Persistent synaptic inhibition of the subthalamic nucleus by high frequency stimulation

Background Deep 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. Objective The 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). Methods Two 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. Results Excitatory 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). Interpretation Persistent 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. ### Competing Interest Statement S.K.K., M.H., W.D.H. have received honoraria, travel funds, and/or grant support from Medtronic (not related to this work). A.M.L. has received honoraria, travel funds, and/or grant support from Medtronic, Boston Scientific, St. Jude-Abbott, and Insightec (not related to this work). A.M.L. is a co-founder of Functional Neuromodulation Ltd. A.A.K. has received honoraria and/or travel funds from Medtronic, Boston Scientific, St. Jude-Abbott, and Stada Pharm (not related to this work). M.R.P. is a co-founder and a shareholder in MyndTec Inc. L.M., L.A.S., H.A., J.R.P.G. have no financial disclosures.