Pathophysiology of parkinsonism

Abstract

The motor signs of Parkinson's disease are thought to result in large part from a reduction of the level of dopamine in the basal ganglia. Over the last few years, many of the functional and anatomical consequences of dopamine loss in these structures have been identified, both in the basal ganglia and in related areas in thalamus and cortex. This knowledge has contributed significantly to our understanding of the link between the degeneration of dopamine neurons in the midbrain and the development of parkinsonism. This review discusses the evidence that implicates electrophysiologic changes (including altered discharge rates, increased incidence of burst firing, interneuronal synchrony, oscillatory activity, and altered sensorimotor processing) in basal ganglia, thalamus, and cortex, in parkinsonism. From these studies, parkinsonism emerges as a complex network disorder, in which abnormal activity in groups of neurons in the basal ganglia strongly affects the excitability, oscillatory activity, synchrony and sensory responses of areas of the cerebral cortex that are involved in the planning and execution of movement, as well as in executive, limbic or sensory functions. Detailed knowledge of these changes will help us to develop more effective and specific symptomatic treatments for patients with Parkinson's disease.

Figure 1

Parkinsonism-related changes in overall activity (‘rate model’) in the basal ganglia-thalamocortical motor circuit. Black arrows indicate inhibitory connections; gray arrows indicate excitatory connections. The thickness of the arrows corresponds to their presumed activity. Abbreviations: CM, centromedian nucleus of thalamus; CMA, cingulate motor area; Dir., direct pathway; D1, D2, dopamine receptor subtypes; GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; Indir., indirect pathway; M1, primary motor cortex; Pf, parafascicular nucleus of the thalamus; PMC, premotor cortex; PPN, pedunculopontine nucleus; SMA, supplementary motor area; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus; VA, ventral anterior nucleus of thalamus; VL, ventrolateral nucleus of thalamus.

Figure 2

Changes in the activity of single cells in GPe, STN or GPi of MPTP-treated monkeys. Shown are examples of separate neurons, recorded with standard extracellular electrophysiologic recording methods in normal and parkinsonian animals. Each data segment is 5 seconds in duration.

Figure 3

Simultaneous independent extracellular electrophysiologic recordings of the activity of several neurons in the globus pallidus in a normal (A) and a parkinsonian monkey (B). Traces represent 2.5 s-long example of neuronal activity. In the normal state (A.), the activity of neighboring neurons was not correlated. In the parkinsonian state (B.), however, episodes of synchronous, episodic bursting developed. For abbreviations, see text. The figure is a reproduction of figure 3 in (Bergman et al., 1998a), with permission.