Abstract
While current dopamine-based drugs seem to be effective for most Parkinson's disease (PD) motor dysfunctions, they produce variable responsiveness for resting tremor. This lack of consistency could be explained by considering recent evidence suggesting that PD resting tremor can be divided into different partially overlapping phenotypes based on the dopamine response. These phenotypes may be associated with different pathophysiological mechanisms produced by a cortical-subcortical network involving even non-dopaminergic areas traditionally not directly related to PD. In this study, we propose a bio-constrained computational model to study the neural mechanisms underlying a possible type of PD tremor: the one mainly involving the serotoninergic system. The simulations run with the model demonstrate that a physiological serotonin increase can partially recover dopamine levels at the early stages of the disease before the manifestation of overt tremor. This result suggests that monitoring serotonin concentration changes could be critical for early diagnosis. The simulations also show the effectiveness of a new pharmacological treatment for tremor that acts on serotonin to recover dopamine levels. This latter result has been validated by reproducing existing data collected with human patients.
Highlights
IntroductionPeople affected by resting tremor exhibit uncontrollable movements involving a body part, for example, the arm, when at rest
Resting tremor is one of the most disabling features of Parkinson’s disease (PD)
We present the results obtained with the model and directed to (i) support the 5-HT role in maintaining homeostasis between DP and indirect pathways (IPs) by affecting DA release (Reed et al, 2013; Sgambato-Faure and Tremblay, 2018); (ii) demonstrate that 5HT dysfunctions can indirectly contribute to the emergence of tremor by producing a DA decrease; (iii) study the effect of a new pharmacological treatment for tremor that acts on 5HT to recover DA levels
Summary
People affected by resting tremor exhibit uncontrollable movements involving a body part, for example, the arm, when at rest. Tremor tends to decrease or stop when they deliberately move the affected part of the body (Deuschl et al, 2000; Kalia and Lang, 2015). Like other PD motor features, tremor is thought to result primarily from the death of dopamine-producing cells in the substantia nigra pars compacta (SNc), an area in the midbrain mainly targeting the striatum. This area is the main input gate of the basal ganglia, subcortical nuclei critical to managing motor behavior. A consistent reduction of striatal dopamine levels causes malfunctioning of the basal ganglia circuits that, in turn, may contribute to the emergence of tremor at rest (Pare et al, 1990; Wichmann and DeLong, 1999; Dovzhenok and Rubchinsky, 2012)
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