Non-stationary discharge patterns in motor cortex under subthalamic nucleus deep brain stimulation: A review

Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) directly modulates the basal ganglia, but how such stimulation impacts the cortex upstream is largely unknown. There is evidence of cortical activation in 6-hydroxydopamine (OHDA)-lesioned rodents and facilitation of motor evoked potentials in Parkinson's disease (PD) patients, but the impact of the DBS settings on the cortical activity in normal vs. Parkinsonian conditions is still debated. Recently, we used point process models to analyze non-stationary activation patterns and interneuronal dependencies in the motor and sensory cortices of non-human primates during STN DBS. We reported that such features are enhanced after treatment with 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP), which causes a consistent PD-like motor impairment, and that high-frequency DBS (≥100Hz) strongly reduces the short-term patterns (period: 3-7ms) both before and after MPTP treatment, while it elicits a short-latency post-stimulus activation. Lowfrequency DBS (≤50Hz), instead, had negligible effects on the non-stationary features while decreased the burstiness of the spike trains. Here, we review these results and further complete our analysis by evaluating the impact of the DBS settings on the predictive power of the point process models fitted on the cortical discharge patterns. In particular, by using tools from the information theory (i.e., receiver operating characteristic curve and information rate), we show that the predictive power of these models is significantly conditioned on the DBS settings, i.e., the probability of spiking of the cortical neurons (which is captured by the point process models) is significantly conditioned on the timely delivery of the DBS input. Furthermore, we show that such dependency increases with the DBS frequency and is significantly larger for high- vs. low-frequency DBS. Overall, the selective suppression of non-stationary features and the increased modulation of the spike probability suggest that high-frequency STN DBS enhances the neuronal activation in motor and sensory cortices, presumably because of reinforcement mechanisms, which perhaps involve the overlap between feedback antidromic and feed-forward orthodromic responses along the basal ganglia-thalamo-cortical loop.