Pathophysiology of Motor Dysfunction in Parkinson's Disease as the Rationale for Drug Treatment and Rehabilitation

Francesca Magrinelli, Alessandro Picelli, Pierluigi Tocco, Angela Federico, Laura Roncari, Nicola Smania, Giampietro Zanette, Stefano Tamburin, Francesca Magrinelli, Alessandro Picelli, Pierluigi Tocco, Angela Federico, Laura Roncari, Nicola Smania, Giampietro Zanette, Stefano Tamburin

Abstract

Cardinal motor features of Parkinson's disease (PD) include bradykinesia, rest tremor, and rigidity, which appear in the early stages of the disease and largely depend on dopaminergic nigrostriatal denervation. Intermediate and advanced PD stages are characterized by motor fluctuations and dyskinesia, which depend on complex mechanisms secondary to severe nigrostriatal loss and to the problems related to oral levodopa absorption, and motor and nonmotor symptoms and signs that are secondary to marked dopaminergic loss and multisystem neurodegeneration with damage to nondopaminergic pathways. Nondopaminergic dysfunction results in motor problems, including posture, balance and gait disturbances, and fatigue, and nonmotor problems, encompassing depression, apathy, cognitive impairment, sleep disturbances, pain, and autonomic dysfunction. There are a number of symptomatic drugs for PD motor signs, but the pharmacological resources for nonmotor signs and symptoms are limited, and rehabilitation may contribute to their treatment. The present review will focus on classical notions and recent insights into the neuropathology, neuropharmacology, and neurophysiology of motor dysfunction of PD. These pieces of information represent the basis for the pharmacological, neurosurgical, and rehabilitative approaches to PD.

Figures

Figure 1
Figure 1
A simplified view of the functional anatomy of the basal ganglia (BG). The main input and output connections and the basic internal circuitry of the BG are shown. Here are represented the direct pathway (panel (a)), the indirect pathway (panel (b)), and the alteration of the balance between the direct and indirect pathways in Parkinson's disease (panel (c)). Blue arrows show the excitatory glutamatergic pathways, red arrows indicate the inhibitory GABAergic pathways, and green arrows mark the dopaminergic pathway. CMA: cingulate motor area; D1: dopamine D1 receptor; D2: dopamine D2 receptor; GPe: external segment of the globus pallidus; GPi: internal segment of the globus pallidus; MC: primary motor cortex; PMC: premotor cortex; SMA: supplementary motor area; SNc: substantia nigra pars compacta; SNr: substantia nigra pars reticulata; STN: subthalamic nucleus; VA/VL: ventral anterior/ventrolateral thalamic nuclei.
Figure 2
Figure 2
The parallel motor, oculomotor, associative, and limbic circuits of the basal ganglia. ACA: anterior cingulate area; CMA: cingulate motor area; DLPFC: dorsolateral prefrontal cortex; FEF: frontal eye fields; GPi: internal segment of the globus pallidus; LOFC: lateral orbitofrontal cortex; MC: primary motor cortex; MD: mediodorsal nucleus of the thalamus; MDpl: mediodorsal nucleus of thalamus, pars lateralis; MOFC: medial orbitofrontal cortex; PMC: premotor cortex; SEF: supplementary eye field; SMA: supplementary motor area; SNr: substantia nigra pars reticulata; VAmc: ventral anterior nucleus of thalamus, pars magnocellularis; VApc: ventral anterior nucleus of thalamus, pars parvocellularis; VLa: anterior ventrolateral nucleus of the thalamus; VLcr: ventrolateral nucleus of thalamus, pars caudalis, rostral division; VLm: ventrolateral nucleus of thalamus, pars medialis; VS: ventral striatum [12, 13].

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