Parkinsonism

Patients with parkinsonism have pathologic involvement of the basal ganglia, which are structures found deep in the brain. The basal ganglia have specific connections with other structures, in particular the thalamus and the cerebral cortex. Several basal ganglia thalamocortical circuits have been described, but it is the motor circuit that is predominantly involved in patients with parkinsonism. In general, there are two parallel motor circuits; one called the direct circuit and the other called the indirect circuit. These circuits serve to turn off various basal ganglia structures, so that, acting with other parts of the brain, human movements (especially of the hands) can be finely controlled. Both of these circuits include cells in the cerebral cortex that have connections with the basal ganglia, the latter structures being the ones not functioning properly in parkinsonism. In the direct pathway, cells expressing GABA (gamma aminobutyric acid) and substance P-chemicals used by these cells to communicate with other cells, project to (globus pallidus interna and substantia nigra pars reticulata) certain parts of the basal ganglia where they have an inhibitory effect on the cell structures. Various feedback mechanisms are required, so that, from these structures there are GABAergic inhibitory projections to the thalamus, which, in turn, has an excitatory projection back to the cortex. In the indirect pathway, there is excitatory projection from the cerebral cortex to another part of the basal ganglia, the striatum. Then, from the striatum there is GABAergic/ enkephalinergic inhibitory projection to the globus pallidus pars externa, which, in turn, a GABAergic inhibitory projection to the subthalamic nucleus. Other feedback loops exist; for example, from the subthalamic nucleus there is excitatory projection to the globus pallidus pars interna and substantia nigra pars reticulatta. Once again, from these structures there is an inhibitory GABAergic projection to the thalamus and the circuit is completed by an excitatory projection from the thalamus back to the cortex. Perhaps the best known of the basal ganglia loops in parkinsonism involves the substantia nigra pars compacta, which uses the neurotransmitter dopamine. This is the neurotransmitter that is reduced in Parkinson's disease—and replaced to provide benefits to patients with the disorder. Again, there is a balance of pathways: the direct pathway has an excitatory influence on the cortex which results in increased movement; while the indirect pathway has an inhibitory influence on the cortex that reduces movement. In parkinsonism there is a general reduction of excitatory input to the cortex, resulting in reduced movement. For example, involvement of substantia nigra pars compacta (as in Parkinson's disease) leads to reduction in dopamine going to the striatum. In parkinsonism, reduction in cells in the substantia nigra pars compacta leads to a reduction in input to the motor cortex, which leads to reduction in movement. Blockage of dopaminergic receptors in the striatum by neuroleptic drugs, such as thioridazine and haloperidol, has a similar effect, leading to drug-induced parkinsonism.