Electrophysiological and metabolic evidence that high‐frequency stimulation of the subthalamic nucleus bridles neuronal activity in the subthalamic nucleus and the substantia nigra reticulata

Abstract

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) has been shown to produce a dramatic alleviation of motor symptoms in patients with advanced Parkinson's disease. Its functional mechanism, however, remains obscure. We used extracellular recording and in situ cytochrome oxidase (CoI) mRNA hybridization to investigate the effects of HFS of the STN on neuronal activity of the STN and the substantia nigra reticulata (SNr) in normal rats and rats with 6-hydroxydopamine (6-OHDA) lesion of the substantia nigra compacta (SNc). To allow detection of spikes and analysis of firing activity, artifacts recorded during stimulation were scaled down using a template subtraction method. In both normal and lesioned rats, the activity of a majority of STN neurons was inhibited during stimulation. In the SNr, HFS also induced an inhibition of the activity of a majority of neurons in normal and lesioned rats. In situ hybridization histochemistry confirmed these results in that it showed a significant decrease in levels of CoI mRNA expression in the STN and SNr in both normal and lesioned rats during stimulation. These data afford an interesting insight into the functional mechanism of deep brain stimulation and support the hypothesis that HFS exerts an inhibitory influence on STN neuronal firing.

Phase relationships support a role for coordinated activity in the indirect pathway in organizing slow oscillations in basal ganglia output after loss of dopamine

“…Interspike interval variability in the STN was more than that in the SNpr; STN ISI CV was 119% greater than that for the SNpr in the lesioned hemisphere and 38% greater than the SNpr ISI CV in control rats. Overall firing rate was also increased after dopamine cell lesion; firing rates of STN neurons ipsilateral to dopamine cell lesions were significantly greater (66%) than those in intact animals ( Table 1).These results are consistent with other studies carried out in urethane anesthetized rats, as well as in rats anesthetized with chloral hydrate, ketamine, or combined urethane-ketamine anesthesia 1-8 weeks after dopamine cell lesion (Hollerman and Grace, 1992;Hassani et al, 1996;Vila et al, 2000;Magill et al, 2001;Ni et al, 2001;Tai et al, 2003). In the present study, differences between intact and lesioned animals were optimized by analyzing activity over a relatively long time period (300 s) and by the use of urethane alone.…”

“…In addition, they provide an opportunity to examine relationships between interconnected nuclei to gain insight into the extent to which firing pattern changes in individual nuclei are linked to broader changes engaging the entire basal ganglia network. In one commonly used animal model of PD, the anesthetized rodent with a unilateral 6-hydroxydopamine (6-OHDA)-induced medial forebrain bundle lesion, a number of studies have found that firing patterns in STN and SNpr become more bursty (Sanderson et al, 1986;MacLeod et al, 1990;Hollerman and Grace, 1992;Burbaud et al, 1995;Hassani et al, 1996;Murer et al, 1997;Rohlfs et al, 1997;Tseng et al, 2000Tseng et al, , 2001aVila et al, 2000;Magill et al, 2001;Ni et al, 2001;Belluscio et al, 2003;Tai et al, 2003). This bursty activity has been shown to be correlated with slow oscillations in cortical EEG (Magill et al, 2001;Tseng et al, 2001b;Belluscio et al, 2003).…”

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.…”

“…In vivo experiments indicate that a small number of STN neurons exhibit higher firing rates during STN HFS, which may result from activation of excitatory presynaptic terminals. 22 Similarly, thalamic neurons in regions that receive predominantly excitatory afferents exhibit an increase in somatic activity during thalamic HFS. 32a For cells exhibiting complex firing patterns during HFS, the delayed excitatory and inhibitory phases likely reflect a combination of intrinsic membrane dynamics and network effects.…”