Milestones in research on the pathophysiology of Parkinson's disease

Abstract

Progress in our understanding of the mechanisms underlying the cardinal motor abnormalities of Parkinson's disease (PD), in particular akinesia and bradykinesia and their treatment, has been remarkable. Notable accomplishments include insights into the functional organization of the basal ganglia and their place in the motor system as components of a family of parallel cortico-subcortical circuits that subserve motor and nonmotor functions and the development of models of the intrinsic organization of the basal ganglia, including delineation of the so-called direct, indirect, and hyperdirect pathways. Studies in primate models of PD have provided insight into the alterations of neuronal activity that are responsible for the motor features of PD, revealing both altered tonic levels of discharge and significant disturbances of the patterns of discharge throughout the motor circuitry and have led to the formulation of circuit models of PD, providing testable hypotheses for research and stimulating the development of new therapies. Most importantly, the discovery that lesions of the subthalamic nucleus, a key node of the indirect pathway, abolish the cardinal features of PD contributed to the renaissance in the use of surgical approaches to treating patients with PD, including ablation and deep brain stimulation.

FIG. 1

Basal ganglia–thalamocortical circuits as proposed by Alexander et al in 1986. See text for details. Abbreviations: ACA, anterior cingulate area; APA, arcuate premotor area; CAUD, caudate nucleus (b) body (h) head; DLC, dorsolateral prefrontal cortex; EC, entorhinal cortex; FEF, frontal eye fields; GPi, internal segment of globus pallidus; HC, hippocampal cortex; ITG, inferior temporal gyrus; LOF, lateral orbitofrontal cortex; MC; motor cortex; MDpl, medialis dorsalis pars paralamellaris; MDmc, medialis dorsalis pars magnocellularis; MDpc, medialis dorsalis pars parvocellularisl PPC, posterior parietal cortex; PUT, putamen; SC, somatosensory cortex; SMA, supplementary motor area; SNr, substantia nigra pars reticulata; STG, superior temporal gyrus; VAmc, ventralis anterior pars magnocellularis; VApc, ventralis anterior pars parvocellularis; VLm, ventralis lateralis pars medialis; VLo, ventralis lateralis pars oralis; VP, ventral pallidum; VS, ventral striatum; cl-, caudolateral; cdm-, cudal dorsomedial; dl-, dorsolateral; l-, lateral; ldm-, lateral dorsomedial; m-, medial; mdm-, medial dorsomedial; pm, posteromedial; rd-, rostrodorsal; rl-, rostrolateral; rm-, rostromedial; vm-, ventromedial; vl-, ventrolateral. The figure and legend were originally published in Alexander et al8 and are used here with permission.

FIG. 2

Functional connectivity within the basal ganglia—thalamocortical circuits under normal and parkinsonian conditions, as proposed by Bergman et al (1990). A: Normal (open arrows, excitatory collections; filled arrows, inhibitory collections. SNc, substantia nigra pars compacta; VL, ventrolateral nucleus of the thalamus). The putamen (the “input” stage of the circuit) is connected with GPi (the “output” stage) by direct and indirect projections (via GPe and the STN). The postulated differential effects of dopamine on the 2 striatal systems are indicated schematically. B: MPTP-induced parkinsonism. After treatment with MPTP, the SNc was damaged. Resulting changes in the overall activity in individual projection systems are indicated as changes in the width of arrows. Inactivation of the nigroputamenal projection increased GPi activity, secondary to an increase in excitatory drive from the STN and a decrease in direct inhibitory input from the striatum. The resulting overinhibition of thalamocortical circuits may account for some of the parkinsonian motor signs. C: Effect of STN lesions in parkinsonism. Inactivation of the STN reduced GPi output to the thalamus toward more normal levels, thus reducing parkinsonian motor signs. The figure and legend were originally published in Bergman et al20 and are used here with permission.

FIG. 3

Changes in the activity of single cells in GPe, STN, or GPi of MPTP-treated monkeys. Shown are example recordings of separate neurons, recorded with standard methods for extracellular electrophysiologic recording in normal and parkinsonian animals. Each data segment is 5 seconds in duration. This figure and the legend were originally published in Galvan and Wichmann115 and are used here with permission.

FIG. 4

Oscillatory local field potential activity in the subthalamic nucleus. Shown is the evolution of the LFP autospectra throughout the “off–on” cycle and the predominant site of recording with respect to 3 bipolar contacts in the STN. In the “off” motor state (left) in a patient with tremor (A), there is a predominant peak at around 5 Hz, whereas in a patient without tremor (B), there is only a peak at around 11–12 Hz that is maximal at the second-most dorsal STN contact. In the “on” 1 dyskinesias motor state (right), the same patient shown in B exhibited a 4- to 10-Hz peak predominantly at the ventral recording site (C) and a 60- to 80-Hz peak at all 3 sites, although the middle contact predominated (D). This figure and the legend were originally published in Alonso-Frech et al and are used here with permission.