Frequency-Dependent Inhibition during Deep Brain Stimulation of Thalamic Ventral Intermediate Nuclei

Deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (Vim) has been a standard therapy for essential tremor. It has been shown that high-frequency (≥100 Hz) DBS suppresses Vim firing and tremor activity; however, the underlying mechanisms are not fully understood. Here, we investigate whether neuronal suppression during high-frequency DBS occurs at cellular levels or is influenced by network-level effects. Using in vivo recordings of Vim neurons, from people of unknown sex, during different DBS frequencies, we detected a positive-going evoked-field potential, quasi-evoked inhibition, during high-frequency Vim-DBS in some recording sites. Interestingly, it was observed that (1) neuronal suppression is stronger in neurons quasi-evoked inhibition, implying that inhibitory engagement during high-frequency DBS can further suppress neuronal firing and (2) quasi-evoked inhibition emerges after the transient burst, i.e., the latter may give rise to the former. By utilizing a novel artifact removal and characterizing dynamics of quasi-evoked inhibitory activity, we showed that the occurrence of inhibitory activity is negatively correlated with firing. We propose a framework that hypothesizes DBS effects at both cellular and network levels, i.e., high-frequency DBS not only depresses synapses but also enables the recruitment of inhibitory neurons. A transient burst in the spiking activity is likely providing sufficient network engagement to recruit inhibitory neurons that are silent during low-frequency DBS. These results suggest that an excitatory-inhibitory balance could regulate Vim activities during high-frequency DBS. Our findings shed light on possible network mechanisms underlying Vim-DBS, which can provide insight for optimizing DBS.