Abstract
Cortico-basal ganglia-thalamocortical circuits are severely disrupted by the dopamine depletion of Parkinson's disease (PD), leading to pathologically exaggerated beta oscillations. Abnormal rhythms, found in several circuit nodes are correlated with movement impairments but their neural basis remains unclear. Here, we used dynamic causal modelling (DCM) and the 6-hydroxydopamine-lesioned rat model of PD to examine the effective connectivity underlying these spectral abnormalities. We acquired auto-spectral and cross-spectral measures of beta oscillations (10–35 Hz) from local field potential recordings made simultaneously in the frontal cortex, striatum, external globus pallidus (GPe) and subthalamic nucleus (STN), and used these data to optimise neurobiologically plausible models. Chronic dopamine depletion reorganised the cortico-basal ganglia-thalamocortical circuit, with increased effective connectivity in the pathway from cortex to STN and decreased connectivity from STN to GPe. Moreover, a contribution analysis of the Parkinsonian circuit distinguished between pathogenic and compensatory processes and revealed how effective connectivity along the indirect pathway acquired a strategic importance that underpins beta oscillations. In modelling excessive beta synchrony in PD, these findings provide a novel perspective on how altered connectivity in basal ganglia-thalamocortical circuits reflects a balance between pathogenesis and compensation, and predicts potential new therapeutic targets to overcome dysfunctional oscillations.
Highlights
In Parkinson’s disease (PD), degeneration of midbrain dopamine neurons severely disrupts neuronal activity in looping circuits formed by cortico-basal ganglia (BG)-thalamocortical connections [1,2,3]
Dynamic causal models for local field potentials (LFPs) data typically comprise connected cortical sources, where each source is described by a neural mass [27]
The differential equations describing neuronal dynamics in the basal ganglia and cortex are identical in their form but have different parameters
Summary
In Parkinson’s disease (PD), degeneration of midbrain dopamine neurons severely disrupts neuronal activity in looping circuits formed by cortico-basal ganglia (BG)-thalamocortical connections [1,2,3]. Studies have shown that excessive oscillations at beta frequencies (13–30 Hz) are a key pathophysiological feature of these Parkinsonian circuits, when recorded at the level of unit activity and/or local field potentials (LFPs) in several key circuit nodes. These nodes include the frontal cortex, subthalamic nucleus (STN), external globus pallidus (GPe) and internal globus pallidus (GPi) [4,5,6,7,8,9]. A recent report has shown that stimulating the STN at beta frequencies exacerbates motor impairments in Parkinsonian rodents [17], in line with similar findings in PD patients [18,19]
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