Regulation Studies Of Absence Epilepsy Using Computational Models

As a subtype of idiopathic generalized epilepsies(IGE),absence epilepsy is recognized to be closely linked with abnormal neural firing activities within the brain,of which the typical characteristic is absence seizures.Due to the abrupt onset and offset,it is difficult to predict absence seizures successfully.During absence seizures,the classical2-4 Hz spike and wave discharges(SWDs)can be observed on the bilateral hemispheres,and accompanied with temporal loss of consciousness.Actually,not only do absence epileptic patients suffer from the extremely high mental pressure,but also the family and society bear a heavy financial burden.Therefore,how to modulate or control absence seizures is an important issue that urgently needs to be addressed.Despite that the genesis of absence seizures is still debated,accumulating evidence has suggested that absence seizures are tightly associated with abnormal interactions between the cerebral cortex(Ctx)and thalamus.Theoretically,appropriately modulating activities within the corticothalamic network might provide a chance to suppress absence seizures.Based on this hypothesis,we use biophysical computational models to investigate the dynamical control mechanisms of absence seizures in the brain,which include the potential functional roles played by the thalamic feed-forward inhibition(FFI)and basal ganglia.The main content of this thesis contains the following three parts:First,the thalamic feed-forward inhibition modulates absence seizures.Anatomically,the specific relay nuclei(SRN)of thalamus not only receive the excitatory projections from the Ctx,but also are driven by the inhibitory signals from the thalamic reticular nucleus(TRN),which also receives the excitatory projections from the Ctx.Together,these pathways(Ctx-TRN-SRN)form the thalamic FFI.To explore the functional roles of the thalamic FFI in terminating absence seizures,we utilize a biophysically based meanfield model of corticothalamic network and find that enhancing the excitatory coupling strength of the Ctx-TRN pathway can successfully suppress absence seizures.Moreover,the inhibitions mediated by gamma-aminobutyric acid A(GABAA)and gammaaminobutyric acid B(GABAB)receptors in the TRN-SRN pathway perform combination roles in modulating absence seizures.Importantly,we can observe the emergence of SWDs at the intermediate level of GABAB inhibition,and the fast and slow simple neural oscillations at the low and high levels of GABAB inhibition,respectively,which suggest that GABAB receptors contribute to triggering the onset of absence seizures.Taken together,the thalamic FFI serves as an intrinsic regulator within thalamus contributing to suppressing absence seizures,which might provide some new insights into the treatment of absence epilepsy.Second,the basal ganglia can bidirectionally control absence seizures through the nigrothalamic pathway.As the output structure of the basal ganglia,substantia nigra pars reticulata(SNr)could modulate activities of corticothalamic network through the direct nigrothalamic pathway,which includes the SNr-TRN and SNr-SRN pathways.Inspired by these,we build a biophysically based mean-field model of the basal gangliacorticothalamic(BGCT)network to investigate the potential roles of the basal ganglia in controlling absence seizures.We find that decreasing the neural activation level of SNr neurons could successfully suppress absence seizures through the isolated SNr-TRN pathway.In contrast,enhancing the activities of SNr neurons could also considerably control absence seizures via the isolated SNr-SRN pathway.Furthermore,due to the competition between the SNr-TRN and SNr-SRN pathways,we find that both enhancing and decreasing the activities of SNr neurons could significantly suppress absence seizures under certain conditions.Thus,in this case,the basal ganglia can bidirectionally control absence seizures.Additionally,the coupling strength of the TRN-SRN pathway could shape this bidirectional control of basal ganglia.These findings reveal that the basal ganglia could birdirectionally control absence seizures for the first time,and provide novel insights into clinical treatments of absence epilepsy.Third,the basal ganglia can control absence seizures through the pallido-cortical pathway.Besides the nigrothalamic pathway,recent experimental studies have identified a new inhibitory pallido-cortical pathway projecting from the globus pallidus external(GPe)segment to the Ctx(i.e.,GPe-Ctx pathway),which might also participate in modulating absence seizures.To examine this hypothesis,we modify the mean-field model of the BGCT network by introducing the GPe-Ctx pathway,through which absence seizures could be significantly terminated.In particular,both enhancing the coupling strength of the GPe-Ctx pathway and increasing the activation level of GPe neurons can considerably control absence seizures.Moreover,changing the activities of GPe neurons through several GPe-related pathways,including the direct and indirect pathways,can also successfully suppress absence seizures.Furthermore,we still find that the basal ganglia can bidirectionally control absence seizures through the nigrothalamic pathway despite inducing the new GPe-Ctx pathway,by which the bidirectional control of basal ganglia could be shaped.These findings not only demonstrate that the basal ganglia can control absence seizures through the GPe-Ctx pathway,but also suggest that the bidirectional control of basal ganglia might be a generalized control mechanism for absence seizures.In summary,using biophysically based mean-field models,we demonstrate that the thalamic FFI and basal ganglia play crucial roles in controlling absence seizures,which might provide testable hypotheses for experimental studies,as well as provide novel insights into clinical treatments of absence epilepsy and related brain diseases.