Project Details
Description
PROJECT SUMMARY/ABSTRACT
The role of synchronized oscillations and changes in coherence and connectivity within the basal ganglia
thalamocortical (BGTC) network in the development of motor signs in Parkinson’s disease (PD) remain under
debate. While deep brain stimulation (DBS) has been an effective therapy for many PD patients, the
mechanism(s) that underlie its therapeutic effect or how these compare to those that result from administration
of L-dopa are not known. To advance DBS therapy we must improve our knowledge of the pathophysiological
changes that underlie the development of PD and how DBS and L-dopa therapies that improve motor signs
affect synchronized oscillations and connectivity in the “broader” BGTC (bBGTC) circuit (STN, GPi, motor
thalamus, motor cortex (MC), supplementary motor area (SMA), premotor and prefrontal cortices (PMC and
DLPFC respectively)). To address these questions, we will record neuronal and local field potential (LFP)
activity simultaneously from 4 cortical (MC, PMC, SMA and DLPFC) and 3 subcortical sites (STN, GPi, and
motor thalamus) in the nonhuman primate MPTP (1methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of
parkinsonism. We will test the hypothesis that synchronized oscillations form across cortical and subcortical
structures, alter the timing of synchronization and desynchronization of neuronal populations in specific
frequency bands during movement and change connectivity patterns found in the normal state. We will
characterize the relative change in synchronized coupling and connectivity in the bBGTC network and
parkinsonian motor signs during DBS (STN, GPi, and STN + GPi) and compare that to the effect of L-dopa,
and L-dopa + DBS (SA1). We will use directional leads to define the relative change in synchronized coupling
and connectivity in the bBGTC network on parkinsonian motor signs and the degree of activation of motor,
associative and limbic circuits during dDBS that steers current into motor versus associative regions of the
STN and GPi (SA2). We will also determine the effect of a closed loop DBS approach on bBGTC connectivity
and motor signs where stimulation is time locked to specific phases of the oscillatory biomarker determined
through each animal’s resonant oscillatory frequency, i.e., phase-locked DBS (plDBS) (SA3). This study will
provide a greater understanding of the pathophysiological changes that occur in bBGTC circuitry in PD, further
delineate the mechanisms underlying the therapeutic effects of DBS and L-dopa, and characterize the relative
effect of dDBS and a novel closed loop DBS approach on network connectivity and motor signs. These data
will provide the rationale upon which current DBS therapies can be improved and future DBS therapies
developed not only for PD but for other neurological and psychiatric disorders.
Status | Active |
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Effective start/end date | 7/1/99 → 1/31/25 |
Funding
- National Institute of Neurological Disorders and Stroke: $583,169.00
- National Institute of Neurological Disorders and Stroke: $317,604.00
- National Institute of Neurological Disorders and Stroke: $470,910.00
- National Institute of Neurological Disorders and Stroke: $599,791.00
- National Institute of Neurological Disorders and Stroke: $553,000.00
- National Institute of Neurological Disorders and Stroke: $534,420.00
- National Institute of Neurological Disorders and Stroke: $470,647.00
- National Institute of Neurological Disorders and Stroke: $532,603.00
- National Institute of Neurological Disorders and Stroke: $591,311.00
- National Institute of Neurological Disorders and Stroke: $481,984.00
- National Institute of Neurological Disorders and Stroke: $576,225.00
- National Institute of Neurological Disorders and Stroke: $590,873.00
- National Institute of Neurological Disorders and Stroke: $578,930.00
- National Institute of Neurological Disorders and Stroke: $532,605.00
- National Institute of Neurological Disorders and Stroke: $473,642.00
- National Institute of Neurological Disorders and Stroke: $326,781.00
- National Institute of Neurological Disorders and Stroke: $583,442.00
- National Institute of Neurological Disorders and Stroke: $532,604.00
- National Institute of Neurological Disorders and Stroke: $457,192.00
- National Institute of Neurological Disorders and Stroke: $577,209.00
- National Institute of Neurological Disorders and Stroke: $591,476.00
- National Institute of Neurological Disorders and Stroke: $578,337.00
- National Institute of Neurological Disorders and Stroke: $995,771.00
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