Parkinson's disease (PD) affects nearly one million people and dystonia affects up to 500,000 people in North America. It is generally accepted that the motor manifestations of PD are due to degeneration of nigrostriatal dopamine neurons with resulting striatal dopamine depletion. The causes of dystonia are more numerous. Recent evidence has indicated that dystonia (involuntary muscle contractions that produce twisting postures) can also be associated with deficiencies in striatal dopamine neurotransmission. In monkeys, it has been shown that unilateral striatal dopamine depletion induced by intracarotid injection of MPTP causes a biphasic disorder with transient dystonia followed by stable parkinsonism. The association of both dystonia and parkinsonism with equivalent degrees of striatal dopamine deficiency raises questions about the fundamental pathophysiology of these conditions. The purpose of this project is to investigate the pathophysiology of parkinsonism and dystonia by recording the activity of globus pallidus neurons before and after the administration of MPTP in monkeys trained to perform a reaching task. Quantitative behavioral methods and PET imaging will be used to measure the severity of dystonia, parkinsonism, and dopamine depletion. The activity of single neurons in globus pallidus internal segment (GPi) and external segment (GPe) will be recording in monkeys before MPTP and in the transient dystonic phase and chronic parkinsonian phase after MPTP.
The specific aims are: 1) to determine to determine the relationship of resting pallidal discharge rates, patterns, and synchronization to dystonia and parkinsonism;2) to determine specific changes in movement-related neuronal activity that accompany dystonia and parkinsonism;3) to determine whether there is loss of somatotopic selectivity in the sensorimotor region of putamen and whether the loss of somatotopic selectivity in globus pallidus is due to abnormal signal processing in the putamen.
These aims will test specific hypotheses of basal ganglia dysfunction related to dystonia and parkinsonism. The results from this study will advance our understanding of the pathophysiology of parkinsonism and dystonia in ways not possible from studies in rodent models or in human subjects. Better understanding of the pathophysiology may lead to new therapies or improved application of currently available therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039821-09
Application #
7775010
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Sieber, Beth-Anne
Project Start
2000-04-10
Project End
2012-02-29
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
9
Fiscal Year
2010
Total Cost
$299,672
Indirect Cost
Name
University of Rochester
Department
Neurology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Augustine, Erika F; Blackburn, Joanna; Pellegrino, Joan E et al. (2013) Myoclonus-dystonia syndrome associated with Russell Silver syndrome. Mov Disord 28:841-2
Brashear, Allison; Mink, Jonathan W; Hill, Deborah F et al. (2012) ATP1A3 mutations in infants: a new rapid-onset dystonia-Parkinsonism phenotype characterized by motor delay and ataxia. Dev Med Child Neurol 54:1065-7
Karimi, Morvarid; Moerlein, Stephen M; Videen, Tom O et al. (2011) Decreased striatal dopamine receptor binding in primary focal dystonia: a D2 or D3 defect? Mov Disord 26:100-6
Burack, M A; Hartlein, J; Flores, H P et al. (2010) In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia. Neurology 74:77-84
Kaufman, Christian B; Mink, Jonathan W; Schwalb, Jason M (2010) Bilateral deep brain stimulation for treatment of medically refractory paroxysmal nonkinesigenic dyskinesia. J Neurosurg 112:847-50
Xiao, J; Zhao, Y; Bastian, R W et al. (2010) Novel THAP1 sequence variants in primary dystonia. Neurology 74:229-38
Khandwala, V J; Burack, M A; Mink, J W et al. (2009) Measurement of upper limb kinematics and joint angle patterns during deep brain stimulation for parkinson's disease. Conf Proc IEEE Eng Med Biol Soc 2009:1553-6
Kumar, Nishant; Lee, John J; Perlmutter, Joel S et al. (2009) Cervical carotid and circle of willis arterial anatomy of macaque monkeys: a comparative anatomy study. Anat Rec (Hoboken) 292:976-84

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