Electrical Stimulation Of Hippocampus Research Articles

Interaction of Sodium Valproate With Low-Frequency Electrical Stimulation During Kindlingn.

Introduction:The interaction between antiepileptic drugs and brain electrical stimulation is a potential therapy to control seizures in patients with pharmacoresistance to drugs. So, the present study aimed to design to determine the effect of a subeffective dose of sodium valproate combined with low-frequency electrical stimulation during kindling.Methods:One tripolar electrode was implanted stereotactically in the CA1 hippocampus of male Wistar rats. One week after surgery, the rats were kindled by electrical stimulation of hippocampus in a rapid manner (12 stimulations/day) for 6 days with sodium valproate alone or combined with low-frequency electrical stimulation (four packages contained 200 monophasic square wave pulses of 0.1-ms duration at 1 Hz, immediately after kindling stimulations). The duration of afterdischarge, maximum latency to stages 4 and 5, and the maximum duration of these stages were recorded by electromadule during kindling.Results:Application of sodium valproate with low-frequency electrical stimulation caused a reduction in cumulative afterdischarge duration. The maximum latency to the onset of stage 5 seizure increased after sodium valproate application alone, without having a significant effect on the fourth stage. Our findings showed reductions in the seizures duration and increasing in the latency times of both stages after the application of sodium valproate with low-frequency electrical stimulation.Conclusion:It seems that usage of sodium valproate with low-frequency electrical stimulation during kindling was more effective to suppress the epileptic activity than its administration alone and may have a critical role on the antiepileptic effects of sodium valproate.

P54-S Somatosensory and motor phenomena elicited by electrical stimulation of hippocampus: insight into the ictal network

Background Direct electrical stimulation of the cortex elicits responses according to the physiology of the stimulated area. In patients with drug resistant epilepsy evaluated for surgical therapy, this method is used for mapping the eloquent cortex and for triggering the patients’ habitual seizures, using intracerebral electrodes. Up to 11% of patients with mesial temporal lobe epilepsy have somatosensory aura, although these structures do not have any somatosensory physiological representation. Material and methods We present the case of a patient with left mesial temporal lobe epilepsy who had somatosensory auras on the right side. Direct electrical stimulation of the left hippocampus, at 50 Hz, elicited the somatosensory auras, while stimulation at 1 Hz elicited myoclonic jerks time-locked to the stimulus. Results and conclusions These unusual responses to cortical stimulation suggest that in patients with epilepsy aberrant neural networks are established, which have an essential role in ictogenesis.

Brian Activities and Spatial Memory Modulated by CA1 Electrical Stimulation

In this research, the effect of hippocampal electrical stimulation on brain waves and spatial memory was studied. The rats were anaesthetized and the electrodes were implanted into the CA1 by stereotaxic instrument. Electrical stimulation with (25 μA) and (100 μA) were induced into CA1; then spatial learning and memory was investigated by Morris water maze test, and then EEG was recorded for each rat. Learning increased in the group stimulated with 25 μA frequency compared to the sham group (P<0.05). This effect increased with high intensity (100 μA) of electrical stimulation. (One-way ANOVA, Tukey's; P=0.041). Also, this current intensity electrical stimulation increases frequency waves of delta (53.88 ± 2.03), reducing the frequency waves of alpha (11.96 ± 0.68), beta (19.72 ± 1.03), and theta (14.42 ± 0.85). Therefore, electrical stimulation strengthened and improved the recall stage (Tukey's: P=0.007). As well as, high-intensity electrical simulation visible impact on brain waves are delta waves, which play important role to consolidation of memory.

Hippocampal electrical stimulation disrupts associative learning when targeted at dentate spikes.

Dentate spikes are fast fluctuations of hilar local-field potentials that take place during rest and are thought to reflect input arriving from the entorhinal cortex to the hippocampus. During dentate spikes, neuronal firing in hippocampal input (dentate gyrus) and output (CA1/CA3) regions is uncoupled. To date, the behavioural significance of dentate spikes is unknown. Here, we provide evidence that disrupting the dentate spike-related uncoupling of the dentate gyrus and the CA1/CA3 subregions for 1h after training retards associative learning. We suggest dentate spikes play a significant role in memory consolidation. Hippocampal electrophysiological oscillations, namely theta and ripples, have been implicated in encoding and consolidation of new memories, respectively. According to existing literature, hippocampal dentate spikes are prominent, short-duration (<30ms), large-amplitude (∼2-4mV) fluctuations in hilar local-field potentials that take place during awake immobility and sleep. Interestingly, previous studies indicate that during dentate spikes dentate gyrus granule cells increase their firing while firing of CA1 pyramidal cells are suppressed, thus resulting in momentary uncoupling of the two hippocampal subregions. To date, the behavioural significance of dentate spikes is unknown. Here, to study the possible role of dentate spikes in learning, we trained adult male Sprague-Dawley rats in trace eyeblink classical conditioning. For 1h immediately following each conditioning session, one group of animals received hippocampal stimulation via the ventral hippocampal commissure (vHC) contingent on dentate spikes to disrupt the uncoupling between the dentate gyrus and the CA1 subregions. A yoked control group was stimulated during immobility, irrespective of brain state, and another control group was not stimulated at all. As a result, learning was impaired only in the group where vHC stimulation was administered contingent on dentate spikes. Our results suggest dentate spikes and/or the associated uncoupling of the dentate gyrus and the CA1 play a significant role in memory consolidation. Dentate spikes could possibly reflect reactivation and refinement of a memory trace within the dentate gyrus triggered by input from the entorhinal cortex.

Effects of neonatal hypoxic-ischemic episodes on late seizure outcomes in C57 black mice

We examined brain injury and seizures in adult C57 black mice (C57/BL6) that underwent neonatal hypoxic-ischemic (HI) episodes. Mouse pups of 7 days-old underwent a ligation of the right common carotid artery and a subsequent hypoxic challenge (8% O2 for 45min). Post-HI mice were implanted with intracranial electrodes at 2-3 months of age, subjected to behavioral/EEG recordings and hippocampal electrical stimulation in next several months and then euthanized for brain histological assessments at ages of 11-12 months. Histological assessment revealed ipsilateral brain infarctions in 9 post-HI animals. Evident motor seizures were found to occur in only 2 animals with histologically identified cystic infarctions but not in the 21 post-HI animals with or without infarctions. In response to the hippocampal stimulation, post-HI animals were less prone than sham controls to evoked motor seizures. We thus suggest that adult C57 black mice may have low propensity of developing epileptic seizures following the neonatal HI episode. Our present observations may be relevant to future investigation of post-HI epileptogenesis in mouse models.

Extraventricular Long-Axis Cannulation of the Hippocampus

Patients with hippocampal epileptogenic foci may benefit from targeted intracranial monitoring of seizures and treatments such as hippocampal electrical stimulation, closed-loop stimulation, and stereotactic laser ablation. Each may benefit from a greater volume of hippocampal coverage with long-axis cannulation. Furthermore, an extraventricular trajectory avoids brain shift and reduces the risk of hemorrhage from ependymal breach. Unfortunately, detailed descriptions of the technical aspects of longitudinal cannulation of the hippocampus remain sparse. To develop a standard protocol for extraventricular longitudinal hippocampal cannulation. Images from 25 patients stereotactically implanted with 27 longitudinal hippocampal devices were retrospectively reviewed to determine the location of the burr hole or twist drill craniostomy. Simulated planning for bilateral occipital trajectories was then performed on a second cohort of 25 patients (50 trajectories) with mesial temporal sclerosis. An entry point derived from these 77 trajectories was subsequently validated on a third cohort of 25 patients (50 trajectories). Extraventricular long-axis hippocampal implantation necessitates a lateral-to-medial and cephalad-to-caudal trajectory that skirts the inferomedial border of the temporal horn. Measurements from 64 trajectories suggested a consensus entry point that successfully facilitated 50 test trajectories as well as frame placement on 4 patients requiring long-axis hippocampal cannulation. Although trajectories must be individually tailored for each patient, we recommend a starting entry point approximately 5.5 cm superior to the external occipital protuberance and 5.5 cm lateral to midline for extraventricular long-axis hippocampal cannulation in adult patients. Identification of this point is particularly important when positioning the stereotactic frame.

Effects of low-frequency electrical stimulation of hippocampus on the expression of GABAA receptor α1 and β2 subunits in kainate-kindled rats

To explore the effects of low-frequency electrical stimulation (LFS) of hippocampus on the expression of GABAA receptor α1 and β2 subunits in the kainite (KA)-kindled rats and explore its underlying rescue mechanism for temporal lobe epilepsy. The SD rats were divided into 4 groups (n = 10):control group:no operation; epilepsy group:KA was stereotactically injected into rat hippocampus to establish KA-kindled model; sham-LFS group:only implanting of electrodes into hippocampus without LFS; LFS group:KA-kindled model with LFS. Then hippocampal tissues were collected and their expressions of GABAA receptor α1 and β2 subunits measured by immunohistochemistry, quantitative-polymerase chain reaction (q-PCR) and Western blot.Nissl staining was performed to detect the number of damaged hippocampal neurons. There were significant decreases of GABAA receptor α1 and β2 subunits in kindled hippocampus (P < 0.01). LFS resulted in an effective rescue, but failed to reach normal levels. The damaged neurons could not be reversed according to Nissl staining. The hippocampal application of LFS may protect against seizures by modulating the expressions of α1 and β2 GABAA receptor subunits.

Frequency dependence of behavioral modulation by hippocampal electrical stimulation

Electrical stimulation offers the potential to develop novel strategies for the treatment of refractory medial temporal lobe epilepsy. In particular, direct electrical stimulation of the hippocampus presents the opportunity to modulate pathological dynamics at the ictal focus, although the neuroanatomical substrate of this region renders it susceptible to altering cognition and affective processing as a side effect. We investigated the effects of three electrical stimulation paradigms on separate groups of freely moving rats (sham, 8-Hz and 40-Hz sine-wave stimulation of the ventral/intermediate hippocampus, where 8- and 40-Hz stimulation were chosen to mimic naturally occurring hippocampal oscillations). Animals exhibited attenuated locomotor and exploratory activity upon stimulation at 40 Hz, but not at sham or 8-Hz stimulation. Such behavioral modifications were characterized by a significant reduction in rearing frequency, together with increased freezing behavior. Logistic regression analysis linked the observed changes in animal locomotion to 40-Hz electrical stimulation independently of time-related variables occurring during testing. Spectral analysis, conducted to monitor the electrophysiological profile in the CA1 area of the dorsal hippocampus, showed a significant reduction in peak theta frequency, together with reduced theta power in the 40-Hz vs. the sham stimulation animal group, independent of locomotion speed (theta range: 4-12 Hz). These findings contribute to the development of novel and safe medical protocols by indicating a strategy to constrain or optimize parameters in direct hippocampal electrical stimulation.

Electrode location and clinical outcome in hippocampal electrical stimulation for mesial temporal lobe epilepsy

PurposeTo study the clinical outcome in hippocampal deep brain stimulation (DBS) for the treatment of patients with refractory mesial temporal lobe epilepsy (MTLE) according to the electrode location. MethodsEight MTLE patients implanted in the hippocampus and stimulated with high-frequency DBS were included in this study. Five underwent invasive recordings with depth electrodes to localize ictal onset zone prior to chronic DBS. Position of the active contacts of the electrode was calculated on postoperative imaging. The distances to the ictal onset zone were measured as well as atlas-based hippocampus structures impacted by stimulation were identified. Both were correlated with seizure frequency reduction. ResultsThe distances between active electrode location and estimated ictal onset zone were 11±4.3 or 9.1±2.3mm for patients with a >50% or <50% reduction in seizure frequency. In patients (N=6) showing a >50% seizure frequency reduction, 100% had the active contacts located <3mm from the subiculum (p<0.05). The 2 non-responders patients were stimulated on contacts located >3mm to the subiculum. ConclusionDecrease of epileptogenic activity induced by hippocampal DBS in refractory MTLE: (1) seems not directly associated with the vicinity of active electrode to the ictal focus determined by invasive recordings; (2) might be obtained through the neuromodulation of the subiculum.

Adenosine Prevents Kindled Seizures—An Effect as Smooth as Silk

Antiepileptic Effects of Silk-Polymer Based Adenosine Release in Kindled Rats. Szybala C, Pritchard EM, Lusardi TA, Li T, Wilz A, Kaplan DL, Boison D. Exp Neurol 2009;219(1):126–135. Pharmacotherapy for epilepsy is limited by high incidence of pharmacoresistance and failure to prevent development and progression of epilepsy. Using the rat hippocampal kindling model, we report on the therapeutic potential of novel silk-based polymers engineered to release the anticonvulsant adenosine. Polymers were designed to release 1,000 ng adenosine per day during a time span of 10 days. In the first experiment, rats were kindled by hippocampal electrical stimulation until all animals reacted with stage 5 seizures. Adenosine-releasing or control polymers were then implanted into the infrahippocampal fissure ipsilateral to the site of stimulation. Subsequently, only recipients of adenosine-releasing implants were completely protected from generalized seizures over a period of 10 days corresponding to the duration of sustained adenosine release. To monitor seizure development in the presence of adenosine, adenosine-releasing or control polymers were implanted prior to kindling. After 30 stimulations—delivered from days 4–8 after implantation—control animals had developed convulsive stage 5 seizures, whereas recipients of adenosine-releasing implants were still protected from convulsive seizures. Kindling was resumed after 9 days to allow expiration of adenosine release. During additional 30 stimulations, recipients of adenosine-releasing implants gradually resumed kindling development at seizure stages corresponding to those when kindling was initially suspended, while control rats resumed kindling development at convulsive seizure stages. Blockade of adenosine A1 receptors did not exacerbate seizures in protected animals. We conclude that silk-based adenosine delivery exerts potent anti-ictogenic effects, but might also have at least partial anti-epileptogenic effects. Thus, silk-based adenosine augmentation holds promise for the treatment of epilepsy.

Antiepileptic effects of silk-polymer based adenosine release in kindled rats

Pharmacotherapy for epilepsy is limited by high incidence of pharmacoresistance and failure to prevent development and progression of epilepsy. Using the rat hippocampal kindling model, we report on the therapeutic potential of novel silk-based polymers engineered to release the anticonvulsant adenosine. Polymers were designed to release 1000 ng adenosine per day during a time span of ten days. In the first experiment rats were kindled by hippocampal electrical stimulation until all animals reacted with stage 5 seizures. Adenosine-releasing or control polymers were then implanted into the infrahippocampal fissure ipsilateral to the site of stimulation. Subsequently, only recipients of adenosine-releasing implants were completely protected from generalized seizures over a period of ten days corresponding to the duration of sustained adenosine release. To monitor seizure development in the presence of adenosine, adenosine-releasing or control polymers were implanted prior to kindling. After 30 stimulations – delivered from days 4 to 8 after implantation – control animals had developed convulsive stage 5 seizures, whereas recipients of adenosine-releasing implants were still protected from convulsive seizures. Kindling was resumed after nine days to allow expiration of adenosine release. During additional 30 stimulations, recipients of adenosine-releasing implants gradually resumed kindling development at seizure stages corresponding to those when kindling was initially suspended, while control rats resumed kindling development at convulsive seizure stages. Blockade of adenosine A 1 receptors did not exacerbate seizures in protected animals. We conclude that silk-based adenosine delivery exerts potent anti-ictogenic effects, but might also have at least partial anti-epileptogenic effects. Thus, silk-based adenosine augmentation holds promise for the treatment of epilepsy.

Dopamine Modulates Temporal Dynamics of Feedforward Inhibition in Rat Prefrontal Cortex In Vivo

Midbrain dopamine (DA) neurons project to pyramidal cells and interneurons of the prefrontal cortex (PFC). At the microcircuit level, interneurons gate inputs to a network and regulate/pattern its outputs. Whereas several in vitro studies have examined the role of DA on PFC interneurons, few in vivo data are available. In this study, we show that DA influences the timing of interneuron firing. In particular, DA had a reductive influence on interneuron spontaneous firing, which in the context of the excitatory response of interneurons to hippocampal electrical stimulation, lead to a temporal focalization of the interneuron response. This suggests that the reductive influence of DA on interneuron excitability is responsible for filtering out weak excitatory inputs. The increase in the temporal precision of interneuron firing is a mechanism by which DA can modulate the temporal dynamics of feedforward inhibition in PFC circuits and can thereby influence cognitive information processing.

Brain Stimulation for Epilepsy: Stimulating Results?

Long-Term Follow-Up of Patients with Thalamic Deep Brain Stimulation for Epilepsy Andrade DM, Zumsteg D, Hamani C, Hodaie M, Sarkissian S, Lozano AM, Wennberg RA Neurology 2006;66:1571–1573 The authors describe long-term follow-up (mean, 5 years) in patients with anterior (AN) (n = 6) or centromedian (n = 2) thalamic deep brain stimulation (DBS) for epilepsy. Five patients (all AN) had 50% seizure reduction, although benefit was delayed in two until years 5 to 6, after changes in antiepileptic drugs. DBS electrode implantation in AN patients was followed by seizure reduction 1 to 3 months before active stimulation, raising the possibility of a beneficial microthalamotomy effect. Hippocampal Electrical Stimulation in Mesial Temporal Lobe Epilepsy Tellez-Zenteno JF, McLachlan RS, Parrent A, Kubu CS, Wiebe S Neurology 2006;66:562–565 Background Adjustable, reversible therapies are needed for patients with pharmacoresistant epilepsy. Electrical stimulation of the hippocampus has been proposed as a possible treatment for mesial temporal lobe epilepsy (MTLE). Methods Four patients with refractory MTLE whose risk to memory contraindicated temporal lobe resection underwent implantation of a chronic stimulating depth electrode along the axis of the left hippocampus. The authors used continuous, subthreshold electrical stimulation (90 μsec, 190 Hz) and a double blind, multiple cross-over, randomized controlled design, consisting of three treatment pairs, each containing two 1-month treatment periods. During each treatment pair the stimulator was randomly turned ON 1 month and OFF 1 month. Outcomes were assessed at monthly intervals in a double blind manner, using standardized instruments and accounting for a washout period. The authors compared outcomes between ON, OFF, and baseline periods. Results Hippocampal stimulation produced a median reduction in seizures of 15%. All but one patient's seizures improved; however, the results did not reach significance. Effects seemed to carry over into the OFF period, and an implantation effect cannot be ruled out. The authors found no significant differences in other outcomes. There were no adverse effects. One patient has been treated for 4 years and continues to experience substantial long-term seizure improvement. Conclusion The authors demonstrate important beneficial trends, some long-term benefits, and absence of adverse effects of hippocampal electrical stimulation in mesial temporal lobe epilepsy. However, the effect sizes observed were smaller than those reported in non-randomized, unblinded studies.

Hippocampal electrical stimulation in mesial temporal lobe epilepsy

Adjustable, reversible therapies are needed for patients with pharmacoresistant epilepsy. Electrical stimulation of the hippocampus has been proposed as a possible treatment for mesial temporal lobe epilepsy (MTLE). Four patients with refractory MTLE whose risk to memory contraindicated temporal lobe resection underwent implantation of a chronic stimulating depth electrode along the axis of the left hippocampus. The authors used continuous, subthreshold electrical stimulation (90 microsec, 190 Hz) and a double blind, multiple cross-over, randomized controlled design, consisting of three treatment pairs, each containing two 1-month treatment periods. During each treatment pair the stimulator was randomly turned ON 1 month and OFF 1 month. Outcomes were assessed at monthly intervals in a double blind manner, using standardized instruments and accounting for a washout period. The authors compared outcomes between ON, OFF, and baseline periods. Hippocampal stimulation produced a median reduction in seizures of 15%. All but one patient's seizures improved; however, the results did not reach significance. Effects seemed to carry over into the OFF period, and an implantation effect cannot be ruled out. The authors found no significant differences in other outcomes. There were no adverse effects. One patient has been treated for 4 years and continues to experience substantial long-term seizure improvement. The authors demonstrate important beneficial trends, some long-term benefits, and absence of adverse effects of hippocampal electrical stimulation in mesial temporal lobe epilepsy. However, the effect sizes observed were smaller than those reported in non-randomized, unblinded studies.

Changes in KCNQ2 immunoreactivity in the amygdala in two rat models of temporal lobe epilepsy

Potassium channels containing the KCNQ2 subunit play an important role in the regulation of neuronal excitability and therefore have been implicated in epilepsy. This study describes the expression of KCNQ2 subunit immunoreactivity in the basolateral amygdala in two rat models of temporal lobe epilepsy, (1) amygdala kindling and (2) spontaneously epileptic rats after status epilepticus induced by hippocampal electrical stimulation. KCNQ2 subunit immunoreactivity was assessed with a commercial antibody raised against a C-terminal part of the KCNQ2 protein. We show that KCNQ2 subunit immunoreactivity is upregulated in the basolateral amygdala in both models and that generalized seizures are required to induce this upregulation. We hypothesize that the upregulation of potassium channels containing the KCNQ2 subunit might represent a mechanism to counteract seizures in experimental temporal lobe epilepsy.

Rate of interictal events and spontaneous seizures in epileptic rats after electrical stimulation of hippocampus and its afferents.

Deep brain stimulation has been used by several investigators to prevent the occurrence of spontaneous seizures in patients with intractable epilepsy. With the kainic acid rat model of spontaneous recurrent seizures, we examined the consequences of subthreshold electrical stimulation of commissural pathways and perforant path on the synaptic plasticity, rate of interictal epileptiform events (IIEs), and spontaneous seizures in kainic acid (KA)-treated rats epileptic rats. Recording microelectrodes were implanted bilaterally in the dentate gyrus and entorhinal cortex. Stimulating electrodes were implanted into the rostral part of the right hippocampus and right perforant path. Stimulation was performed daily with 200 Hz/0.5-s duration trains, 10-min duration 1-Hz train, or 2-h, 1-Hz train and 2-h duration, 50-Hz trains. Integrated amplitude of evoked potentials, rate of IIE, and spontaneous seizures was analyzed before and after stimulation. High-frequency tetani evoked long-term potentiation in 50% of epileptic rats compared with 100% of control rats. No long-term depression was observed after 1-Hz train. Decrease rate of IIE was found during 1-Hz and 50-Hz stimulation and returned to the basal level within 30-60 min. No significant change of the spontaneous seizure rate was found. Epileptic brain is less prone to plastic changes compared with the normal brain. Daily 2-h electrical stimulation with either low or high frequency does not have a long-term effect on the rate of interictal events and spontaneous seizures.

Centromedian-thalamic and hippocampal electrical stimulation for the control of intractable epileptic seizures.

The following two different modulatory procedures to control intractable epileptic seizures are presented: (1) chronic electrical stimulation of the centromedian-thalamic nucleus (ESCM) for control of generalized tonic-clonic seizures and atypical absences, and (2) subacute hippocampal stimulation (SAHCS) and chronic hippocampal stimulation for control of nonlesional temporal lobe seizures. The ESCM antiepileptic effect seems to be the result of activation of a nonspecific reticulothalamocortical system responsible for generalized electrocortical responses (recruiting, desynchronization, negative direct current shifts, and three spike-wave complexes per second). The success of the ESCM procedure depends on the following predictor factors: case selection (primary and secondary tonic-clonic seizures and atypical absences of the Lennox Gastaut syndrome), ventriculographic and electrophysiologic definition of the optimal stereotactic targets (based on the anterior commissure, posterior commissure, and the vertical line perpendicular to the posterior commissure and electrocortical recruiting responses), periodic electrophysiologic monitoring of the reliability of ESCM in the absence of the patient's subjective sensations and with totally internalized subcutaneous stimulation systems (by recording scalp electrocortical recruiting, desynchronizing, and direct current responses), quantitative evaluation of clinical and EEG improvement, and analysis of the ON and OFF effects, taking into account a long-lasting (possibly plastic) effect of ESCM. SAHCS blocks clinical and EEG signs of temporal lobe epileptogenesis with no additional damage of the stimulated hippocampal tissue. Preliminary results suggest that this antiepileptic effect is, at least in part, the result of a physiologic inhibition of the stimulated hippocampal tissue, because after SAHCS the authors found the following: (1) increased threshold and decreased duration, propagation, and blockage of the clinical signs accompanied with the hippocampal afterdischarge; (2) flattening of the hippocampal-evoked response recovery cycles; (3) single photon emission computed tomographic hypoperfusion; and (4) increased concentration of benzodiazepine receptor binding at the stimulated hippocampal region. Chronic hippocampal stimulation persistently blocked temporal lobe epileptogenesis in one patient under open protocols during 24 months with no apparent additional alterations in recent memory.

Seizures induce phase shifts of rat circadian rhythms

Rationale: Epileptic seizures may alter neuroendocrinological cycles. Light pulses induce phase shifts in circadian rhythms. Using hippocampal-kindled rats to ensure maximal clinical expression, we determined if seizures likewise induce phase shifts. Methods: We monitored the circadian rhythm of temperature (CRT) with intraperitoneal radiotelemetry in rats ( n=21) isolated from time cues and light for 3-week trials. Seizures were triggered with hippocampal electrical stimulation at different circadian phases. Optimized, least-error phase shifts were calculated from preictal and postictal CRTs. Induced seizures were referenced to CRT ( t max=00:00, 24-h circadian cycle). Results: Phase shifts (individual responses=57) differed across the circadian cycle. Rather than forming a clear phase–response curve, phase shifts were especially variable between 00:00 and 06:00 h. Conclusions: This study demonstrates that electrically-induced seizures induce advances and delays in CRT in a phase-dependent fashion but in a pattern different from typical light-induced phase shifts. Disorders of circadian regulation may contribute to some of the altered endogenous cycles associated with epilepsy.

Topiramate reduces neuronal injury after experimental status epilepticus

Prolonged seizures are associated with injury to vulnerable neurons, particularly in the hippocampus. Identification of compounds that attenuate injury after prolonged seizures could be of value in the management of refractory status epilepticus. We hypothesized that topiramate, an anticonvulsant with multiple mechanisms of action, would attenuate hippocampal neuronal injury when given after experimental status epilepticus. Limbic status epilepticus was induced in adult male Wistar rats for 140 min by unilateral hippocampal electrical stimulation. Rats then received intraperitoneal injections of either vehicle ( n=6) or topiramate at 20 mg/kg ( n=6), 40 mg/kg ( n=7) or 80 mg/kg ( n=7). Three days later, hippocampal sections were processed for neuronal degeneration using a silver impregnation stain. Seizure-induced damage was assessed by measuring the density of silver staining in hippocampal regions CA1, CA3 and dentate hilus. Administration of topiramate at each dose was associated with a significant reduction in staining density bilaterally in area CA1 and the dentate hilus. Reduction in staining density in area CA3 was seen contralateral to the side of stimulation at the two higher topiramate doses only. The results indicate that administration of topiramate after experimental status epilepticus can attenuate seizure-induced hippocampal neuronal injury.

Memory function during low intensity hippocampal electrical stimulation in patients with temporal lobe epilepsy

Hippocampal memory dysfunction is a main symptom of mesiotemporal lobe epilepsy (TLE). It may increase after temporal lobectomy for seizure relief. The aim of this study was to assess the ability of psychometry during hippocampal electrical stimulation to predict post‐operative memory deficits and thereby to contribute to lateralization of the epileptogenic zone. A computerized memory test was performed during low intensity hippocampal stimulation in nine patients with TLE during invasive presurgical evaluation. The following results were obtained: speech dominant hippocampal stimulation induced subtle verbal memory deficits in patients with the epileptogenic zone in the speech dominant hemisphere and normal baseline memory performance. Verbal memory deficits could not be induced in patients with the epileptogenic zone in the speech dominant hemisphere and pre‐existing memory deficits, or if the seizure origin was contralateral to speech dominance. Thus it was possible to lateralize the epileptogenic zone in patients with normal baseline memory performance by revealing hippocampal dysfunction only during electrical stimulation. Post‐operative psychometric testing demonstrated that the individual risk for impairment of verbal memory performance following temporal lobectomy could be predicted correctly. In conclusion, psychometry during hippocampal stimulation may allow prediction of memory deficits following temporal lobectomy and improve determination of the epileptogenic zone.