Persistent synaptic inhibition of the subthalamic nucleus by high frequency stimulation

Steiner, L. A.; Kuehn, A. A.; Geiger, J. R.; Alle, H.; Popovic, M.; Kalia, S.; Hodaie, M.; Lozano, A.; Hutchison, W. D.; Milosevic, L.

doi:10.1101/2021.10.20.465131

bioRxiv · 10.1101/2021.10.20.465131

Persistent synaptic inhibition of the subthalamic nucleus by high frequency stimulation

Steiner, L. A.·Kuehn, A. A.·Geiger, J. R.·Alle, H.·Popovic, M.·Kalia, S.·Hodaie, M.·Lozano, A.·Hutchison, W. D.·Milosevic, L.

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Abstract

BackgroundDeep brain stimulation (DBS) provides symptomatic relief in a growing number of neurological indications, but local synaptic dynamics in response to electrical stimulation that may relate to its mechanism of action have not been fully characterized. ObjectiveThe objectives of this study were to (1) study local synaptic dynamics during high frequency extracellular stimulation of the subthalamic nucleus (STN), and (2) compare STN synaptic dynamics with those of the neighboring substantia nigra pars reticulata (SNr). MethodsTwo microelectrodes were advanced into the STN and SNr of patients undergoing DBS surgery for PD. Neuronal firing and evoked field potentials (fEPs) were recorded with one microelectrode during stimulation from an adjacent microelectrode. ResultsExcitatory and inhibitory fEPs could be discerned within the STN and their amplitudes predicted bidirectional effects on neuronal firing (p = .007). There were no differences between STN and SNr inhibitory fEP dynamics at low stimulation frequencies (p > .999). However, inhibitory neuronal responses were sustained over time in STN during high frequency stimulation, but not SNr (p < .001) where depression of inhibitory input was coupled with a return of neuronal firing (p = .003). InterpretationPersistent inhibitory input to the STN suggests a local synaptic mechanism for the suppression of subthalamic firing during high frequency stimulation. Moreover, differences in the resiliency versus vulnerability of inhibitory inputs to the STN and SNr suggest a projection source- and frequency-specificity for this mechanism. The feasibility of targeting electrophysiologically-identified neural structures may provide insight into how DBS achieves frequency-specific modulation of neuronal projections.

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Steiner, L. A., Kuehn, A. A., Geiger, J. R., Alle, H., Popovic, M., Kalia, S., Hodaie, M., Lozano, A., Hutchison, W. D., Milosevic, L.. 2021-10-21. Persistent synaptic inhibition of the subthalamic nucleus by high frequency stimulation. https://doi.org/10.1101/2021.10.20.465131

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