Laminar analysis of spindles and of spikes of the spike and wave discharge of feline generalized penicillin epilepsy

doi:10.1016/0013-4694(82)90101-8

Electroencephalography and Clinical Neurophysiology

Volume 53, Issue 1, January 1982, Pages 1-13

https://doi.org/10.1016/0013-4694(82)90101-8 Get rights and content

Abstract

Intracortical laminar profiles of spindles and spikes of spike and wave complexes in feline generalized penicillin epilepsy were studied using two methods: (i) sequential microelectrode recordings at various cortical depths, and (ii) simultaneous recordings at multiple cortical depths using a fine multicontact electrode. Raw EEG data and EEG epochs averaged with respect to peaks of surface EEG waves were analyzed. Spindles and the spikes of the spike and wave complexes showed similar laminar profiles. This supports the hypothesis that the two are basically the same cortical electrophysiological phenomenon, the spike being a spindle wave enhanced and slightly altered because of the penicillin-induced increased cortical excitability. The latter causes the weight of the thalamic input to shift from superficial to more deep lying synapses. Both surface negative and surface positive phases of spindles and of spikes of spike and wave complexes show similar laminar profiles, those of the former suggesting activation of excitatory synapses in the superficial cortical layers, those of the latter suggesting activation of more deeply located excitatory synapses. The profiles generally conform to the dipole hypothesis of cortical electrogenesis and suggest that spindles and spikes of spike and wave complexes are generated by the same pyramidal neurons, probably through activation of the same sets of synapses. Some inconstant and relatively minor deviations of the laminar profiles from the pattern predicted by the dipole theory of cortical electrogenesis were encountered and are tentatively explained in the light of some of the complexities of the microanatomical organization of mammalian neocortex.

Résumé

Les auteurs étudient les profils intra-corticaux laminaires des fuseaux et des pointes des complexes pointe-ondes dans l'épilepsie généralisée à la pénicilline chez le chat à l'aide de deux méthodes: (i) enrigistrement séquentiel par micro-électrodes à différentes profondeurs du cortex, et (ii) enregistrement simultané à de multiples profondeurs corticales au moyen d'une électrode fine à contacts multiples. Les données EEG brutes et les époques EEG moyennes sont analysées par rapport aux pics des ondes EEG de surface. Les fuseaux et les pointes des complexes pointe-ondes montrent des profils laminaires semblables. Ceci est en faveur de l'hypothèse suivant laquelle ces deux phénomènes constituent fondamentalement un même phénomène électro-physiologique cortical, la pointe étant une onde l'un fuseau agrandie et légèrement déformée du fait de l'accroissement de l'excitabilité corticale induite par la pénicilline. Ceci fait que le poids de l'afférence thalamique varie des synapses superficielles aux synapses plus profondes. Les phases surface négatives et surface positives des fuseaux et des pointes des complexes pointe-ondes montrent des profils laminaires semblables, celles des phases négatives soulevant l'hypothèse d'une activation des synapses excitatrices dans les couches corticales superficielles, celles des phases positives soulevant l'hypothèse d'une activation des synapses excitatrices localisées plus profondément. Ces profils sont dans l'ensemble conformes à l'hypothèse d'un dipole à l'origine de l'électrogénèse corticale et suggèrent que les fuseaux et les pointes des complexes pointe-ondes prennent leur origine dans les mêmes neurones pyramidaux, probablement au travers d'une activation des mêmes réseaux de synapses. Quelques déviations inconstantes et relativement mineures par rapport aux profils laminaires du pattern prédit par la théorie du dipole de l'électrogénèse corticale se rencontrent et sont provisoirement expliquées à la lumière de certaines des complexités de l'organisation microanatomique de néo-cortex des mammifères.

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Absence seizures associated with bilaterally synchronized 3 Hz spike-and-wave discharges (SWDs) are prevalent in a form of genetic generalized epilepsy (Berg et al., 2010), referred to as childhood absence epilepsy (CAE). Early studies questioned based on the feline generalized penicillin epilepsy animal model whether SWDs are focal at onset or generalized and whether their origin is cortical or thalamic (e.g. Avoli and Gloor, 1982; Kostopoulos et al., 1982). Later studies in genetic rat models of CAE, provided experimental evidence that implicated a cortical onset zone in the deep layers of the somatosensory cortex followed by cortico-thalamo-cortical network interactions to maintain the SWDs (Meeren et al., 2002; Polack et al., 2007; Lüttjohann and van Luijtelaar, 2015).
Our objective was to unravel the dynamics underlying spike-and-wave discharges (SWDs) characteristic for childhood absence epilepsy.
SWDs were recorded for a cohort of 28 children using magnetoencephalography. Non-linear association analyses and a graph theoretical metric of local connectedness (LoC) were utilized in a sliding window starting one s before till four s after ictal onset.
A focal pattern of bilateral frontal and parietal areas with high LoC during the spikes alternated by generalized patterns during the waves was found for all children studied during generalization of the SWDs. In the interval preceding the generalization a focal parietal region was most often (16/28) encountered and less often an occipital (4/28), temporal (5/28) or frontal (3/28) region. 55% of the children with a parietal/occipital focal onset became seizure free after the administration of two anti-epileptic drugs, and only 12.5% with a temporal/frontal focal onset.
The transition from the interictal to the ictal state is for some of the children characterized by dominant LoC at either the parietal/occipital and for others at the frontal/temporal region.
The focal onset of the SWDs varies in location among the children with a clinical similar profile, who, however, seemingly are differing with regard to seizure control.
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As the exhausted excitatory pyramidal neurons and inhibitory interneurons recover gradually, the net effect is from the subtraction of two opposite activities: ADs are sustained and evolved or ADs are terminated. Both polyspikes and spike-waves have an intermittent slow wave component, which represents the long phase of membrane repolarization followed by hyperpolarization (Kandel and Spencer, 1961; Kostopoulos et al., 1982; Sugaya et al., 1964). Thus, ADs will be more likely to terminate automatically in polyspikes and spike-waves.
To investigate the properties of afterdischarges (ADs) from intracerebral electrical stimulation (ES) in patients with epilepsy who underwent stereotactic electroencephalography (SEEG) and determine the relationship between epileptogenic zone (EZ) or irritative zone (IZ) and ADs.
We retrospectively analyzed 10 patients with intractable epilepsy who underwent SEEG. ESs were delivered following the given parameters: bipolar, biphasic, 50 Hz, 0.2 ms pulse duration, 0.5–10 mA. The properties of ADs were documented, including their incidence, location, threshold, morphology and evolution.
A total of 213 ADs (5%) were elicited by 4701 trains of ES. Stimulation through contacts implanted in the hippocampus (59%) generally evoked more ADs than contacts elsewhere (19%). AD thresholds for hippocampal stimulation were significantly lower than those for stimulation in grey matter. Polyspikes (58%) were the most common AD morphology. Evolution occurred more commonly with sequential spikes (47%) than with other AD morphologies (14%). There was no significant correlation between the location of ADs and EZ. However, ADs were significantly more frequently localized to IZ than areas outside IZ (P < 0.05).
There seemed to be a lack of correlation between the location of ADs and EZ. However, ADs were more likely to be elicited in IZ.
Pharmacologically Induced Animal Models of Absence Seizures
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Understanding absence seizures demands complementary research approaches using diverse animal models, including ones induced by a variety of chemical agents. The characteristics, induction methods, and validation criteria met by several animal models are reviewed, along with a critical comparison of their advantages, limitations, and main contributions to epileptology. The distinction between typical and atypical absence seizures (TAS and AAS) in humans is considered in the respective animal analogs. Emphasis is given to the TAS models produced acutely by systemic administration of γ-hydroxybutyrate (GHB) in the rat, and penicillin in the cat (FGPE), while the validation of other TAS models is considered less complete. Among their contributions to epileptology, GHB first showed the importance of GABA_B receptors and tonic inhibition on neurons and glia, while the FGPE first established the current generators and corticothalamic circuit pacing of generalized 3 Hz spike-and-wave discharges. The lifelong occurrence of absences in rats after prepubertal injection of AY-9944 is presented as a chronic model of AAS, allowing experimentation of the limbic involvement, the cognitive impairment, and the worse outcome characterizing the AAS, compared to TAS.
Benign rolandic and occipital epilepsies of childhood
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An increase of the age-related, area-specific cortical excitability has been hypothesized to be at the basis of the origin of BECTS.31,47,48 This increased excitability of the cortex is able to transform the thalamic volley that normally induces sleep spindles in a mechanism inducing epileptic discharges, as shown in animals49,50 and in humans.51 Due to the age-related regional hyperexcitability, the cortex could react with spikes to the thalamocortical volleys that generate spindles, even in physiologic conditions in predisposed children.
Reduced NREM sleep instability in benign childhood epilepsy with centro-temporal spikes
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An increase of the age-related, area-specific cortical excitability has been hypothesized to be at the basis of the origin of BERS (Ferri et al., 2000; Guerrini et al., 1997; Tassinari et al., 1988). This increased excitability of the cortex is able to transform the thalamic volley that normally induces sleep spindles in a mechanism inducing epileptiform discharges, as shown in animals (Kostopoulos et al., 1982; Steriade and Amzica, 1994) and in humans (Kellaway et al., 1980; Kellaway, 1985). Due to the age-related regional hyperexcitability, the cortex could react with spikes to the thalamocortical volleys that generate spindles in physiological conditions in predisposed children.
To analyze sleep architecture and NREM sleep instability by means of the cyclic alternating pattern (CAP) in children with benign epilepsy with rolandic spikes (BERS).
Ten children with BERS, drug free at the time of the study and 10 age-matched normal controls were included in this study. Sleep was visually scored for sleep architecture and CAP using standard criteria.
Sleep architecture in BERS showed only few significant differences vs. controls with a reduction of total sleep time, sleep efficiency, and REM sleep percentage. CAP analysis revealed several significant differences: reduced total CAP rate, mainly in sleep stage 2, and reduced EEG slow oscillations and arousals during stages N1 and N2.
Sleep architecture is not importantly affected in BERS but CAP analysis reveals a decrease of NREM instability, mainly in sleep stage 2. Since there is a spindle-related spike activation in BERS, we speculate that the decrease of CAP and of EEG slow oscillations and arousals might be linked with the inhibitory action of spindling activity and spikes on arousals.
CAP analysis discloses sleep structure abnormalities in children with BERS not shown by the classical sleep scoring. Spike activity and CAP A1 subtypes seem to be mutually exclusive probably because centro-temporal spikes disturb the physiological synchronization mechanisms needed for the generation of slow-wave components of CAP.
Global and focal aspects of absence epilepsy: The contribution of genetic models
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The cortico-reticular theory of absence epilepsy explains the origin of the bilateral generalized spike-wave discharges (SWDs) characterizing absence seizures via a subcortical pacemaker that is responsible for both normal sleep spindles and pathological SWDs. This pacemaker is the reticular thalamic nucleus (RTN); it produces spontaneous oscillations together with thalamic relay cells and the cortex in an assembled thalamo-cortico-thalamic network. Recently, Meeren et al. [2002. Cortical focus drives widespread corticothalamic networks during spontaneous absence seizures in rats. Journal of Neuroscience 22, 1480–1495.] proposed a focal theory of absence epilepsy based on experimental findings in the WAG/Rij rat, a genetic model of absence epilepsy: the somatosensory cortex contains a focus that initiates a cascade of events that ultimately leads to the occurrence of the bilateral and generalized SWDs if the state of the thalamo-cortical circuitry is favorable.
Pharmacological, neurochemical, and neurophysiological data are presented and reviewed here that suggest SWDs might emerge from spontaneous oscillating neurons in the somatosensory cortex during both wakefulness and drowsiness. There is evidence for a variety of neurobiological changes, including a deficient global (parvalbumin) and local GABA-ergic (neurophysiological) system in the neocortex, which may explain why specifically the perioral region of the somatosensory cortex is hyperexcitable and the initiation site of 10 Hz oscillations. The neuronal cortical and subcortical circuitry that produces SWDs is part of a large oscillatory system involved in generating cerebral rhythms associated with vibrissal movements.
It needs to be established whether similar or comparable pathophysiological processes are also present in humans. Our hypothesis can be readily tested in other models and in humans considering that it is very specific and can be subjected to experimental verification.

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^☆: This work was supported by Grant MT-3140 awarded by the Medical Research Council of Canada to Dr. P. Gloor.

²: Dr. G. Kostopoulos is an MRC Scholar.

^∗: We thank to Mrs. Schiller and Mr. E. Puodziunas for technical assistance, Miss G. Robillard and Mrs. K. Douglas for secretarial assistance and Dr. R. Dykes for his helpful comments in preparing this paper.

³: Dr. M. Avoli was a NATO Fellow.

⁴: Dr. Andrea Pellegrini's present address is: Clinica Neurologica dell'Università, via Giustiani 1, 35100 Padova, Italy.

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Laminar analysis of spindles and of spikes of the spike and wave discharge of feline generalized penicillin epilepsyAnalyse laminaire des fuseaux et des pointes des décharges de pointe-ondes dans l'épilepsie généralisée à la pénicilline chez le chat☆

Abstract

Résumé

Electroenceph. clin. Neurophysiol.

Electroenceph. clin. Neurophysiol.

Electroenceph. clin. Neurophysiol.

Exp. Neurol.

Electroenceph. clin. Neurophysiol.

Electroenceph. clin. Neurophysiol.

Electroenceph. clin. Neurophysiol.

Brain Res.

Electroenceph. clin. Neurophysiol.

Electroenceph. clin. Neurophysiol.

Exp. Neurol.

Exp. Neurol.

Electroenceph. clin. Neurophysiol.