Functional circuitry effect of ventral tegmental area deep brain stimulation: Imaging and neurochemical evidence of mesocortical and mesolimbic pathway modulation

Megan L. Settell, Paola Testini, Shinho Cho, Jannifer H. Lee, Charles D. Blaha, Hang J. Jo, Kendall H Lee, Hoon Ki Min

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background: The ventral tegmental area (VTA), containing mesolimbic and mesocortical dopaminergic neurons, is implicated in processes involving reward, addiction, reinforcement, and learning, which are associated with a variety of neuropsychiatric disorders. Electrical stimulation of the VTA or the medial forebrain bundle and its projection target the nucleus accumbens (NAc) is reported to improve depressive symptoms in patients affected by severe, treatment-resistant major depressive disorder (MDD) and depressive-like symptoms in animal models of depression. Here we sought to determine the neuromodulatory effects of VTA deep brain stimulation (DBS) in a normal large animal model (swine) by combining neurochemical measurements with functional magnetic resonance imaging (fMRI). Methods: Animals (n = 8 swine) were implanted with a unilateral DBS electrode targeting the VTA. During stimulation (130 Hz frequency, 0.25 ms pulse width, and 3 V amplitude), fMRI was performed. Following fMRI, fast-scan cyclic voltammetry in combination with carbon fiber microelectrodes was performed to quantify VTA-DBS-evoked dopamine release in the ipsilateral NAc. In a subset of swine, the blood oxygen level-dependent (BOLD) percent change evoked by stimulation was performed at increasing voltages (1, 2, and 3 V). Results: A significant increase in VTA-DBS-evoked BOLD signal was found in the following regions: the ipsilateral dorsolateral prefrontal cortex, anterior and posterior cingulate, insula, premotor cortex, primary somatosensory cortex, and striatum. A decrease in the BOLD signal was also observed in the contralateral parahippocampal cortex, dorsolateral and anterior prefrontal cortex, insula, inferior temporal gyrus, and primary somatosensory cortex (Bonferroni-corrected < 0.001). During neurochemical measurements, stimulation time-locked changes in dopamine release were recorded in the NAc, confirming that mesolimbic dopaminergic neurons were stimulated by DBS. In the parametric study, BOLD signal changes were positively correlated with stimulation amplitude. Conclusions: In this study, the modulation of the neural circuitry associated with VTA-DBS was characterized in a large animal. Our findings suggest that VTA-DBS could affect the activity of neural systems and brain regions implicated in reward, mood regulation, and in the pathophysiology of MDD. In addition, we showed that a combination of fMRI and electrochemically-based neurochemical detection platform is an effective investigative tool for elucidating the circuitry involved in VTA-DBS.

Original languageEnglish (US)
Article number104
JournalFrontiers in Neuroscience
Volume11
Issue numberMAR
DOIs
StatePublished - Mar 3 2017

Fingerprint

Ventral Tegmental Area
Deep Brain Stimulation
Neuroimaging
Nucleus Accumbens
Magnetic Resonance Imaging
Oxygen
Somatosensory Cortex
Swine
Dopaminergic Neurons
Gyrus Cinguli
Major Depressive Disorder
Depression
Prefrontal Cortex
Reward
Dopamine
Animal Models
Medial Forebrain Bundle
Treatment-Resistant Depressive Disorder
Motor Cortex
Microelectrodes

Keywords

  • Deep brain stimulation
  • Depression
  • Fast-scan cyclic voltammetry
  • Functional magnetic resonance
  • Ventral tegmental area

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Functional circuitry effect of ventral tegmental area deep brain stimulation : Imaging and neurochemical evidence of mesocortical and mesolimbic pathway modulation. / Settell, Megan L.; Testini, Paola; Cho, Shinho; Lee, Jannifer H.; Blaha, Charles D.; Jo, Hang J.; Lee, Kendall H; Min, Hoon Ki.

In: Frontiers in Neuroscience, Vol. 11, No. MAR, 104, 03.03.2017.

Research output: Contribution to journalArticle

Settell, Megan L. ; Testini, Paola ; Cho, Shinho ; Lee, Jannifer H. ; Blaha, Charles D. ; Jo, Hang J. ; Lee, Kendall H ; Min, Hoon Ki. / Functional circuitry effect of ventral tegmental area deep brain stimulation : Imaging and neurochemical evidence of mesocortical and mesolimbic pathway modulation. In: Frontiers in Neuroscience. 2017 ; Vol. 11, No. MAR.
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AU - Testini, Paola

AU - Cho, Shinho

AU - Lee, Jannifer H.

AU - Blaha, Charles D.

AU - Jo, Hang J.

AU - Lee, Kendall H

AU - Min, Hoon Ki

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