Spike-and-wave discharges of absence seizures as a transformation of sleep spindles: the continuing development of a hypothesis
Introduction
If the Hippocratic rejection of supernatural causes of disease is the foundation of a scientific theory of medicine, its most powerful tool and justification is probably the identification of the particular physiological mechanism which is disturbed in each symptom of pathology. This approach is particularly obvious in epilepsy research.It can be traced in the ancient ‘disturbance of humours in the brain’, in Hughlings Jackson's ‘excessive firing of neurons’ and was the fruitful connecting thread of the long research tradition in epileptogenesis developed at the Montreal Neurological Institute by W. Penfield, H. Jasper, P. Gloor and their collaborators (see Jasper, 1990). A relevant example is the proposal by Pierre Gloor (1978) that spike and wave discharges (SWDs) characterizing absence epilepsy may develop by the same thalamocortical (TC) circuits which normally create sleep spindles under certain conditions of cortical hyperexcitability. Based in the beginning on experimental EEG observations, it acquired strong support from single unit studies in the model of feline generalized penicillin epilepsy (FGPE) and became a hypothesis, i.e. it offered a tentative explanation about how SWDs may develop and it guided further work towards a better explanation. Subsequent in vivo and in vitro experiments in several animal models of absence epilepsy, human EEG studies and computer modelling provided ways of testing the consequences and ramifications of this hypothesis, extended it and highlightedits possible alternatives. Above all, the hypothesis stood up to the recent revelations of the fundamental ionic and circuit mechanisms underlying spindle generation in thalamus and through them actually acquired new impetus and continues to develop. Whether confirmed or denied, Gloor's hypothesis may be shown to have been a kind of Archimedean lever for starting to lift the heavy cover over the mechanisms underlying absence epilepsy and possibly other phenomena dependent on thalamocortical oscillations.
Section snippets
Sleep spindles
Electroencephalographic spindle oscillations are considered as the main correlate of sleep initiation and the epitome of EEG synchronization during the early stages (mainly the second) of quiescent sleep. The EEG features, the clinical significance and the prevailing ideas on the neuronal mechanisms underlying spindles have been extensively reviewed (Gloor, 1983, Jankel and Niedermeyer, 1985, Steriade and Llinas, 1988, Dijk, 1995, McCormick and Bal, 1997, Steriade, 1997, Steriade, 1998,
Spike and wave discharges of absence seizures
In typical primary generalized absence seizures as seen predominantly in children (classical petit mal), patients show brief episodes of ‘loss’ or ‘clouding of consciousness’, which are electrographically characterized by 3–3.5 c/s SWDs (Dreifuss, 1990, Loiseau et al., 1995, Niedermeyer, 1996, Niedermeyer, 1999b, Janz, 1997, Panayiotopoulos, 1999, Stefan and Carter Snead, 1997). As the scientific definition of consciousness is still elusive, one has to note that the ‘loss of consciousness’ is a
SWDs as a transformation of spindles
A posteriori, experimental findings consistent with common mechanisms underlying sleep spindles and SWDs are abundant in early relevant studies (see Jasper, 1990 and historical reviews mentioned above). In the 1970s Gloor and his collaborators were able to revisit the suggestions made by these studies (a) in the light of then advanced knowledge of thalamic and cortical synaptic physiology provided by intracellular recordings and transmitter histochemistry, its role in generating EEG waves, as
Recent developments
Probably the single most important development in the evolution of our ideas about mechanisms underlying SWDs and the one which rekindled interest in the reviewed hypothesis was the elucidation of mechanisms underlying spindles (Jahnsen and Llinas, 1984, Steriade and Llinas, 1988). The work of Mircea Steriade (recently reviewed in Steriade et al., 1994, Steriade, 1999), which has been most influential in shaping our understanding of the mechanisms underlying sleep spindles, has given rise to an
Some future questions
Although several of the basic components of the originally proposed mechanism for development of SWDs by transformation of spindles have gained acceptance from the above new developments, other questions remain unanswered and new ones have surfaced with the advanced understanding of the brain and the techniques available today. Some of these questions are as follows.
(a) What causes cortical hyperexcitability or at least increased response to TC volleys? Candidate mechanisms include an imbalance
Conclusions
The value of scientific hypotheses is probably less related to whether they were correct or incorrect and more related to whether they were instrumental in further research and clear enough to be experimentally tested (and eventually falsified – in the sense that Popper (1959) used the word). Far from offering a complete explanation of SWDs generation, or being better than other relevant hypotheses, on the basis of the here presented account of recent studies, I believe that the reviewed
Acknowledgements
I am grateful to Drs P. Ktonas, G. van Luijtelaar, R. Naquet and M. Shouse for their most helpful comments on the manuscript.
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