Parkinson's disease as a system-level disorder

Abstract

Traditionally, the basal ganglia have been considered the main brain region implicated in Parkinson's disease. This single area perspective gives a restricted clinical picture and limits therapeutic approaches because it ignores the influence of altered interactions between the basal ganglia and other cerebral components on Parkinsonian symptoms. In particular, the basal ganglia work closely in concert with cortex and cerebellum to support motor and cognitive functions. This article proposes a theoretical framework for understanding Parkinson's disease as caused by the dysfunction of the entire basal ganglia-cortex-cerebellum system rather than by the basal ganglia in isolation. In particular, building on recent evidence, we propose that the three key symptoms of tremor, freezing, and impairments in action sequencing may be explained by considering partially overlapping neural circuits including basal ganglia, cortical and cerebellar areas. Studying the involvement of this system in Parkinson's disease is a crucial step for devising innovative therapeutic approaches targeting it rather than only the basal ganglia. Possible future therapies based on this different view of the disease are discussed.

Figure 1

Graphical summary of the systems-level view to the study of PD proposed in this article. Pivoting on evidence supporting the integrated nature of BG, Ctx, and Cer, largely interacting through Thal, and the involvement of Cer and Ctx in PD, the view urges studying PD by focusing on the BG–Ctx–Cer system rather than on BG in isolation. Studying how such system affects PD is a crucial step to draw a more articulated clinical picture of the disease and to devise innovative therapeutic approaches. BG, basal ganglia; Cer, cerebellum; Ctx, cortex; PD, Parkinson’s disease.

Figure 2

Schema of the basal ganglia-cortical-cerebellar (BG–Ctx–Cer) system involved in three PD motor symptoms, in particular tremor, freezing, and action sequence impairments. The arrows indicate glutamatergic excitatory connections whereas lines ending with a filled circle represent inhibitory GABAergic projections. The bidirectional arrows linking Thal and Ctx include both the BG-cortical and the cerebellar-cortical channels (note that Cer sectors within Thal could be partially overlapped with those of BG, see Ref. for more details). The dashed lines within Thal represent the cerebellar target sectors within Thal through which the Cer reaches Str.^, BG, basal ganglia; Cer, cerebellum; Ctx, cortex; GPe, external globus pallidus; GPi, internal globus pallidus; M1, primary motor cortex; PPN, pedunculopontine nucleus; PN, pontine nuclei; pre-SMA, pre-supplementary motor area; Str, striatum; STN, subthalamic nucleus; SNr, substantia nigra pars reticulata; SNc, substantia nigra pars compacta; SMA, supplementary motor area; Thal, thalamus.

Figure 3

Cortical–subcortical circuit underlying Parkinson’s disease (PD) tremor. The red arrows indicate the anatomical pathways through which the elements of the cortical–subcortical system may interact to produce tremor in PD.

Figure 4

Cortical–subcortical circuit possibly underlying Parkinson’s disease (PD) freezing. The red arrows indicate the anatomical pathways through which the elements of the cortical–subcortical system interact between them to produce freezing.

Figure 5

Cortical–subcortical circuit possibly underlying Parkinson’s disease (PD) action sequencing impairments. The red arrows indicate the anatomical pathways through which the elements of the cortical–subcortical system interact between them to produce action sequencing impairments.