Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons

Abstract

To clarify the mechanism underlying improvement of parkinsonian signs by high-frequency electrical stimulation (HFS) of the subthalamic nucleus (STN), we investigated the effects of STN HFS on neuronal activity of the internal and external segment of the globus pallidus (GPi and GPe, respectively) in two rhesus monkeys rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. A scaled-down version of the chronic stimulating electrode used in humans, consisting of four metal contacts 0.50 mm in length each separated by 0.50 mm, was implanted through a cephalic chamber targeting the STN. Histological reconstruction revealed that the cathode was located in the STN in both monkeys. Extracellular recordings from a total of 110 pallidal neurons during STN stimulation were performed. Poststimulus time histograms of single neurons triggered by 2 Hz STN stimulation pulses at 2.4-3.0 V revealed short-latency excitations at 2.5-4.5 and 5.5-7.0 msec after stimulation onset and inhibitions at 1.0-2.5, 4.5-5.5, and 7.0-9.0 msec for both GPe and GPi neurons. These short-latency responses were present with 136 Hz stimulation, at voltages effective for alleviation of parkinsonian signs, resulting in a significant increase in mean discharge rate and a stimulus-synchronized regular firing pattern. These results indicate that activation of the STN efferent fibers and resultant changes in the temporal firing pattern of neurons in GPe and GPi underlie the beneficial effect of HFS in the STN in Parkinson's disease and further support the role of temporal firing patterns in the basal ganglia in the development of Parkinson's disease and other movement disorders.

Figures

Fig. 1.

Location of the electrode contacts and neurons recorded during 136 Hz at 1.8 V in monkey R7160 and at 3.0 V in monkey R370, and changes in the firing rate. The cathode of the stimulation electrode was located in the posteromedial portion of the STN in monkey R7160 and on the posterior portion of the STN in monkey R370, 1 mm lateral to that of monkey R7160. Scale bars, 5 mm. OT, Optic tract; Ret, thalamic reticular nucleus;SN, substantia nigra; STR, striatum;TH, thalamus.

Fig. 2.

Effect of STN stimulation on movement and rigidity. The total movement time of the limbs was measured by raters blinded to the experimental condition (S.P. and M.O.) from seven recordings for each stimulation condition. Without stimulation, the monkeys sat quietly with little movement of the extremities (bradykinesia) on the side contralateral to the MPTP injection. Stimulation at 136 Hz was associated with increased movement on both sides in monkey R7160 (A) and monkey R370 (B). Increases in movement time were larger on the side contralateral to STN stimulation in both monkeys (right side in R7160, left side in R370). Asterisks indicate a significant difference in the on versus off stimulation condition: *p < 0.05, ***p < 0.001; apost hoc analysis (Tukey's honestly significant difference). C, Stimulation at 136 Hz, 3.0 V (top, stimulation signals recorded from the chamber) reduced biceps brachii EMGs (second trace, surface EMGs) induced by manual elbow extension (bottom trace) in monkey R370.

Fig. 3.

Overlay of 50 sweeps of neuronal activity of a GPi cell during 2 Hz (top), 136 Hz (middle), and 157 Hz (bottom) stimulation at 3.0 V (R370). Depolarization (negative potential) is shown as an upward deflection. Each stimulation frequency is associated with excitation peaks at 2.5–4.0 msec and 5.5–7.0 msec after the onset of stimulation. Short-latency excitation was greater and more tightly coupled to each stimulation pulse during higher-frequency stimulation.Arrows indicate residual stimulation artifacts after artifact template subtraction.

Fig. 4.

Rasters (A) and ISI histograms (B) of GPi neuronal activity (R370). The firing changed from an irregular pattern with varying ISIs into a high-frequency regular pattern with most ISIs occurring at 4 or 8 msec during 136 Hz, 3.0 V stimulation.

Fig. 5.

A, B, Examples of neuronal responses occurring during STN stimulation in a GPi and GPe cell, respectively. Top traces show analog signal overlays of 100 sweeps made by triggering at 10 msec intervals in the prestimulation (before start of stimulation) period and by triggering on the stimulation pulse in the on-stimulation period.Arrows indicate residual stimulation artifacts after artifact template subtraction. Middle traces display PSTHs reconstructed from successive 7.0 msec time periods in the prestimulation period and from the interstimulus periods, in the on-stimulation period. The first PSTH bin is omitted in the on-stimulation period because of signal saturation and residual stimulation artifacts. *Significant increase at p< 0.01; † significant decrease at p< 0.01; Wilcoxon signed rank test. Bottom plotsrepresent the mean firing rate calculated every 1 sec on the basis of the PSTH illustrating the time course of the firing rate.C, An example of the time course of the change in firing rate of a GPi neuron during prolonged 136 Hz STN stimulation. Increased mean discharge rates in this neuron were sustained during the 5 min stimulation period. The thick bars indicate the stimulation period.

Fig. 6.

Change in the mean firing rate of GPe and GPi neurons during 136 Hz STN stimulation in the two monkeys.A–C, Monkey R7160. During 1.4 V stimulation, the firing rates did not change significantly in either GPe or GPi, but during 1.8 V stimulation, the mean discharge rate increased significantly, and the percentage of neurons displaying a change in the firing rate showed a strong shift to excitation in both GPe and GPi. D–F, Monkey R370. Stimulation of 2.0 V did not induce a significant change in the firing rate, but 3.0 V stimulation increased the firing rate significantly and shifted the percentage of neurons to excitation in both GPe and GPi. Asterisks indicate a significant difference in on versus off stimulation conditions. Significant differences: *p < 0.01, **p < 0.001, ***p < 0.001; t test.