The goal of this study is to identify the specific neurophysiological changes in the basal ganglia thalamic network that underlie the development and severity of bradykinesia, rigidity and tremor, the three cardinal motor signs of Parkinson's disease (PD). This will be done by comparing single neuron activity during normal, mild, moderate and severe parkinsonian symptoms in the same monkeys using sequential low doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Structures that will be examined include the internal and external segments of the globus pallidus (GPi and GPe, respectively), the subthalamic nucleus (STN), and the motor thalamus including ventralis anterior, ventralis lateralis pars oralis, and ventralis posterior lateralis pars oralis.
Specific aims 1 and 2 will determine the characteristics of neuronal activity at these nodal points within the basal ganglia network that underlie the development of bradykinesia, rigidity and tremor and characterize the evolution of changes in neuronal activity that occur with increasing severity of these motor signs.
Specific aim 2 will also determine the relative effect of fiber sparing lesions of each thalamic subnucleus on individual motor signs.
Specific aim 3 will assess the causal role of the particular changes in neurophysiological activity found to occur in specific aims 1 and 2. This will be done by reproducing these neurophysiological changes in the STN and GPi in normal monkeys and augmenting them in mildly parkinsonian monkeys using externally programmed implanted stimulators at these nodal points. By examining the neurophysiological changes that occur at different stages of PD and relating them to the occurrence and severity of individual motor symptoms, we will be able to clarify the neuronal basis underlying the development and severity of motor signs associated with PD. This will in turn provide the rationale from which to base the development of promising new therapies such as deep brain stimulation and gene therapy that are directed at modulating neuronal activity in the basal ganglia thalamic circuit. The goal of this study is to identify the specific changes in the activity of brain cells in the basal ganglia that cause the movement problems in Parkinson's disease (PD). People with PD develop specific problems with movement manifested as slowness (bradykinesia), stiffness (rigidity), and uncontrollable rhythmic movements in the extremities and face (tremor). This study will identify the specific changes in brain activity that cause each motor symptom and determine how they are related to increasing severity of each symptom. The results of this study will provide the understanding necessary for the refinement of current and development of future therapies, e.g., deep brain stimulation and gene therapy, directed at modulating the neuronal activity in the basal ganglia thalamic circuit responsible for the development of PD motor symptoms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS058945-06
Application #
8214519
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Sieber, Beth-Anne
Project Start
2008-02-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2015-01-31
Support Year
6
Fiscal Year
2012
Total Cost
$593,619
Indirect Cost
$200,494
Name
University of Minnesota Twin Cities
Department
Neurology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Zhang, Simeng; Connolly, Allison T; Madden, Lauren R et al. (2018) High-resolution local field potentials measured with deep brain stimulation arrays. J Neural Eng 15:046019
Wang, Jing; Johnson, Luke A; Jensen, Alicia L et al. (2017) Network-wide oscillations in the parkinsonian state: alterations in neuronal activities occur in the premotor cortex in parkinsonian nonhuman primates. J Neurophysiol 117:2242-2249
Escobar Sanabria, David; Johnson, Luke A; Nebeck, Shane D et al. (2017) Parkinsonism and vigilance: alteration in neural oscillatory activity and phase-amplitude coupling in the basal ganglia and motor cortex. J Neurophysiol 118:2654-2669
Muralidharan, A; Jensen, A L; Connolly, A et al. (2016) Physiological changes in the pallidum in a progressive model of Parkinson's disease: Are oscillations enough? Exp Neurol 279:187-196
Connolly, Allison T; Jensen, Alicia L; Bello, Edward M et al. (2015) Modulations in oscillatory frequency and coupling in globus pallidus with increasing parkinsonian severity. J Neurosci 35:6231-40
Dorval, Alan D; Muralidharan, Abirami; Jensen, Alicia L et al. (2015) Information in pallidal neurons increases with parkinsonian severity. Parkinsonism Relat Disord 21:1355-61
Connolly, Allison T; Jensen, Alicia L; Baker, Kenneth B et al. (2015) Classification of pallidal oscillations with increasing parkinsonian severity. J Neurophysiol 114:209-18
Kobayashi, K; Liu, C C; Jensen, A L et al. (2013) Thalamic post-inhibitory bursting occurs in patients with organic dystonia more often than controls. Brain Res 1541:81-91
Cooper, Scott E; McIntyre, Cameron C; Fernandez, Hubert H et al. (2013) Association of deep brain stimulation washout effects with Parkinson disease duration. JAMA Neurol 70:95-9
Vitek, Jerrold L; Lyons, Kelly E; Bakay, Roy et al. (2010) Standard guidelines for publication of deep brain stimulation studies in Parkinson's disease (Guide4DBS-PD). Mov Disord 25:1530-7

Showing the most recent 10 out of 12 publications