Opposing signals out of balance

Voluntary movement is controlled by the cooperation of two neuronal systems: the pyramidal and extrapyramidal systems. The extrapyramidal system is responsible for balancing excitatory and inhibitory impulses. The uncoordinated, poorly regulated movements associated with PD result from a disruption of this system.²²

Within the basal ganglia of the brain is a region known as the corpus striatum. This region receives stimulatory and inhibitory impulses from other parts of the brain, which are coordinated by the subthalamic nucleus. When these signals are in balance, normal movement is maintained. Most stimulatory impulses originate in the cerebral cortex, whereas the majority of the inhibitory signals come from within the substantia nigra. This region is where the signaling molecule dopamine is produced and stored, and degeneration of dopamine-producing neurons in the substantia nigra results in the symptoms of PD.²²

The nigrostriatal neuronal pathways

Impulses from the substantia nigra are transmitted to the thalamus via two nigrostriatal neuronal pathways: the direct pathway and the indirect pathway.²²

• Direct pathway—stimulation of this pathway by dopamine increases excitatory output from the thalamus
• Indirect pathway—activation of this pathway by dopamine decreases excitatory output from the thalamus

These pathways work in concert to ensure that the appropriate amount of inhibition is sent to the thalamus, controlling movement by balancing inhibitory and excitatory signals.²²

The effects of dopaminergic cell loss

The degeneration of dopaminergic neurons is believed to be the primary cause of the motor symptoms of PD. The reason for this loss is not known, but its impact is clear. The gradual degeneration and death of these neurons result in a progressive loss of inhibitory signaling that eventually results in the symptoms of PD. These symptoms do not become evident until approximately 50%–75% of dopamine-producing cells have been damaged or destroyed.²²

The depletion of dopamine-producing cells leads to decreased activity in the direct pathway, and increased activity in the indirect pathway. This leads to an overall increase in inhibitory signals to the thalamus, causing the cardinal signs of PD: tremor at rest, bradykinesia, and rigidity.²²

The appearance of Lewy bodies

Intraneuronal inclusions known as "Lewy bodies"—which are also found in the brains of patients with Alzheimer’s disease—are present in the brains of PD patients at autopsy. It is believed that these bodies play a role in motor dysfunction and they are consistent with the appearance of cardinal PD symptoms. Lewy bodies are also believed to contribute to the development of dementia and other cognitive changes seen in PD, although the mechanism behind this is unknown.²²