On the Origin of Tremor in Parkinson's Disease

TL;DR

This paper presents a conductance-based model demonstrating how variations in dopamine-modulated connections within the basal ganglia-thalamo-cortical loop can generate Parkinsonian tremor, offering insights into potential therapeutic targets.

Contribution

It introduces a novel computational model linking dopamine levels to tremor generation via the basal ganglia-thalamo-cortical loop, explaining tremor suppression mechanisms.

Findings

Dopamine decrease in the loop induces tremor-like oscillations.

Restoring dopamine levels suppresses tremor oscillations.

Disrupting the loop prevents tremor generation.

Abstract

The exact origin of tremor in Parkinson's disease remains unknown. We explain why the existing data converge on the basal ganglia-thalamo-cortical loop as a tremor generator and consider a conductance-based model of subthalamo-pallidal circuits embedded into a simplified representation of the basal ganglia-thalamo-cortical circuit to investigate the dynamics of this loop. We show how variation of the strength of dopamine-modulated connections in the basal ganglia-thalamo-cortical loop (representing the decreasing dopamine level in Parkinson's disease) leads to the occurrence of tremor-like burst firing. These tremor-like oscillations are suppressed when the connections are modulated back to represent a higher dopamine level (as it would be the case in dopaminergic therapy), as well as when the basal ganglia-thalamo-cortical loop is broken (as would be the case for ablative anti-parkinsonian surgeries). Thus, the proposed model provides an explanation for the basal ganglia-thalamo-cortical loop mechanism of tremor generation. The strengthening of the loop leads to tremor oscillations, while the weakening or disconnection of the loop suppresses them. The loop origin of parkinsonian tremor also suggests that new tremor-suppression therapies may have anatomical targets in different cortical and subcortical areas as long as they are within the basal ganglia-thalamo-cortical loop.