Functional Circuitry Effect of Ventral Tegmental Area Deep Brain Stimulation: Imaging and Neurochemical Evidence of Mesocortical and Mesolimbic Pathway Modulation

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.

A novel re-attachable stereotactic frame for MRI-guided neuronavigation and its validation in a large animal and human cadaver model

“…In addition, an important aspect of our re-attachable stereotactic frame system is that it enables more complex and chronic neuromodulation experiments in mock-human large animal models of DBS (Min et al 2012, Knight et al 2013, Paek et al 2015, Gibson et al 2016, Settell et al 2017). Such studies are critical for a better understanding of the latent therapeutic mechanisms of DBS therapies, for investigating chronic DBS-induced neuroplasticity, and for discovering feedback mechanisms to optimize therapy in closed-loop designed DBS systems.…”

“…The subject group consisted of five normal domestic male pigs, weighing 30 ± 5 kg, with the ventral tegmental area (VTA) chosen as the DBS target for proof of principle (Settell et al 2017). Each subject was intubated, and sedation was maintained with isoflurane (1%–3%) throughout the surgical procedure.…”

Approaches to neuromodulation for schizophrenia

“…In a mechanistic model (model 3) of SZ, high dopamine levels in the striatum accompanied decreased dopamine levels in the prefrontal cortex from mesocortical VTA dopaminergic neurons 27. Stimulating VTA increases dopamine in the VS/NAc and increases activation of cortical structures such as DLPFC in swine, supporting the idea that negative symptoms of SZ may be treated by targeting VTA 77. Likewise, cognitive deficits caused by low dopamine levels in the cortex may be reduced.…”

Resting‐state functional connectivity modulates the BOLD activation induced by nucleus accumbens stimulation in the swine brain

“…It is clear that NAc‐DBS induced its own BOLD activation pattern, as stimulating targets have their own unique, target‐specific modulation effects (Gibson et al, ; Knight et al, ; Krack et al, ; Min et al, ; Paek et al, ; Settell et al, ). However, it is unclear which specific neurobiological mechanism mediates broadly distributed BOLD activation patterns.…”

“…In particular, we observed changes in inter‐regional functional connectivity (rsFC), focused on brain regions that evoked a significant BOLD response to NAc‐DBS, including executive, limbic, thalamic, and sensorimotor networks. Furthermore, we also conducted rsFC mapping (Biswal, Zerrin Yetkin, Haughton, & Hyde, ; Fox, Halko, Eldaief, & Pascual‐Leone, ) for each subject prior to the DBS implantation surgery in order to collect information on the relationship between the strength of rsFC and BOLD activation, as a potential action mechanism of DBS, which has been overlooked in previous DBS‐fMRI studies (Gibson et al, ; Min et al, ; Paek et al, ; Settell et al, ). The use of a large animal model in our study is presumably more representative of the human brain anatomy (Van Gompel et al, ) than small animal models (Albaugh et al, ), and therefore, our findings should be assumed to be general in nature, in terms of understanding the therapeutic effects of human DBS.…”