Deep brain stimulation (DBS) of either the internal segment of the globus pallidus (GPO or the subthalamic nucleus (STN) is an effective treatment for most if not all symptoms of Parkinson's disease (PD). Several aspects of the reduction of symptoms with DBS provide tantalizing hints that different symptoms may be mediated by distinct pathways and/or physiological processes involving the motor and premotor cortices. The goals of this project are to use a non-human primate model of PD to gain a better understanding of the cortical mechanisms by which DBS produces clinical benefit, as well as to determine if different symptoms have different neuroanatomic/physiologic substrates. Animals will perform tasks that measure symptom-relevant behavioral parameters: movement selection/initiation/sequencing (akinesia), movement kinematics (bradykinesia), and rigidity. Neuronal activity at multiple locations in the four principal motor cortices [in different animals, primary motor (M1), ventral premotor (PMv), dorsal premotor (PMd), or mesial premotor (SMA)] will be monitored using a multielectrode array. Single cell activity will be assessed for changes in resting firing rate, task-related activity, and cell-to-cell interactions (synchronized firing) in response to DBS in GPI or STN before and after animals are rendered parkinsonian by intracarotid infusion of MPTP. The predictions are that: DBS-related changes in resting discharge will not be correlated with specific changes in symptoms. Increased activity and synchrony in SMA will be associated with reduced akinesia. Increases of the same in M1 will accompany reduced bradykinesia. Reductions in rigidity will be linked with a drop in M1 responses to passive movement and increased directional specificity in movement related activity. In addition, DBS may reduce abnormally-increased activity in PMv and PMd These hypotheses will be tested in three specific aims:
Specific aim I will study the interacting effects of DBS and the type of motor task being performed.
Specific aims 2 and 3 will identify cortical activities that change in concert with the time course (SA 2) and parametric relations (SA 3, DBS location, frequency, and strength) of symptom reduction with DBS. The results of these experiments will improve understanding of both the neuronal basis of different symptoms of PD and the mechanisms of action of DBS. Ultimately, these studies will advance a more complete pathophysiologic model of PD by incorporating the full array of parkinsonian symptoms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS044551-02
Application #
6619689
Study Section
Special Emphasis Panel (ZNS1-SRB-A (01))
Program Officer
Quinn, Kevin J
Project Start
2002-08-01
Project End
2007-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
2
Fiscal Year
2003
Total Cost
$323,831
Indirect Cost
Name
University of California San Francisco
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Pasquereau, Benjamin; DeLong, Mahlon R; Turner, Robert S (2016) Primary motor cortex of the parkinsonian monkey: altered encoding of active movement. Brain 139:127-43
McCairn, Kevin W; Turner, Robert S (2015) Pallidal stimulation suppresses pathological dysrhythmia in the parkinsonian motor cortex. J Neurophysiol 113:2537-48
Zimnik, Andrew J; Nora, Gerald J; Desmurget, Michel et al. (2015) Movement-related discharge in the macaque globus pallidus during high-frequency stimulation of the subthalamic nucleus. J Neurosci 35:3978-89
Pasquereau, Benjamin; Turner, Robert S (2011) Primary motor cortex of the parkinsonian monkey: differential effects on the spontaneous activity of pyramidal tract-type neurons. Cereb Cortex 21:1362-78
Shimamoto, S A; Larson, P S; Ostrem, J L et al. (2010) Physiological identification of the human pedunculopontine nucleus. J Neurol Neurosurg Psychiatry 81:80-6
Desmurget, Michel; Turner, Robert S (2010) Motor sequences and the basal ganglia: kinematics, not habits. J Neurosci 30:7685-90
McCairn, Kevin W; Turner, Robert S (2009) Deep brain stimulation of the globus pallidus internus in the parkinsonian primate: local entrainment and suppression of low-frequency oscillations. J Neurophysiol 101:1941-60
Christine, Chadwick W; Langston, J William; Turner, Robert S et al. (2009) The neurophysiology and effect of deep brain stimulation in a patient with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism. J Neurosurg 110:234-8
Schrock, Lauren E; Ostrem, Jill L; Turner, Robert S et al. (2009) The subthalamic nucleus in primary dystonia: single-unit discharge characteristics. J Neurophysiol 102:3740-52
Sani, Sepehr; Shimamoto, Shoichi; Turner, Robert S et al. (2009) Microelectrode recording in the posterior hypothalamic region in humans. Neurosurgery 64:ons161-7; discussion ons167-9

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