View source for Spike-and-wave oscillations

== Testing the predictions of the models ==

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[[Image:Bal20002.jpg|thumb|400px|right|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 GABA<sub>B</sub> receptors
(modified from Bal et al., 2000).]]
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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 GABA<sub>B</sub> 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 GABA<sub>B</sub> receptors (only in a subset of connections in
cerebral cortex).  It was shown that no detectable GABA<sub>B</sub> 
responses are observed if the presynaptic neuron fires isolated 
spikes, but strong GABA<sub>B</sub> IPSPs are evoked for prolonged 
discharges patterns (at least 3 spikes at 100 Hz), as predicted.

A second main prediction was that <i>physiologically intact</i>
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
GABA<sub>B</sub> 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 GABA<sub>B</sub> 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 GABA<sub>A</sub> and GABA<sub>B</sub> responses, and is in
agreement with predictions of the model (see Fig. 3 in Destexhe,
1999).

Finally, it was shown that in the <i>Wag-Rij</i> 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.

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