Stimulation of zona incerta selectively modulates pain in humans

Charles W Lu,Daniel E Harper,Asra Askari,Matthew S Willsey,Philip P Vu,Parag G Patil,Steven E Harte,Andrew D Schrepf

doi:10.1038/s41598-021-87873-w

Charles W Lu, Daniel E Harper + Show 6 more

Open Access

https://doi.org/10.1038/s41598-021-87873-w

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Abstract

Stimulation of zona incerta in rodent models has been shown to modulate behavioral reactions to noxious stimuli. Sensory changes observed in Parkinsonian patients with subthalamic deep brain stimulation suggest that this effect is translatable to humans. Here, we utilized the serendipitous placement of subthalamic deep brain stimulation leads in 6 + 5 Parkinsonian patients to directly investigate the effects of zona incerta stimulation on human pain perception. We found that stimulation at 20 Hz, the physiological firing frequency of zona incerta, reduces experimental heat pain by a modest but significant amount, achieving a 30% reduction in one fifth of implants. Stimulation at higher frequencies did not modulate heat pain. Modulation was selective for heat pain and was not observed for warmth perception or pressure pain. These findings provide a mechanistic explanation of sensory changes seen in subthalamic deep brain stimulation patients and identify zona incerta as a potential target for neuromodulation of pain.

Highlights

Stimulation of zona incerta in rodent models has been shown to modulate behavioral reactions to noxious stimuli
Modulation was specific to heat pain and did not significantly alter perception of non-painful heat or mechanical pain. These findings provide a mechanistic explanation of sensory changes seen in subthalamic Deep brain stimulation (DBS) patients and identify zona incerta as a potential target for neuromodulation of pain
This study evaluates a new form of DBS for pain and demonstrates that stimulation of zona incerta achieves a modest but significant analgesic effect in human subjects

Summary

Introduction

Stimulation of zona incerta in rodent models has been shown to modulate behavioral reactions to noxious stimuli. We utilized the serendipitous placement of subthalamic deep brain stimulation leads in 6 + 5 Parkinsonian patients to directly investigate the effects of zona incerta stimulation on human pain perception. Modulation was selective for heat pain and was not observed for warmth perception or pressure pain These findings provide a mechanistic explanation of sensory changes seen in subthalamic deep brain stimulation patients and identify zona incerta as a potential target for neuromodulation of pain. Multiple studies show that this effect is not explained by motor improvements alone[18, 19], indicating an independent mechanism by which subthalamic stimulation ameliorates pain symptoms Taken together, these observations strongly suggest that stimulation of zona incerta modulates pain perception. We utilized the serendipitous placement of subthalamic DBS leads in patients with Parkinson disease to directly evaluate the effects of zona incerta DBS on human perception of experimental heat

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