Deep brain stimulation has revolutionized the treatment of PD and renewed the exploration of surgical therapy for a wide range of neurological disorders including tremor, dystonia, obsessive compulsive disorder, depression, Tourette syndrome, addiction, pain and epilepsy. Despite the widespread use of DBS, its mechanism of action remains unclear. Debate continues over whether the beneficial effects of DBS are directly related to inhibition, excitation, changes in pattern, or some other as yet undetermined effect on neuronal activity. Three major issues limit the interpretation of previous studies that have sought to address the mechanism of action of DBS: 1) examining the effects of DBS on neuronal activity where behavioral state cannot be assessed (e.g. brain slices or anesthetized animals), 2) monitoring the effects of DBS at the site of stimulation without examining the effect on brain regions to which the stimulated site projects, and 3) examining the effects of DBS only after stimulation has been discontinued due to the problems associated with electrical stimulation artifacts. The results from many of these studies have been contradictory, likely secondary to the variety of conditions under which the experiments have been conducted. In addition most of these studies do not assess the effect of stimulation on neuronal activity during movement, the state during which most of the therapeutic effect of DBS is directed nor do they address the changes in neuronal activity at a network level. To address these limitations we propose to examine the effect of therapeutic DBS in the STN and GPi in monkeys performing a reaching task, while simultaneously recording from multiple nodal points in the basal ganglia thalamocortical network. Neuronal activity will be assessed under four conditions;at rest and during movement with and without stimulation. This study will provide significant insight into the changes in network activities that underlie the therapeutic effect of GPi and STN DBS on parkinsonian motor signs.
The goal of this study is to understand how electrical stimulation in the brain improves the motor symptoms associated with Parkinson's disease (PD). An animal model of PD will be used to study the effect of therapeutic deep brain stimulation on the electrical activity of different brain structures that are thought to function abnormally in PD. The areas stimulated will be the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi), two structures now used to treat idiopathic PD in patients. This study is unique because it will investigate neuronal activity during movement from many different brain structures at the same time;most previous work has only studied one neuron at a time during rest. By recording from many different brain structures simultaneously during movement we will begin to understand how these structures work together to produce movement, what goes wrong during PD, and how electrical stimulation changes brain activity to improve symptoms. The results of this study will provide the rationale to help develop better ways to stimulate currently targeted brain regions, identify new targets that may be more effective than current ones, and develop new technology that will allow us to optimize the therapeutic effect of DBS for the treatment of PD and other neurological disorders.
|Muralidharan, Abirami; Zhang, Jianyu; Ghosh, Debabrata et al. (2017) Modulation of Neuronal Activity in the Motor Thalamus during GPi-DBS in the MPTP Nonhuman Primate Model of Parkinson's Disease. Brain Stimul 10:126-138|
|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|
|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|
|Johnson, Luke A; Nebeck, Shane D; Muralidharan, Abirami et al. (2016) Closed-Loop Deep Brain Stimulation Effects on Parkinsonian Motor Symptoms in a Non-Human Primate - Is Beta Enough? Brain Stimul 9:892-896|
|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|
|Johnson, Luke A; Xu, Weidong; Baker, Kenneth B et al. (2015) Modulation of motor cortex neuronal activity and motor behavior during subthalamic nucleus stimulation in the normal primate. J Neurophysiol 113:2549-54|
|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; Muralidharan, Abirami; Hendrix, Claudia et al. (2015) Local field potential recordings in a non-human primate model of Parkinsons disease using the Activa PC + S neurostimulator. J Neural Eng 12:066012|
|Agnesi, Filippo; Muralidharan, Abirami; Baker, Kenneth B et al. (2015) Fidelity of frequency and phase entrainment of circuit-level spike activity during DBS. J Neurophysiol 114:825-34|
|Agnesi, Filippo; Connolly, Allison T; Baker, Kenneth B et al. (2013) Deep brain stimulation imposes complex informational lesions. PLoS One 8:e74462|
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