Modeling plasticity during epileptogenesis by long short term memory neural networks.

Understanding the pathogenesis of epilepsy including changes in synaptic pathways can improve our knowledge about epilepsy and development of new treatments. In this regard, data-driven models such as artificial neural networks, which are able to capture the effects of synaptic plasticity, can play an important role. This paper proposes long short term memory (LSTM) as the ideal architecture for modeling plasticity changes, and validates this proposal via experimental data. As a special class of recurrent neural networks (RNNs), LSTM is able to track information through time and control its flow via several gating mechanisms, which allow for maintaining the relevant and forgetting the irrelevant information. In our experiments, potentiation and depotentiation of motor circuit and perforant pathway as two forms of plasticity were respectively induced by kindled and kindled + transcranial magnetic stimulation of animal groups. In kindling, both procedure duration and gradual synaptic changes play critical roles. The stimulation of both groups continued for six days. Both after-discharge (AD) and seizure behavior as two biologically measurable effects of plasticity were recorded immediately post each stimulation. Three classes of artificial neural networks-LSTM, RNN, and feedforward neural network (FFNN)-were trained to predict AD and seizure behavior as indicators of plasticity during these six days. Results obtained from the collected data confirm the superiority of LSTM. For seizure behavior, the prediction accuracies achieved by these three models were 0.91 ± 0.01, 0.77 ± 0.02, and 0.59 ± 0.02%, respectively, and for AD, the prediction accuracies were 0.82 ± 0.01, 0.74 ± 0.08 and 0.42 ± 0.1, respectively.

Clinical significance of bilateral epileptiform discharges in temporal lobe epilepsy.

OBJECTIVE: The aim of the current study was to investigate the rate and clinical significance of bitemporal interictal epileptiform discharges (IEDs) in a large cohort of patients with temporal lobe epilepsy (TLE). METHODS: The data used in this study were collected at the Epilepsy Care Unit, Namazi Hospital, Shiraz University of Medical sciences, Shiraz, Iran, from 2008 to 2020. Inclusion criteria were a confirmed diagnosis of TLE based on the clinical grounds (history and the described seizure semiology) and a 2-hour interictal video-electroencephalography (EEG) monitoring. The EEG recording of each patient included both sleep (about 90 minutes) and wakefulness (about 30 minutes). RESULTS: 532 patients were included in this study [420 patients (79%) had unilateral IEDs, and 112 patients (21%) had bilateral IEDs]. Patients with bilateral IEDs less often had auras with their seizures and had higher frequencies of seizures (as a trend for focal to bilateral tonic-clonic seizures and significantly in focal seizures with impaired awareness) compared with those who had unilateral IEDs. Patients with bilateral epileptiform discharges showed a trend to experiencing ictal injury more frequently. Brain MRI findings were different between these two groups (p = 0.0001). CONCLUSION: It is important to recognize that a patient with TLE has unilateral vs. bilateral IEDs. Bilateral IEDs in a patient with TLE may suggest a more severe disease (with a higher risk for ictal injuries and other significant consequences of frequent seizures). It may also suggest a somewhat different etiology.

Interaction of sigma-1 receptor modulators with seizure development in pentylenetetrazole-induced kindled mice.

This study aimed to investigate the effects of sigma receptor modulators, opipramol and BD-1063, on epileptogenesis in pentylenetetrazole (PTZ)-kindling model of epilepsy. Mice (n = 6/group) were received PTZ (30 mg/kg), PTZ plus opipramol (5 or 10 mg/kg), PTZ plus opipramol (5 mg/kg) plus BD-1063 (5 mg/kg, a selective sigma-1 receptor antagonist), and PTZ plus BD-1063 on alternate days for 15 days. Opipramol (5 and 10 mg/kg) + PTZ groups became fully kindled and had higher seizure scores compared to the PTZ group. In contrast, the PTZ plus BD-1063 and the PTZ plus opipramol (5 mg/kg) plus BD-1063 group did not show full kindling. These findings indicate that opipramol has a pro-convulsant effect, which is possibly mediated through activation of sigma-1 receptors.

Improved Stage Categorization of PTZ-Induced Kindling and Late Enhanced Neurogenesis in PTZ Kindled Mice.

BACKGROUND: There is no universally accepted behavioral scoring to define the early development of pentylenetetrazole (PTZ) kindling. Therefore, studies investigating alterations of neurogenesis in the PTZ model were mainly focused on full kindled animals rather than early stages of kindling. This study aimed to determine an appropriate behavioral index for categorizing stages of PTZ kindling progress and to evaluate neurogenesis during PTZ kindling. MATERIALS AND METHODS: Twenty-four mice were intraperitoneally injected with a sub-convulsive dose of PTZ (40mg/kg) every other day until they became full kindled. The first occurrence of different seizure behaviors and their durations were recorded during kindling development, and the different stages of kindling were categorized. Neurogenesis was evaluated in the lateral subventricular zone (SVZ) at each stage of kindling by immunofluorescence staining. RESULTS: First occurrence of restlessness, motionless staring, hind limb tonic extension, Straub's tail, myoclonic jerk, and tonic-clonic were sequentially observed in more than 80% of animals with increasing PTZ injections. The duration of the myoclonic jerk was significantly longer than the other seizure behaviors. The significantly higher percentage of BrdU-positive cells was found in SVZ of mice showing tonic-clonic in comparison to other seizure behaviors. CONCLUSION: A hierarchy behavior was observed during the kindling process when considering the first occurrence of seizure behaviors. We defined the first occurrence of restlessness, motionless, hind limb tonic extension and Straub's tail behaviors as an early phase, myoclonic jerk as a borderline phase and tonic-clonic as a late phase of PTZ-induced kindling. Our results indicated an enhanced SVZ neurogenesis at the late phase of kindling.

Effect of Recombinant Insulin-like Growth Factor-2 Injected into the Hippocampus on Memory Impairment Following Hippocampal Intracerebral Hemorrhage in Rats.

BACKGROUND: Insulin-like growth factor 2 (IGF-2) is a growth factor and an anti-inflammatory cytokine that plays a pivotal role in memory. In this study, we examined the effect of recombinant IGF-2 on memory impairment due to intracerebral hemorrhage (ICH). Avoidance and recognition memory, locomotor activity, neurological deficit score (NDS), and the level of the IGF-2 gene expression were evaluated. MATERIALS AND METHODS: To induce ICH, 100 µL of autologous blood was injected into the left hippocampus of male Sprague Dawley rats. Recombinant IGF-2 was injected into the damaged hippocampus 30 minutes after the induction of ICH. Then, over two weeks, NDS, locomotor activity, passive avoidance, and novel object recognition (NOR) test were evaluated. Finally, the level of IGF-2 gene expression was evaluated by using the real-time polymerase chain reaction technique. RESULT: Our results indicated that recombinant IGF-2 injection significantly increased step-through latency (P<0.001) and total time spent in the dark box (P<0.01). However, no significant difference was seen in recognition memory and NDS. Locomotor activity did not significantly change in any group. A significantly reduced level of IGF-2 was observed after two weeks (P<0.05). CONCLUSION: The results of this study show that a single dose of recombinant IGF-2 injection can influence hippocampus-dependent memories. Importantly, IGF-2 did not change locomotor activity and NDS after two weeks, which probably represents its specific function in memory.

Repetitive transcranial magnetic stimulation decreases the kindling induced synaptic potentiation: effects of frequency and coil shape.

The present study was aimed to investigate the effects of repetitive transcranial magnetic stimulation (rTMS) on kindling-induced synaptic potentiation and to study the effect of frequency and coil shape on rTMS effectiveness. Seizures were induced in rats by perforant path stimulation in a rapid kindling manner (12 stimulations/day). rTMS was applied at different frequencies (0.5, 1 and 2 Hz), using either figure-8 shaped or circular coils at different times (during or before kindling stimulations). rTMS had antiepileptogenic effect at all frequencies and imposed inhibitory effects on enhancement of population excitatory postsynaptic potential slope and population spike amplitude when applied during kindling acquisition. Furthermore, it prevented the kindling-induced changes in paired pulse indices. The inhibitory effect of rTMS was higher at the frequency of 1 Hz compared to 0.5 and 2 Hz. Application of rTMS 1Hz by circular coil imposed a weaker inhibitory action compared with the figure-8 coil. In addition, the results showed that pretreatment of animals by both coils had similar preventing effect on kindling acquisition as well as kindling-induced synaptic potentiation. Obtained results demonstrated that the antiepileptogenic effect of low frequency rTMS is accompanied with the preventing of the kindling induced potentiation. This effect is dependent on rTMS frequency and slightly on coil-type.

Effect of low-frequency electrical stimulation parameters on its anticonvulsant action during rapid perforant path kindling in rat.

Low frequency stimulation (LFS) may be considered as a new potential therapy for drug-resistant epilepsy. However, the relation between LFS parameters and its anticonvulsant effects is not completely determined. In this study, the effect of some LFS parameters on its anticonvulsant action was investigated in rats. In all animals, stimulating and recording electrodes were implanted into the perforant path and dentate gyrus, respectively. In one group of animals, kindling stimulations were applied until rats achieved a fully kindled state. In other groups, different patterns of LFS were applied at the end of kindling stimulations during twenty consecutive days. In the first experiment the effect of LFS pulse numbers was investigated on its anticonvulsant action. Animals were divided randomly into three groups and 1, 4, and 8 packages of LFS (each pack contains 200 pulses, 0.1 ms pulse duration at 1 Hz) were applied five minutes after termination of kindling stimulations. Obtained results showed that 4 packages of LFS had the strongest anticonvulsant effects. Therefore, this pattern (4 packages) was used in the next experiment. In the second experiment, 4 packages of LFS were applied at intervals of 30 s and 30 min after termination of kindling stimulations. The strongest anticonvulsant effect was observed in the group received LFS at the interval of 30 s. Therefore, this pattern was selected for the third experiment. In the third experiment the effect of LFS at frequencies of 0.25 Hz and 5 Hz was investigated. The group of animals which received LFS at the frequency of 0.25 Hz showed somehow stronger anticonvulsant effect. The results indicate that different parameters of LFS have important role in induction of LFS anticonvulsant effects. Regarding this view, it seems that the slower LFS frequency and the shorter interval between LFS and kindling stimulations, the stronger anticonvulsant effect will be observed. But there is no direct relation between number of pulses and the magnitude of anticonvulsant effect of LFS.