TY - JOUR
T1 - Deep brain stimulation of midbrain locomotor circuits in the freely moving pig
AU - Chang, Stephano J.
AU - Santamaria, Andrea J.
AU - Sanchez, Francisco J.
AU - Villamil, Luz M.
AU - Saraiva, Pedro Pinheiro
AU - Benavides, Francisco
AU - Nunez-Gomez, Yohjans
AU - Solano, Juan P.
AU - Opris, Ioan
AU - Guest, James D.
AU - Noga, Brian R.
N1 - Funding Information:
This work was supported by the Department of Defense (DOD) award SCI140238/W81XWH1510584 to BRN and JDG and National Institutes of Neurological Disorders and Stroke (NINDS) grant R01 NS089972 . SJC was supported by a research fellowship from the Neurosurgery Research and Education Foundation ( GR010471 ) and the UBC Clinician Investigator Program. This work was additionally supported by NIH grant 1S10OD023579-01 for the VS120 Slide Scanner housed at the University of Miami Miller School of Medicine Analytical Imaging Core Facility. We would like to acknowledge Marcia Boulina and all of the staff in the Diabetes Research Institute Analytical Imaging Core Facility for their help with histological imaging, Jose Rodriguez for accommodating neuroimaging needs for our animals, and all the staff in our Division of Veterinary Resources, without whom this work would not have been possible.
Publisher Copyright:
© 2021
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/5/1
Y1 - 2021/5/1
N2 - Background: Deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR) has been studied as a therapeutic target in rodent models of stroke, parkinsonism, and spinal cord injury. Clinical DBS trials have targeted the closely related pedunculopontine nucleus in patients with Parkinson's disease as a therapy for gait dysfunction, with mixed reported outcomes. Recent studies suggest that optimizing the MLR target could improve its effectiveness. Objective: We sought to determine if stereotaxic targeting and DBS in the midbrain of the pig, in a region anatomically similar to that previously identified as the MLR in other species, could initiate and modulate ongoing locomotion, as a step towards generating a large animal neuromodulation model of gait. Methods: We implanted Medtronic 3389 electrodes into putative MLR structures in Yucatan micropigs to characterize the locomotor effects of acute DBS in this region, using EMG recordings, joint kinematics, and speed measurements on a manual treadmill. Results: MLR DBS initiated and augmented locomotion in freely moving micropigs. Effective locomotor sites centered around the cuneiform nucleus and stimulation frequency controlled locomotor speed and stepping frequency. Off-target stimulation evoked defensive and aversive behaviors that precluded locomotion in the animals. Conclusion: Pigs appear to have an MLR and can be used to model neuromodulation of this gait-promoting center. These results indicate that the pig is a useful model to guide future clinical studies for optimizing MLR DBS in cases of gait deficiencies associated with such conditions as Parkinson's disease, spinal cord injury, or stroke.
AB - Background: Deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR) has been studied as a therapeutic target in rodent models of stroke, parkinsonism, and spinal cord injury. Clinical DBS trials have targeted the closely related pedunculopontine nucleus in patients with Parkinson's disease as a therapy for gait dysfunction, with mixed reported outcomes. Recent studies suggest that optimizing the MLR target could improve its effectiveness. Objective: We sought to determine if stereotaxic targeting and DBS in the midbrain of the pig, in a region anatomically similar to that previously identified as the MLR in other species, could initiate and modulate ongoing locomotion, as a step towards generating a large animal neuromodulation model of gait. Methods: We implanted Medtronic 3389 electrodes into putative MLR structures in Yucatan micropigs to characterize the locomotor effects of acute DBS in this region, using EMG recordings, joint kinematics, and speed measurements on a manual treadmill. Results: MLR DBS initiated and augmented locomotion in freely moving micropigs. Effective locomotor sites centered around the cuneiform nucleus and stimulation frequency controlled locomotor speed and stepping frequency. Off-target stimulation evoked defensive and aversive behaviors that precluded locomotion in the animals. Conclusion: Pigs appear to have an MLR and can be used to model neuromodulation of this gait-promoting center. These results indicate that the pig is a useful model to guide future clinical studies for optimizing MLR DBS in cases of gait deficiencies associated with such conditions as Parkinson's disease, spinal cord injury, or stroke.
KW - Cuneiform nucleus
KW - Deep brain stimulation
KW - Defensive behavior
KW - Locomotion
KW - Mesencephalic locomotor region
KW - Pig
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U2 - 10.1016/j.brs.2021.02.017
DO - 10.1016/j.brs.2021.02.017
M3 - Article
AN - SCOPUS:85102295642
VL - 14
SP - 467
EP - 476
JO - Brain Stimulation
JF - Brain Stimulation
SN - 1935-861X
IS - 3
ER -