Autonomous oscillations and phase-locking in a biophysically detailed model of the STN-GPe network
Authors: Koelman Lucas A. , Lowery Madeleine M. 
Published: April 2019

The aim of this study was to understand the relative role of autonomous oscillations and patterning by exogenous oscillatory inputs in the generation of pathological oscillatory activity within the subthalamic nucleus (STN) - external globus pallidus (GPe) network in Parkinson’s disease. A biophysically detailed model that accounts for the integration of synaptic currents and their interaction with intrinsic membrane currents in dendritic structures within the STN and GPe was developed. The model was used to investigate the development of beta-band synchrony and bursting within the STN-GPe network by changing the balance of excitation and inhibition in both nuclei, and by adding exogenous oscillatory inputs with varying phase relationships through the hyperdirect cortico-subthalamic and indirect striato-pallidal pathways. The model showed an intrinsic susceptibility to beta-band oscillations that was manifest in weak autonomously generated oscillations within the STN-GPe network and in selective amplification of exogenous beta-band synaptic inputs near the network’s endogenous oscillation frequency. The resonant oscillation frequency was determined by the net level of excitatory drive in the loop. Intrinsically generated oscillations were too weak to support a pacemaker role for the STN-GPe network, however, they were considerably amplified by sparse cortical beta inputs when their frequency range overlapped and were further amplified by striatal beta inputs that promoted anti-phase firing of the cortex and GPe, resulting in maximum transient inhibition of STN neurons. The model elucidates a mechanism of cortical patterning of the STN-GPe network through feedback inhibition whereby intrinsic susceptibility to beta-band oscillations can lead to phase locked spiking under parkinsonian conditions. These results point to resonance of endogenous oscillations with exogenous patterning of the STN-GPe network as a mechanism of pathological synchronization, and a role for the pallido-striatal feedback loop in amplifying beta oscillations.

Author summary

Exaggerated beta-frequency neuronal synchrony is observed throughout the basal ganglia in Parkinson’s disease and is reduced with medication and during deep brain stimulation. The power of beta-band oscillations is increasingly used as a biomarker to guide antiparkinsonian therapies. Despite their importance as a clinical target, the mechanisms by which pathological beta-band oscillations are generated are not yet clearly understood. In vitro electrophysiological recordings support a theory of enhanced phase locking of the reciprocally connected subthalamo-pallidal network to beta-band cortical inputs but this has not yet been clearly demonstrated in a model. We present a new model of the subthalamo-pallidal network consisting of biophysically detailed cell models that captures the interaction between synaptic and intrinsic currents in dendritic structures. The model shows how phase locking of subthalamic and pallidal neurons and exaggerated bursting in subthalamic neurons can arise from the interaction of these currents when the balance of excitation and inhibition is changed and how phase locking is amplified under specific phase relationships between cortical and striatal beta inputs.