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ABSTRACT: Subthalamic nucleus deep brain stimulation (STN DBS) ameliorates motor symptoms of Parkinson's disease, but the precise mechanism is still unknown. Here, using a large animal (pig) model of human STN DBS neurosurgery, we utilized fast-scan cyclic voltammetry in combination with a carbon-fiber microelectrode (CFM) implanted into the striatum to monitor dopamine release evoked by electrical stimulation at a human DBS electrode (Medtronic 3389) that was stereotactically implanted into the STN using MRI and electrophysiological guidance. STN electrical stimulation elicited a stimulus time-locked increase in striatal dopamine release that was both stimulus intensity- and frequency-dependent. Intensity-dependent (1-7V) increases in evoked dopamine release exhibited a sigmoidal pattern attaining a plateau between 5 and 7V of stimulation, while frequency-dependent dopamine release exhibited a linear increase from 60 to 120Hz and attained a plateau thereafter (120-240Hz). Unlike previous rodent models of STN DBS, optimal dopamine release in the striatum of the pig was obtained with stimulation frequencies that fell well within the therapeutically effective frequency range of human DBS (120-180Hz). These results highlight the critical importance of utilizing a large animal model that more closely represents implanted DBS electrode configurations and human neuroanatomy to study neurotransmission evoked by STN DBS. Taken together, these results support a dopamine neuronal activation hypothesis suggesting that STN DBS evokes striatal dopamine release by stimulation of nigrostriatal dopaminergic neurons.
Neuroscience Letters 03/2010; 475(3):136-40. · 2.11 Impact Factor
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Kendall H Lee,
Charles D Blaha,
Paul A Garris,
Pedram Mohseni,
April E Horne,
Kevin E Bennet,
Filippo Agnesi,
Jonathan M Bledsoe,
Deranda B Lester, Chris Kimble,
Hoon-Ki Min,
Young-Bo Kim,
Zang-Hee Cho
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ABSTRACT: Deep Brain Stimulation (DBS) provides therapeutic benefit for several neuropathologies including Parkinson's disease (PD), epilepsy, chronic pain, and depression. Despite well established clinical efficacy, the mechanism(s) of DBS remains poorly understood. In this review we begin by summarizing the current understanding of the DBS mechanism. Using this knowledge as a framework, we then explore a specific hypothesis regarding DBS of the subthalamic nucleus (STN) for the treatment of PD. This hypothesis states that therapeutic benefit is provided, at least in part, by activation of surviving nigrostriatal dopaminergic neurons, subsequent striatal dopamine release, and resumption of striatal target cell control by dopamine. While highly controversial, we present preliminary data that are consistent with specific predications testing this hypothesis. We additionally propose that developing new technologies, e.g., human electrometer and closed-loop smart devices, for monitoring dopaminergic neurotransmission during STN DBS will further advance this treatment approach.
Neuromodulation 04/2009; 12(2):85-103. · 1.19 Impact Factor
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PhD Kendall H. Lee MD,
Charles D. Blaha PhD,
Paul A. Garris PhD,
Pedram Mohseni PhD,
April E. Horne MBA,
Kevin E. Bennet MBA,
Filippo Agnesi MS,
Jonathan M. Bledsoe MD,
Deranda B. Lester MS, Chris Kimble MS,
Hoon-Ki Min MS,
PhD Young-Bo Kim MD,
Zang-Hee Cho PhD
[show abstract]
[hide abstract]
ABSTRACT: Deep brain stimulation (DBS) provides therapeutic benefit for several neuropathologies, including Parkinson disease (PD), epilepsy, chronic pain, and depression. Despite well-established clinical efficacy, the mechanism of DBS remains poorly understood. In this review, we begin by summarizing the current understanding of the DBS mechanism. Using this knowledge as a framework, we then explore a specific hypothesis regarding DBS of the subthalamic nucleus (STN) for the treatment of PD. This hypothesis states that therapeutic benefit is provided, at least in part, by activation of surviving nigrostriatal dopaminergic neurons, subsequent striatal dopamine release, and resumption of striatal target cell control by dopamine. While highly controversial, we present preliminary data that are consistent with specific predications testing this hypothesis. We additionally propose that developing new technologies (e.g., human electrometer and closed-loop smart devices) for monitoring dopaminergic neurotransmission during STN DBS will further advance this treatment approach.
Neuromodulation 03/2009; 12(2):85 - 103. · 1.19 Impact Factor
