Deep brain stimulation (DBS) of the subthalamic nucleus (STN) dramatically improves motor function and quality of life in PD yet may alter cognitive skills and mood (Progress Report). Our studies and others suggest that functional organization of basal ganglia-thalamocortical (BGTC) circuits and their course through STN underlies these effects. We hypothesize based on preliminary data that DBS focused in ventral STN (V-STN) selectively alters cognition and mood whereas motor benefit is widely distributed. We propose that this functional organization of STN will produce downstream effects in relevant pathways. In people with PD, we will compare the effects of unilateral monopolar DBS through selected V-STN and dorsal STN (D-STN) contacts on quantified motor, cognitive, and mood function with DBS-induced rCBF responses and presurgical MRI-based resting state functional connectivity (rs-fcMRI) networks. We found that rs-fcMRI identified key cortical and BGTC networks that are disrupted in PD and can provide an anchor for interpretation of downstream effects seen with rCBF responses. These studies have great potential to extend our understanding of the functional anatomy of the STN by delineating its role in motor, cognitive and mood behaviors in PD. These studies could reveal valuable insights into the clinical action of DBS and the pathophysiology of cognitive, mood and motor symptoms of PD. However, the importance of these studies goes beyond the specifics of DBS treatment for PD. We can take this unique opportunity to investigate the function of selected brain pathways in the region of the STN and how they affect cognitive, mood and motor function. Such basic observations have importance for understanding STN function and how impairments lead to disabilities in other basal ganglia disorders. These studies also have the potential to help refine DBS targeting, inform future development of new electrode design to shape current spread and improve programming strategies for optimal clinical benefit from STN DBS.

Public Health Relevance

Parkinson disease (PD) affects nearly one million people in North American and leads to substantial disability for many. Deep brain stimulation (DBS) has been a dramatic advance, yet there are still many unknowns about how this new therapy works. This proposal has the potential to reveal valuable insights into the clinical action of DBS and the pathophysiology of non-motor as well as motor manifestations of PD. However, the importance of these studies goes well beyond the specifics of DBS treatment for PD. We also can take advantage of this unique opportunity to investigate the function of selected brain pathways and how they affect cognitive, mood and motor function. Such basic observations have importance for understanding normal function as well as how impairments lead to disabilities in other basal ganglia related disorders with motor or cognitive dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041509-13
Application #
8729026
Study Section
Special Emphasis Panel (ZRG1-BDCN-C (02))
Program Officer
Sieber, Beth-Anne
Project Start
2001-04-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
13
Fiscal Year
2014
Total Cost
$510,393
Indirect Cost
$174,608
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Jinnah, H A; Comella, Cynthia L; Perlmutter, Joel et al. (2018) Longitudinal studies of botulinum toxin in cervical dystonia: Why do patients discontinue therapy? Toxicon 147:89-95
Ibanez, Laura; Dube, Umber; Davis, Albert A et al. (2018) Pleiotropic Effects of Variants in Dementia Genes in Parkinson Disease. Front Neurosci 12:230
Milchenko, Mikhail; Norris, Scott A; Poston, Kathleen et al. (2018) 7T MRI subthalamic nucleus atlas for use with 3T MRI. J Med Imaging (Bellingham) 5:015002
Milchenko, Mikhail; Snyder, Abraham Z; Campbell, Meghan C et al. (2018) ESM-CT: a precise method for localization of DBS electrodes in CT images. J Neurosci Methods 308:366-376
Hardt, Joshua I; Perlmutter, Joel S; Smith, Christopher J et al. (2018) Pharmacokinetics and Toxicology of the Neuroprotective e,e,e-Methanofullerene(60)-63-tris Malonic Acid [C3] in Mice and Primates. Eur J Drug Metab Pharmacokinet 43:543-554
Maiti, Baijayanta; Perlmutter, Joel S (2018) PET Imaging in Movement Disorders. Semin Nucl Med 48:513-524
Takeda, Atsushi; Perlmutter, Joel S (2017) Striatal molecular imaging of presynaptic markers: Ready, fire, aim. Neurology 88:1388-1389
Ibanez, Laura; Dube, Umber; Saef, Benjamin et al. (2017) Parkinson disease polygenic risk score is associated with Parkinson disease status and age at onset but not with alpha-synuclein cerebrospinal fluid levels. BMC Neurol 17:198
Ibanez, Laura; Dube, Umber; Budde, John et al. (2017) TMEM230 in Parkinson's disease. Neurobiol Aging 56:212.e1-212.e3
Han, Junbin; Liu, Hui; Liu, Chunling et al. (2017) Pharmacologic characterizations of a P2X7 receptor-specific radioligand, [11C]GSK1482160 for neuroinflammatory response. Nucl Med Commun 38:372-382

Showing the most recent 10 out of 133 publications