From sleep spindles of natural sleep to spike and wave discharges of typical absence seizures: is the hypothesis still valid?

Abstract

The temporal coincidence of sleep spindles and spike-and-wave discharges (SWDs) in patients with idiopathic generalized epilepsies, together with the transformation of spindles into SWDs following intramuscular injection of the weak GABAA receptor (GABAAR) antagonist, penicillin, in an experimental model, brought about the view that SWDs may represent ‘perverted’ sleep spindles. Over the last 20 years, this hypothesis has received considerable support, in particular by in vitro studies of thalamic oscillations following pharmacological/genetic manipulations of GABAARs. However, from a critical appraisal of the evidence in absence epilepsy patients and well-established models of absence epilepsy it emerges that SWDs can occur as frequently during wakefulness as during sleep, with their preferential occurrence in either one of these behavioural states often being patient dependent. Moreover, whereas the EEG expression of both SWDs and sleep spindles requires the integrity of the entire cortico-thalamo-cortical network, SWDs initiates in cortex while sleep spindles in thalamus. Furthermore, the hypothesis of a reduction in GABAAR function across the entire cortico-thalamo-cortical network as the basis for the transformation of sleep spindles into SWDs is no longer tenable. In fact, while a decreased GABAAR function may be present in some cortical layers and in the reticular thalamic nucleus, both phasic and tonic GABAAR inhibitions of thalamo-cortical neurons are either unchanged or increased in this epileptic phenotype. In summary, these differences between SWDs and sleep spindles question the view that the EEG hallmark of absence seizures results from a transformation of this EEG oscillation of natural sleep.

Sleep Spindles – As a Biomarker of Brain Function and Plasticity

“…In our opinion SWDs do not develop from spindles (any more than humans developed from apes); they develop from the same TC circuit under different conditions -a thesis with solid experimental support to which the above paper subscribes to. The transition from spindles to SWD was just what was observed in the particular FGPE model (awake cats under fentanyl and curare successively injected with pentobarbital and penicillin [97]) and gave major support to the hypothesis that SWDs develop from the same TC circuits as spindles. Further more it was these experiments in FGPE, which first argued in favor of above (b -not compromised GABA inhibition) and (cprimacy of cortical mechanisms) [9,69,91,92,93,99,100].…”

Sleep spindles are generated in the absence of T-type calcium channel-mediated low-threshold burst firing of thalamocortical neurons

“…It has been proposed that TC oscillations occurring during sleep spindles and SWDs of absence seizures share common elements and mechanisms (11). Clinical observations of the temporal coincidence between sleep spindles and SWDs and experimental findings showing that penicillin, a weak GABA A R antagonist, induces the transformation of sleep spindles into SWDs gave rise to the view that SWDs may be a perverted form of sleep spindles (34). Previous studies have found that Ca V 3.1 −/− mice are resistant to GABA B receptor agonist-induced SWDs (13), and that deletion of Ca V 3.1 completely suppresses or markedly reduces SWDs in genetic mouse models of absence seizures (35), implying that Ca V 3.1 T-type Ca 2+ channels play a crucial role in the genesis of SWDs.…”

Animal models of epilepsy: use and limitations

“…Absence seizures produce spike-and-wave discharges (SWD; ~3 Hz) manifested on the normal EEG background as long as the behavioral activity remains halted 125,127. Similarities of SWD and sleep spindles, in addition to the transformation from spindles to SWD in cats injected with systemic penicillin (a GABA A antagonist), suggest a link between absence seizures and superficial stages of sleep 128. However, such a relationship is now uncertain, as absence seizures are also frequent during wakefulness, previous hypotheses of shared GABA A -dependent mechanisms are no longer supported, and SWD generation depends on thalamo-cortico-thalamic networks, whereas spindles are of thalamic origin 128,129…”