The striatum is the input structure that receives direct projections from nearly the entire cerebral cortex. The intermediate structures of the basal ganglia (the STN, GPe, and SNpc) primarily project to other basal ganglia nuclei. The output structures (the GPi, SNpr, and ventral pallidum) primarily project to various regions of the thalamus, which projects back to the cerebral cortex. The basal ganglia facilitate motor, motivational, cognitive, and affective processes (163–165). The key to understanding the role of the basal ganglia lies in understanding its basic anatomic organizational profile, which is characterized by cortico-basal ganglia–thalamocortical loops, originally discovered by Alexander and colleagues [2].

The most fundamental anatomic scheme of cortical–basal ganglia connections is characterized by four connectional profiles. In the direct pathway, projections originate from the cortex, which projects to the striatum (the caudate and putamen), from the striatum to the globus pallidus interna (GPi), and from there, to the thalamus, which send its projections back to the cortex where the circuit originated. The indirect pathway is characterized by circuits that originate in the cortex, which again projects to the striatum. But from there, the circuit projects to the external segment of the globus pallidus (GPe). The GPe then projects to the subthalamic nucleus (STN) which projects to the GPi.

Activity within the direct pathway selects a perception or a behavior by releasing GPi inhibition on the thalamus, which activates a specific region of cortex. Activity within the indirect pathway results in increasing pallidal inhibition on the thalamus, therefore suppressing cortical activity. (The reader is referred to Utter et al. [164]; Koziol and Budding [5]; Middleton [163]; and Lichter and Cummings [165] for additional explanations if this is necessary.) These pathways, which are known as components of the fronto-striatal system, are believed to be dysfunctional in ADHD [115, 166, 167].