Figure 1.

Circuitries involved in generation, propagation, and modulation of focal or focal to bilateral tonic-clonic seizures emanating from limbic/cortical structures as in temporal lobe epilepsies. For a better overview, only one hemisphere is shown, although interhemispheric epileptic networks are crucial for secondary generalization of seizures [32]. Seizure activity emanating from limbic circuitry or neocortical regions does not spread randomly through the brain but rather involves specific anatomical routes [12,33,34,35,36,37]. Targeting the seizure focus in the neocortex (highlighted in blue) or the subcortical temporal lobe network comprising hippocampus, dentate gyrus, amygdala, entorhinal, perirhinal, and piriform cortices (highlighted in yellow) is an obvious approach for intracranial drug delivery. Brain areas remote to the seizure focus play an important role in the control and propagation of different types of epilepsies/seizures. The basal ganglia (highlighted in red), especially the substantia nigra pars reticulata (SNr) and the subthalamic nucleus (STN), have been profoundly investigated in preclinical studies as a common seizure gating and control mechanism, being relatively nonselective as to the type of seizure or seizure origin they can influence [36,38,39]. Therefore, these regions are highly attractive targets for the investigation of therapeutic intracranial drug delivery approaches. Further structures, including thalamic regions and brainstem regions (highlighted in green), are also investigated in this respect. Refer to the text for more details. a+p, anterior+posterior subregions of SNr; AN, anterior thalamic nucleus; CM, centromedian thalamic nucleus; DLPFC, dorsolateral prefrontal cortex; GABA, gamma-aminobutyric acid; GPe, external globus pallidus; GPi, internal globus pallidus; MD, mediodorsal thalamus; NAcc, nucleus accumbens; OFC, orbitofrontal cortex; PPN, pedunculopontine nucleus; SNc, substantia nigra pars compacta; VA, ventral anterior nucleus; VA, ventral anterior thalamic nucleus; VL, ventral lateral thalamic nucleus; VM, ventromedial thalamic nucleus.