Theta waves, neural spikes and seizures can propagate by ephaptic coupling in vivo.

Electric field coupling has been shown to be responsible for non-synaptic neural activity propagation in hippocampal slices and cortical slices. Epileptiform and slow-wave sleep activity can propagate by electric field coupling without using synaptic connections at speeds of ~0.1 m/s in vitro. However, the characteristics of the events that can propagate using electric field coupling through a volume conductor in vivo have not been studied. Thus, we tested the hypothesis that various types of neural signals such as interictal spikes, theta waves and seizures could propagate in vivo across a transection in the hippocampus. We induced epileptiform activity in 4 rats under anesthesia by injecting 4-aminopyridine in the temporal region of the hippocampus, four recording electrodes were inserted along the longitudinal axis of the hippocampus. A transection was made between the electrodes to study the propagation of the neural activity. Although 54% of the interictal spikes could propagate through the cut, only those spikes with a high amplitude and short duration had a high probability to do so. 70% of seizure events could propagate through the cut but parameters distinguishing between propagating and non-propagating seizure events could not be identified. Theta activity was also observed to propagate at a mean speed of 0.16 ± 0.12 m/s in the characteristic range of propagation using electric field coupling through the transection. The electric field volume conduction mechanism was confirmed by showing that propagation was blocked by placing a dielectric layer within the cut. The speed of propagation was not affected by the transection thereby providing further evidence that various types of neural signals including activity in the theta range can propagate by electric field coupling in-vivo.

Subthreshold Oscillating Waves in Neural Tissue Propagate by Volume Conduction and Generate Interference.

Subthreshold neural oscillations have been observed in several brain regions and can influence the timing of neural spikes. However, the spatial extent and function of these spontaneous oscillations remain unclear. To study the mechanisms underlying these oscillations, we use optogenetic stimulation to generate oscillating waves in the longitudinal hippocampal slice expressing optopatch proteins. We found that optogenetic stimulation can generate two types of neural activity: suprathreshold neural spikes and subthreshold oscillating waves. Both waves could propagate bidirectionally at similar speeds and go through a transection of the tissue. The propagating speed is independent of the oscillating frequency but increases with increasing amplitudes of the waves. The endogenous electric fields generated by oscillating waves are about 0.6 mV/mm along the dendrites and about 0.3 mV/mm along the cell layer. We also observed that these oscillating waves could interfere with each other. Optical stimulation applied simultaneously at each slice end generated a larger wave in the middle of the tissue (constructive interference) or destructive interference with laser signals in opposite phase. However, the suprathreshold neural spikes were annihilated when they collided. Finally, the waves were not affected by the NMDA blocker (APV) and still propagated in the presence of tetrodotoxin (TTX) but at a significantly lower amplitude. The role of these subthreshold waves in neural function is unknown, but the results show that at low amplitude, the subthreshold propagating waves lack a refractory period allowing a novel analog form of preprocessing of neural activity by interference independent of synaptic transmission.

Delta oscillation underlies the interictal spike changes after repeated transcranial direct current stimulation in a rat model of chronic seizures.

BACKGROUND: Transcranial direct current stimulation (tDCS) provides a noninvasive polarity-specific constant current to treat epilepsy, through a mechanism possibly involving excitability modulation and neural oscillation. OBJECTIVE: To determine whether EEG oscillations underlie the interictal spike changes after tDCS in rats with chronic spontaneous seizures. METHODS: Rats with kainic acid-induced spontaneous seizures were subjected to cathodal tDCS or sham stimulation for 5 consecutive days. Video-EEG recordings were collected immediately pre- and post-stimulation and for the subsequent 2 weeks following stimulation. The acute pre-post stimulation and subacute follow-up changes of interictal spikes and EEG oscillations in tDCS-treated rats were compared with sham. Ictal EEG with seizure behaviors, hippocampal brain-derived neurotrophic factor (BDNF) protein expression, and mossy fiber sprouting were compared between tDCS and sham rats. RESULTS: Interictal spike counts were reduced immediately following tDCS with augmented delta and diminished beta and gamma oscillations compared with sham. Cathodal tDCS also enhanced delta oscillations in normal rats. However, increased numbers of interictal spikes with a decrease of delta and theta oscillations were observed in tDCS-treated rats compared with sham during the following 2 weeks after stimulation. Resuming tDCS suppressed the increase of interictal spike activity. In tDCS rats, hippocampal BDNF protein expression was decreased while mossy fiber sprouting did not change compared with sham. CONCLUSIONS: The inverse relationship between the changes of delta oscillation and interictal spikes during tDCS on and off stimulation periods indicates that an enhanced endogenous delta oscillation underlies the tDCS inhibitory effect on epileptic excitability.

Neural recruitment by ephaptic coupling in epilepsy.

OBJECTIVE: One of the challenges in treating patients with drug-resistant epilepsy is that the mechanisms of seizures are unknown. Most current interventions are based on the assumption that epileptic activity recruits neurons and progresses by synaptic transmission. However, several experimental studies have shown that neural activity in rodent hippocampi can propagate independently of synaptic transmission. Recent studies suggest these waves are self-propagating by electric field (ephaptic) coupling. In this study, we tested the hypothesis that neural recruitment during seizures can occur by electric field coupling. METHODS: 4-Aminopyridine was used in both in vivo and in vitro preparation to trigger seizures or epileptiform activity. A transection was made in the in vivo hippocampus and in vitro hippocampal and cortical slices to study whether the induced seizure activity can recruit neurons across the gap. A computational model was built to test whether ephaptic coupling alone can account for neural recruitment across the transection. The model prediction was further validated by in vitro experiments. RESULTS: Experimental results show that electric fields generated by seizure-like activity in the hippocampus both in vitro and in vivo can recruit neurons locally and through a transection of the tissue. The computational model suggests that the neural recruitment across the transection is mediated by electric field coupling. With in vitro experiments, we show that a dielectric material can block the recruitment of epileptiform activity across a transection, and that the electric fields measured within the gap are similar to those predicted by model simulations. Furthermore, this nonsynaptic neural recruitment is also observed in cortical slices, suggesting that this effect is robust in brain tissue. SIGNIFICANCE: These results indicate that ephaptic coupling, a nonsynaptic mechanism, can underlie neural recruitment by a small electric field generated by seizure activity and could explain the low success rate of surgical transections in epilepsy patients.

Transcranial direct current stimulation alleviates seizure severity in kainic acid-induced status epilepticus rats.

Status epilepticus (SE) is a state of prolonged and repeated seizures that can lead to permanent brain damage or life-threatening conditions. Transcranial direct current stimulation (tDCS) non-invasively provides a polarity-specific electric current to modulate brain excitability. Little is known about the therapeutic potential of tDCS in SE. Here, we aim to determine the tDCS effects on seizure severity, EEG and post-SE consequences in rats with kainic acid (KA)-induced SE. Rats were subjected to cathodal tDCS or sham stimulation over the dorsal hippocampus for 5 days. KA was intraperitoneally injected to induce SE. We used continuous video-EEG recording to monitor seizure activity, immunostaining and Timm staining to evaluate neuron counts and mossy fiber sprouting, and ELISA for Brain-derived neurotrophic factor (BDNF) protein measurement. Two featured EEG patterns, gamma ranged high-frequency polyspikes and low-frequency spike-and-wave complexes, were identified in the hippocampal CA1 of KA-induced SE rats. tDCS elicited a significant decrease in severe seizures of Racine stages 4-5 in KA-induced SE rats. tDCS-treated rats manifested diminished high-frequency oscillation during SE, decreased chronic spontaneous spike activities and mossy fiber sproutings compared to sham. tDCS-treated rats also exhibited significantly lower hippocampal BDNF protein levels than sham immediately and 4 weeks after SE. A positive correlation between the hippocampal BDNF level and the seizure severity of SE was found. Altogether, our results show that repeated cathodal tDCS can mitigate seizure severity, alter ictal EEG pattern and reduce the chronic adverse consequences in KA-induced SE rats, supporting the therapeutic potential of tDCS in severe prolonged epileptic seizures.

Sonic Hedgehog is expressed by hilar mossy cells and regulates cellular survival and neurogenesis in the adult hippocampus.

Sonic hedgehog (Shh) is a multifunctional signaling protein governing pattern formation, proliferation and cell survival during embryogenesis. In the adult brain, Shh has neurotrophic function and is implicated in hippocampal neurogenesis but the cellular source of Shh in the hippocampus remains ill defined. Here, we utilize a gene expression tracer allele of Shh (Shh-nlacZ) which allowed the identification of a subpopulation of hilar neurons known as mossy cells (MCs) as a prominent and dynamic source of Shh within the dentate gyrus. AAV-Cre mediated ablation of Shh in the adult dentate gyrus led to a marked degeneration of MCs. Conversely, chemical stimulation of hippocampal neurons using the epileptogenic agent kainic acid (KA) increased the number of Shh+ MCs indicating that the expression of Shh by MCs confers a survival advantage during the response to excitotoxic insults. In addition, ablation of Shh in the adult dentate gyrus led to increased neural precursor cell proliferation and their migration into the subgranular cell layer demonstrating that MCs-generated Shh is a key modulator of hippocampal neurogenesis.

Self-propagating, non-synaptic epileptiform activity recruits neurons by endogenous electric fields.

It is well documented that synapses play a significant role in the transmission of information between neurons. However, in the absence of synaptic transmission, neural activity has been observed to continue to propagate. Previous studies have shown that propagation of epileptiform activity takes place in the absence of synaptic transmission and gap junctions and is outside the range of ionic diffusion and axonal conduction. Computer simulations indicate that electric field coupling could be responsible for the propagation of neural activity under pathological conditions such as epilepsy. Electric fields can modulate neuronal membrane voltage, but there is no experimental evidence suggesting that electric field coupling can mediate self-regenerating propagation of neural activity. Here we examine the role of electric field coupling by eliminating all forms of neural communications except electric field coupling with a cut through the neural tissue. We show that 4-AP induced activity generates an electric field capable of recruiting neurons on the distal side of the cut. Experiments also show that applied electric fields with amplitudes similar to endogenous values can induce propagating waves. Finally, we show that canceling the electrical field at a given point can block spontaneous propagation. The results from these in vitro electrophysiology experiments suggest that electric field coupling is a critical mechanism for non-synaptic neural propagation and therefore could contribute to the propagation of epileptic activity in the brain.

Slow periodic activity in the longitudinal hippocampal slice can self-propagate non-synaptically by a mechanism consistent with ephaptic coupling.

KEY POINTS: Slow periodic activity can propagate with speeds around 0.1 m s-1 and be modulated by weak electric fields. Slow periodic activity in the longitudinal hippocampal slice can propagate without chemical synaptic transmission or gap junctions, but can generate electric fields which in turn activate neighbouring cells. Applying local extracellular electric fields with amplitude in the range of endogenous fields is sufficient to modulate or block the propagation of this activity both in the in silico and in the in vitro models. Results support the hypothesis that endogenous electric fields, previously thought to be too small to trigger neural activity, play a significant role in the self-propagation of slow periodic activity in the hippocampus. Experiments indicate that a neural network can give rise to sustained self-propagating waves by ephaptic coupling, suggesting a novel propagation mechanism for neural activity under normal physiological conditions. ABSTRACT: Slow oscillations are a standard feature observed in the cortex and the hippocampus during slow wave sleep. Slow oscillations are characterized by low-frequency periodic activity (<1 Hz) and are thought to be related to memory consolidation. These waves are assumed to be a reflection of the underlying neural activity, but it is not known if they can, by themselves, be self-sustained and propagate. Previous studies have shown that slow periodic activity can be reproduced in the in vitro preparation to mimic in vivo slow oscillations. Slow periodic activity can propagate with speeds around 0.1 m s-1 and be modulated by weak electric fields. In the present study, we show that slow periodic activity in the longitudinal hippocampal slice is a self-regenerating wave which can propagate with and without chemical or electrical synaptic transmission at the same speeds. We also show that applying local extracellular electric fields can modulate or even block the propagation of this wave in both in silico and in vitro models. Our results support the notion that ephaptic coupling plays a significant role in the propagation of the slow hippocampal periodic activity. Moreover, these results indicate that a neural network can give rise to sustained self-propagating waves by ephaptic coupling, suggesting a novel propagation mechanism for neural activity under normal physiological conditions.

Slow moving neural source in the epileptic hippocampus can mimic progression of human seizures.

Fast and slow neural waves have been observed to propagate in the human brain during seizures. Yet the nature of these waves is difficult to study in a surgical setting. Here, we report an observation of two different traveling waves propagating in the in-vitro epileptic hippocampus at speeds similar to those in the human brain. A fast traveling spike and a slow moving wave were recorded simultaneously with a genetically encoded voltage sensitive fluorescent protein (VSFP Butterfly 1.2) and a high speed camera. The results of this study indicate that the fast traveling spike is NMDA-sensitive but the slow moving wave is not. Image analysis and model simulation demonstrate that the slow moving wave is moving slowly, generating the fast traveling spike and is, therefore, a moving source of the epileptiform activity. This slow moving wave is associated with a propagating neural calcium wave detected with calcium dye (OGB-1) but is independent of NMDA receptors, not related to ATP release, and much faster than those previously recorded potassium waves. Computer modeling suggests that the slow moving wave can propagate by the ephaptic effect like epileptiform activity. These findings provide an alternative explanation for slow propagation seizure wavefronts associated with fast propagating spikes.

Propagating Neural Source Revealed by Doppler Shift of Population Spiking Frequency.

Electrical activity in the brain during normal and abnormal function is associated with propagating waves of various speeds and directions. It is unclear how both fast and slow traveling waves with sometime opposite directions can coexist in the same neural tissue. By recording population spikes simultaneously throughout the unfolded rodent hippocampus with a penetrating microelectrode array, we have shown that fast and slow waves are causally related, so a slowly moving neural source generates fast-propagating waves at ∼0.12 m/s. The source of the fast population spikes is limited in space and moving at ∼0.016 m/s based on both direct and Doppler measurements among 36 different spiking trains among eight different hippocampi. The fact that the source is itself moving can account for the surprising direction reversal of the wave. Therefore, these results indicate that a small neural focus can move and that this phenomenon could explain the apparent wave reflection at tissue edges or multiple foci observed at different locations in neural tissue. SIGNIFICANCE STATEMENT: The use of novel techniques with an unfolded hippocampus and penetrating microelectrode array to record and analyze neural activity has revealed the existence of a source of neural signals that propagates throughout the hippocampus. The source itself is electrically silent, but its location can be inferred by building isochrone maps of population spikes that the source generates. The movement of the source can also be tracked by observing the Doppler frequency shift of these spikes. These results have general implications for how neural signals are generated and propagated in the hippocampus; moreover, they have important implications for the understanding of seizure generation and foci localization.

Seizure reduction through interneuron-mediated entrainment using low frequency optical stimulation.

Low frequency electrical stimulation (LFS) can reduce neural excitability and suppress seizures in animals and patients with epilepsy. However the therapeutic outcome could benefit from the determination of the cell types involved in seizure suppression. We used optogenetic techniques to investigate the role of interneurons in LFS (1Hz) in the epileptogenic hippocampus. Optical low frequency stimulation (oLFS) was first used to activate the cation channel channelrhodopsin-2 (ChR2) in the Thy1-ChR2 transgenic mouse that expresses ChR2 in both excitatory and inhibitory neurons. We found that oLFS could effectively reduce epileptiform activity in the hippocampus through the activation of GAD-expressing hippocampal interneurons. This was confirmed using the VGAT-ChR2 transgenic mouse, allowing for selective optical activation of only GABA interneurons. Activating hippocampal interneurons through oLFS was found to cause entrainment of neural activity similar to electrical stimulation, but through a GABAA-mediated mechanism. These results confirm the robustness of the LFS paradigm and indicate that GABA interneurons play an unexpected role of shaping inter-ictal activity to decrease neural excitability in the hippocampus.

Suppression of acute seizures by theta burst electrical stimulation of the hippocampal commissure using a closed-loop system.

This study investigated the effects of electrical stimulation with theta burst stimulation (eTBS) on seizure suppression. Optimal parameters of eTBS were determined through open-loop stimulation experiments and then implemented in a close-loop seizure control system. For the experiments, 4-aminopyridine (4-AP) was injected into the right hippocampus of Sprague-Dawley rats to induce an acute seizure. eTBS was applied on the ventral hippocampal commissure and the effects of eTBS with different combinations of burst frequency and number of pulses per burst were analyzed in terms of seizure suppression. A closed-loop seizure control system was then implemented based on optimal eTBS parameters. The efficiency of the closed-loop eTBS was evaluated and compared to that of high frequency stimulation. The results show that eTBS induced global suppression in the hippocampus and this was sustained even after the application of eTBS. The optimal parameter of eTBS in the open-loop stimulation experiments was a burst frequency at 100Hz with nine pulses in a burst. The eTBS integrated with the on-off control law yielded less actions and cumulative delivered charge, but induced longer after-effects of seizure suppression compared to continuous high frequency stimulation (cHFS). To conclude, eTBS has suppressive effects on 4-AP induced seizure. A closed-loop eTBS system provides a more effective way of suppressing seizure and requires less effort compared to cHFS. eTBS may be a novel stimulation protocol for effective seizure control.

Seizure suppression by high frequency optogenetic stimulation using in vitro and in vivo animal models of epilepsy.

BACKGROUND: Electrical high frequency stimulation (HFS) has been shown to suppress seizures. However, the mechanisms of seizure suppression remain unclear and techniques for blocking specific neuronal populations are required. OBJECTIVE: The goal is to study the optical HFS protocol on seizures as well as the underlying mechanisms relevant to the HFS-mediated seizure suppression by using optogenetic methodology. METHODS: Thy1-ChR2 transgenic mice were used in both vivo and in vitro experiments. Optical stimulation with pulse trains at 20 and 50 Hz was applied on the focus to determine its effects on in vivo seizure activity induced by 4-AP and recorded in the bilateral and ipsilateral-temporal hippocampal CA3 regions. In vitro methodology was then used to study the mechanisms of the in vivo suppression. RESULTS: Optical HFS was able to generate 82.4% seizure suppression at 50 Hz with light power of 6.1 mW and 80.2% seizure suppression at 20 Hz with light power of 2.0 mW. The suppression percentage increased by increasing the light power and saturated when the power reached above-mentioned values. In vitro experimental results indicate that seizure suppression was mediated by activation of GABA receptors. Seizure suppression effect decreased with continued application but the suppression effect could be restored by intermittent stimulation. CONCLUSIONS: This study shows that optical stimulation at high frequency targeting an excitatory opsin has potential therapeutic application for fast control of an epileptic focus. Furthermore, electrophysiological observations of extracellular and intracellular signals revealed that GABAergic neurotransmission activated by optical stimulation was responsible for the suppression.

TRPV1 antagonist capsazepine suppresses 4-AP-induced epileptiform activity in vitro and electrographic seizures in vivo.

Transient receptor potential vanilloid 1 (TRPV1) is a cation-permeable ion channel found in the peripheral and central nervous systems. The membrane surface expression of TRPV1 is known to occur in neuronal cell bodies and sensory neuron axons. TRPV1 receptors are also expressed in the hippocampus, the main epileptogenic region in the brain. Although, previous studies implicate TRPV1 channels in the generation of epilepsy, suppression of ongoing seizures by TRPV1 antagonists has not yet been attempted. Here, we evaluate the role of TRPV1 channels in the modulation of epileptiform activity as well as the anti-convulsant properties of capsazepine (CZP), an established TRPV1 competitive antagonist, using in vitro and in vivo models. To this end, we used 4-aminopyridine (4-AP) to trigger seizure-like activity. We found that CZP suppressed 4-AP induced epileptiform activity in vitro (10-100µM) and in vivo (50mg/kg s.c.). In contrast, capsaicin enhanced 4-AP induced epileptiform activity in vitro (1-100µM) and triggered bursting activity in vivo (100µM dialysis perfusion), which was abolished by the TRPV1 antagonist CZP. To further investigate the mechanisms of TRPV1 modulation, we studied the effect of capsaicin and CZP on evoked potentials. Capsaicin (1-100µM) and CZP (10-100µM) increased and decreased, respectively, the amplitude of extracellular field evoked potentials in a concentration-dependent manner. Additional in vitro studies showed that the effect of the TRPV1 blocker on evoked potentials was similar whether the response was orthodromic or antidromic, suggesting that the effect involves interference with membrane depolarization on cell bodies and axons. The fact that CZP could act directly on axons was confirmed by decreased amplitude of the compound action potential and by an increased delay of both the antidromic potentials and the axonal response. Histological studies using transgenic mice also show that, in addition to the known neural expression, TRPV1 channels are widely expressed in alvear oligodendrocytes in the hippocampus. Taken together, these results indicate that activation of TRPV1 channels leads to enhanced excitability, while their inhibition can effectively suppress ongoing electrographic seizures. These results support a role for TRPV1 channels in the suppression of convulsive activity, indicating that antagonism of TRPV1 channels particularly in axons may possibly be a novel target for effective acute suppression of seizures.

On-off control of burst high frequency electrical stimulation to suppress 4-AP induced seizures.

OBJECTIVE: The goal of this study was to investigate, using model simulations and animal experiments, the efficiency and the side effects of burst high frequency stimulation combined with on-off control in seizure suppression. APPROACH: A modified mathematical hippocampal seizure model was created to provide evidence of the eligibility of this approach. In the experimental setup, two recording electrodes were inserted into bilateral septal CA1 of the hippocampus, and a stimulation electrode was placed on the ventral hippocampal commissure of a rat. After seizures had been induced by 4-aminopyridine treatment, on-off control stimulation was used to suppress the seizures at 20 s intervals. The stimulation time, cumulative charge and post-stimulation suppression were used to assess the effects of burst duration. MAIN RESULTS: The results showed that burst stimulation could suppress the seizures during the control period and burst stimulation of a shorter duration could keep the seizure suppressed with less effort. By decreasing the burst duration, the cumulative stimulation time became shorter, the delivered cumulative charge became lower, and the cumulative time of post-stimulation suppression became longer. SIGNIFICANCE: The on-off control stimulation not only prolonged the duration of suppression but also avoided the side effects of the conversion of seizure patterns. In particular, decreasing the specified burst duration increased the efficiency of the burst stimulation.

High frequency stimulation can suppress globally seizures induced by 4-AP in the rat hippocampus: an acute in vivo study.

BACKGROUND: High frequency stimulation (HFS) on the hippocampus can locally suppress epileptiform activity in-vitro and decrease seizure frequency in vivo. In-vitro HFS on the ventral commissural tract, a novel target, was shown to block the axonal conduction and suppress activity in the CA1 and CA3 neuron. OBJECTIVE: To study the spatial extent of seizure suppression by HFS applied on the tract and focus site in an in vivo experiment. METHODS: Five adult Sprague-Dawley rats were used for the study. Six electrodes were placed on the septal, middle, and temporal hippocampus bilaterally to simultaneously record seizure activity in the entire hippocampus. Seizure activity was induced by injecting 4-aminopyridine (4-AP) into the right middle part of the hippocampus. Following induction, HFS (100 Hz) was applied to the tract and the focus site at 100, 300 and 500 µA. RESULTS: The induced seizure activity was dominated by two patterns, high frequency spiking and pseudo-periodic spikes. Either tract or focus site stimulation could generate suppression of only the pseudo-periodic spikes. The suppression rates were dependent on stimulation amplitude (P < 0.005, chi square test). However, HFS also caused conversion of the seizure pattern. The conversion rates increased with higher stimulation amplitudes and were higher with focus site stimulation (P < 0.01, Fisher's exact test). CONCLUSIONS: The results of this study have two practical implications [1], both tract and focus site stimulation can produce global suppression of hippocampus and [2] the choice of stimulation parameters is critical in order to produce suppression, but not conversion, of seizure pattern.

Description and computational modeling of the whole course of status epilepticus induced by low dose lithium-pilocarpine in rats.

The main purposes of this study were (1) to describe the whole course of status epilepticus induced by a low dose lithium-pilocarpine model in rats, including depth-EEG from the hippocampus, ECoG from cortex and gross behaviors, and (2) to investigate the possible changes of the intrinsic neural network in the hippocampus during the status epilepticus by model simulation. The course of the induced status epilepticus was divided into baseline, pre-ictal, episodic, onset, continuous, and convalescence stages. At the pre-ictal stage, the main component of the spectrum of the depth-EEG shifted before seizure activity first appeared in the hippocampus at the episodic stage and propagated to the cortex at the onset stage. Model simulation indicated that the changes of depth-EEG of the whole course could be simulated by changes of the loop gains and the inputs of the neural network. The excitatory and inhibitory loops were first enhanced in the pre-ictal stage. The isolated seizures in the episodic stage were caused by variations of inputs from other pyramidal cells. The gain of slow inhibitory loop gradually decreased, leading to the onset of status epilepticus. Different types of waveforms in the status epilepticus corresponded to the different ratio of excitatory and inhibitory influence, caused by different levels of inhibition. Finally, in the convalescence stage, the gains of the excitatory loop and the inhibitory loop both changed toward the base line, recovering the balance. The changes of the parameters in the model were compatible with the experimental results in the literature.