Effects of high-frequency stimulation on epileptiform activity in vitro: ON/OFF control paradigm

Purpose: To determine the effects of high‐frequency electrical stimulation on electrographic seizure activity during and after stimulation (ON‐effect and OFF‐effect). Methods: The modulation and suppression of epileptiform activity during (ON‐effect) and after (OFF‐effect) high‐frequency electrical stimulation was investigated using the high‐K⁺ and picrotoxin hippocampal slice epilepsy models. Uniform sinusoidal fields (50 Hz) were applied with various intensity levels for 1 min across brain slices. Extracellular and intracellular activity were monitored during and after stimulation. Results: The ON‐effects of high‐frequency stimulation were highly variable across individual slices and models; ON‐effects included modulation of activity, pacing, partial suppression, or activity resembling spreading‐depression. On average, epileptic activity, measured as power in the extracellular fields, increased significantly during stimulation. Following the termination of electrical stimulation, a robust poststimulation suppression period was observed. This OFF suppression was observed even at relatively moderate stimulation intensities. The duration of OFF suppression increased with stimulation intensity, independent of ON‐effects. Antagonism of GABA _A function did not directly effect OFF suppression duration. Conclusions: The present results suggest that “rational” seizure control protocols using intermittent high‐frequency electrical stimulation should control for both ON and OFF effects.     

Electrical Stimulation of the Mammillary Nuclei Increases Seizure Threshold to Pentylenetetrazol in Rats

Summary: High-frequency electrical stimulation of mammillary nuclei (MN) of rat posterior hypothalamus resulted in a significant increase in seizure threshold induced by pentylenetetrazol (PTZ). The anticonvulsant effect was frequency and intensity specific. Stimulation at 100 Hz (1–5V, 30–200 μA) afforded protection against EEG and behavioral manifestations of PTZ seizures. Stimulation of either low frequency (5 Hz), high intensities (8–20 V, 300–800 μA), or outside the histologically verified MN target region did not increase seizure threshold. In some instances, high-intensity stimulation of MN alone elicited spike-wave epileptiform EEG activity accompanied by either arrest of behavior or myoclonic seizures. In animals with ongoing seizure activity, electrical stimulation of MN disrupted the high-voltage synchronous wave forms on cortical EEG. These data support the concept that electrical perturbation of MN in hypothalamus may functionally inhibit generalization of paroxysmal activity required for expression of the EEG and, in particular, the behavioral component of PTZ seizures. These studies provide additional insight into forebrain-brainstem interactions mediating generalized seizure expression.     

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

BackgroundHigh 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.ObjectiveTo study the spatial extent of seizure suppression by HFS applied on the tract and focus site in an in vivo experiment.MethodsFive 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.ResultsThe 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).ConclusionsThe 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.     

Electric cortical stimulation suppresses epileptic and background activities in neocortical epilepsy and mesial temporal lobe epilepsy.

OBJECTIVE: To evaluate the suppressive effect of electric cortical stimulation upon the seizure onset zone and the non-epileptic cortex covered by subdural electrodes in patients with neocortical epilepsy and mesial temporal lobe epilepsy (MTLE). METHODS: Four patients with medically intractable focal epilepsy had implanted subdural electrodes for preoperative evaluation. Cortical functional mapping was performed by intermittently repeating bursts of electric stimulation, which consisted of 50 Hz alternating square pulse of 0.3 ms duration, 1-15 mA, within 5 s. The effect of this stimulation on the seizure onset zones and on the non-epileptic areas was evaluated by comparing spike frequency and electrocorticogram (ECoG) power spectra before and after stimulation. A similar comparison was performed in stimulation of 0.9 Hz of the seizure onset zones for 15 min. RESULTS: When the seizure onset zone was stimulated with high frequency, spike frequency decreased by 24.7%. Logarithmic ECoG power spectra recorded at stimulated electrode significantly decreased in 10-32 Hz band by high frequency stimulation of the seizure onset zone, and in 14-32 Hz band by high frequency stimulation of the non-epileptic area. Low frequency stimulation of the seizure onset zone produced 18.5% spike reduction and slight power decrease in 12-14 Hz. CONCLUSIONS: Both high and low frequency electric cortical stimulation of the seizure onset zone have a suppressive effect on epileptogenicity. Reduction of ECoG fast activities after electric cortical stimulation suggests the augmentation of inhibitory mechanisms in human cortex.     

A comprehensive electrographic and behavioral analysis of generalized tonic-clonic seizures of GEPR-9s

This study records noise-free intracerebral EEG of the genetically epilepsy prone rat (GEPR-9), along with behavioral correlates, during a seizure on unanesthetized freely behaving unrestrained animals. The GEPR-9 exhibits acoustically triggered generalized tonic-clonic seizures, and often times the EEG, recorded with conventional techniques, has resulted in data with imbedded movement artifact. For noise-free video-EEG recordings, we used a previously developed system that consists of a head connector with a FET preamplifier and battery, signal conditioning device (5000x gain, 1 Hz-100 Hz filters), A/D converter and video/PC-PC/video computer boards for recording image data. Each animal was implanted with three monopolar/referential electrodes chosen among the following areas: cortex, inferior colliculus, reticular formation and caudal medulla. The video-EEG data were quite similar for all recorded animals: (1) basal desynchronized EEG before sound stimulus; (2) increase in EEG frequency after stimulus and before seizure onset; (3) high-amplitude polyspikes during massive myoclonic thrusts with or without a very fast running episode; (4) an electrodecremental response during tonic extension; (5) wave and spike complex during forelimb and hindlimb tonic rigidity and posttonic clonus; (6) low-amplitude EEG during postictal depression. Time sequenced spectral analysis also highlights the epileptiform EEG pattern during seizure with high reproducibility between animals. While testing seizure naive GEPR-9s, there was a clear evolution from modest epileptiform EEG activity on the first acoustic stimulation to progressively higher amplitude, duration and frequency epileptiform EEG activity throughout seizure repetition.     

Iron-induced experimental cortical seizures: Electroencephalographic mapping of seizure spread in the subcortical brain areas

The iron-induced model of post-traumatic chronic focal epilepsy in rats was studied by depth-electrode mapping to investigate the spread of epileptiform activity into subcortical brain structures after its onset in the cortical epileptic focus. Electrical seizure activity was recorded in the hippocampal CA1 and CA3 areas, amygdala and caudate-putamen, in rats with iron-induced chronic cortical focal epilepsy. These experiments showed that the epileptiform activity with its onset in the cortical focus synchronously propagated into the studied subcortical brain areas. Seizure behaviours seemed to increase in correspondence with the spread of the epileptic electrographic activity in subcortical areas. Comparison of the cortical focus electroencephalographic and associated multiple-unit action potential recordings with those from the subcortical structures showed that the occurrence and evolution of the epileptiform activity in the subcortical structures were in parallel with that in the cortical focus. The intracerebral anatomic progression and delineation of seizure spread (mapped by field potential (EEG) and multiple-unit action potentials (MUA) recordings) indicated participation of these regions in the generalization of seizure activity in this model of epilepsy. The seizure-induced activation of the hippocampus appeared to evolve into an epileptic focus independent of the cortical focus. The present study demonstrates the propagation of epileptic activity from the cortical focus into the limbic and basal ganglia regions. Treatment of iron-induced epileptic rats with ethosuximide, an anti-absence drug, resulted in suppression of the epileptiform activity in the cortical focus as well as in the subcortical brain areas.     

Increased high-frequency oscillations precede in vitro low-Mg seizures

PURPOSE: High-frequency oscillations (HFOs) in the range of > or = 80 Hz have been recorded in neocortical and hippocampal brain structures in vitro and in vivo and have been associated with physiologic and epileptiform neuronal population activity. Frequencies in the fast-ripple range (> 200 Hz) are believed to be exclusive to epileptiform activity and have been recorded in vitro, in vivo, and in epilepsy patients. Although the presence of HFOs is well characterized, their temporal evolution in the context of transition to seizure activity is not well understood. METHODS: With an in vitro low-magnesium model of spontaneous seizures, we obtained extracellular field recordings (hippocampal regions CA1 and CA3) of interictal, preictal, and ictal activity. Recordings were subjected to power-frequency analysis, in time, by using a local multiscale Fourier transform. The power spectrum was computed continuously and was quantified for each epileptiform discharge into four frequency ranges spanning subripple, ripple, and two fast-ripple frequency bands. RESULTS: A statistically significant increasing trend was observed in the subripple (0-100 Hz), ripple (100-200 Hz), and fast-ripple 1 (200-300 Hz) frequency bands during the epoch corresponding to the transition to seizure (preictal to ictal). CONCLUSIONS: Temporal patterns of HFOs during epileptiform activity are indicative of dynamic changes in network behavior, and their characterization may offer insights into pathophysiologic processes underlying seizure initiation.     

Suppression of Interictal Spikes and Seizures by Stimulation of the Vagus Nerve

The effects of electrical stimulation of the vagus nerve, a proposed treatment for patients with intractable epilepsy, on focal interictal spikes produced by penicillin and EEG secondarily generalized seizures induced by pentylenetetrazol were assessed in rats. Interictal spike frequency was reduced by 33% during 20 s of stimulation (p < 0.001) and remained low for ≤3 min. Amplitude of residual spikes was also decreased. Cardiac and respiratory rates were suppressed. Cooling the nerve proximal to the point of stimulation abolished the EEG and respiratory effects. A similar reduction in spike frequency of 39% was obtained by heating the animals' tail (p < 0.01). Vagal stimulation at onset of seizures reduced mean seizure duration from 30.2 ± 15.7 s without stimulation to 5.0 ± 1.8 s (p < 0.01). Only the EEG equivalent of the clonic phase of the seizure was affected. These findings suggest that vagus nerve stimulation can be a potent but nonspecific method to reduce cortical epileptiform activity, probably through an indirect effect mediated by the reticular activating system.     

High frequency stimulation can block axonal conduction

High frequency stimulation (HFS) is used to control abnormal neuronal activity associated with movement, seizure, and psychiatric disorders. Yet, the mechanisms of its therapeutic action are not known. Although experimental results have shown that HFS suppresses somatic activity, other data has suggested that HFS could generate excitation of axons. Moreover it is unclear what effect the stimulation has on tissue surrounding the stimulation electrode. Electrophysiological and computational modeling literature suggests that HFS can drive axons at the stimulus frequency. Therefore, we tested the hypothesis that unlike cell bodies, axons are driven by pulse train HFS. This hypothesis was tested in fibers of the hippocampus both in-vivo and in-vitro. Our results indicate that although electrical stimulation could activate and drive axons at low frequencies (0.5–25 Hz), as the stimulus frequency increased, electrical stimulation failed to continuously excite axonal activity. Fiber tracts were unable to follow extracellular pulse trains above 50 Hz in-vitro and above 125 Hz in-vivo. The number of cycles required for failure was frequency dependent but independent of stimulus amplitude. A novel in-vitro preparation was developed, in which, the alveus was isolated from the remainder of the hippocampus slice. The isolated fiber tract was unable to follow pulse trains above 75 Hz. Reversible conduction block occurred at much higher stimulus amplitudes, with pulse train HFS (> 150 Hz) preventing propagation through the site of stimulation. This study shows that pulse train HFS affects axonal activity by: (1) disrupting HFS evoked excitation leading to partial conduction block of activity through the site of HFS; and (2) generating complete conduction block of secondary evoked activity, as HFS amplitude is increased. These results are relevant for the interpretation of the effects of HFS for the control of abnormal neural activity such as epilepsy and Parkinson's disease.     

Low frequency stimulation of ventral hippocampal commissures reduces seizures in a rat model of chronic temporal lobe epilepsy

Purpose: To investigate the effects of low frequency stimulation (LFS) of a fiber tract for the suppression of spontaneous seizures in a rat model of human temporal lobe epilepsy. Methods: Stimulation electrodes were implanted into the ventral hippocampal commissure (VHC) in a rat post‐status epilepticus (SE) model of human temporal lobe epilepsy (n = 7). Two recording electrodes were placed in the CA3 regions bilaterally and neural data were recorded for a minimum of 6 weeks. LFS (60 min train of 1 Hz biphasic square wave pulses, each 0.1 ms in duration and 200 μA in amplitude, followed by 15 min of rest) was applied to the VHC for 2 weeks, 24 h a day. Key Findings: The baseline mean seizure frequency of the study animals was 3.7 seizures per day. The seizures were significantly reduced by the application of LFS in every animal (n = 7). By the end of the 2‐week period of stimulation, there was a significant, 90% (<1 seizure/day) reduction of seizure frequencies (p < 0.05) and a 57% reduction during the period following LFS (p < 0.05) when compared to baseline. LFS also resulted in a significant reduction of hippocampal interictal spike frequency (71%, p < 0.05), during 2 weeks of LFS session. The hippocampal histologic analysis showed no significant difference between rats that received LFS and SE induction and those that had received only SE‐induction. None of the animals showed any symptomatic hemorrhage, infection, or complication. Significance: Low frequency stimulation applied at a frequency of 1 Hz significantly reduced both the excitability of the neural tissue as well as the seizure frequency in a rat model of human temporal lobe epilepsy. The results support the hypothesis that LFS of fiber tracts can be an effective method for the suppression of spontaneous seizures in a temporal lobe model of epilepsy in rats and could lead to the development of a new therapeutic modality for human patients with temporal lobe epilepsy.     

Electrical and chemical long-term depression do not attenuate low-Mg2+-induced epileptiform activity in the entorhinal cortex

PURPOSE: Low-frequency electrical and magnetic stimulation of cortical brain regions has been shown to reduce cortical excitability and to decrease the susceptibility to seizures in humans and in vivo models of epilepsy. The induction of long-term depression (LTD) or depotentiation of a seizure-related long-term potentiation has been proposed to be part of the underlying mechanism. With the low-Mg(2+)-model of epilepsy, this study investigated the effect of electrical LTD, chemical LTD, and depotentiation on the susceptibility of the entorhinal cortex to epileptiform activity. METHODS: The experiments were performed on isolated entorhinal cortex slices obtained from adult Wistar rats and mice. With extracellular recording techniques, we studied whether LTD induced by (a) three episodes of low-frequency paired-pulse stimulation (3 x 900 paired pulses at 1 Hz), and by (b) bath-applied N-methyl-D-aspartate (NMDA, 20 microM) changes time-to-onset, duration, and frequency of seizure-like events (SLEs) induced by omitting MgSO(4) from the artificial cerebrospinal fluid. Next we investigated the consequences of depotentiation on SLEs themselves by applying low-frequency stimulation after onset of low-Mg(2+)-induced epileptiform activity. RESULTS: LTD, induced either by low-frequency stimulation or by bath-applied NMDA, had no effect on time-to-onset, duration, and frequency of SLEs compared with unconditioned slices. Low-frequency stimulation after onset of SLEs did not suppress but induced SLEs that lasted for the time of stimulation and were associated with a simultaneous increase of the extracellular K(+) concentration. CONCLUSIONS: Our study demonstrates that neither conditioning LTD nor brief low-frequency stimulation decreases the susceptibility of the entorhinal cortex to low-Mg(2+)-induced epileptiform activity. The present study does not support the hypothesis that low-frequency brain stimulation exerts its anticonvulsant effect via the induction of LTD or depotentiation.     

High-frequency and brief-pulse stimulation pulses terminate cortical electrical stimulation-induced afterdischarges

Brief-pulse stimulation at 50 Hz has been shown to terminate afterdischarges observed in epilepsy patients. However, the optimal pulse stimulation parameters for terminating cortical electrical stimulation-induced afterdischarges remain unclear. In the present study, we examined the effects of different brief-pulse stimulation frequencies (5, 50 and 100 Hz) on cortical electrical stimulation-induced after-discharges in 10 patients with refractory epilepsy. Results demonstrated that brief-pulse stimulation could terminate cortical electrical stimulation-induced afterdischarges in refractory epilepsy patients. In conclusion, (1) a brief-pulse stimulation was more effective when the afterdischarge did not extend to the surrounding brain area. (2) A higher brief-pulse stimulation frequency (especially 100 Hz) was more likely to terminate an afterdischarge. (3) A low current intensity of brief-pulse stimulation was more likely to terminate an afterdischarge.     

Interictal to ictal transition in human temporal lobe epilepsy: insights from a computational model of intracerebral EEG.

In human partial epilepsies and in experimental models of chronic and/or acute epilepsy, the role of inhibition and the relationship between the inhibition and excitation and epileptogenesis has long been questioned. Besides experimental methods carried out either in vitro (human or animal tissue) or in vivo (animals), pathophysiologic mechanisms can be approached by direct recording of brain electrical activity in human epilepsy. Indeed, in some clinical presurgical investigation methods like stereoelectroencephalography, intracerebral electrodes are used in patients suffering from drug resistant epilepsy to directly record paroxysmal activities with excellent temporal resolution (in the order of 1 millisecond). The study of neurophysiologic mechanisms underlying such depth-EEG activities is crucial to progress in the understanding of the interictal to ictal transition. In this study, the authors relate electrophysiologic patterns typically observed during the transition from interictal to ictal activity in human mesial temporal lobe epilepsy (MTLE) to mechanisms (at a neuronal population level) involved in seizure generation through a computational model of EEG activity. Intracerebral EEG signals recorded from hippocampus in five patients with MTLE during four periods (during interictal activity, just before seizure onset, during seizure onset, and during ictal activity) were used to identify the three main parameters of a model of hippocampus EEG activity (related to excitation, slow dendritic inhibition and fast somatic inhibition). The identification procedure used optimization algorithms to minimize a spectral distance between real and simulated signals. Results demonstrated that the model generates very realistic signals for automatically identified parameters. They also showed that the transition from interictal to ictal activity cannot be simply explained by an increase in excitation and a decrease in inhibition but rather by time-varying ensemble interactions between pyramidal cells and local interneurons projecting to either their dendritic or perisomatic region (with slow and fast GABAA kinetics). Particularly, during preonset activity, an increasing dendritic GABAergic inhibition compensates a gradually increasing excitation up to a brutal drop at seizure onset when faster oscillations (beta and low gamma band, 15 to 40 Hz) are observed. These faster oscillations are then explained by the model feedback loop between pyramidal cells and interneurons targeting their perisomatic region. These findings obtained from model identification in human temporal lobe epilepsy are in agreement with some results obtained experimentally, either on animal models of epilepsy or on the human epileptic tissue.     

BDNF-TrkB signaling pathway is involved in pentylenetetrazoleevoked progression of epileptiform activity in hippocampal neurons in anesthetized rats

Pentylenetetrazole（PTZ）is a widely-used convulsant used in studies of epilepsy;its subcutaneous injection generates an animal model with stable seizures.Here,we compared the ability of PTZ via the intravenous and subcutaneous routes to evoke progressive epileptiform activity in the hippocampal CA1 neurons of anesthetized rats.The involvement of the BDNF-TrkB pathway was then investigated.When PTZ was given intravenously,it induced epileptiform bursting activity at a short latency in a dose-dependent manner.However,when PTZ was given subcutaneously,it induced a slowly-developing pattern of epileptogenesis;first,generating multiple population-spike peaks,then spontaneous interictal discharge-like spike,leading to the final ictal discharge-like,highly synchronized bursting firing in the CA1 pyramidal layer of the hippocampus.K252a,a TrkB receptor antagonist,when given by intracerebroventricular injection,significantly reduced the probability of multiple population spike peaks induced by subcutaneous injection of PTZ,delayed the latency of spontaneous spikes,and reduced the burst frequency.Our results indicate that PTZ induces a progressive change of neuronal epileptiform activity in the hippocampus,and the BDNF-TrkB signaling pathway is mainly involved in the early phases of epileptogenesis,but not the synchronized neuronal burst activity associated with epileptic seizure in the PTZ animal model.These results provide basic insights into the changing pattern of hippocampal neuronal activity during the development of the PTZ seizure model,and establish an in vivo seizure model useful for future electrophysiological studies of epilepsy.     

Temporally irregular electrical stimulation to the epileptogenic focus delays epileptogenesis in rats

BackgroundVariation in the temporal patterns of electrical pulses in stimulation trains has opened a new field of opportunity for the treatment of neurological disorders, such as pharmacoresistant temporal lobe epilepsy. Whether this novel type of stimulation affects epileptogenesis remains to be investigated.ObjectiveThe purpose of this study was to analyze the effects of temporally irregular deep brain stimulation on kindling-induced epileptogenesis in rats.MethodsTemporally irregular deep brain stimulation was delivered at different times with respect to the kindling stimulation. Behavioral and electrographic changes on kindling acquisition were compared with a control group and a temporally regular deep brain stimulation-treated group. The propagation of epileptiform activity was analyzed with wavelet cross-correlation analysis, and interictal epileptiform discharge ratios were obtained.ResultsTemporally irregular deep brain stimulation delivered in the epileptogenic focus during the interictal period shortened the daily afterdischarge duration, slowed the progression of seizure stages, diminished the generalized seizure duration and interfered with the propagation of epileptiform activity from the seizure onset zone to the ipsi- and contralateral motor cortex. We also found a negative correlation between seizure severity and interictal epileptiform discharges in rats stimulated with temporally irregular deep brain stimulation.ConclusionThese results provide evidence that temporally irregular deep brain stimulation interferes with the establishment of epilepsy by delaying epileptogenesis by almost twice as long in kindling animals. Thus, temporally irregular deep brain stimulation could be a preventive approach against epilepsy.     

Intramuscular penicillin epilepsy in the cat: effects of chronic cerebellar stimulation.

Experiments were performed on chronically prepared cats to determine the effect of cerebellar stimulation on generalized “centrencephalic” epilepsy produced by large intramuscular injections of penicillin. Diffuse epileptiform activity developed approximately 1 hr after penicillin injection. Recording of electrical activity from cerebellar structures indicated prominent paroxysmal activity to be present during cortical epileptiform activity. Cerebellar stimulation at 10 and 100 Hz resulted in prompt and significant decrease in the number and amplitude of paroxysmal events. Mesencephalic reticular formation stimulation also reduced the amount of abnormal activity, but, in contrast to cerebellar stimulation, this reduction did not outlast the stimulus period. Inhibition by cerebellar stimulation is attributed to activation of fastigial bulbar pathways.     

Swine model for translational research of invasive intracranial monitoring

Focal cortical epilepsy is currently studied most effectively in humans. However, improvement in cortical monitoring and investigational device development is limited by lack of an animal model that mimics human acute focal cortical epileptiform activity under epilepsy surgery conditions. Therefore, we assessed the swine model for translational epilepsy research. Swine were used due to their cost-effectiveness, convoluted cortex, and comparative anatomy. The anatomy has all the same brain structures as the human, and in similar locations. Focal subcortical injection of benzyl-penicillin produced clinical seizures correlating with epileptiform activity demonstrating temporal and spatial progression. Swine were evaluated under five different anesthesia regimens. Of the five regimens, conditions similar to human intraoperative anesthesia, including continuous fentanyl with low dose isoflorane, was the most effective for eliciting complex, epileptiform activity after benzyl-penicillin injection. The most complex epileptiform activity (spikes, and high frequency activity) was then repeated reliably in nine animals, utilizing 14 swine total. There were 20.1 ± 10.8 [95% confidence interval (CI) 11.8-28.4] epileptiform events with > 3.5 Hz activity occurring per animal. Average duration of each event was 46.3 ± 15.6 (95% CI 44.0-48.6) s, ranging from 20-100 s. In conclusion, the acute swine model of focal cortical epilepsy surgery provides an animal model that mimics human surgical conditions with a large brain and gyrated cortex, and is relatively inexpensive among animal models. Therefore, we feel this model provides a valuable, reliable, and novel platform for translational studies of implantable hardware for intracranial monitoring.     

A bistable computational model of recurring epileptiform activity as observed in rodent slice preparations

We describe a computational model of epileptiform activity mimicking the activity exhibited by an animal model of epilepsy in vitro. The computational model permits generation of synthetic data to assist in the evaluation of new algorithms for epilepsy treatment via adaptive neurostimulation. The model implements both single-compartment pyramidal neurons and fast-spiking interneurons, arranged in a one-dimensional network using both excitatory and inhibitory synapses. The model tracks changes in extracellular ion concentrations, which determine the reversal potentials of membrane currents. Changes in simulated ion concentration provide positive feedback which drives the system towards the epileptiform state. One mechanism of positive feedback explored by this model is the conversion of pyramidal cells from regular spiking to intrinsic bursting as extracellular potassium concentration increases. One of the main contributions of this work is the development of a slow depression mechanism that enforces seizure termination. The network spontaneously leaves the seizure-like state as the slow depression variable decreases. This is one of the first detailed computational models of epileptiform activity, which exhibits realistic transitions between inter-seizure and seizure states, and back, with state durations similar to the in vitro model. We validate the computational model by comparing its state durations to those of the biological model. We also show that electrical stimulation of the computational model achieves seizure suppression comparable to that observed in the in vitro model.     

The Effect of Vagus Nerve Stimulation on Epileptiform Activity Recorded from Hippocampal Depth Electrodes

PURPOSE: To assess the effect of vagus nerve stimulation (VNS) on interictal epileptiform activity in the human hippocampus. Clinical studies have established the efficacy of vagus nerve stimulation in patients with epilepsy (VNS Study Group, 1995), although the electrophysiologic effects of VNS on the human hippocampus and mesial temporal lobe structures remain unknown. METHODS: We report a case study in which a patient with an implanted VNS underwent intracranial electrode recording before temporal lobectomy for intractable complex partial seizures. Epileptiform spikes and sharp waves were recorded from a depth electrode placed in the patient's left hippocampus. Spike frequencies and sharp-wave frequencies before and during VNS were compared using both a 5- and a 30-Hz stimulus. Different stimulation rates were tested on different days, and all analyses were performed using a Student's t test. RESULTS: We found no significant differences in spike frequency between baseline periods and stimulation at 5 and 30 Hz. In contrast, stimulation at 30 Hz produced a significant decrease in the occurrence of epileptiform sharp waves compared with the baseline, whereas stimulation at 5 Hz was associated with a significant increase in the occurrence of epileptiform sharp waves. CONCLUSIONS: VNS produces a measurable electrophysiologic effect on epileptiform activity in the human hippocampus. Although a clinical response to VNS did not occur in our patient before surgery, 30-Hz VNS suppressed interictal epileptiform sharp waves that were similar in appearance to those seen during the patient's actual seizures. In contrast, 5-Hz stimulation appeared to increase the appearance of interictal sharp waves.     

Neurostimulators in epilepsy

A review of electrical stimulation in patients with refractory epilepsy, including animal and human data, shows that there is anatomic and physiologic evidence supporting the role of the thalamus in epilepsy. The most recent reports in patients with refractory epilepsy suggest that deep brain stimulation and cortical electrical stimulation of the anterior thalamic nucleus and hippocampus may reduce seizure frequency in patients with refractory partial and secondarily generalized seizures. This has led to a multicenter, prospective randomized trial called the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE trial) that is currently being conducted at several centers in the United States. There is also a multicenter clinical trial for patients with refractory partial epilepsy treated with a cranially implanted responsive neurostimulator (RNS) system. Preliminary reports from the RNS system feasibility trial (the NeuroPace trial) suggest that electrographic seizures can be detected before they evolve into clinical seizures, and that electrical stimulation of the epileptogenic zone can then terminate the electrographic seizures. The preliminary data in patients using deep brain stimulation of the anterior thalamic nucleus and hippocampus, and cortical stimulation studies of the epileptogenic zone are promising and suggest a reduction in seizure frequency in some patients with refractory partial and secondarily generalized seizures. The exact mechanism of action and the best parameters used during electrical stimulation remain unknown and are the subject of ongoing research.