(A) A schematic representation of key parts of the brain involved in the motor circuit, including the cortex, basal ganglia (caudate nucleus, putamen, globus pallidus, subthalamic nucleus, and substantia nigra), and thalamus. (B) A simplified schematic of the normal motor circuit. The neurotransmitter GABA provides an inhibitory signal, while glutamate stimulates activity. Dopamine stimulates via the D1 receptor but provides an inhibitory signal via the D2 receptor. Movement signals are initiated in the cortex, transmitted to the striatum, and then travel in two different loops. In the direct pathway, dopamine provides an excitatory signal that triggers a net effect of stimulating the motor cortex. In contrast, in the indirect pathway, dopamine provides an inhibitory signal and has a net effect of inhibiting the cortex. In Parkinson’s disease, the loss of dopamine-producing cells in the substantia nigra primarily affects the indirect pathway and causes an increase in the inhibitory signal from the striatum to the globus pallidus externus, which reduces its normal constraint on the subthalamic nucleus. Thus, in Parkinson’s disease patients, increased outputs from the subthalamic nucleus and subsequently the globus pallidus internus are responsible for many of the movement symptoms caused by the loss of dopamine-producing cells.