Subthalamic high frequency stimulation resets subthalamic firing and reduces abnormal oscillations

Abstract

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.

Mechanisms and Targets of Deep Brain Stimulation in Movement Disorders

“…Multiple studies have shown that HFS reduced, but did not completely block, neuronal activity. 19,22,27 Moreover, somatic inhibition could appear after a single stimulus pulse, 18 and both inhibition and recovery from inhibition occurred at latencies consistent with GABAergic postsynaptic current kinetics. 27 The fact that in vitro slices are often disconnected from their afferent inputs could explain the different results observed between the two experimental preparations.…”

“…7,17 Consistent with this hypothesis are several studies showing that HFS in either the subthalamic nucleus (STN) or globus pallidus pars interna (GPi) suppresses somatic activity around the stimulated electrode. [18][19][20][21][22][23][24][25][26][27] For example, Meissner et al 27 recorded STN neuronal activity for For movement disorders, deep brain stimulation is an effective therapy that, similar to surgical ablation, encompasses several therapeutic targets within the sensorimotor network. DBS targets are indicated by lightning bolts.…”

“…92 Experimental evidence has also suggested that STN HFS decreases neuronal burst activity in the STN and its target nuclei. 20,27,37 As a result, reduction of pathological activity and its transmission through the network could be responsible for amelioration of motor symptoms during DBS.…”

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

“…The early finding that DBS of the STN or GPi results in clinical benefits that are strikingly similar to those of lesioning at these sites for tremor and PD, respectively, suggested initially that DBS may act by inhibiting neurons in the area of stimulation [269][270][271]. This view was supported by the demonstration that some neurons in the vicinity of the stimulation site in STN and GPi in experimental animals and in patients with PD are, indeed, inhibited [272][273][274][275], perhaps by depolarization block or the release of GABA from terminals of afferents to the stimulated area [276][277][278][279][280].…”

Mechanisms of Deep Brain Stimulation in Movement Disorders as Revealed by Changes in Stimulus Frequency

“…21 A similar decrease in STN neuron firing rates was observed during STN high-frequency stimulation (HFS) of Parkinsonian monkeys. 22 Such somatic inhibition may occur by either activation of the axons of inhibitory afferents, 23 presynaptic depression at excitatory afferent axon terminals, 24 and/or depolarization-induced blockade of somatic ion channels. 25 On the other hand, there is abundant evidence that suggests that the efferent axons of the stimulated nucleus are activated by high frequency DBS.…”