Dopamine depletion leads to pathological synchronization of distinct basal ganglia loops in the beta band

Abstract

Motor symptoms of Parkinson’s Disease (PD) are associated with dopamine deficits and pathological oscillation of basal ganglia (BG) neurons in the β range ([12-30] Hz). However, how dopamine depletion affects the oscillation dynamics of BG nuclei is still unclear. With a spiking neurons model, we here capture the features of BG nuclei interactions leading to oscillations in dopamine-depleted condition. We highlight that both the loop between subthalamic nucleus (STN) and Globus Pallidus pars externa (GPe) and the loop between striatal fast spiking and medium spiny neurons and GPe display resonances in the β range, and synchronize to a common β frequency through interaction. Crucially, the synchronization depends on dopamine depletion: the two loops are largely independent for high levels of dopamine, but progressively synchronize as dopamine is depleted due to the increased strength of the striatal loop. The model is validated against recent experimental reports on the role of cortical inputs, STN and GPe activity in the generation of β oscillations. Our results highlight the role of the interplay between the GPe-STN and the GPe-striatum loop in generating sustained β oscillations in PD subjects, and explain how this interplay depends on the level of dopamine. This paves the way to the design of therapies specifically addressing the onset of pathological β oscillations.

Structural constraints on the emergence of oscillations in multi-population neural networks

“…We would like to note that recently, Ortone et al, 2023 and Azizpour Lindi et al, 2023 have provided a more quantitative explanation of the experimental observation by Crompe et al, 2020 . They also eventually resort to the D2-Proto-Arky cycle to explain BG oscillations in the absence of STN.…”

Dopamine-dependent cerebellar dysfunction enhances beta oscillations and disrupts motor learning in a multiarea model

“…To conclude, our model highlights the importance of considering the cerebellum in experimental and computational studies aimed at investigating PD and represents an improvement over previous models that only reproduced a single area (27,55), using oversimplified mass models (28) and did not explicitly model the cerebellum (56). Our approach paves the way for a unified physiopathological framework explaining Parkinsonian brain activity quantitatively across complexity scales.…”

Beta–Gamma Phase-Amplitude Coupling as a Non-Invasive Biomarker for Parkinson’s Disease: Insights from Electroencephalography Studies

“…In PD, the degeneration of neurons in substantia nigra results in the loss of nigrostriatal dopaminergic projections. Dopamine has an integral function in regulating the operation of the striatum and the depletion of this neurotransmitter in the basal ganglia region causes severe disruptions in the BG network (cortico-basal ganglia-thalamo-cortical loop, (CBGTC)) [ 59 ]. The loss of dopaminergic inputs to the striatum leads to hypoactivity of pro-kinetic direct pathway striatal projection neurons (bearing excitatory D1 receptors) and hyperactivity of anti-kinetic indirect pathway striatal projection neurons (bearing inhibitory D2 receptors), which is thought to explain the bradykinesia and rigidity symptoms commonly observed in PD [ 1 ].…”