Focal Cortical Seizures Research Articles

Localized chemogenetic silencing of inhibitory neurons: a novel mouse model of focal cortical epileptic activity.

Focal cortical epilepsies are frequently refractory to available anticonvulsant drug therapies. One key factor contributing to this state is the limited availability of animal models that allow to reliably study focal cortical seizures and how they recruit surrounding brain areas in vivo. In this study, we selectively expressed the inhibitory chemogenetic receptor, hM4D, in GABAergic neurons in focal cortical areas using viral gene transfer. GABAergic silencing using Clozapine-N-Oxide (CNO) demonstrated reliable induction of local epileptiform events in the electroencephalogram signal of awake freely moving mice. Anesthetized mice experiments showed consistent induction of focal epileptiform-events in both the barrel cortex (BC) and the medial prefrontal cortex (mPFC), accompanied by high-frequency oscillations, a known characteristic of human seizures. Epileptiform-events showed propagation indication with favored propagation pathways: from the BC on 1 hemisphere to its counterpart and from the BC to the mPFC, but not vice-versa. Lastly, sensory whisker-pad stimulation evoked BC epileptiform events post-CNO, highlighting the potential use of this model in studying sensory-evoked seizures. Combined, our results show that targeted chemogenetic inhibition of GABAergic neurons using hM4D can serve as a novel, versatile, and reliable model of focal cortical epileptic activity suitable for systematically studying cortical ictogenesis in different cortical areas.

Validating EEG, MEG and Combined MEG and EEG Beamforming for an Estimation of the Epileptogenic Zone in Focal Cortical Dysplasia.

MEG and EEG source analysis is frequently used for the presurgical evaluation of pharmacoresistant epilepsy patients. The source localization of the epileptogenic zone depends, among other aspects, on the selected inverse and forward approaches and their respective parameter choices. In this validation study, we compare the standard dipole scanning method with two beamformer approaches for the inverse problem, and we investigate the influence of the covariance estimation method and the strength of regularization on the localization performance for EEG, MEG, and combined EEG and MEG. For forward modelling, we investigate the difference between calibrated six-compartment and standard three-compartment head modelling. In a retrospective study, two patients with focal epilepsy due to focal cortical dysplasia type IIb and seizure freedom following lesionectomy or radiofrequency-guided thermocoagulation (RFTC) used the distance of the localization of interictal epileptic spikes to the resection cavity resp. RFTC lesion as reference for good localization. We found that beamformer localization can be sensitive to the choice of the regularization parameter, which has to be individually optimized. Estimation of the covariance matrix with averaged spike data yielded more robust results across the modalities. MEG was the dominant modality and provided a good localization in one case, while it was EEG for the other. When combining the modalities, the good results of the dominant modality were mostly not spoiled by the weaker modality. For appropriate regularization parameter choices, the beamformer localized better than the standard dipole scan. Compared to the importance of an appropriate regularization, the sensitivity of the localization to the head modelling was smaller, due to similar skull conductivity modelling and the fixed source space without orientation constraint.

Hemifacial spasm is not affected by state of consciousness: a case report

Background Hemifacial spasm (HFS) is a movement disorder caused by mechanical compression of the facial nerve after it has left the brainstem and is characterized by brief or sustained twitching of the muscles innervated by that nerve. Often we observe spasm in an awakening situation. Actually contractions persist during sleep. To our knowledge, there were no reports on how HFS manifests under disturbance of consciousness. Here, we report a case of primary HFS in which the patient's symptoms persisted in a coma.Case presentationA 74-year-old female with right-sided primary HFS for 20 years and had received botulinum toxin injections in our hospital. Unfortunately she was carried to emergency department after traumatic right pneumothorax by accident. During the emergency treatment, she lost consciousness due to simultaneous cardiac arrest and respiratory arrest. She was then admitted to the emergency intensive care unit for further treatment. During her hospitalization, she was in a coma with stable vital signs and persisting symptoms of HFS. Thus, a multidisciplinary consultation was requested to identify whether it was focal cortical seizures involving the right-side facial muscles. Physical examination revealed brief involuntary clonic or tonic contractions accompanied with the ‘Babinski-2 sign’. A combination of relevant data, including her past history, clinical presentation and a negative computed tomography scan of the head, led to a diagnosis of right-sided HFS. As the symptoms of HFS are not life-threatening, the use of anticonvulsants is unnecessary.ConclusionsFor the layperson, it is crucial to seek a multidisciplinary consultation to obtain a correct diagnosis.

Delineation of the epileptogenic zone by Phase-amplitude coupling in patients with Bottom of Sulcus Dysplasia

PurposeThe removal of the bottom of sulcus dysplasia (BOSD) often includes the gyral crown; however, this method has been controversial. We hypothesized that the epileptogenic zone of the BOSD does not include the gyral crown. To reveal the depth and extent of the epileptogenic zone of the BOSD, we applied the two electrophysiological modalities: (1) the occurrence rate (OR) of high-frequency oscillations (HFOs) and (2) modulation index (MI), reflecting the strength of phase-amplitude coupling between HFOs and slow oscillations. MethodsWe investigated the ripples [80–200 Hz] and fast ripples [200–300 Hz]) in HFOs and MI (HFOs [80–300 Hz] and slow oscillations [3–4 Hz]). We opened the sulcus at the BOSD and implanted the subdural electrodes directly over the MRI visible lesion. All patients (n = 3) underwent lesionectomy and the gyral crown was preserved. ResultsPathological findings demonstrated focal cortical dysplasia type IIb and seizure freedom was achieved. The OR of the HFOs was not significantly different between the BOSD and the gyral crown. In contrast, the MI between HFOs and slow oscillations in the BOSD was significantly higher than that in the gyral crown. ConclusionHigh MI values distinguished the epileptogenic BOSD from the non-epileptogenic gyral crowns. MI could be a more informative biomarker of epileptogenicity than the OR of HFOs in a subset of patients with the BOSD.

Comparison of fiber tract low frequency stimulation to focal and ANT stimulation in an acute rat model of focal cortical seizures

BackgroundCurrent implementations of direct brain stimulation for epilepsy in patients involve high-frequency (HFS) electrical current and targeting of grey matter. Studies have shown that low-frequency (LFS) fiber-tract stimulation may also prove effective. To compare the efficacy of high-frequency grey matter stimulation to the low-frequency fiber tract stimulation technique a well-controlled set of experiments using a single animal model of epilepsy is needed. ObjectiveThe goal of this study was to determine the relative efficacy of different direct brain stimulation techniques for suppressing seizures using an acute rat model of focal cortical seizures. Methods4-AP was injected into the S1 region of cortex in rodents over 3 h. LFPs were recorded from the seizure focus and mirror focus to monitor seizure frequency during the experiments. CC-LFS, HFS-ANT, Focal-HFS, or a transection of the CC was applied. ResultsStimulation of the CC yielded a 65% ±14% (p = 0.0014) reduction of seizures in the focus and a 97% ±15% (p = 0.0026) reduction in the mirror focus (n = 7). By comparison transection of the CC produced a 65% ±18% reduction in the focus and a non-statistically significant reduction of 57% ±18% (p = 0.1381) in the mirror focus (n = 5). All other methods of stimulation failed to have a statistically significant effect on seizure suppression. ConclusionsLFS of the CC is the only method of stimulation to significantly reduce seizure frequency in this model of focal cortical seizures. These results support the hypothesis that LFSof fiber tracts has significant potential for seizure control.

Acute Focal Seizures Start As Local Synchronizations of Neuronal Ensembles.

Understanding seizure formation and spread remains a critical goal of epilepsy research. We used fast in vivo two-photon calcium imaging in male mouse neocortex to reconstruct, with single-cell resolution, the dynamics of acute (4-aminopyridine) focal cortical seizures as they originate within a spatially confined seizure initiation site (intrafocal region), and subsequently propagate into neighboring cortical areas (extrafocal region). We find that seizures originate as local neuronal ensembles within the initiation site. This abnormal hyperactivity engages increasingly larger areas in a saltatory fashion until it breaks into neighboring cortex, where it proceeds smoothly and is then detected electrophysiologically (LFP). Interestingly, PV inhibitory interneurons have spatially heterogeneous activity in intrafocal and extrafocal territories, ruling out a simple role of inhibition in seizure formation and spread. We propose a two-step model for the progression of focal seizures, where neuronal ensembles activate first, generating a microseizure, followed by widespread neural activation in a traveling wave through neighboring cortex during macroseizures.SIGNIFICANCE STATEMENT We have used calcium imaging in mouse sensory cortex in vivo to reconstruct the onset of focal seizures elicited by local injection of the chemoconvulsant 4-aminopyridine. We demonstrate at cellular resolution that acute focal seizures originate as increasingly synchronized local neuronal ensembles. Because of its spatial confinement, this process may at first be undetectable even by nearby LFP electrodes. Further, we establish spatial footprints of local neural subtype activity that correspond to consecutive steps of seizure microprogression. Such footprints could facilitate determining the recording location (e.g., inside/outside an epileptogenic focus) in high-resolution studies, even in the absence of a priori knowledge about where exactly a seizure started.

Focal cortical dysplasia II-related seizures originate from the bottom of the dysplastic sulcus: A stereoelectroencephalography study

ObjectivesFocal cortical dysplasia (FCD) II is a frequently observed histopathological substrate in epilepsy surgery. In the present study, we explored the spatial distribution of epileptogenic activities across FCD II lesions using stereoelectroencephalography. MethodsPatients with histopathologically confirmed type II FCDs and who had at least one depth electrode that go through the wall of the dysplastic sulcus from the surface to the bottom were included. The dysplastic sulci were divided into the bottom and non-bottom parts manually, and contacts were defined as bottom or non-bottom contacts according to their locations. Factors (bottom location, pathological subtype, magnetic resonance imaging manifestation, and presence of bottom-of-sulcus dysplasia) potentially associated with earliest onset identified by conventional visual analysis, epileptogenicity index (EI), and standardized number of high-frequency oscillations (HFOs) were analyzed. Linear regression analyses between distance (from the location of the analyzed contact to the bottom of the sulcus) and EI value and HFO number were performed. ResultsSixteen patients with 19 depth electrodes containing 112 valid contacts were included. Bottom location was the sole factor significantly associated with earliest onset (P < 0.001), EI value (P < 0.001), and HFO number (P < 0.001). Most earliest onsets were recorded by the bottom contacts, bottom contacts had higher EI value (0.81 ± 0.28 vs. 0.31 ± 0.24, P < 0.001) and more HFOs (0.78 ± 0.28 vs. 0.35 ± 0.31, P < 0.001) than non-bottom contacts. Moreover, the EI value (R = −0.72, P < 0.001) and HFO number (R = −0.64, P < 0.001) were significantly negatively correlated with distance, regardless of histopathological subtype, MRI manifestation, or absence of bottom-of-sulcus dysplasia. ConclusionSeizure onsets and interictal HFOs most often arise from the bottom part of a sulcus with type II FCD. SignificanceThe findings of the present study contribute to intracranial electrode selection, trajectory planning, and, later on, resection of this kind of malformation.

When a Good Cop Turns Bad: The Pro-Ictal Action of Parvalbumin Expressing Interneurons During Seizures.

KCC2 Overexpression Prevents the Paradoxical Seizure-Promoting Action of Somatic Inhibition Magloire, V., Cornford, J., Lieb, A., Kullmann, D. M., and Pavlov, I. Nat. Commun. 10, 1225. doi:10.1038/s41467-019-08933-4. Although cortical interneurons are apparently well-placed to suppress seizures, several recent reports have highlighted a paradoxical role of perisomatic-targeting parvalbumin-positive (PV+) interneurons in ictogenesis. Here, we use an acute in vivo model of focal cortical seizures in awake behaving mice, together with closed-loop optogenetic manipulation of PV+ interneurons, to investigate their function during seizures. We show that photo-depolarization of PV+ interneurons rapidly switches from an anti-ictal to a pro-ictal effect within a few seconds of seizure initiation. The pro-ictal effect of delayed photostimulation of PV+ interneurons was not shared with dendrite-targeting somatostatin-positive (SOM+) interneurons. We also show that this switch can be prevented by overexpression of the neuronal potassium-chloride co-transporter KCC2 in principal cortical neurons. These results suggest that strategies aimed at improving the ability of principal neurons to maintain a trans-membrane chloride gradient in the face of excessive network activity can prevent interneurons from contributing to seizure perpetuation.

KCC2 overexpression prevents the paradoxical seizure-promoting action of somatic inhibition

Although cortical interneurons are apparently well-placed to suppress seizures, several recent reports have highlighted a paradoxical role of perisomatic-targeting parvalbumin-positive (PV+) interneurons in ictogenesis. Here, we use an acute in vivo model of focal cortical seizures in awake behaving mice, together with closed-loop optogenetic manipulation of PV+ interneurons, to investigate their function during seizures. We show that photo-depolarization of PV+ interneurons rapidly switches from an anti-ictal to a pro-ictal effect within a few seconds of seizure initiation. The pro-ictal effect of delayed photostimulation of PV+ interneurons was not shared with dendrite-targeting somatostatin-positive (SOM+) interneurons. We also show that this switch can be prevented by overexpression of the neuronal potassium-chloride co-transporter KCC2 in principal cortical neurons. These results suggest that strategies aimed at improving the ability of principal neurons to maintain a trans-membrane chloride gradient in the face of excessive network activity can prevent interneurons from contributing to seizure perpetuation.

Corpus callosum low-frequency stimulation suppresses seizures in an acute rat model of focal cortical seizures.

Low-frequency fiber-tract stimulation has been shown to be effective in treating mesial temporal lobe epilepsies through activation of the hippocampal commissure in rodents and human patients. The corpus callosum is a major pathway connecting the two hemispheres of the brain; however, few experiments have documented corpus callosum stimulation. The objective is to determine the efficacy of corpus callosum stimulation at low frequencies to suppress cortical seizures. 4-Aminopyridine was injected in the primary motor cortex of 24 rats under anesthesia. Recording electrodes were placed in the contralateral motor cortex and hippocampus. Three pairs of stimulating electrodes were inserted into the corpus callosum along its longitudinal axis. Local field potentials were recorded 1hour before, during, and after stimulation to determine the effect of stimulation on seizure duration. Stimulation was delivered from each pair of electrodes independently in separate experiments. Furthermore, electrical stimulation was applied to the region of the corpus callosum with the highest degree of innervation of the seizure focus to compare the efficacy of different stimulation frequencies (1-30Hz) on seizure suppression. Corpus callosum stimulation was effective at suppressing seizures at 10Hz by 76% (P<0.05, n=5) and at 20Hz by 95% (P<0.0001, n=14). Stimulation at frequencies of 1 and 30Hz did not have a significant effect on reducing the total time spent seizing (P>0.9999, n=5). Furthermore, stimulation was only effective at suppressing seizures when the pair of electrodes was placed within the section of corpus callosum containing fibers innervating the seizure focus. Secondarily generalized seizures in the hippocampus were eliminated when seizures in the cortical focus were suppressed. Low-frequency fiber-tract stimulation of the corpus callosum suppresses both cortical and cortically induced hippocampal seizures in an acute model of focal cortical seizures. The stimulation paradigm is selective, as it is only effective when targeted to specific regions of the corpus callosum that project maximally to cortical regions generating the seizure activity. Selective placement of stimulation electrodes along the corpus callosum could be used as a patient-specific treatment for cortical epilepsies.

Focal cortical seizures start as standing waves and propagate respecting homotopic connectivity

Focal epilepsy involves excessive cortical activity that propagates both locally and distally. Does this propagation follow the same routes as normal cortical activity? We pharmacologically induced focal seizures in primary visual cortex (V1) of awake mice, and compared their propagation to the retinotopic organization of V1 and higher visual areas. We used simultaneous local field potential recordings and widefield imaging of a genetically encoded calcium indicator to measure prolonged seizures (ictal events) and brief interictal events. Both types of event are orders of magnitude larger than normal visual responses, and both start as standing waves: synchronous elevated activity in the V1 focus and in homotopic locations in higher areas, i.e. locations with matching retinotopic preference. Following this common beginning, however, seizures persist and propagate both locally and into homotopic distal regions, and eventually invade all of visual cortex and beyond. We conclude that seizure initiation resembles the initiation of interictal events, and seizure propagation respects the connectivity underlying normal visual processing.

Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia.

The discovery of mutations in DEPDC5 in familial focal epilepsies has introduced a novel pathomechanism to a field so far dominated by ion channelopathies. DEPDC5 is part of a complex named GAP activity toward RAGs (GATOR) complex 1 (GATOR1), together with the proteins NPRL2 and NPRL3, and acts to inhibit the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) pathway. GATOR1 is in turn inhibited by the GATOR2 complex. The mTORC1 pathway is a major signaling cascade regulating cell growth, proliferation, and migration. We aimed to study the contribution of GATOR complex genes to the etiology of focal epilepsies and to describe the associated phenotypical spectrum. We performed targeted sequencing of the genes encoding the components of the GATOR1 (DEPDC5, NPRL2, and NPRL3) and GATOR2 (MIOS, SEC13, SEH1L, WDR24, and WDR59) complex in 93 European probands with focal epilepsy with or without focal cortical dysplasia. Phospho-S6 immunoreactivity was used as evidence of mTORC1 pathway activation in resected brain tissue of patients carrying pathogenic variants. We identified four pathogenic variants in DEPDC5, two in NPRL2, and one in NPRL3. We showed hyperactivation of the mTORC1 pathway in brain tissue from patients with NPRL2 and NPRL3 mutations. Collectively, inactivating mutations in GATOR1 complex genes explained 11% of cases of focal epilepsy, whereas no pathogenic mutations were found in GATOR2 complex genes. GATOR1-related focal epilepsies differ clinically from focal epilepsies due to mutations in ion channel genes by their association with focal cortical dysplasia and seizures emerging from variable foci, and might confer an increased risk of sudden unexplained death in epilepsy (SUDEP). GATOR1 complex gene mutations leading to mTORC1 pathway upregulation is an important cause of focal epilepsy with cortical malformations and represents a potential target for novel therapeutic approaches.

Characteristics of a primate model of focal motor cortical seizures suitable for preclinical testing of therapies like DBS

Background and objective: Generating and characterizing primate models of epileptic seizures are important for understanding pathophysiology of diseases and establishing preclinical efficacy of novel therapies like Deep Brain Stimulation. A focal motor epilepsy model is described here. Method: Seizures were obtained after intracortical penicillin injection into the motor strip through a cannula in two awake monkeys and electrocorticograms were recorded by epidural screws. Seizures were analyzed and compared for number, average duration of each seizure and total duration of ictal activity. Pharmaco-resistance for antiepileptic drug was tested by administration of Diazepam during seizures. Results: A motor status with seizures mimicking those seen in Kojevnikov’s syndrome was easily generated several minutes after penicillin injection and lasted 24 h on an average. The model thus characterized appears stable and consistent. There is no significant variation between experiments in individual primate as well as between two specimens. Diazepam though reduced the total duration of seizures, failed to abolish behavioural seizures. Conclusion: This model represents a good alternative model for preclinical research aiming at testing novel therapies because seizures are obtained on demand, last up to 24 h after a single penicillin injection, are stable and resistant to Diazepam.

085 Isolated cortical vein thrombosis: a report of seven cases

BackgroundCerebral venous thrombosis accounts for <5% of all strokes. Cortical vein thrombosis (CVT) is even rarer and usually coexists with sinus thrombosis but can present in isolation. As a group...

The Therapeutic Potential of Focal Cooling for Neocortical Epilepsy

The therapy of the focal cortical epilepsies remains unsatisfactory. Close to a third of patients fail to gain adequate control with antiepileptic drugs and a portion of those who do, experience unacceptable side effects. Morever, the favorable response rate after surgical resection, approximately 60%, is not nearly as high as the response rate of complex partial seizures caused by mesial temporal sclerosis. The suppressive effect of cooling on neuronal activity has been recognized for over a century. Therefore, we have begun to explore the possible application of cooling as a therapy for focal cortical seizures. In initial brain slice experiments, we found that cooling to 20 degrees C could rapidly terminate paroxysmal activity. Then we developed an in vivo model of focal seizures using a local injection of the convulsant 4-aminopyridine and found that cooling the injected area to less than 24 degrees C with a thermoelectric Peltier device aborted seizures within a few seconds. Other laboratories have independently confirmed our initial observations. More recent experiments from our laboratory have shown that cooling, per se, is not associated with significant cortical damage, even at surface temperatures as low as 5 degrees C. Advances in the fabrication of extremely thin thermoelectric devices, less than a few hundred microns thick, has raised the possibility of incorporating an implantable cooling unit into a closed loop seizure detection and treatment system.

The Effect of Electrical Stimulation and Lesioning of the Anterior Thalamic Nucleus on Kainic Acid–Induced Focal Cortical Seizure Status in Rats

The present study aimed to clarify the effect of electrical stimulation and lesioning of the anterior nucleus of the thalamus (ANT) on kainic acid (KA)-induced focal cortical seizures in a rat model. To address the mechanism underlying these anticonvulsant actions, cerebral glucose metabolism after ANT electrical stimulation and lesioning was also examined. Wistar rats were divided into five major groups: control (n = 9), unilateral (n = 9), and bilateral (n = 9) ANT electrical stimulation, and unilateral (n = 9) and bilateral (n = 9) ANT lesioning. After KA injection, average clinical-seizure frequencies in each group were measured. Electrical stimulation of ANT was introduced after induction of seizure status epilepticus. Stimulation was on for 30 min and off for 30 min per 60-min cycle. Local cerebral glucose utilization (LCGU) was also measured by using [(14)C] 2-deoxyglucose autoradiography in three groups of rats: control (n = 7), bilateral ANT stimulation (n = 7), and bilateral ANT lesioning (n = 7). Unilateral ANT electrical stimulation and lesioning significantly reduced clinical seizure frequency, compared with control animals. Strikingly, no animals treated with bilateral ANT procedures demonstrated any clinical seizure. LCGU was markedly increased in the sensorimotor cortex, striatum, thalamus, mammillary body, and midbrain tegmentum of control group rats after KA injection, but no increase in LCGU was noted in rats treated with bilateral ANT lesioning or stimulation. The electrical stimulation and lesioning of ANT suppressed focal cortical clinical seizures induced by KA injection. Additionally, an analysis of cerebral metabolic changes indicated that these procedures might suppress the function as amplifier and synchronizer of seizure activity.

Magnetic seizure therapy: development of a novel intervention for treatment resistant depression

Electroconvulsive therapy (ECT) is the most effective and most rapidly acting treatment for severe treatment resistant major depression, but its use is limited by its cognitive side effects. Magnetic seizure therapy (MST) is a new form of convulsive therapy using high-dosage repetitive transcranial magnetic stimulation (rTMS) to induce focal cortical seizures under anesthesia. MST is under study as a means of reducing the side effects of ECT through the enhanced control over the sites of seizure initiation and topography of seizure propagation afforded by the relative focality of rTMS. This review traces the stages in the development of MST, from device development, to preclinical testing, to clinical trials. The results of a study on the comparative safety of chronic MST and electroconvulsive shock in non-human primates support the safety of both interventions, and indicate that the seizures induced by MST are more focal and have less impact on deeper brain structures. This non-human primate model and a controlled clinical trial in patients with major depression, suggest that MST may induce fewer side effects and less amnesia than ECT. Ongoing work will yield the first data on the antidepressant efficacy of MST. If ultimately shown to be effective, MST could represent a new, less invasive option for patients with severe treatment resistant depression or other disorders who would otherwise require ECT.

The role of subcortical structures in human epilepsy

Like normal cerebral function, epileptic seizures involve widespread network interactions between cortical and subcortical structures. Although the cortex is often emphasized as the site of seizure origin, accumulating evidence points to a crucial role for subcortical structures in behavioral manifestations, propagation, and, in some cases, initiation of epileptic seizures. Extensive previous studies have shown the importance of subcortical structures in animal seizure models, but corresponding human studies have been relatively few. We review the existing evidence supporting the importance of the thalamus, basal ganglia, hypothalamus, cerebellum, and brain stem in human epilepsy. We also propose a “network inhibition hypothesis” through which focal cortical seizures disrupt function in subcortical structures (such as the medial diencephalon and pontomesencephalic reticular formation), leading secondarily to widespread inhibition of nonseizing cortical regions, which may in turn be responsible for behavioral manifestations such as loss of consciousness during complex partial seizures.

Multiple subpial transection in kainic acid-induced focal cortical seizure.

Experimental animal studies on multiple subpial transection (MST) to modify epilepsy have been limited, and its mechanism of therapeutic benefit remains unclear. We examined the effect of MST on the electroencephalogram and cerebral glucose metabolism using a focal cortical epilepsy model in rats. Focal cortical seizures were induced by injecting kainic acid into the left sensorimotor cortex (SMC). Epileptic activity propagated from the focus to neighboring cortex, then to the contralateral SMC. All animals developed right forelimb clonus and/or secondarily generalized convulsions. Sagittal cortical transections on both sides of the focus suppressed the propagation to the ipsilateral hemisphere. However, epileptic activity was not suppressed in the focus and contralateral SMC, and clinical seizures infrequently occurred even following MST. In [14C]2-deoxyglucose autoradiograms, MST did not affect glucose metabolism in naive animals. During focal seizures, MST reduced focal hypermetabolism in the left SMC, although the ipsilateral caudate nucleus, thalamus, and opposite SMC still demonstrated hypermetabolism. These results suggest that MST suppressed focal epileptic activity and its propagation to the neighboring cortical areas. However, clinical seizures were not completely inhibited because vertical interactions between the focus and subcortical areas were preserved. Glucose metabolic changes provided evidence of conserved cortical function following MST.

Kainic Acid-Induced Focal Cortical Seizure Is Associated with an Increase of Synaptophysin Immunoreactivity in the Cortex

Aberrant neural sprouting of mossy fiber terminals in the supragranular layer of dentate gyrus is consistently observed following seizures in an animal model of epilepsy. It is also observed in hippocampi taken from epileptic patients with hippocampal sclerosis. The aberrant neural sprouting with synaptic reorganization is one of the proposed cellular mechanisms underlying epileptogenesis. It is not known whether aberrant synaptogenesis can be induced in the cortex, as in hippocampus, by seizure activity. In this study, synaptic terminals in the cortex were measured after focal cortical seizures by a semiquantitative image analysis of synaptophysin immunoreactivity. Brief intracortical perfusion of kainic acid induced focal status epilepticus and destructive cortical lesions. Synaptophysin immunoreactivity was significantly increased in the area where kainic acid was perfused. The increase of synaptophysin immunoreactivity, indicating an increase of synaptogenesis, was observed at 2 and 4 weeks after focal cortical seizures. This result suggests that kainic acid-induced seizure activity is associated with long-lasting synaptogenesis in the cortex. Studies centering on the physiological consequences of aberrant synaptogenesis may lead to additional understanding of the mechanisms underlying cortical epileptogenesis.