Basal Ganglia Cortical Coupling and Connectivity Changes in PD and DBS

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.