Understanding Parkinson's disease and deep brain stimulation: Role of monkey models

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Abstract

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder affecting over 10 million people worldwide. In the 1930s and 1940s there was little understanding regarding what caused PD or how to treat it. In a desperate attempt to improve patients' lives different regions of the neuraxis were ablated. Morbidity and mortality were common, but some patients' motor signs improved with lesions involving the basal ganglia or thalamus. With the discovery of L-dopa the advent of medical therapy began and surgical approaches became less frequent. It soon became apparent, however, that medical therapy was associated with side effects in the form of drug-induced dyskinesia and motor fluctuations and surgical therapies reemerged. Fortunately, during this time studies in monkeys had begun to lay the groundwork to understand the functional organization of the basal ganglia, and with the discovery of the neurotoxin MPTP a monkey model of PD had been developed. Using this model scientists were characterizing the physiological changes that occurred in the basal ganglia in PD and models of basal ganglia function and dysfunction were proposed. This work provided the rationale for the return of pallidotomy, and subsequently deep brain stimulation procedures. In this paper we describe the evolution of these monkey studies, how they provided a greater understanding of the pathophysiology underlying the development of PD and provided the rationale for surgical procedures, the search to understand mechanisms of DBS, and how these studies have been instrumental in understanding PD and advancing the development of surgical therapies for its treatment.

Original languageEnglish (US)
Pages (from-to)26259-26265
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number52
DOIs
StatePublished - Dec 26 2019

Bibliographical note

Funding Information:
This paper results from the Arthur M. Sackler Colloquium of the National Academy of Sciences, “Using Monkey Models to Understand and Develop Treatments for Human Brain Disorders,” held January 7–8, 2019, at the Arnold and Mabel Beckman Center of the National Academies of Sciences and Engineering in Irvine, CA. NAS colloquia began in 1991 and have been published in PNAS since 1995. From February 2001 through May 2019 colloquia were supported by a generous gift from The Dame Jillian and Dr. Arthur M. Sackler Foundation for the Arts, Sciences, & Humanities, in memory of Dame Sackler’s husband, Arthur M. Sackler. The complete program and video recordings of most presentations are available on the NAS website at http://www.nasonline.org/using-monkey-models. Author contributions: J.L.V. and L.A.J. designed research; J.L.V. and L.A.J. performed research; J.L.V. and L.A.J. contributed new reagents/analytical tools; J.L.V. and L.A.J. analyzed data; J.L.V. wrote the paper; and J.L.V. and L.A.J. edited and revised the paper and figures. Conflict of interest statement: J.L.V. serves as a consultant for Medtronic, Boston Scientific, and Abbott and serves on the scientific advisory board for Surgical Information Sciences. This article is a PNAS Direct Submission. Published under the PNAS license. 1To whom correspondence may be addressed. Email: vitek004@umn.edu. First published December 23, 2019.

Funding Information:
ACKNOWLEDGMENTS. This work was supported by NIH National Institute of Neurological Disorders and Stroke Grants R01 NS037019, R37 NS077657, and P50 NS098573 (to J.L.V.); Grant R01 NS058945 (to J.L.V. and L.A.J.); and Grant R01 NS110613 (to L.A.J.). Additional support was provided by MnDRIVE (Minnesota's Discovery, Research and Innovation Economy) Brain Conditions Program and an Engdall Philanthropic Donation.

Keywords

  • Basal ganglia
  • Deep brain stimulation
  • MPTP
  • Nonhuman primate
  • Parkinson's disease

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