Deciphering the modulatory role of direct pedunculopontine nucleus-cortical circuitry in absence seizure dynamics: A...

Pedunculopontine nucleus (PPN) has extensive projections with numerous brain tissues, and it has become an important target for clinical intervention in neurological diseases. In this study, we integrate the PPN into a typical corticothalamic-basal ganglia dynamical model to systematically investigate the mechanisms by which PPN-related projections regulate spike-and-wave discharges (SWDs) in absence seizures. We find that the glutamatergic (GLU) cortical-PPN projection can significantly control SWDs, through signal transmission via two GLU PPN-thalamic pathways. The coupling weights in PPN-thalamic pathways have a critical impact on the control pattern. We observe that bidirectional suppression of SWDs may be achieved by modulating the coupling strength in the GLU PPN-cortical projection. Furthermore, we analyze that, although from a computational perspective, the GLU PPN-substantia nigra pars reticulata (SNr) projection can potentially achieve control over SWDs through the SNr-thalamic pathways, this control method might be biologically challenging to implement. Finally, we observe that the reciprocal GLU projections between the PPN and the subthalamic nucleus (STN) play a regulatory role in the activity of basal ganglia, yet they do not exhibit a significant suppressive effect on SWDs. For the first time, we emphasize from a computational perspective that is the direct communication between the PPN and the cerebral cortex, rather than the communication between the PPN and the basal ganglia, might have a significant effect on the regulation of absence seizures. As a crucial component of the brainstem, the findings in this paper further elucidate the potential functions of the PPN in regulating brain activity.