Fig. 8: A summary of the effect of hyperpolarizing MCS on cortical programming and motor control in PD and normal subjects.

a A table summarizing the experimental findings on the MC activities, together with the presumed subcortical (subthalamic and striatal) mechanisms, for the making of behavioral consequences in normal and PD animals with or without MCS. The enlarged MU units are probably adaptive changes for the impaired striatal lateral inhibition in PD. More cortical input to striatum may then partly compensate for the enhanced down state in medium spiny neurons (of direct pathways, dMSNs) to restore the impaired striatal lateral inhibition due to dopaminergic deprivation. MCS further enlarges MU units to enhance the compensation and thus even smoother flow of motor commands and behavioral agility. b Schematic drawings depicting the effect of MCS. Different MC units (or motor engrams in a broad sense) are shown in arrows of different colors, with the size denoting the amplitude. The “automatic” serial changes in MC engrams are consequences of subcortical processing including striatal lateral inhibition, which is impaired in PD. With the adaptively larger MC units in PD, striatal lateral inhibition is partially restored, but MC engrams and flow of engram changes may still be deformed or ineffective, leading to decreased MU spatiotemporal changes upon movement (and decrease in varieties as well as speed of movement). MCS further enlarges MC units and compensates for the impaired lateral inhibition to restore “effective” engram changes leading to agile and adequate locomotor activities (although the engrams may still be somewhat distorted or “incorrect”). However, propulsive movement may occasionally occur because of the decreased likelihood of modification by the other units due to the subnormal striatal lateral inhibition. Propulsion could also rarely happen with MCS in normal subjects, but with smaller extent and shorter duration because of the intact striatal lateral inhibition. c The locomotor deficits in PD could be effectively rectified by hyperpolarizing MCS and depolarizing STN DBS, which increase MC and decrease STN burst discharges, respectively. A delicate tuning and/or combination of MCS and STN DBS as well as low-dose pharmacotherapies based on mechanistic considerations and key clinical parameters may provide a better practice to achieve the spirit of individualized and precision medicine for PD.