Erik Middlebrooks

The globus pallidus externus (GPe) is an important node in the basal ganglia circuitry that has been shown to be dysfunctional in numerous disorders, such as Parkinson disease and dystonia. Despite this, there has been relatively little investigation of the GPe in the realm of neuromodulation, with far more focus on the more medial globus pallidus internus (GPi). Nevertheless, a beneficial effect of GPe stimulation has been observed, such as with stimulation of contacts lying within the GPe in patients who had been originally targeted in the GPi for dystonia. Additionally, rodent studies suggested beneficial effects of GPe stimulation in multiple forms of basal ganglia dysfunction. Despite these findings, little is known about the extent of connectivity arising from the GPe in humans, including the functional divisions within the nucleus. While basal ganglia have historically been considered to function primarily in motor circuitry, more recent evidence confirms the presence of a tripartite division of other subcortical nuclei, such as the subthalamic nucleus and GPi. In this study, we were able to show a similar tripartite division of the GPe with a posterior sensorimotor portion, middle associative portion, and anterior limbic portion. Improved understanding of the functional anatomy of the GPe may serve to benefit future studies on neuromodulation of this nucleus that has historically been disregarded in functional neurosurgery.

Since this study, our group and others have continued to explore the role of the GPe in various neurologic disorders and neuromodulation. A recent study on deep brain stimulation (DBS) for obsessive-compulsive disorder (OCD) found that the distribution of the electrical field overlapping the anteromedial GPe was one of the factors explaining clinical improvement.¹

Interestingly, based on our findings, this would relate to the anterior limbic portion of the GPe. This is important, as the same limbic network has been implicated in the treatment of OCD in other targets, such as the anterior limbic portion of the subthalamic nucleus. In addition to therapeutic effects, the GPe may play a key role in undesired side effects of DBS. Our group has recently shown that stimulation-induced dyskinesias in GPi DBS are explained by off-target stimulation of the associative/sensorimotor segment of the GPe.² Lastly, we have also recently explored the use of GPe DBS for treatment of insomnia. Insomnia is a debilitating condition that may occur in isolation or may commonly be seen with other neurodegenerative disorders, such as Parkinson disease. The GPe has previously been implicated as a regulator over the reticular thalamic nucleus and sleep network, with GPe lesions resulting in profound sleep loss. Using this connectomic model of the GPe, we were able to determine the GPe region with greatest connectivity to this sleep network as a DBS target, which resulted in a substantial improvement in rapid eye movement and deep sleep in a first-in-human study.³

In summary, the GPe may serve as an important structure in neuromodulation with extensive network connectivity beyond the motor network, including limbic and associative networks. The tripartite division mirrors that observed in other basal ganglia nuclei, such as the subthalamic nucleus and GPi. This division provides insights into the documented effects of GPe stimulation in various disorders, such as dystonia, OCD, and Parkinson disease.

References

1. Naesström M, Johansson J, Hariz M, et al. Distribution of electric field in patients with obsessive compulsive disorder treated with deep brain stimulation of the bed nucleus of stria terminalis. Acta Neurochir (Wien) 2022;164:193–202
2. Tsuboi T, Charbel M, Peterside DT, et al. Pallidal connectivity profiling of stimulation-induced dyskinesia in Parkinson's disease. Mov Disord 2021;36:380–88
3. Castillo PR, Middlebrooks EH, Grewal SS, et al. Globus pallidus externus deep brain stimulation treats insomnia in a patient with Parkinson disease. Mayo Clin Proc 2020;95:419–22

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