Spike-and-wave oscillations

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Alain Destexhe (2007), Scholarpedia, 2(2):1402. doi:10.4249/scholarpedia.1402 revision #91799 [link to/cite this article]
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Curator: Alain Destexhe

Figure 1: Human electroencephalogram (EEG) recording of an absence seizure consisting of slow (about 3 Hz) oscillations with spike-and-wave patterns. The EEG was taken from a 24-hour recording of a 10 year-old child with no treatment (original data from Destexhe, 1992).

The term spike-and-wave refers to a pattern of the electroencephalogram (EEG) typically observed during epileptic seizures. In particular, one of the most common type of epileptic manifestations, the absence seizure (also called "petit mal"), displays a clear-cut oscillation consisting of generalized and bilaterally synchronous spike-and-wave EEG patterns recurring at a frequency of about 3 Hz in humans (see Figure 1). The mechanisms underlying the genesis of such spike-and-wave seizures is the subject of this article.


Experimental models of generalized spike-and-wave seizures

Absence seizures with spike-and-wave patterns typically occur during childhood in a small proportion of human subjects, and in many instances, this type of epilepsy disappears with adolescence. Very similar seizures have been observed in a number of animal models. Cats treated with penicillin (either parenteral, see Prince and Farrell, 1969, or directly applied to the brain) or with convulsant drugs such as bicuculline, can develop absence-type of epileptic seizures, characterized by very similar EEG patterns as in human absence (see below). Some genetically-selected strains of rats (such as the Wag-Rij or GAERS) also show spontaneous seizures with spike-and-wave patterns occurring at a faster frequency (around 5-10 Hz) compared to cats and humans. In these experimental models, the behavioral correlates (the "absence") and the responsiveness to medications are also very similar to human absence.

Figure 2: Local field potential (LFP) recordings of spike-and-wave seizures in cats. A. Position of 6 bipolar recording electrodes in parietal cortex. B. Spindle oscillations obtained in control conditions (barbiturate anesthesia). C. "Thalamocortical" seizure obtained after infusion of bicuculline to cerebral cortex. D. "Intracortical" seizure obtained in another experiment following a similar protocol as in C, but after ablation of the thalamus (modified from Destexhe et al., 2001; original data from Steriade and Contreras, 1998).

The main advantage of experimental models is that a number of electrophysiological and pharmacological investigations can be performed, with the aim of better understanding the disease and design better therapies. A large body of literature exists for the electrophysiological correlates of spike-and-wave seizures, and in particular the first intracellular recordings (Pollen, 1964) revealed that the "spike" component is invariably associated with neuronal firing, while the "wave" is associated with a hyperpolarization of neurons, suggesting an active role of inhibition. However, no neurons were observed to selectively fire during the "wave", which remained a mystery for many years.

In the last decades, experimental models led to tremendous progress towards identifying the brain structures involved in absence seizures, and their cellular correlates. A large body of experimental results point to critical role for the thalamus in absence seizure generation:

  1. Spike-and-wave seizures disappear following thalamic lesions or by inactivating the thalamus (Pellegrini et al., 1979; Avoli and Gloor, 1981; Vergnes and Marescaux, 1992).
  2. Cortical and thalamic cells fire prolonged discharges in phase with the "spike" component, while the "wave" is characterized by a silence in all cell types (Pollen, 1964; Steriade, 1974; Fisher and Prince, 1977b; Avoli et al., 1983; McLachlan et al., 1984; Buzsaki et al., 1988; Inoue et al., 1993; McCormick and Hashemiyoon, 1998; Seidenbecher et al., 1998; Staak and Pape, 2001).
  3. Spindle oscillations, which are generated by thalamic circuits (Steriade et al., 1993; 2003), can be gradually transformed into spike-and-wave discharges and all manipulations that promote or antagonize spindles have the same effect on spike-and-wave seizures (Kostopoulos et al., 1981a, 1981b; McLachlan et al., 1984).
  4. Knock-out mice lacking the gene for the T-type calcium current in thalamic relay cells display a resistance to absence seizures (Kim et al., 2001), which clearly demonstrates that the thalamus, and in particular the T-type current mediated bursting of thalamic cells, are involved in this type of seizure activity.

Although these experiments would suggest a thalamic site for the genesis of seizures, experimental models also show that the cortex plays a critical role:

  1. Thalamic injections of high doses of GABAA antagonists, such as penicillin (Ralston and Ajmone-Marsan, 1956; Gloor et al., 1977) or bicuculline (Steriade and Contreras, 1998) led to 3-4 Hz oscillations with no sign of spike-and-wave discharge.
  2. Injection of the same drugs to the cortex, with no change in the thalamus, resulted in seizure activity with spike-and-wave patterns (Fisher and Prince, 1977a; Gloor et al., 1977; Steriade and Contreras, 1998).
  3. The threshold for epileptogenesis was much lower in the cortex compared to the thalamus (Steriade and Contreras, 1998).
  4. Diffuse application of a dilute solution of penicillin to the cortex resulted in spike-and-wave seizures although the thalamus was intact (Gloor et al., 1977).
  5. An important proportion of thalamic neurons are steadily hyperpolarized and completely silent during cortical seizures with spike-and-wave patterns (Steriade and Contreras, 1995; Lytton et al., 1997; Pinault et al., 1998).
  6. A form of spike-and-wave activity can be observed in cortex following thalamic inactivation or thalamectomy (Marcus and Watson, 1966; Pellegrini et al., 1979; Steriade and Contreras, 1998).

Taken together, data on experimental models show that both thalamus and cortex are necessary to generate seizures. However, how to generate a coherent framework that accounts for all these sometimes contrasting data, constitutes a major challenge, and also a strong motivation for building computational models.

Computational models of generalized spike-and-wave seizures

Figure 3: Scheme of the thalamocortical circuits and its essential cellular components. A. Network consisting of several layers of neurons, pyramidal (PY) cells and interneurons (IN) for cortex, and thalamocortical (TC) and thalamic reticular (RE) cells for the thalamus. These cells were interconnected via synaptic connections using glutamate (AMPA) and GABA (GABAA and GABAB receptors). B. Intrinsic properties of the neurons; PY cells displayed spike-frequency adaptation ("regular spiking" cells), and both thalamic cell types generated bursts of action potentials. All cells were simulated using Hodgkin and Huxley (1952) type models (modified from Destexhe, 1998).

Computational models have been used for decades to investigate mechanisms of epileptogenesis, and probably the largest part of this theoretical effort concerns focal seizures, or seizures involving the hippocampal formation and limbic structures. Focal seizures, like absence seizures, are related to natural oscillatory mechanisms present in the central nervous system. In the case of focal seizures, the pathological oscillation seems related to "fast" oscillation types in cortex and hippocampus (for a recent review, see Traub et al., 2005). The present review focuses on models of generalized spike-and-wave seizures, which are linked to a different type of oscillation (sleep spindles) and different brain structures, namely the cerebral cortex (intracortical spike-and-wave seizures) and the thalamus (thalamocortical spike-and-wave seizures), as detailed in the two sections that follow. Some of the predictions of the models have been tested experimentally, as also overviewed here.

Modeling the genesis of spike-and-wave EEG patterns

As a first step to model seizures, computational models were designed to model the genesis of spike-and-wave EEG patterns (Destexhe, 1998). One of the main motivation of such a model was to explain the observation that the "spike" is associated with firing of all cell types in cortex (including interneurons; see Steriade, 1974), while the "wave" is associated with hyperpolarization and neuronal silence (see above). In particular, this model explored the hypothesis that slow K+ currents, triggered by the firing of the cells during the "spike", underlies the hyperpolarization and the "wave". This hypothesis was tested in computational models of cortical pyramidal cells, bombarded by synaptic inputs according to the firing schemes observed in experimental models. The model consisted of a network of unconnected cells, from which extracellular field potentials were simulated by linear summation of all current sources (which were here synaptic) according to Coulomb's law.

This model successfully accounted for the following observations:

  • With moderate discharges of excitatory and inhibitory neurons, the simulated field potentials consisted in negative deflections, consistent with the typical EEG patterns seen during spindle oscillations;
  • With stronger discharges, the deflections became prominent and formed a negative "spike";
  • Subsequent to the "spike", a positive "wave" could be generated, and consisted of hyperpolarizations due to K+ currents.
  • The coexistence between "normal" (spindle-like) and "abnormal" (spike-and-wave) patterns required that the K+ currents were very nonlinearly dependent on the cellular discharges.

K+ current needed to be negligible for moderate discharges, but very powerful for strong discharges. This nonlinear dependency was explained in this model by the nonlinearity intrinsic to the transduction mechanism of GABAB receptor-mediated responses (Destexhe and Sejnowski, 1995).

Modeling the genesis of spike-and-wave oscillations in cortical circuits

As reviewed above, the simplest structure displaying spike-and-wave seizures is the cerebral cortex, as shown in the isolated cortex or athalamic preparations in cats (Marcus and Watson, 1966; Pellegrini et al., 1979; Steriade and Contreras, 1998). Computational models were designed to account for such intracortical seizure generation based on different mechanisms. One model (Destexhe et al., 2001) postulated that the oscillation arises from inhibition-rebound interactions internal to cortex. This model was based on the following ingredients:

  1. the presence of a small proportion of rebound-bursting neurons in cortex (called "LTS cells"; see de la Pena and Geijo-Barrientos, 1996).
  2. The presence of GABAB-mediated inhibition in cortex, and in particular its highly nonlinear stimulus-response dependency (Thomson and Destexhe, 1999). In such a model, when fast inhibition (GABAA-mediated) was antagonized (mimicking the action of bicuculline in the experiments), all neuron types produced prolonged discharges, which generated the "spike" in the EEG. These prolonged discharges activated (GABAB-mediated) K+ currents and hyperpolarization in pyramidal neurons, which stopped the discharges and generated a positive slow "wave" in the simulated EEG.
  3. At the offset of GABAB IPSPs, a fraction of pyramidal cells generated a rebound burst, entraining the entire network in prolonged discharges and restarting the oscillation cycle.

Another type of model of cortical seizures was based on a slightly different mechanism (Timofeev et al., 2002). This model included interconnected pyramidal neurons and interneurons and pyramidal cells had a hyperpolarization-activated (Ih) current, which could also produce rebound properties. The seizure was generated in this case by an elevated extracellular K+ concentration in a focus, leading to particularly strong rebound properties of Ih-containing pyramidal neurons, entraining the entire network in slow hypersynchronized oscillations.

Thus, computational models show that networks of excitatory and inhibitory neurons can generate forms of seizure activity. In both cases, the oscillation was due to mutual interactions between rebound properties and strong K+ currents, which can generate spike-and-wave patterns in the EEG. Note that this intracortical spike-and-wave oscillation is typically of low frequency (1-2 Hz), and the "spike" component is usually less pronounced compared to the typical absence patterns (see analysis in Destexhe et al., 2001). These two features were observed experimentally in athalamic cats (Marcus and Watson, 1966; Pellegrini et al., 1979; Steriade and Contreras, 1998; see also conclusions below).

Modeling the genesis of generalized spike-and-wave oscillations in thalamocortical circuits

Figure 4: Thalamocortical model of spike-and-wave seizures. A. Spindle oscillations around 10 Hz obtained in the model in "control" conditions. The simulated local field potentials (LFP) displayed negative deflections. B. After suppressing GABAA-mediated inhibition selectively in cortex, the model exhibited slow (2-3 Hz) oscillations, which were more synchronized. These oscillations generated LFPs consisting of spike-and-wave patterns. C. Detail of a cycle of the oscillation showing the role of GABAB-mediated inhibition and thalamic rebound. D. Progressive transformation from spindle oscillations to spike-and-wave patterns for different percentages of cortical fast inhibition (100% = control as in A, 0% = total suppression of GABAA inhibition as in B; modified from Destexhe, 1998).

As seen above, although cortical circuits can generate some form of spike-and-wave activity, this activity is likely to be different from the typical absence seizures. In particular, experiments (reviewed in Section 1) have shown that an intact thalamus is necessary. This paradoxical observation was investigated by computational models of the thalamocortical system (Destexhe, 1998, 1999). The structure of these models is schematized in Figure 3, it contained two thalamic cell types (TC and RE cells), and two types of cortical neurons (RS and FS cells - see Figure 4). TC and RE cells generated bursts of action potentials due to the presence of a T-type calcium current, while RS cells contained slow K+ currents responsible for the spike-frequency adaptation typical of these cells.

Such thalamocortical models explored the hypothesis that the 3 Hz oscillation arises from intact thalamic circuits under the action of an excessively strong cortical feedback. The model showed that, if one takes into account the nonlinear properties of GABAB receptors, then strong corticothalamic feedback can "switch" thalamic circuits into a slow oscillatory mode around 3 Hz. This strong feedback was consequent to an increased cortical excitability, and thus, such a system could generate spike-and-wave oscillations, and a progressive transformation from spindle to spike-and-wave activity as cortical excitability was increased (see Figure 4). The mechanism was that, due to increased cortical excitability, corticothalamic feedback becomes strong enough to activate prolonged discharges in thalamic neurons and evoke IPSPs in relay cells dominated by the GABAB component. This slow inhibition sets the frequency to about 3 Hz and the oscillation is generated by a thalamocortical loop in which the thalamus is intact (see details in Destexhe, 1998). Therefore, if the cortex is inactivated during spike-and-wave, this model predicts that the thalamus should resume generating spindle oscillations, as observed experimentally in cats treated with penicillin (Gloor et al., 1979). A form of "fast" spike-and-wave activity (5-10 Hz), similar to rats and mice, could also be simulated by the same model, based on a different balance between GABAA and GABAB receptors (Destexhe, 1999). The type of "fast" spike-and-wave absence seizures of the WagRij rat genetic model was also modeled based on coexisting attractor dynamics (Suffczynski et al., 2004).

Similarly to the intracortical models reviewed above, the mechanism of spike-and-wave oscillation depended on rebound mechanisms, but in this case the rebound was provided by thalamic neurons. This is in agreement with the resistance to seizure in mice lacking the T-type current responsible for rebound bursts in thalamic neurons (Kim et al., 2001). The thalamocortical model postulates that during the negative EEG "spike", the hyperexcitable cortex undergoes runaway excitation and entrains a prolonged firing of all cell types (including thalamic cells); after a few tens of milliseconds, the GABAB-mediated inhibition (as well as intrinsic currents) evoked strong K+ currents in excitatory cells, stopping the synchronous discharges, while generating a positive "wave" in the EEG. At the offset of these strong K+ currents, thalamic cells produce synchronized rebound bursts, which entrain the whole circuit into the next cycle.

Testing the predictions of the models

Figure 5: Physiologically intact thalamic circuits can be forced to oscillate at 3 Hz through intense corticothalamic feedback. A. Scheme of the experimental paradigm in thalamic slices, a TC cell (recorded intracellularly) triggered the electric stimulation of corticothalamic fibers. A. For moderate stimulation intensity, the system displayed spindle oscillations at around 8 Hz. B. For strong stimulation, the thalamic circuit switched to a slower (around 3 Hz) and more synchronized oscillatory mode. The latter was dependent on GABAB receptors (modified from Bal et al., 2000).

The thalamocortical model of spike and wave seizures reviewed above accounts for a large body of experimental data on cat and rat experimental models, and rested on two main predictions. The first prediction was that GABAB responses needed to be highly nonlinear and that this nonlinearity should arise from mechanisms intrinsic to the synapse (Destexhe and Sejnowski, 1995). This prediction was tested experimentally using dual recordings in thalamic slices (Kim et al., 1997) and in cortical slices (Thomson and Destexhe, 1999). In both structures, single-axon connections between inhibitory and excitatory neurons demonstrated the presence of GABAB receptors (only in a subset of connections in cerebral cortex). It was shown that no detectable GABAB responses are observed if the presynaptic neuron fires isolated spikes, but strong GABAB IPSPs are evoked for prolonged discharges patterns (at least 3 spikes at 100 Hz), as predicted.

A second main prediction was that physiologically intact thalamic circuits, which normally oscillate around 10 Hz, can be switched to a slower oscillatory mode around 3 Hz by the action of corticothalamic feedback. This switching should be dependent on GABAB receptors. These predictions were tested in thalamic slices following electrical stimulation of corticothalamic fibers (Bal et al., 2000; Blumenfeld and McCormick, 2000). These experiments showed that it is indeed possible to switch normal thalamic circuits to 3 Hz (see Fig. 5), and that this switching depends on GABAB receptors, exactly as predicted by the model.

It was found recently that the antiepileptic drug vigabatrin strongly affects spike-and-wave discharges in rats (Bouwman et al., 2003). This drug increases GABA concentrations by inhibiting GABA transaminase, one of the major enzymes implicated in GABA degradation. In particular, Bouwman et al. (2003) demonstrated that vigabatrin decreases the frequency of spike-and-wave discharges (from 7.5 Hz to 5.6 Hz), as well as prolongs the duration of seizures (from 1.04 sec to 1.52 sec). This effect occurs presumably through boosting of both GABAA and GABAB responses, and is in agreement with predictions of the model (see Fig. 3 in Destexhe, 1999).

Finally, it was shown that in the Wag-Rij rat genetic model of absence epilepsy, the seizure seems to start in a focus located in somatosensory cortex (Meeren et al., 2002). This observation is not necessarily inconsistent with the present thalamocortical model. It is conceivable that a given cortical area may have higher excitability, and starts the seizure within the loop defined with its associated thalamic nucleus, and later spreads to the whole thalamocortical system, even if some areas are not hyperexcitable (or less hyperexcitable). These points should be considered in future models.


Figure 6: Summary of the different types of spike-and-wave complexes in experiments and models. A. Spike-and-wave pattern during human absence seizures (from Fig 1). B. Spike-and-wave patterns in cats, obtained by infusion of convulsants to cortex either in the intact thalamocortical system (top) or after removal of the thalamus (bottom). Both traces are modified from Fig 2. C. Spike-and-wave patterns simulated by computational models reproducing the conditions in B (top trace from Fig 4; bottom trace from Destexhe et al., 2001).

In conclusion, computational models have contributed the following points to the understanding of spike-and-wave seizures:

  • The typical "spike" and "wave" pattern of the EEG is known to be related to "firing" and "silence", respectively. Computational models can reproduce these characteristic features based on the fact that the high level of firing during the "spike" produces a subsequent hyperpolarization mediated by slow K+ currents during the "wave" (a mixture of GABAB synaptic currents and intrinsic K+ conductances). The fact that no positive wave is observed for moderate discharges (such as during spindle oscillations) can be explained by the nonlinearity of GABAB currents.
  • Several models have reproduced the conditions for the genesis of such pathological patterns. A form of spike-and-wave can be generated intracortically, through mutual inhibition-rebound interactions. In this case, the spike-and-wave oscillation is slow (around 1.5-2 Hz), and the "spike" component is relatively modest (see Figure). It can also be generated by the thalamocortical system, in which case the oscillation is around 2-4 Hz and the spike component is more pronounced, as observed experimentally.
  • Models have explored a mechanism for spike-and-wave oscillation which depends on one key element: the thalamus can be switched to a slow 3 Hz oscillation by excessively strong corticothalamic feedback. Such a switch also depends on the nonlinearity of GABAB currents. This switching mechanism was identified experimentally and forms the basis of a "corticothalamic" scheme, in which the pathological oscillation is generated by an increased cortical excitability acting on a physiologically intact thalamus. Whether this increased cortical excitability is diffuse or focal, should be investigated by future models and experiments.

A detailed overview of models of absence seizures, and how they relate to the oscillatory mechanisms during sleep, has been given in Destexhe and Sejnowski (2001).


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See Also

Cortex, Electroencephalogram, Epilepsy, Fast Oscillations, Hippocampus, Thalamocortical Circuit, Thalamocortical Oscillations, Thalamus

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