High-frequency stimulation of the anterior subthalamic nucleus reduces stereotyped behaviors in primates

Abstract

Growing evidence shows that dysfunction of the limbic basal ganglia (BG) network is implicated in repetitive behaviors, such as obsessive compulsive disorder (OCD) and Tourette's syndrome (TS), in humans. Because deep brain stimulation (DBS) of the posterior subthalamic nucleus (STN), which modulates the sensorimotor BG network, is beneficial in movement disorders, stimulation of the anterior, limbic STN might improve intractable behavioral disorders. We therefore evaluated the effect of anterior STN stimulation on the repetitive behaviors induced in two monkeys after bicuculline-induced dysfunction of the limbic external globus pallidus. DBS in the anterior STN dramatically reduced the stereotypies, but had no effect on the performance of a simple food retrieval task. Stimulations outside the STN were less effective in reducing the stereotypies. Electrode trajectories, reconstructed postmortem, confirmed that the effective contacts were in the anterior STN. DBS in the limbic STN might therefore provide relief from the severe stereotyped behaviors observed in OCD and TS.

Figure 1.

A, Radiographic control of an electrode implanted in the STN. B, Section counterstained with cresyl violet showing the trace of the stimulation electrode in the anteromedial STN in monkey B. C, C′, Schematic representation of the brain section corresponding to the center of the stimulation contact 0, indicated by a cross (+) in monkey A and monkey B, respectively. The gray areas represent the electrode trace. D, D′, Reconstruction of the electrodes (blue) and the STN (green) from regularly spaced brain sections (50 μm thickness), viewed laterally in monkey A and monkey B, respectively. E, E′, The STN (green), putamen (Pu, red), caudate nucleus (Cd, pink), and the electrode (blue), as seen on regularly spaced brain sections. Thal, Thalamus. Scale bar, 1 mm.

Figure 2.

A, Representation of the associative (Ass), limbic (Limb), and sensorimotor (SM) territories of the GPe illustrated in green, blue, and yellow, respectively. B, Localization of the injection sites in the anterior part of GPe in monkeys A (triangles) and B (circles). C, Mean total duration of behaviors by periods of 180 s for DBS challenges at contact 0. Values are given for monkey A (black bars), B (gray bars), and both (white bars). The error bars show the SEM. **p < 0.01; ***p < 0.001. D, Results of individual stimulation challenges at contact 0. Duration of stereotypies by periods of 180 s is given in three conditions: control, injection alone, and injection with stimulation for monkey A (black lines) and monkey B (gray lines).