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Penicillin-Induced Interictal Discharges from the Cat Hippocampus. I. Characteristics and Topographical Features
... A common method of modeling epilepsy in animals is to introduce chemoconvulsants to the brain that create an imbalance between inhibitory and excitatory forces in networks of neurons, which is thought to be the basis of most epileptic activity (McCormick and Contreras 2001). Previous studies have shown that chemoconvulsants that locally block inhibition produce consistent epileptiform discharges on the cortex (Chagnac-Amitai and Connors 1989a; Miles et al. 1988), although more complicated responses are seen in tissue farther from the site of application due to competing depolarizing and hyperpolarizing influences in the network (Dichter and Spencer 1969a;Prince and Wilder 1967). These studies are limited, however, by their inability to continuously record from a large area of the brain and capture the spatiotemporal progression from healthy to seizing tissue. ...
... Early studies using GABA antagonists to reduce inhibition showed that large, predominantly negative LFP spikes near the chemoconvulsant (focus) were associated with a mass depolarization of neurons (Dichter and Spencer 1969a;Matsumoto and Marsan 1964;Miles et al. 1984;Prince and Wilder 1967). In the cat primary visual cortex, horizontal connections between regions are predominantly excitatory and mainly synapse on large pyramidal cells in layer V and layers II/III (Schmidt and Lowel 2002). ...
... Positive spiking on the cortical surface outside of the focus has been seen in many similar models, a phenomenon known as "surround inhibition" in which a barrage of synaptic currents from the focus results in strong, recurrent inhibition in nearby tissue where GABA is still active (Dichter and Spencer 1969a;Prince and Wilder 1967;Trevelyan et al. 2007). Studies using high-resolution recordings of seizures in humans posit that local failure of inhibition allows neurons to be recruited into the focus, whereas inhibition in tissue farther from the focus remains intact and plays a role in determining seizure dynamics (Eissa et al. 2017;Schevon et al. 2012). ...
New devices that use targeted electrical stimulation to treat refractory localization-related epilepsy have shown great promise, though it is not well known which targets most effectively prevent the initiation and spread of seizures. To better understand how the brain transitions from healthy to seizing on a local scale, we induced focal epileptiform activity in the visual cortex of five anesthetized cats with local application of the GABAAblocker picrotoxin while simultaneously recording local field potentials on a high-resolution electrocorticography array and laminar depth probes. Epileptiform activity appeared in the form of isolated events, revealing a consistent temporal pattern of ictogenesis across animals with interictal events consistently preceding the appearance of seizures. Based on the number of spikes per event, there was a natural separation between seizures and shorter interictal events. Two distinct spatial regions were seen: an epileptic focus that grew in size as activity progressed, and an inhibitory surround that exhibited a distinct relationship with the focus both on the surface and in the depth of the cortex. Epileptiform activity in the cortical laminae was seen concomitant with activity on the surface. Focus spikes appeared earlier on electrodes deeper in the cortex, suggesting that deep cortical layers may be integral to recruiting healthy tissue into the epileptic network and could be a promising target for interventional devices. Our study may inform more effective therapies to prevent seizure generation and spread in localization-related epilepsies.
... Experiments using these drugs have shown a very consistent response in neocortical and hippocampal preparations: large amplitude, regularly recurring spike-like discharges near the site of application, analogous to interictal spikes, as well as longer epileptiform events or seizures (Prince & Wilder 1967;Dichter & Spencer 1969a;Miles et al. 1988;Chagnac-Amitai & Connors 1989). An early experiment found that in a direct application of penicillin on cat neocortex, the majority of nearby cells exhibited large PDSs during the spike-like discharges, while cells farther away mostly showed hyperpolarization. ...
... However, during longer ictal events, the neurons in the surround stopped exhibiting inhibition and instead showed the typical PDS of those in the epileptogenic focus (Prince & Wilder 1967). Further studies showed not just a focus and surround, but an intermediate zone in which cells exhibited both hyperpolarization and depolarization during the interictal spikes (Dichter & Spencer 1969a). It was posited that during these events penicillin disproportionately increased recurrent excitation in the focus while recurrent inhibition remained strong in the surround, until eventually the more prolonged action of inhibition in the focus overcame and terminated the discharge. ...
... The large repetitive spikes at the beginning of all experiments are a hallmark of seizure models using GABA antagonists, as described in Chapter 2. They have been seen in many different species, in different brain regions, and in both in vivo and slice preparations (Dichter & Spencer 1969a;Dichter & Spencer 1969b;Miles et al. 1988;Prince & Wilder 1967;Chagnac-Amitai & Connors 1989). Studies at a cellular level have shown that the spikes are associated with a mass depolarization of neurons in the focus, caused by the lack of GABA-mediated inhibition. ...
In one-third of epilepsy patients, antiepileptic drugs do not effectively control seizures, leaving resective surgery as the primary treatment option. In the absence of discrete focal lesions, long-term outcome after surgery is modest and often associated with side effects. In many cases, surgery cannot be performed due to the lack of a discrete region generating seizures. For these reasons, new therapeutic technologies have been developed to treat drug-resistant epilepsy with electrical stimulation. These devices are promising, but the efficacy of first-generation implants has been limited. The work in this thesis aims to advance current approaches to seizure monitoring and control by developing better hardware and building the foundational knowledge behind the cortical dynamics underlying seizure generation, propagation and neural stimulation. In this thesis, I first develop new technologies that sample local field potentials on the cortical surface with high spatial and temporal resolutions. These devices capture complex spatiotemporal patterns of epileptiform activity that are not detected on current clinical electrodes. By adding stimulation functionalities to these arrays, we position them as an ideal candidate for responsive, therapeutic neurostimulation. Next, I explore the effect of direct electrical stimulation in the cortex by recording responses with high spatial resolution on the surface and within the cortical laminae. The findings detail the capabilities and limitations of electrical stimulation as a means of modulating seizures. Finally, I use the same three-dimensional recording paradigm in feline neocortex to investigate the genesis and propagation of epileptiform activity in an isolated, chemically-induced epilepsy model. These experiments demonstrate that important circuit elements involved in seizure propagation are found deeper in the cortex and are not reflected in surface recordings. My investigations also present potential stimulation strategies to more effectively disrupt the spread of seizures in the neocortex. It is my hope that the results of this work will inform future technologies to better detect and prevent seizures, ultimately improving the lives of drug-resistant epilepsy patients through the next generation of implantable devices.
... One of the early identified possible roles of inhibition in epileptiform discharges was that of a restraint, or an 'inhibitory surround' that would function to oppose the spread of epileptic activity, thus creating an area of uncorrelated and sparsely propagating activity around the epileptogenic zone (Prince and Wilder, 1967). This phenomenon has been particularly well documented in human patients or drug-induced models of neocortical epilepsy in relation to ictal events (Prince and Wilder, 1967; Dichter and Spencer, 1969a, b; Trevelyan et al., 2006; Trevelyan, 2009; Sabolek et al., 2012; Schevon et al., 2012; Trevelyan and Schevon, 2013). Alternatively, it has been proposed that GABAergic transmission could initiate the synchronization process leading to paroxysmal discharges in the hippocampal formation of patients with drug-resistant TLE (Alvarado-Rojas et al., 2013). ...
... Alternatively, it has been proposed that GABAergic transmission could initiate the synchronization process leading to paroxysmal discharges in the hippocampal formation of patients with drug-resistant TLE (Alvarado-Rojas et al., 2013). Although this debate has yet to be resolved, it is clear that the relation between interictal spiking and single-cell activity depends both on the type of epilepsy and the recording site, and is more heterogeneous than simple paroxysmal depolarization shifts (Prince and Wilder, 1967; Dichter and Spencer, 1969a, b; Trevelyan et al., 2006; Zhou et al., 2007; Trevelyan, 2009; Keller et al., 2010; Truccolo et al., 2011; Sabolek et al., 2012; Schevon et al., 2012; Alvarado-Rojas et al., 2013; Feldt Muldoon et al., 2013; Trevelyan and Schevon, 2013). ...
... We found that during interictal spikes, CA1 inhibition is synchronized, which leads to the quieting of neurons in the pyramidal cell layer. Therefore, we identify a dysfunction of the CA1 feedforward inhibitory microcircuit that potentially acts as an inhibitory brake to the propagation of epileptiform dynamics from the hippocampus to the rest of the brain (Prince and Wilder, 1967; Dichter and Spencer, 1969a, b; Trevelyan et al., 2006; Trevelyan, 2009; Sabolek et al., 2012; Schevon et al., 2012; Trevelyan and Schevon, 2013), and contributes to a functional deafferentation of the subiculum (Cohen et al., 2002; Wozny et al., 2003), even in the absence of hippocampal sclerosis. This finding challenges the intuitive view that epilepsy results from an imbalance of inhibitory and excitatory action in favour of runaway excitation and instead supports earlier work (Prince, 1968; Velazquez and Carlen, 1999; Cohen et al., 2002; Klaassen et al., 2006; Zhou et al., 2007; Marchionni and Maccaferri, 2009; Avoli and de Curtis, 2011; Huberfeld et al., 2011) as well as theoretical predictions (Li et al., 2008) indicating that the GABAergic microcircuits that are spared in the course of epileptogenesis contribute in shaping interictal discharges. ...
Epilepsy is characterized by recurrent seizures and brief, synchronous bursts called interictal spikes that are present in-between seizures and observed as transient events in EEG signals. While GABAergic transmission is known to play an important role in shaping healthy brain activity, the role of inhibition in these pathological epileptic dynamics remains unclear. Examining the microcircuits that participate in interictal spikes is thus an important first step towards addressing this issue, as the function of these transient synchronizations in either promoting or prohibiting seizures is currently under debate. To identify the microcircuits recruited in spontaneous interictal spikes in the absence of any proconvulsive drug or anaesthetic agent, we combine a chronic model of epilepsy with in vivo two-photon calcium imaging and multiunit extracellular recordings to map cellular recruitment within large populations of CA1 neurons in mice free to run on a self-paced treadmill. We show that GABAergic neurons, as opposed to their glutamatergic counterparts, are preferentially recruited during spontaneous interictal activity in the CA1 region of the epileptic mouse hippocampus. Although the specific cellular dynamics of interictal spikes are found to be highly variable, they are consistently associated with the activation of GABAergic neurons, resulting in a perisomatic inhibitory restraint that reduces neuronal spiking in the principal cell layer. Given the role of GABAergic neurons in shaping brain activity during normal cognitive function, their aberrant unbalanced recruitment during these transient events could have important downstream effects with clinical implications.
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... Field burst discharges were observed Haas and Jefferys, 1984 In vitro Rat Hippocampal-entorhinal slices with pilocarpine application Pilocarpine induced two types of ISs Nagao et al., 1996 In Field potentials superimposed by population spikes were found to appear spontaneously Köhling et al., 1998 In vivo Cat Hippocampal penicillin focus model The pyramidal cells in the center of the penicillin focus exhibited large depolarizing potentials followed by long-lasting hyperpolarizations Dichter and Spencer, 1969a In vivo Rat Amygdala kindling model Spontaneous ISs were induced in the awake kindled rat Fitz and McNamara, 1979 In vivo Rat Cortical freeze lesion model ISs were observed in a zone adjacent to microgyria produced by focal cortical freeze lesions Jacobs et al., 1996 In vivo Rat or cat ...
... Dichter and Spencer described the gross characteristics of the penicillin-induced ISs from the cat hippocampus: these surface negative-positive discharges were often >1-2 mV in amplitude, lasted for 200-500 ms, and were usually followed by a hyperpolarization which lasted for 300-2000 ms. (Dichter and Spencer, 1969a). Other studies in various in vivo animal models, such as the kindling procedure (Fitz and McNamara, 1979), cortical freeze-lesion model (Jacobs et al., 1996), cortical metal iron injection model (Willmore et al., 1978), KA chronic model (Cavalheiro et al., 1982), and self-sustaining limbic SE model (Lothman et al., 1990) have also validated the presence of ISs and its all-or-none property. ...
Interictal electroencephalogram (EEG) patterns, including high-frequency oscillations (HFOs), interictal spikes (ISs), and slow wave activities (SWAs), are defined as specific oscillations between seizure events. These interictal oscillations reflect specific dynamic changes in network excitability and play various roles in epilepsy. In this review, we briefly describe the electrographic characteristics of HFOs, ISs, and SWAs in the interictal state, and discuss the underlying cellular and network mechanisms. We also summarize representative evidence from experimental and clinical epilepsy to address their critical roles in ictogenesis and epileptogenesis, indicating their potential as electrophysiological biomarkers of epilepsy. Importantly, we put forwards some perspectives for further research in the field.
... Історія дослідження епілепсії показує, що іноді теоретична досконалість моделі йде всупереч експериментальної придатності, це накладає певні обмеження та вимагає обережності при остаточному виборі моделі для застосування. Хоча дослідники епілепсії широко використовували собак, нелюдських приматів і особливо котів [24,25] до 1980-х років, щури та миші з набутими формами епілепсії стали, безумовно, найпоширенішими представниками лабораторних тварин для тваринних моделей. Широке та історичне використання гризунів часто робить їх типовими тваринами для епілептичних експериментів. ...
Епілепсії охоплюють широкий спектр клінічних, поведінкових і електрофізіологічних проявів та відноситься до числа найбільш динамічних захворювань в неврології. Класичний підхід стверджує, що раптові судоми є характерною ознакою епілепсії, але сучасне технологічне обладнання дозволило встановити циклічні ознаки при безпосередньому запису електричної діяльності головного мозку. Вкрай широке розповсюдження та великі економічні збитки, що наносить епілепсія, а також втрата працездатності та інвалідізація пацієнтів викликали потребу у ретельному дослідженні цієї патології. Відповідно, для вивчення цього захворювання на тваринах був запропонований широкий спектр тваринних моделей, тобто гострих і хронічних протоколи індукції судом. Дослідження епілепсії мають довгу історію порівняльних досліджень анатомічних структур та фізіологічних показників у різних видів ссавців. Однак, лише порівняно обмежена кількість моделей епілепсії, переважно з застосуванням гризунів, отримала розповсюдження у більшості експериментальних досліджень. У багатьох випадках вказані тваринні моделі були обрані або за зручність, або завдяки звичності, але у кожному окремому випадку саме дослідник повинен обирати кінцевий варіант моделі епілепсії керуючись технічним чи експериментальним обґрунтуванням. Наразі у якості експериментальних тварин почали використовувати Danio rerio (Даніо-реріо), рибу родини Cyprinidae (карпових), її значно простіший за своєю будовою та фізіологією мозок, у порівнянні з ссавцями, дозволяє отримати значні переваги при експериментальних дослідженнях. У роботі наданий аналіз сучасного стану методології дослідження епілептичних станів на різних тваринних моделях. Розглянуті недоліки та переваги окремих найбільш поширених моделей, проведене порівняння моделей між собою.
... Hyperexcitation in normal brain tissues can also be achieved by pharmacologically downregulating neurotransmitter-or voltage-gated ion channels inhibiting neuronal activity, such as GABA-A receptors or potassium channels [100,101], or by enhancing neurotransmitteror voltage-gated ion channels that excite neuronal activity, such as glutamate receptors or sodium channels [102]. For instance, blocking GABA A receptor-mediated inhibition by administering GABA A receptor antagonists (bicuculline, picrotoxin or penicillin) could induce epileptiform discharges in cortical regions both in vivo [100,103,104] and in vitro [105][106][107]. Contrarily, these epileptic effects can be reversed by increasing synaptic inhibition [108] or decreasing excitation [109]. ...
Normal development and function of the central nervous system involves a balance between excitatory and inhibitory neurotransmission. Activity of both excitatory and inhibitory neurons is modulated by inhibitory signalling of the GABAergic and glycinergic systems. Mechanisms that regulate formation, maturation, refinement, and maintenance of inhibitory synapses are established in early life. Deviations from ideal excitatory and inhibitory balance, such as down-regulated inhibition, are linked with many neurological diseases, including epilepsy, schizophrenia, anxiety, and autism spectrum disorders. In the mammalian forebrain, GABA is the primary inhibitory neurotransmitter, binding to GABA receptors, opening chloride channels and hyperpolarizing the cell. We review the involvement of down-regulated inhibitory signalling in neurological disorders, possible mechanisms for disease progression, and targets for therapeutic intervention. We conclude that transgenic models of disrupted inhibitory signalling—in GAD67+/− and VGAT−/− mice—are useful for investigating the effects of down-regulated inhibitory signalling in a range of neurological diseases.
... Since 1950, the gold standard for localizing the onset of epileptic seizure has been the electroencephalogram (EEG) signals [7]. Localized abnormal discharges or changes in EEG frequency indicate the onset of attacks [8], [9]. While there are many EEG-based seizure detection algorithms in the literature, only a few are used in the clinical setting-where the recommendation is to have less than 1 false alarm (FA) per 24 hours (hrs) and more than 75% sensitivity [10] for nonpatient specific seizure detection. ...
Background
Electroencephalogram (EEG) monitoring and objective seizure identification is an essential clinical investigation for some patients with epilepsy. Accurate annotation is done through a time-consuming process by EEG specialists. Computer-assisted systems for seizure detection currently lack extensive clinical utility due to retrospective, patient-specific, and/or irreproducible studies that result in low sensitivity or high false positives in clinical tests. We aim to significantly reduce the time and resources on data annotation by demonstrating a continental generalization of seizure detection that balances sensitivity and specificity.
Methods
This is a prospective inference test of artificial intelligence on nearly 14,590 hours of adult EEG data from patients with epilepsy between 2011 and 2019 in a hospital in Sydney, Australia. The inference set includes patients with different types and frequencies of seizures across a wide range of ages and EEG recording hours. The artificial intelligence (AI) is a convolutional long short-term memory network that is trained on a USA-based dataset. The Australian set is about 16 times larger than the US training dataset with very long interictal periods (between seizures), which is way more realistic than the training set and makes our false positives highly reliable. We validated our inference model in an AI-assisted mode with a human expert arbiter and a result review panel of expert neurologists and EEG specialists on 66 sessions to demonstrate achievement of the same performance with over an order-of-magnitude reduction in time.
Findings
Our inference on 1,006 EEG recording sessions on the Australian dataset achieved 76.68% with nearly 56 [0, 115] false alarms per 24 hours on average, against legacy ground-truth annotations by human experts, conducted independently over nine years. Our pilot test of 66 sessions with a human arbiter, and reviewed ground truth by a panel of experts, confirmed an identical human performance of 92.19% with an AI-assisted system, while the time requirements reduce significantly from 90 to 7.62 minutes on average.
Interpretation
Accurate and objective seizure counting is an important factor in epilepsy. An AI-assisted system can help improve efficiency and accuracy alongside human experts, particularly in low and middle-income countries with limited expert human resources.
Fundings
SOAR Fellowship from The University of Sydney, a Microsoft AI for Accessibility grant, and a Research Training Program (RTP) support provided by the Australian Government.
Research in context
Evidence before this study
During the development of our artificial intelligence (AI) system, we did a systematic review of the scientific literature with search via PubMed for research articles published on seizure detection with the following inclusion criteria: (1) Tests or inference evaluation is conducted on large-scale clinical EEG data; (2) Generalization is attempted or potentials for generalization is considered, e.g., in commercialized tools; (3) Seizure detection delay and real-time (aka. online) operation were not considered critical in this context as long as the test was conducted on raw EEG data. Note that ICU seizure detection or portable seizure alert systems are relying on detection delay and real-time needs. Our keywords include “prospective seizure detection”, “automated seizure detection”, “non-patient specific seizure detection”, “seizure detection on continuous EEG”, and “deep learning-based seizure detection” and “machine learning-based seizure detection”. We found that the only two categories of works meet our criteria: two research papers published in 2020 and works published by commercial tools developers. We cited a recent review of 89 deep learning-based seizure detection, all of which are retrospective. One work from Stanford reported seizure detection on all ages (pediatric to adult ages) using post-acquisition EEG recordings and provided an avenue for independent evaluation by providing a test on a publicly available Temple University Hospital (TUH) EEG dataset. The other work pivoted on algorithmic-assisted real-time seizure risk monitoring in continuous EEG in neonatal intensive care unit (NICU) with 128 neonates (32 with seizures) showing about 20% improvement in seizure identification over 130 neonates (38 with seizures) with no algorithmic assistance.
Commercial tools we studied are Encevis (EpiScan), Besa, and Persyst. There is a recent comparative study on these tools on 81 patients. Encevis is reported as the best performing tool, and hence we provided a comparative study with Encevis ver. 1.9.2. Encevis is also the only tool that provided an avenue for comparative study on publicly available EEG data. The Stanford work, published in 2020, confirms many false positives with Persyst 13. We excluded our tests on Persyst 14 as it highly under-performed relative to Encevis. Only Stanford’s work provides code availability. We compared our results with Stanford’s work outcome and provided pilot test results with the Encevis (EpiScan) tool on the Australian dataset, which shows a considerably lower sensitivity.
Added value of this study
To the best of our knowledge, the current study is the first continental generalization that demonstrates the potential to achieve an expert human-level seizure recognition rate in a clinical setting and in just a fraction of time. The two datasets used in this study are recorded with different infrastructure, which adds to the independence of inference from hardware types and improves clinical utility. This is particularly important as 80% of patients with epilepsy live in low and middle-income countries with limited resources, particularly EEG specialists and neurologists.
Implications of all the available evidence
Our results support the potential benefits of deep learning AI in clinical settings for seizure recognition and its contribution to significant sensitivity over available solutions. Our AI-assisted system achieves more than a ten-fold increase in time efficiency and reports identical performance to human experts for EEG interpretation with access to great neurophysiology support and auxiliary data. Our findings, particularly our tests on an available commercial tool, recommend that the evaluation, test, or inference in AI systems be performed on different datasets, with diverse infrastructures, and on large-scale and realistic sets with long interictal periods.
... The waveform of an IED reflects the summation of the signals of multiple synapses and neurons generating it: thus, IEDs can provide insight into the basic mechanism of epilepsy. For example, research has shown that the initial sharp-wave in IEDs corresponds to the synchronization of excitatory postsynaptic potentials (EPSPs), whereas the subsequent slow-afterwave corresponds to inhibitory silence of action potentials [4][5][6][7][8]. The sharp-wave can be preceded by a low-voltage, positive polarity component (a positive pre-potential), corresponding to EPSP synchronization over deep cortical laminae [9]. ...
Purpose:
In between seizures, the brain of a patient with epilepsy will generate isolated, sporadic discharges (interictal epileptiform discharges [IEDs]). IED identification enables clinicians to diagnose epilepsy, and an understanding of IED waveforms may yield new insights into basic epilepsy mechanisms. I show that intracranial EEGs disclose a previously unreported negative polarity, low-voltage pre-potential at IED onset (i.e., a negative wave [n-wave]). I describe the features of n-waves and propose a plausible mechanism of their generation.
Method:
In intracranial EEGs of the human neocortex, I assessed n-waves' occurrence, anatomical location, amplitude, kinetics, and association with the subsequent positive pre-potential. I computed a model simulation of IED onset to identify plausible mechanisms behind n-wave generation.
Results:
N-waves manifested in 40% of patients, in zones with and without seizures, and without a statistically significant prevalence in their anatomical location. These waveforms exhibited voltages of 140+42 μV and durations of 39.9+12.2 msec and were coupled with a positive pre-potential. In simulations of IED onset, n-waves can be generated by sequential recruitment of distinct microfoci over superficial cortical laminae.
Conclusions:
N-waves represent an overlooked component of IED waveforms. They prolong the duration of IED onset and can facilitate synaptic hypersynchrony. They may also be associated with chronic epilepsy.
... This was also accompanied by a small and brain-region-specific increase of neuronal synchrony between nearby neurons. Consistent with previous reports (Dichter and Spencer, 1969;Paz and Huguenard, 2015;Prince and Wilder, 1967;Trevelyan et al., 2007), we observed that this enhanced preictal neuronal activity and synchrony was mainly confined to inhibitory-neuron rich brain regions, where inhibitory surround broke down upon exposure to the GABA A antagonistic proconvulsant PTZ. Interestingly, among the five major brain regions that we monitored, the optic tectum and the cerebellum were the most prominent brain regions to show significant alterations during the preictal period, followed by the thalamus and the brainstem. ...
Brain activity and connectivity alters drastically during epileptic seizures. Throughout this transition, brain networks shift from a balanced resting state to a hyperactive and hypersynchronous state, spreading across the brain. It is however less clear which mechanisms underlie these state transitions. By studying neuronal and glia activity across the zebrafish brain, we observed striking differences between these networks. During the preictal period, neurons displayed a small increase in synchronous activity only locally, while the entire glial network was highly active and strongly synchronized across large distances. We observed that the transition from a preictal state to a generalized seizure leads to an abrupt increase in neuronal activity and connectivity, which is accompanied by a strong functional coupling between glial and neuronal networks. Optogenetic activation of glia induced strong and transient burst of neuronal activity, emphasizing a potential role for glia-neuron connections in the generalization of epileptic seizures.
... Numerous reports suggest the activity of GABAergic interneurons regulates seizure-like activity (Dichter & Spencer, 1969;Prince & Wong, 1981;Schwartz & Bonhoeffer, 2001;Trevelyan et al. 2006Trevelyan et al. , 2007bTrevelyan, 2009). The period immediately before ictal events can be characterized by an increased interneuron firing that reaches its peak at ictal onset, while the activity of principal cells does not change until after initiation (Ziburkus et al. 2006;Lévesque et al. 2016). ...
Key points:
The medial entorhinal cortex (mEC) has an important role in initiation and propagation of seizure activity. Several anatomical relationships exist in neurophysiological properties of mEC neurons; however, in the context of hyperexcitability, previous studies often considered it as a homogeneous structure. Using multi-site extracellular recording techniques, ictal-like activity was observed along the dorso-ventral axis of the mEC in vitro in response to various ictogenic stimuli. This originated predominantly from ventral areas, spreading to dorsal mEC with a surprisingly slow velocity. Modulation of inhibitory tone was capable of changing the slope of ictal initiation, suggesting seizure propagation behaviours are highly dependent on levels of GABAergic function in this region. A distinct disinhibition model also showed, in the absence of inhibition, a prevalence for interictal-like initiation in ventral mEC, reflecting the intrinsic differences in mEC neurons. These findings suggest the ventral mEC is more prone to hyperexcitable discharge than the dorsal mEC, which may be relevant under pathological conditions.
Abstract:
The medial entorhinal cortex (mEC) has an important role in the generation and propagation of seizure activity. The organization of the mEC is such that a number of dorso-ventral relationships exist in neurophysiological properties of neurons. These range from intrinsic and synaptic properties to density of inhibitory connectivity. We examined the influence of these gradients on generation and propagation of epileptiform activity in the mEC. Using a 16-shank silicon probe array to record along the dorso-ventral axis of the mEC in vitro, we found 4-aminopyridine application produces ictal-like activity originating predominantly in ventral areas. This activity spreads to dorsal mEC at a surprisingly slow velocity (138 μm s-1 ), while cross-site interictal-like activity appeared relatively synchronous. We propose that ictal propagation is constrained by differential levels of GABAergic control since increasing (diazepam) or decreasing (Ro19-4603) GABAA receptor activation, respectively, reduced or increased the slope of ictal initiation. The observation that ictal activity is predominately generated in ventral mEC was replicated using a separate 0-Mg2+ model of epileptiform activity in vitro. By using a distinct disinhibition model (co-application of kainate and picrotoxin) we show that additional physiological features (for example intrinsic properties of mEC neurons) still produce a prevalence for interictal-like initiation in ventral mEC. These findings suggest that the ventral mEC is more likely to initiate hyperexcitable discharges than the dorsal mEC, and that seizure propagation is highly dependent on levels of GABAergic expression across the mEC.
... 67,68 This evidence was later corroborated by experiments aimed at identifying the cellular and pharmacological mechanisms underlying epileptiform synchronization. First, it was shown that drugs capable of inducing focal interictal-like discharges preparations in vivo 69,70 and in vitro 71 were GABA A receptor antagonists, and that the occurrence of this type of epileptiform activity was characterized by reduction in recurrent and/or feed-forward inhibition. 72,73 Second, it was reported that the onset of electrographic seizures induced by repetitive activation of hippocampal inputs are associated with rapid fading of IPSPs. ...
This review centers on the discoveries made during more than six decades of neuroscience research on the role of gamma-amino-butyric acid (GABA) as neurotransmitter. In doing so, special emphasis is directed to the significant involvement of Canadian scientists in these advances. Starting with the early studies that established GABA as an inhibitory neurotransmitter at central synapses, we summarize the results pointing at the GABA receptor as a drug target as well as more recent evidence showing that GABA
A
receptor signaling plays a surprisingly active role in neuronal network synchronization, both during development and in the adult brain. Finally, we briefly address the involvement of GABA in neurological conditions that encompass epileptic disorders and mental retardation.
RESUMÉ: Le chemin long et sinueux pour que le GABA soit reconnu comme un neurotransmetteur.
Cette revue est axée sur les découvertes réalisées durant plus de six décennies de recherche en neurosciences sur l’acide gamma-aminobutyrique (GABA) comme neurotransmetteur. À cet effet, nous mettons une emphase particulière sur le rôle significatif de chercheurs canadiens dans ce domaine de recherche. En prenant comme point de départ les premières études qui ont établi que le GABA était un neurotransmetteur au niveau de synapses centrales, nous faisons le sommaire des résultats identifiant le récepteur GABA comme étant une cible thérapeutique ainsi que des données plus récentes montrant que la signalisation du récepteur GABAA joue, de façon surprenante, un rôle actif dans la synchronisation du réseau neuronal, tant au cours du développement que dans le cerveau adulte. Finalement, nous traitons brièvement du rôle de GABA dans les maladies neurologiques incluant les troubles épileptiques et l’arriération mentale.
... We previously proposed the terms 'ictal core territory' and 'ictal penumbra' to distinguish between two qualitatively different activity patterns during seizures (Schevon et al., 2012; Trevelyan and Schevon, 2013; Weiss et al., 2015). These concepts arose from a large body of animal studies describing epileptiform activity in terms of localized, intense, hypersynchronous discharges (ictal core), with many neurons displaying PDSs (Kandel and Spencer, 1961a; Matsumoto and Marsan, 1964; Traub and Wong, 1982), associated with a marked inhibitory response in surrounding territories (penumbra) (Prince and Wilder, 1967; Dichter and Spencer, 1969a, b; Wong and Prince, 1990; Schwartz and Bonhoeffer, 2001; Timofeev et al., 2002; Timofeev and Steriade, 2004; Suner et al., 2005; Trevelyan et al., 2006, 2007; Cammarota et al., 2013), which appears to restrain the propagation of the focal pathophysiology. Note however , that even in the penumbra, there is typically increased firing over baseline activity levels (Schevon et al., 2012). ...
Spike-sorting algorithms have been used to identify the firing patterns of isolated neurons ('single units') from implanted electrode recordings in patients undergoing assessment for epilepsy surgery, but we do not know their potential for providing helpful clinical information. It is important therefore to characterize both the stability of these recordings and also their context. A critical consideration is where the units are located with respect to the focus of the pathology. Recent analyses of neuronal spiking activity, recorded over extended spatial areas using microelectrode arrays, have demonstrated the importance of considering seizure activity in terms of two distinct spatial territories: the ictal core and penumbral territories. The pathological information in these two areas, however, is likely to be very different. We investigated, therefore, whether units could be followed reliably over prolonged periods of times in these two areas, including during seizure epochs. We isolated unit recordings from several hundred neurons from four patients undergoing video-telemetry monitoring for surgical evaluation of focal neocortical epilepsies. Unit stability could last in excess of 40 h, and across multiple seizures. A key finding was that in the penumbra, spike stereotypy was maintained even during the seizure. There was a net tendency towards increased penumbral firing during the seizure, although only a minority of units (10-20%) showed significant changes over the baseline period, and notably, these also included neurons showing significant reductions in firing. In contrast, within the ictal core territories, regions characterized by intense hypersynchronous multi-unit firing, our spike sorting algorithms failed as the units were incorporated into the seizure activity. No spike sorting was possible from that moment until the end of the seizure, but recovery of the spike shape was rapid following seizure termination: some units reappeared within tens of seconds of the end of the seizure, and over 80% reappeared within 3 min (τrecov = 104 ± 22 s). The recovery of the mean firing rate was close to pre-ictal levels also within this time frame, suggesting that the more protracted post-ictal state cannot be explained by persistent cellular neurophysiological dysfunction in either the penumbral or the core territories. These studies lay the foundation for future investigations of how these recordings may inform clinical practice.
© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.
... Overall, no coherent relationship has been found between seizure and interictal spike occurrence. For instance, pioneering animal studies on acute seizures induced by topical application of proepileptic agents, such as penicillin, to the cortex suggested that the transition to seizure is characterized by acceleration of interictal spikes (Dichter and Spencer 1969;Ayala et al. 1973). Similar findings were also reproduced in acute, drug-induced seizures in in vitro models (Chamberlin et al. 1990). ...
The neurophysiological patterns that correlate with partial (focal) seizures are well defined in humans by standard electroencephalogram (EEG) and presurgical depth electrode recordings. Seizure patterns with similar features are reproduced in animal models of partial seizures and epilepsy. However, the network determinants that support interictal spikes, as well as the initiation, progression, and termination of seizures, are still elusive. Recent findings show that inhibitory networks are prominently involved at the onset of these seizures, and that extracellular changes in potassium contribute to initiate and sustain seizure progression. The end of a partial seizure correlates with an increase in network synchronization, which possibly involves both excitatory and inhibitory mechanisms.
Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
... Feed-forward inhibition can also be relevant to intra-areal cortical excitation. It is largely responsible for surround inhibition, which was documented decades ago in pioneering studies of acute neocortical or hippocampal seizures in felines 41,42 . Recently, both feed- forward and surround inhibition have been investigated with optical and electrophysiological methods to study the spread of seizures from a focal zone that initiates epileptic seizures-the "ictogenic" zone. ...
Epileptic seizures represent dysfunctional neural networks dominated by excessive and/or hypersynchronous activity. Recent progress in the field has outlined two concepts regarding mechanisms of seizure generation, or ictogenesis. First, all seizures, even those associated with what have historically been thought of as 'primary generalized' epilepsies, appear to originate in local microcircuits and then propagate from that initial ictogenic zone. Second, seizures propagate through cerebral networks and engage microcircuits in distal nodes, a process that can be weakened or even interrupted by suppressing activity in such nodes. We describe various microcircuit motifs, with a special emphasis on one that has been broadly implicated in several epilepsies: feed-forward inhibition. Furthermore, we discuss how, in the dynamic network in which seizures propagate, focusing on circuit 'choke points' remote from the initiation site might be as important as that of the initial dysfunction, the seizure 'focus'.
This chapter describes a patient with pharmacoresistant non-lesional focal epilepsy who underwent partial precuneus resection and multiple subpial transections due to the overlap of the ictal onset node with functional motor cortex. We discuss various techniques for multiple subpial transections, their indications, and outcomes. We also present the contemporary alternatives to multiple subpial transections (i.e., neuromodulation). We analyze ictal semiologies such as paresthesias, grasping, the Jacksonian march, and focal motor (tonic, clonic, myoclonic) seizures. We shed light on post-ictal Todd’s paresis and pre-ictal premonitory symptoms (prodromes) that are distinct from focal aware seizures (auras). Finally, we discuss the etiologies of cerebellar hypometabolism as well as the factors that contribute to global cerebral atrophy.
In this chapter we shall argue for a notion that will strike many as paradoxical, even absurd: we shall argue that neuronal circuitry allowing conscious perception to occur will, by its very nature, also allow for the possibility of epilepsy – not necessarily all the time but certainly after various perturbations.
Electroencephalogram (EEG) monitoring and objective seizure identification is an essential clinical investigation for some patients with epilepsy. Accurate annotation is done through a time-consuming process by EEG specialists. Computer-assisted systems for seizure detection currently lack extensive clinical utility due to the retrospective, patient-specific, and/or irreproducible studies that result in low sensitivity or high false positives in clinical tests. We aim to significantly reduce the time and resources on data annotation by demonstrating a continental generalization of seizure detection that balances sensitivity and specificity. This is a prospective inference test of artificial intelligence on nearly 14,590 h of adult EEG data from patients with epilepsy between 2011 and 2019 in a hospital in Sydney, Australia. The inference set includes patients with different types and frequencies of seizures across a wide range of ages and EEG recording hours. Artificial intelligence (AI) is a convolutional long short-term memory network that is trained on a USA-based dataset. The Australian set is about 16 times larger than the US training dataset with very long interictal periods (between seizures), which is way more realistic than the training set and makes our false positives highly reliable. We validated our inference model in an AI-assisted mode with a human expert arbiter and a result review panel of expert neurologists and EEG specialists on 66 sessions to demonstrate achievement of the same performance with over an order-of-magnitude reduction in time. Our inference on 1,006 EEG recording sessions on the Australian dataset achieved 76.68% with nearly 56 [0, 115] false alarms per 24 h on average, against legacy ground-truth annotations by human experts, conducted independently over nine years. Our pilot test of 66 sessions with a human arbiter, and reviewed ground truth by a panel of experts, confirmed an identical human performance of 92.19% with an AI-assisted system, while the time requirements reduced significantly from 90 to 7.62 min on average. Accurate and objective seizure counting is an important factor in epilepsy. An AI-assisted system can help improve efficiency and accuracy alongside human experts, particularly in low and middle-income countries with limited expert human resources.
Epilepsy is not one disorder but many diverse syndromes with one common element: seizures. Therefore, a description of epilepsy actually addresses the epilepsies. Notably, there are many disorders of the central nervous system other than epilepsy where seizures occur, either transiently or as a comorbid condition. Therefore, the impact of seizures and epilepsy is broad and easy to underestimate. Here a clinical overview is provided, followed by a summary of the current understanding of neurobiological mechanisms. In addition, treatment is addressed, emphasizing antiepileptic drugs, which are the first line of therapy for individuals with epilepsy.
Neurons and glial cells are endowed with membranes that express a rich repertoire of ion channels, transporters, and receptors. The constant flux of ions across the neuronal and glial membranes results in voltage fluctuations that can be recorded from the extracellular matrix. The high frequency components of this voltage signal contain information about the spiking activity, reflecting the output from the neurons surrounding the recording location. The low frequency components of the signal, referred to as the local field potential (LFP), have been traditionally thought to provide information about the synaptic inputs that impinge on the large dendritic trees of various neurons. In this review, we discuss recent computational and experimental studies pointing to a critical role of several active dendritic mechanisms that can influence the genesis and the location-dependent spectro-temporal dynamics of LFPs, spanning different brain regions. We strongly emphasize the need to account for the several fast and slow dendritic events and associated active mechanisms –– including gradients in their expression profiles, inter- and intra-cellular spatio-temporal interactions spanning neurons and glia, heterogeneities and degeneracy across scales, neuromodulatory influences, and activity-dependent plasticity — towards gaining important insights about the origins of LFP under different behavioral states in health and disease. We provide simple but essential guidelines on how to model LFPs taking into account these dendritic mechanisms, with detailed methodology on how to account for various heterogeneities and electrophysiological properties of neurons and synapses while studying LFPs.
The objectives of this theses were (i) to determine the kinetics of carbamazepine (CBZ), a well established antiepileptic drug and levetiracetam, a new antiepileptic drug presently undergoing clinical evaluation in a freely behaving rat model, (ii) to test the efficacy of these drugs on electrographic seizures in animals injected with tetanus toxin, and to determine the relationship between their efficacy and their corresponding concentrations in blood and cerebrospinal fluid (CSF), and finally (iii) to evaluate the antiepileptic properties of levetiracetam on bicuculline induced epileptiform bursts in the hippocampal slice. The first objective entailed the development of a freely behaving rat model which allowed concurrent blood and CSF sampling and consequently pharmacokinetic characteristics of a drug over a relatively chronic period (7 days). Under anaesthesia a cisterna magna catheter, for CSF sampling, a jugular vein catheter, for blood sampling, and an intraperitoneal osmotic minipump set to deliver CBZ or levetiracetam were implanted. CSF and blood samples were collected on days 1, 2, 4, 6 and 7 post-surgery at timed intervals and analysed for CBZ and carbamazepine epoxide (CBZ-E; the primary pharmacological active metabolite of CBZ) or levetiracetam content by high performance liquid chromatography. The serum and CSF concentration versus time profiles of CBZ and CBZ-E, exhibited biphasic characteristics; the first phase involved rapid appearance of CBZ and CBZ-E in blood and CSF compartments followed by a gradual increase until maximum concentrations were achieved. During the second phase, CBZ exhibited a marked acceleration in its metabolism (autoinduction), as indicated by a dramatic reduction and a subsequent gradual decline in both CBZ and CBZ-E blood and CSF concentrations. However, in contrast to CBZ, chronic levetiracetam administration was not associated with autoinduction. Following its acute and chronic administration, levetiracetam appeared in blood and CSF compartments and thereafter concentrations rose linearly until maximum concentrations were achieved. The second objective related to the efficacy of CBZ and levetiracetam in the in vivo tetanus toxin model of epilepsy. Under anaesthesia, tetanus toxin was injected, and a bipolar electrode placed in the hippocampus. Initial EEG recordings began 1-2 days post-surgery and continued for 5-7 days. A minipump with CBZ/levetiracetam was then implanted intraperitoneally and continuous EEG and video recordings were undertaken for a further 7 days. The animals developed a chronic limbic epilepsy, characterized by the occurrence of spontaneous interictal spikes, polyspikes, nongeneralised and generalised seizures. Both CBZ and levetiracetam exhibited efficacy in this model, involving a reduction in the maximum number of seizures occurring per day and a reduction in the total number of generalised seizures over the period analysed. However, a statistically significant result was only achieved following administration of the highest dose of levetiracetam (16 mg/kg/h; p=0.0004). Furthermore, at all doses studied a significant reduction in the duration of generalised seizures was observed following administration of CBZ (p<0.0001) and levetiracetam (p<0.0001). The final objective related to the efficacy of levetiracetam in an in vitro hippocampal slice model of epileptiform activity. Hippocampal slices were made epileptic via bath application of bicuculline and raised extracellular potassium. This activity took the form of trains of population bursts with a distinctive biphasic pattern lasting several seconds. Levetiracetam (200 and 400 μmol/1) significantly (p<0.0001) reduced the overall duration of these seizure-like events without influencing the biphasic pattern. In conclusion this thesis demonstrates that CBZ and levetiracetam possess different kinetic characteristics. Whilst CBZ exhibited complex and undesirable kinetics, levetiracetams were simple and predictable. Additionally, although CBZ and levetiracetam significantly reduced seizure generalisation in vivo, a statistically significant reduction was only achieved with the highest levetiracetam dose studied. Levetiracetam also appeared to attenuate the prolonged ictalform discharges in the disinhibited in vitro slice. Overall, these findings suggest that whereas levetiracetam does not effect epileptogenesis per se it does reduce seizure severity and, particularly, seizure generalisation in vivo in predominantly disinhibitory models.
Human epilepsies encompass a wide variety of clinical, behavioral and electrical manifestations. Correspondingly, studies of this disease in nonhuman animals have brought forward an equally wide array of animal models, i.e. species and acute or chronic seizure induction protocols. Epilepsy research has a long history of comparative anatomical and physiological studies on a range of mostly mammalian species. Nonetheless, a relatively limited number of rodent models emerged as the primary choices for most epilepsy-related investigations. In many cases these animal models are selected based on convenience or tradition, though technical or experimental rationale does, and should, factor into these decisions. More complex mammalian brains and, especially, genetic model organisms including zebrafish have been studied less but offer significant advantages that are being widely recognized.
Objective:
This study looks for differences in the waveforms of interictal epileptiform discharges (IEDs) between cortices expressing only isolated discharges (green-spikes zones) vs those manifesting seizures (red-spikes zones): these can help to understand ictogenesis mechanisms and improve clinical decision in surgical epilepsy. Typical IEDs are triphasic, exhibiting in sequence: a negative-sharp-wave, a positive-baseline-shift and a negative-slow-wave. Negative-slow-waves are thought to reflect neurophysiological inhibition: their features at a focus' edge may reflect peripheral inhibition, a mechanism characterized in experimental models, curbing seizures' spread. This might be weakened in red-spikes.
Methods:
A retrospective review of human intracranial EEGs was performed, comparing green- and red-spikes for their peripheral slow-waves' amplitudes. Green- and red-spikes were also compared also for the amplitudes of their negative-sharp-waves and positive-baseline-shifts, as well as for their spread pathways.
Results:
Green-spikes exhibit more pronounced peripheral slow-waves than red-spikes. They also exhibit more pronounced positive-baseline-shifts, and more frequent propagation pathways' shifts.
Conclusions:
Peripheral slow-waves' amplitudes correlate with seizures' suppression and may reflect neurophysiological peripheral inhibition.
Significance:
This study suggests a novel approach to reading intracranial EEGs: amplitudes measures of IEDs waveforms are technically simple, may help identifying epileptogenic zones and indicate the spatial distribution of underlying ictogenesis mechanisms.
The synchronized activity of neuronal networks under physiological conditions is mirrored by specific oscillatory patterns of the EEG that are associated with different behavioral states and cognitive functions. Excessive synchronization can however lead to focal epileptiform activity characterized by interictal and ictal discharges in epileptic patients and animal models. This review focusses on studies that have addressed epileptiform synchronization in temporal lobe regions by employing in vitro and in vivo recording techniques. First, we consider the role of ionotropic and metabotropic excitatory glutamatergic transmission in seizure generation as well as the paradoxical role of GABAA signaling in initiating and perhaps maintaining focal seizure activity. Second, we address non-synaptic mechanisms (which include voltage-gated ionic currents and gap junctions) in the generation of epileptiform synchronization. For each mechanism, we discuss the action of anti-epileptic drugs that are presumably modulating excitatory or inhibitory signaling and voltage-gated currents to prevent seizures in epileptic patients. These findings provide insights into the mechanisms of seizure initiation and maintenance thus leading to the development of specific pharmacological treatments for focal epileptic disorders.
The inhibitory restraint necessary to suppress aberrant activity can fail when inhibitory neurons cease to generate action potentials as they enter depolarization block. We investigate possible bifurcation structures that arise at the onset of seizure-like activity resulting from depolarization block in inhibitory neurons. Networks of conductance-based excitatory and inhibitory neurons are simulated to characterize different types of transitions to the seizure state, and a mean field model is developed to verify the generality of the observed phenomena of excitatory-inhibitory dynamics. Specifically, the inhibitory population's activation function in the Wilson-Cowan model is modified to be non-monotonic to reflect that inhibitory neurons enter depolarization block given strong input. We find that a physiological state and a seizure state can coexist, where the seizure state is characterized by high excitatory and low inhibitory firing rate. Bifurcation analysis of the mean field model reveals that a transition to the seizure state may occur via a saddle-node bifurcation or a homoclinic bifurcation. We explain the hysteresis observed in network simulations using these two bifurcation types. We also demonstrate that extracellular potassium concentration affects the depolarization block threshold; the consequent changes in bifurcation structure enable the network to produce the tonic to clonic phase transition observed in biological epileptic networks.
electrodes into the hippocampus. The properties of these spikes were studied in the chronic experiment. Furthermore, the electrical activities of the hippocampus and the behavior of the animal were studied in the rabbit in which the theta-input to the hippocampus was partially or totally removed. And the following results were obtained.
1) In either a relaxed or a drowsy state, the EEG spikes appeared in both hippocampi. Very often the EEG spike in one of the hippocampi appeared in synchrony with that in the other. The amplitude and the duration of the EEG spike were 0.5.2mV and 100.300msec, respectively.
2) EEG spikes were depressed when the theta activity was enhanced. It was demonstrated that the depression was due to the changes in the intrinsic hippocampal activities, and not due to the enhancement of the theta activity itself.
3) When the septum was totally destroyed, the hippocampus showed a low voltage fast wave which was further accentuated by sensory stimulations.
4) When the septum was destroyed unilaterally, both hippocampi exhibited the theta activity.
5) As compared with normal animals, those having lesions in the septum or the entorhinal cortex more easily developed seizure discharges. Furthermore the duration of these discharges was longer than that in normal animals.
6) The behavior of the animal without the theta activity following the total destruction of the septum did not show any alteration in the daily life except for a hypersensitivity to sensory stimulations.
Evidence indicates that there are multiple sites in the hippocampal pyramidal cell dendrites which are capable of producing spikes. The multiple spikes generated there summate and form an excessive, prolonged depolarization known as the inactivation response (IR). Despite the fact that the IR consists of multiple components, the IR behaves in all-or-nothing fashion. This is explained as follows. Namely, in the dendrites there is a portion which is of low threshold for spike generation (the dendritic trigger zone) whereas the other portions in the dendrites are of high threshold. The spike of the dendritic trigger zone triggers spikes in the high threshold portions of the dendrites, resulting in the IR. Since the spike in the trigger zone is produced in all-or-nothing fashion, the IR thereby triggered is of necessity triggered in all-or-nothing fashion.
It is known that the spike originating in the somatic trigger zone conducts along the axon therewith carrying the informations arising within the cell onto the target cell. This is called the first carrier system for the sake of convenience. On the other hand, the IR is thought to produce a spike burst down in the axon while inactivating the soma spikes. A corollary from this is that once the IR is produced, the burst discharge thereby set up in the axon becomes the only means through which the informations are carried to the next cell. Consequently, the IR-triggered information carrying system is called the second carrier system, in contradistinction to the first carrier system mentioned above. Evidently then, the neuron with well developed dendrites has two independent systems for carrying informations to its target cell. It should be noted that although the second carrier system originates in the dendrites, not only the axo-dendritic input, but also the axo-somatic input can put this system into operation as evidenced by generation of the IR by current injection into the cell body. On the other hand, both inputs are also capable of activating the first carrier system, provided that the IR is not produced. In the second carrier system the informations are translated into the changes of the discharge pattern of the IR-triggered burst while in the first carrier system they are expressed as those of the discharge pattern of the single spike of the somatic trigger zone. A possibility has been pointed out that the parameters of the IR-triggered burst, i. e., the carrier of the second carrier system, are altered through a process leading to a plastic change.
The changes in the electrophysiological properties of the dendrites during seizure, including kindled seizure, have been discussed, especially from the viewpoint of plasticity.
When a dose of actinomycin D was intrathecally injected into higher animals (dogs and cats), these animals experienced generalized seizures after a latent period of several days.
The critical seizure producing quantity was 0.025mg on the dog. Actinomycin D combines with DNA in the nervous tissue of the brain, this may be the cause of the seizure effect.
When the same dose (0.025mg) of actinomycinic acid, which has a chemical structure resembling that of actinomycin D, but does not combine with DNA in the tissue, was injected into the cerebro-spinal fluid of the dog, the animals did not show any behavioural change.
Electroencephalographic studies of the actinomycin D seizure were carried out on the cat. Several days after the administration of actinomycin D, the animal showed the typical generalized seizure discharges. A generalized seizure discharge induced by actinomycin D began with the occurrence of frequent spikes in group in all of recording sites, then the repetition of a spike and wave complex or a polyspike and wave complex followed. The intervals of each spike and wave complex gradually grew longer, and the seizure discharge stopped.
After the actinomycin D administration, the electroencephalogram sometimes showed remarkable spike discharges occurring in the hippocampal region. They occurred mostly in hippocampus, but to a lesser degree spike discharges occurred in the other regions.
In the preconvulsive state after the actinomycin D administration, regular waves of 8 cps occasionally appeared simultaneously with the occurrence of myoclonic jerks.
In the case of the injection of actinomycinic acid into the cat, no significant change occurred on the electroencephalogram.
However, the injection of DNA into the cerebrospinal fluid, simultaneously performed, with the injection of actinomycin D, did not stop the seizure effect of the latter.
Methionine sulfoximine, characterized by a seizure effect with a long latent period, was also injected into the cerebro-spinal fluid of the dog. The critical seizure producing quantity was 0.18mg. These two convulsants with long latent period, the actinomycin D and the methionine sulfoximine, did not produce seizure effects when combined in different proportions.
Three butyric acid derivatives (GABA, GABOB and S-GABA) did not arrest the actinomycin D seizure effect.
In this chapter, we shall review what is known about the cellular mechanisms of epileptic events in vitro. Our main concern is to understand the electrical events that neurons generate during a fit, and to understand what kinds of interactions (synaptic and nonsynaptic) between neurons underlie the fit. We further seek to comprehend which intrinsic properties of neurons are required for epilepsy or that at least facilitate epileptogenesis. Our method consists of making experimental observations of seizure phenomena in the hippocampal slice, attempting to reproduce the observations with simulation models on a large computer, and testing the models with further experiments. We shall emphasize underlying mechanisms that are as independent as possible of physiological and pharmacological details. This provides a clear conceptual framework in which to interpret diverse experiments. Such an approach is necessary because epilepsy involves understanding the behavior of a population of neurons. Our work has lead to models that illuminate the underlying mechanisms of two types of epileptic events: interictal spikes and tonic seizures.
Impairment of inhibitory synaptic mechanisms plays an important role in epileptogenesis. Epileptiform activity can be elicited by drugs that decrease GABA-mediated inhibition (such as bicuculline and penicillin) and can be suppressed by topical application of GABA. The effectiveness of some widely used antiepileptic drugs such as sodium valproate, benzodiazepines and barbiturates has been related to their GABA-ergic activity. Sodium valproate increases brain GABA content by inhibiting its metabolic conversion to succinate. Benzodiazepines bind to specific membrane receptors and displace an endogenous protein which inhibits GABA activity. These observations have improved the understanding of basic epileptogenic mechanisms and have promoted the development of new antiepileptic drugs. The anticonvulsant effects in experimental models and in man of some new compounds that inhibit GABA-transaminase (γ-acetylenic GABA and γ-vinyl GABA) or act as GABA-receptors agonists (LS-76002) look particularly promising. Brain monoamines have also been implicated in the pathophysiology of epilepsy. Chemical or mechanical lesions of serotonin-containing raphe neurons have been reported to enhance the occurrence and magnitude of seizures induced by different experimental procedures, while electrical stimulation of raphe nuclei significantly increases the threshold for seizures induced by amigdaloid kindling. These effects might be related to the inhibition exerted by ascending and descending serotonergic pathways on their targets. However, a comprehensive review of experimental and clinical studies failed to show a well-defined relationship between serotonin and epilepsy. At present the serotonergic system seems to be implicated only in very special cases of epileptiform phenomena (e.g. myoclonus), in which serotonin precursors have shown a beneficial effect in both experimental models and humans.
Its aim is to impair the capacity of cortical tissue to generate sufficient neuronal synchrony to produce epileptiform discharges, without interfering with its capability to mediate normal physiologic
transactions. (Frank Morrell 1989; Figure
161-1
)
The hippocampus is part of the limbic system. It represents the most simple of the cortical regions and is comprised of several, strip-like cortical elements, adjoining each other. The overall position of the hippocampus in the rodent brain is indicated in Fig. 1A. Here, the outline of the hippocampus is drawn superimposed on the lateral aspect of the brain. In rodents, it has a relatively large volume. On ascending the phylogenetic scale its relative size decreases. The absolute volume increases, however, and is highest in man and whales. Dorsally and anteriorally it borders the septal region whereas the amygdala nuclear complex is found anterior :and medial to its temporal pole. Along its caudal border lies the entorhinal area which is part of the hippocampal gyrus.
Investigation into the physiological properties of central nervous system (CNS) neurons and the pharmacological actions of clinically important drugs on the CNS have progressed in parallel over the past two decades. The suggestion that most interneuronal communication is mediated by release of chemical neurotransmitters (Krnjevic, 1974) has stimulated research into all aspects of synaptic transmission including regulation of synthesis and release of neurotransmitter from presynaptic terminals, properties of pre- and postsynaptic neurotransmitter receptors, properties of neurotransmitter-coupled ionic channels, and neuroanatomical distribution of specific neurotransmitters.
Understanding the mechanisms which underlie the transition between interictal and ictal activity is one of the most critical issues in the study of epilepsy. In all forms of epilepsy, the electrical activity in most parts of the brain is normal most of the time. A seizure occurs when neurons in many parts of the brain, including those parts which are normal, develop synchronized activity. In primary generalized epilepsy, the transition between interictal and ictal activity occurs abruptly and without obvious behavioral or electrophysiological warning. In focal epilepsy, the transition appears to occur first in a focal area of abnormality and then spreads to both adjacent and distant areas of normal brain. The phenomena which occur at the cellular level during such transitions have not been well characterized in either the human epilepsies or in most animal models of epilepsy, and therefore relatively few hypotheses have been developed to explain the transition to seizure.
It is over a century since Fritsch and Hitzig, Ferrier, and Jackson laid down the experimental and clinical basis for functional localization in persons both with and without seizure disorders, and it is over 50 years since Foerster, Penfield, and their collaborators began applying these insights systematically to the surgical treatment of intractable seizures.
There is perhaps more information available today regarding the properties of hippocampal pyramidal cells than of any other CNS cell type except the spinal cord motoneuron. The hippocampus, with the associated dentate granule cell region, has been studied intensively with electrophysiological techniques. The reasons for such interest and study are several, ranging from the technical accessibility of hippocampal neurons to their hypothesized role in learning and memory (see Isaacson and Pribram, 1975; Swanson et al. 1982; Seifert, 1983).
Most of what is known about the microphysiology and biophysics of synaptic transmission has derived from the study of just three preparations: the vertebrate and arthropod neuromuscular junctions and the squid giant synapse (Katz, 1969; Martin, 1977; Takeuchi, 1977). Although the general facts and laws gleaned from these three classical preparations probably apply also to cortical synapses, this inference remains an article of faith. Furthermore, there are structural and functional specializations in the cortex that cannot readily be addressed in the three classical preparations.
It is well established that seizure activity of the cerebral cortex is accompanied by slow potential changes which have been labelled as “steady” or “DC” potential shifts. With generalized seizure discharges or direct recordings from an active focus, these potential deviations are usually surface-negative in polarity and finally turn over to a positive deflection which corresponds to the post-ictal silent period (for references see O’Leary and Goldring 1964, Caspers and Speckmann 1969, Gumnit
et al. 1970).
Human epilepsies encompass a wide variety of clinical, behavioral and electrical manifestations. Correspondingly, studies of this disease in nonhuman animals have brought forward an equally wide array of animal models; that is, species and acute or chronic seizure induction protocols. Epilepsy research has a long history of comparative anatomical and physiological studies on a range of mostly mammalian species. Nonetheless, a relatively limited number of rodent models have emerged as the primary choices for most investigations. In many cases, these animal models are selected on the basis of convenience or tradition, although technical or experimental rationale does, and should, factor into these decisions. More complex mammalian brains and genetic model organisms including zebrafish have been studied less, but offer substantial advantages that are becoming widely recognized.
Objective
Experimental epilepsy foci are surrounded by an enhanced inhibition zone. We looked for evidence of peripheral inhibition in human epilepsy foci by analyzing the waveforms of discharges. The sharp-wave of an epileptic discharge is thought to reflect EPSP synchronization, and the subsequent slow-wave to reflect inhibition. Ratios of amplitudes of the sharp- and slow-waves in human EEGs may show how excitatory and inhibitory processes relate to discharge spread implicating peripheral inhibition in human epilepsy, too.
Method
In electrocorticography from 10 adult patients we compared amplitudes of sharp-waves and of slow-waves and their ratios in each electrodes as a function of their distance from the highest sharp-wave electrode.
Results
Sharp-wave amplitude decreases as a function of electrode distance from the highest sharp-wave electrode, but the slow-wave voltage exhibits a slight increase. The ratio slow-wave/sharp-wave increases several-fold within 2-3 centimeters from the highest sharp-wave electrode.
Conclusion
In human cortex epileptic discharges at the periphery of a focus exhibit a prevalent slow-wave consistent with a possible local enhanced inhibition.
Significance
Waveform analysis of electrocorticography epileptic discharges suggests the presence in human neocortex of surround inhibition, a basic mechanism limiting the spread of epileptic activity, long studied in experimental models.
The present study on rats and cats aimed to clarify the role played by hypoxia, hypercapnia and acidosis in spontaneous arrest of seizures.
In most experiments cortical pO 2 declined during seizure activity, whereas pCO 2 increased. Occasionally, however, reverse reactions occurred. Since the increase in cortical blood flow varied over a wide range, it could account for the fact that gas tension did not always change in the same direction or to the same degree during a seizure. Cessation of seizure activity was independent of the degree and direction of the changes in gas tension.
When seizures were arrested by experimentally produced hypoxia, cortical and spinal neurons always showed a distinct depolarization. When convulsive discharges were suppressed by artificial increase in PCO 2 most units were concomitantly hyperpolarized.
When seizures ceased spontaneously, both cortical and spinal neurons showed a steep re‐ and hyperpolarization, independent of concomitant fluctuations in local gas tension.
The findings lead to the conclusion that the degree of hypoxia and hypercapnia usually encountered during prolonged seizure activity does not reach the critical level sufficient to depress seizure activity. It must be assumed that spontaneous seizure termination is based, primarily, on neuronal processes.
RESUME
Cette étude se propose de préciser, chez les rats et les chats, le rôle de l'hypoxie, de l'hypercapnie et de l'acidose dans l'arrêt des crises spontanées.
Dans la majorité des expériences, Ia pO 2 au niveau cortical diminue pendant la crise, tandis que la pCO 2 augmente, quoique occasionnellement, on ait observé le contraire.
La très grande variabilité de l'augmentation de la circulation sanguine cérébrale pouvait rendre compte du fait que pendant une crise, la tension des gaz ne changeait pas toujours dans le même sens ou dans les mêmes limites. L'arrêt de la crise était indépendant du degré et du type des modifications de la tension des gaz.
Lorsque les crises étaient arrêtées à la suite d'une anoxie provoquée expérimentalement, on a toujours observé une dépolarisation des neurones corticaux spinaux.
Lorsque les décharges convulsives étaient supprimées par une augmentation artificielle de la pCO 2 , la majorité des neurones était parallèlement hyperpolarisée.
Lorsque les crises s'arrêtaient spontanément, les neurones du cortex et de la moelle montraient une rapide repolarisation et ensuite une hyperpolarisation indépendamment des fluctuations concomitantes de la tension des gaz.
Ces données amènent à la conclusion que le degré d'hypoxie et d'hypercapnie qu'on observe habituellement pendant des crises prolongées n'atteint pas un niveau suffisant pour déprimer l'activité paroxystique.
On doit en tirer la conclusion que l'arrêt spontané d'une crise est dûà des processus nerveux.
Although there is a great multiplicity of normal brain electrical activities, one can observe defined, relatively abrupt, transitions between apparently normal rhythms and clearly abnormal, higher amplitude, "epileptic" signals; transitions occur over tens of ms to many seconds. Transitional activity typically consists of low-amplitude very fast oscillations (VFO). Examination of this VFO provides insight into system parameters that differentiate the "normal" from the "epileptic." Remarkably, VFO in vitro is generated by principal neuron gap junctions, and occurs readily when chemical synapses are suppressed, tissue pH is elevated, and [Ca(2+)]o is low. Because VFO originates in principal cell axons that fire at high frequencies, excitatory synapses may experience short-term plasticity. If the latter takes the form of potentiation of recurrent synapses on principal cells, and depression of these on inhibitory interneurons, then the stage is set for synchronized bursting - if [Ca(2+)]o recovers sufficiently. Our hypothesis can be tested (in part) in patients, once it is possible to measure brain tissue parameters (pH, [Ca(2+)]o) simultaneously with ECoG.
The chapter focuses on seizure prediction for clinical applications that has expanded into a field dedicated to understanding seizure generation. Seizure prediction is an important aim of clinical management and treatment, in the absence of completely controlling a patient's epilepsy. One of the strongest motivations for seizure prediction research is its potential for driving a therapeutic device. The chapter explores two potential methods of implementing an implantable antiepileptic device based on seizure prediction. The exact way in which a practical seizure prediction device might be employed will depend on algorithm performance and the results of ongoing research into delivering responsive therapy. It is not clear how intervention will be controlled by seizure prediction algorithms, as algorithm performance will be the primary determinant of this implementation. Several strategies have been suggested, one of them, therapeutic intervention, will escalate as the probability of seizure onset increases over time and another strategy that has been suggested models developing seizures as a critical system, similar to avalanches and volcanoes. With the advent of new brain sensors, stimulation technologies, and the availability of large data sets of continuous EEG recordings for collaborative research, the progress toward understanding seizure generation and preventing its occurrence is accelerating.
Résumé
(1)Une technique d'enregistrement juxtacellulaire, chez le chat respirant spontanément et non anesthésié, est décrite.(2)Les activités cellulaires des neurones relais thalamo-corticaux du corps genouillé latéral (GL) ont été analysées pendant la stimulation électrique répétitive du cortex visuel homotopique et la post-décharge épileptique (PDE) qui suit.(3)La zone de projection, dans le GL, de la PDE est très limitée: seuls, 30% de 47 neurones testés ont été activés.(4)La stimulation à 50 c/sec s'accompagne d'une facilitation de la transmission cortico-thalamique. Celle-ci est mise en évidence par la suppression des IPSP, qui font normalement suite au potentiel d'action (PA) antidromique, et leur remplacement par des PA répétitifs.(5)Pendant les ondes corticales de la PDE, des bouffées de PA à haute fréquence sont enregistrées dans les axones cortico-thalamiques. Cette période s'accompagne, dans les neurones relais, de dépolarisations rythmiques prolongées (50 à 300 msec), associées à une inactivation temporaire du générateur de PA. Des dépolarisations inactivantes similaires sont également enregistrées pendant le sommeil paradoxal.(6)Pendant les silences séparant les bouffées paroxystiques, la transmission synaptique des influx afférents du tractus optique est facilitée.(7)L'origine orthodromique des PA, pendant la PDE, a été vérifiée par des tests de collision.
1.
Connections of FD with area CA3 are organized topically. In response to stimulation of FD a focus of maximal activity is found in area CA3 and it is displaced by 0.7–1.0 mm rostrally to the point of stimulation of FD, which corresponds to the oblique course of the mossy fibers. The focus of activity is bounded on both sides by zones with predominantly inhibitory responses of CA3 neurons to stimulation of FD; in more remote parts responses are absent.
2.
Neurons of area CA3 lying in the zone of activity where they give gradually potentiated responses to stimulation of FD become areactive to sensory stimuli. Outside this zone normal reactivity to sensory stimuli is preserved.
3.
During electrical stimulation of FD in conjunction with the action of sensory stimuli responses of area CA3 cells to electrical stimuli may be considerably changed (strengthened or depressed).
4.
Suggestions are made regarding the role of impulses arriving from FD in the processes of extinction of sensory responses of neurons in hippocampal area CA3.
A comparative analysis was made of the functional characteristics of connections between hippocampal areas CA3 and CA1 (Schaffer's collaterals) in experiments in vivo on unanesthetized rabbits and in vitro on surviving slices of guinea pig hippocampus, with extracellular recording in area CA1. In the case of electrical stimulation of the collaterals in vitro, post-activational inhibition was weak, responses of inhibition of spontaneous discharges were absent, and low frequencies of stimulation were more effective than in vivo. Posttetanic changes were found more frequently in experiments in vitro and they lasted longer than in vivo. The predominant effect of tetanization under normal conditions was depression, but during incubation it was facilitation of responses. The possible causes of these differences are discussed.
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