Circuit mechanisms of spike-wave discharge: are there similar underpinnings for centrotemporal spikes?

Comparisons of Generalized Absence and Benign Focal Epilepsies In the context of exploring the underlying circuit pathology of benign focal epilepsy (BFE) it is perhaps useful to consider similarities to generalized absences (GA), about which we have learned a great deal from animal models in recent years. Although there are clear differences in the clinical presentation of the two syndromes, especially the focal nature of BFE compared to the widely generalized activity of GA, similarities include some EEG findings and pharmacology. On the EEG, a variable fraction of BFE patients will exhibit diffuse spike and wave discharge, these can be modulated by arousal level, and often occur during sleep. This EEG finding, which is typical of GA, is sometimes seen in additional to the Rolandic sharp waves that are characteristic of BFE. This suggests that similar, but not completely overlapping, circuits may be involved in the genesis of such activity. Similarities in pharmacology support this idea. For example, carbamazepine may exacerbate both GA and BFE. Vigabatrin, which enhances inhibitory responses in the brain, and can promote GA activity, has been reported to increase EEG abnormalities in BFE. In the following section, we will summarize the proposed inhibitory mechanisms of GA, and speculate how similar mechanisms may be invoked in rolandic spike activity. Thalamocortical Circuitry of Generalized Absence Epilepsy An integrated, recurrent synaptic loop that tightly binds thalamic and cortical circuits, and mediates sensory perception and modulation of arousal, has been described (Steriade and Llinas, 1988). Briefly, this circuit is composed of interconnected regions in dorsal thalamus, thalamic reticular nucleus (TRN), and cortex. Normally, sensory information is relayed through dorsal thalamus to the appropriate cortical region. Thalamocortical fibers traverse the TRN and emit recurrent excitatory collaterals that mediate activation of TRN neurons. The TRN cells, which are uniformly GABAergic, provide a powerful and widespread feedback inhibition onto dorsal thalamus (Huguenard and Prince, 1994a;Cox et al., 1996). Synaptic inhibition of dorsal thalamic neurons can lead to rebound activation, which has the potential to initiate reverberant activity in this circuit (Steriade et al., 1993;Huguenard and Prince, 1994a). It is proposed that divergence within this system may allow for the generalization of spike wave discharge in GA. For example, some TRN cells can project to widespread regions of dorsal thalamus in rat (Cox et al., 1996) and mouse (Scheibel and Scheibel, 1966). Exacerbation of GA by pro-GABAergic drugs is consistent with a strong inhibitory component to these seizures. Hypersynchronous thalamocortical activity in mouse mutants: implications for pathogenesis An important synaptic element in the thalamocortical circuit is a demonstrated reciprocal connectivity between TRN cells (Scheibel and Scheibel, 1966;Steriade and Deschenes, 1984;Ulrich and Huguenard, 1995). It has been proposed that this can either promote or desynchronize thalamocortical oscillations (Steriade et al., 1993). In a recent study (Huntsman et al., 1999), we have shown that mutant mice that were devoid of a particular GABAA subunit (β3) lacked functional connectivity between TRN cells. These mice had absence seizures and a very high degree of widespread hypersynchrony in isolated thalamic slices. These findings suggest that the reciprocal interconnections between TRN cells normally serve to desynchronize thalamocortical activity and prevent widespread, i.e. generalized, activity. Further, the view that the TRN network itself drives the generation of GA is not supported. These results are consistent with reports in ferret (von Krosigk et al., 1993) and rat (Huguenard and Prince, 1994b) thalamic slices, where pharmacological upor downregulation of intra-RTN inhibition can suppress or promote intrathalamic epileptiform activity, respectively.