Physiologic evidence reflects this balanced architecture, one excitatory and the other inhibitory within the individual circuits. The direct striatomedial pallidonigral pathway is activated by glutaminergic projections from the sensorimotor cortex and by dopaminergic nigral (pars compacta)—striatal projections. Activation of this direct pathway inhibits the internal pallidum, which, in turn, disinhibits the ventrolateral and ventroanterior nuclei of the thalamus. As a consequence, thalamocortical drive is enhanced and cortically initiated movements are facilitated. The indirect circuit arises from putaminal neurons that contain gamma-aminobutyric acid (GABA) and smaller amounts of enkephalin. These striatal projections have an inhibitory effect on the medial pallidum, which, in turn, disinhibits the subthalamic nucleus through GABA release, providing subthalamic drive to the internal pallidum and substantia nigra pars reticulata. The net effect is thalamic inhibition, which reduces thalamocortical input to the precentral motor fields and impedes voluntary movement. These complex anatomic and physiologic relationships have been summarized in numerous schematic diagrams similar to Fig. 4-4 and those by Lang and Lozano and by Standaert and Young.
Restated, the current view is that enhanced conduction through the indirect pathway leads to hypokinesia by increasing pallidothalamic inhibition, whereas enhanced conduction through the direct pathway results in hyperkinesia by reducing pallidothalamic inhibition. The direct pathway has been conceived by Marsden and Obeso as facilitating cortically initiated movements and the indirect pathway as suppressing potentially conflicting and unwanted motor patterns. Dopamine released by the pars reticulata of the substantia nigra helps maintain the normal balance between the direct and indirect pathways. In Parkinson disease a loss of dopaminergic input from the substantia nigra diminishes activity in the direct pathway and increases activity in the indirect pathway; the net effect is to increase inhibition of the thalamic nuclei and to reduce excitation of the cortical motor system.
Further insight into these systems and into the mechanism of Parkinson disease came from the discovery that the parkinsonian syndrome is largely reproduced in humans and primates by the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This toxin was discovered when drug abusers self-administered an analogue of meperidine. The molecule binds with high affinity to monoamine oxidase (MAO), an extraneural enzyme that transforms it to pyridinium, a metabolite that is bound by melanin in the dopaminergic nigral neurons and destroys the cells, probably by interfering with mitochondrial function. In monkeys made parkinsonian by the administration of MPTP, electrophysiologic studies have shown increased activity in the internal globus pallidus and decreased activity in the external globus pallidus, as predicted from the above described models. The end result is increased inhibition of thalamocortical neurons.
However, crude lesions of either or both parts of the pallidum, such as infarcts, hemorrhages, and tumors, even beyond their unilateral location, do not cause the full parkinsonian syndrome. Perhaps it is because the subtle imbalance is not reproduced between the internal and external pallidal circuits that exist in Parkinson disease. More specifically, the internal segment is part of the direct and indirect pathway, one excitatory and the other inhibitory, whereas the external segment is only influenced by the indirect pathway. Indeed, striking improvements in parkinsonian symptoms are obtained, paradoxically, by placing lesions in the internal pallidum (pallidotomy) as discussed in Chap. 38.