilepsy is characterised by recurrent unprovoked seizures. Antiepileptic drug discovery in animal models starts with the assumption that the experimental seizure model mimics human seizure. Hence a drug which suppresses ictogenesis or inhibits epileptogenesis in animal model is a potential antiepileptic drug for human and it needs further investigation. Phenytoin and Carbamazepine were identified with the help of relatively simple models like Maximal electroshock seizure and the pentylenetetrazole test. Lots of drugs were discovered with the help of these models but a big portion of patients still remains resistant to the available antiepileptic drugs. Again these simple seizure models are increasingly being questioned, are they providing us same type of drugs with same kind of mechanism of action? This question brings the importance of newer animal models that target epileptogenesis, pharmacoresistant epilepsy and models which mimic human epilepsy more closely. There is increased concern on agents for epilepsy disease modification and prevention. To solve these unmet needs, the research scientist must have a thorough knowledge of available animal models of epilepsy so that he can pick up the best model for his research. In this article, we are reviewing the diversity of animal models of epilepsy and their implications in antiepileptic drug discovery