Subthalamic high frequency stimulation resets subthalamic firing and reduces abnormal oscillations

High frequency stimulation (HFS) of the subthalamic nucleus (STN) is a well-established therapeutic approach for the treatment of late-stage Parkinson's disease. Although the underlying cause of this illness remains a mystery, changes in firing rate and synchronized activity in different basal ganglia nuclei have been related to its symptoms. Here we investigated the impact of STN-HFS on firing rate as well as correlated and oscillatory activity in the STN network in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned non-human primates by using simultaneous extracellular single-unit recordings. STN-HFS reduced (i) the firing rate of STN neurons, (ii) the oscillatory activity at an individual STN neuron level as well as (iii) the correlated and oscillatory activity between pairs of STN neurons, while contralateral rigidity was improved. A detailed analysis showed that the decrease of mean firing rate resulted from the resetting of firing probability to virtually zero by the stimulus pulse. Subsequently, STN neurons resumed their activity after a mean duration of 2.9 +/- 0.1 ms and their firing probability returned to baseline values approximately 7 ms after the onset of the stimulus pulse, the recovery of the firing probability being represented by a sigmoid function. Thus, the overall decrease of the mean firing rate resulted from the repetition of this dynamical process with a frequency of 130 Hz (interstimulus interval approximately 7.7 ms), allowing the neuron to fire with its baseline firing rate only for a very short period. Although the mechanisms underlying the desynchronization of neuronal activity in the STN network remain unclear, the resetting of STN neuron firing probability by the electrical stimulus would rather be expected to increase oscillatory activity at an individual neuron level as well as correlated and oscillatory activity between pairs of STN neurons. However, assuming the resetting of firing rate to be the consequence of a transient GABAergic inhibition through excitation of presynaptic GABAergic axon terminals, different recovery periods of STN neurons might delay the appearance of synchronized oscillations, particularly if they are not generated locally. In conclusion, our study provides new evidence that STN-HFS decreases oscillatory activity in the STN network. Although the exact relation between oscillatory activity and Parkinson's disease symptoms remains to be determined, the present results suggest that STN-HFS might at least partially exert its beneficial effects through the reduction of oscillatory activity in the STN network and consequently in the entire cortex-basal ganglia-cortex network.