Parkinsonism: evolving pathophysiologic concepts

The link between the hallmark pathology in Parkinson's disease, i.e., dopamine loss in the basal ganglia, and the behavioral signs of parkinsonism, remains mysterious. This presentation will review our knowledge of system-level changes in brain activity in parkinsonism.

The most commonly discussed models of the changes in brain activity that lead to parkinsonism were developed twenty years ago, and were strongly based on anatomical considerations and changes in the firing rates of basal ganglia neurons in dopamine-depleted animals. The most important change noted was an increase in the activity of neurons in the basal ganglia output nuclei. A simple anatomic argument was used to link these changes to the striatal loss of dopamine. Since that time, a plethora of new findings has emerged, indicating that the changes in firing rate may be less important than changes in other aspects of basal ganglia activity. Changes in oscillatory activity in the beta- and gamma-bands of frequencies have been observed to be important, as have changes in non-linear firing characteristics such as increases in the bursting activity of individual basal ganglia neurons. Studies in animals and humans have also shown that the ensemble activity of basal ganglia neurons appears to be altered in parkinsonism, with the emergence of pathological levels of synchronization between neighboring neurons. Perhaps most importantly, parkinsonism has emerged as a circuit disorder in which the focal loss of dopamine in the basal ganglia has significant down-stream effects on the activity of other areas of the brain, specifically the thalamus, portions of the cortex, and the brainstem.

Many questions in this field remain unanswered. The links between dopamine loss and the changes in firing patterns have not been identified, and the relationship between the electrical changes in the basal ganglia-thalamocortical circuitry and parkinsonian motor signs remains unclear. The significance of anatomical changes that are secondary to long-term dopamine loss, such as loss of the dendritic spines of striatal medium spiny neurons, and the role of non-dopaminergic or extra-basal ganglia pathology in parkinsonism also need to be elucidated. Addressing these questions will be essential for the development of more effective pharmacological and surgical strategies to treat parkinsonian patients.