Recruitment of the Indirect Pathway by Subthalamic Deep Brain Stimulation

Background: Deep brain stimulation (DBS) of the subthalamic nucleus is a therapeutic neurocircuit intervention to treat symptoms of Parkinson’s disease (PD). Recently, evoked resonant neural activity (ERNA) has been described as a signature of subthalamic DBS that scales with therapeutic efficacy, but the single neuron and synaptic bases underlying ERNA remain unsubstantiated. Methods: We combine STN microelectrode recordings in PD patients undergoing DBS surgery with computational mesocircuit modelling to test different circuit montages and short-term synaptic dynamics necessary for the emergence of ERNA and use mapping of ERNA hotspots to test the relation of ERNA to clinical improvement achieved by DBS. Results: High frequency stimulation (HFS) of the STN resulted in ERNA waveforms predictive of patterned inhibition of action potential firing. At HFS, depression of the first peak of ERNA was coupled to the emergence of a second peak. Computational modelling revealed that this relationship could be explained by (i) distinct synaptic dynamics in the reciprocal STN- external-pllidum (GPe)-loop and (ii) self-inhibition within GPe via recruitment of axon-collaterals. Finally, electrophysiological mapping localized the highest ERNA amplitudes within the STN and was able to predict clinical improvement achieved by DBS. Interpretation: These multi-modal findings suggest that concurrent antidromic and orthodromic activations of the indirect pathway by subthalamic DBS produce a spatially defined neuronal circuit signature that is predictive of its therapeutic potential. Research Category and Technology and Methods Translational Research: 1. Deep Brain Stimulation (DBS) Keywords: DBS mechanism of action, Synpatic mechanisms, ERNA, Indirect pathway