Settell Megan L, Testini Paola, Cho Shinho, Lee Jannifer H, Blaha Charles D, Jo Hang J, Lee Kendall H, Min Hoon-Ki
Department of Neurologic Surgery, Mayo ClinicRochester, MN, USA; Mayo Graduate School, Mayo ClinicRochester, MN, USA.
Department of Neurologic Surgery, Mayo ClinicRochester, MN, USA; Department of Surgery, Mayo ClinicRochester, MN, USA.
Front Neurosci. 2017 Mar 3;11:104. doi: 10.3389/fnins.2017.00104. eCollection 2017.
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). Animals ( = 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). 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. 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.
腹侧被盖区（VTA）包含中脑边缘和中脑皮质多巴胺能神经元，与涉及奖赏、成瘾、强化和学习的过程有关，而这些过程与多种神经精神疾病相关。据报道，电刺激VTA或内侧前脑束及其投射靶点伏隔核（NAc）可改善重度、难治性重度抑郁症（MDD）患者的抑郁症状以及抑郁症动物模型中的类抑郁症状。在此，我们试图通过将神经化学测量与功能磁共振成像（fMRI）相结合，来确定VTA深部脑刺激（DBS）在正常大型动物模型（猪）中的神经调节作用。动物（n = 8头猪）单侧植入靶向VTA的DBS电极。在刺激期间（频率130 Hz、脉冲宽度0.25 ms、幅度3 V），进行fMRI。fMRI之后，结合碳纤维微电极进行快速扫描循环伏安法，以量化VTA-DBS诱发的同侧NAc中多巴胺释放。在一部分猪中，在逐渐增加电压（1、2和3 V）时进行刺激诱发的血氧水平依赖（BOLD）百分比变化。在以下区域发现VTA-DBS诱发的BOLD信号显著增加：同侧背外侧前额叶皮质、前扣带回和后扣带回、脑岛、运动前皮质、初级体感皮质和纹状体。在对侧海马旁皮质、背外侧和前额叶前皮质、脑岛、颞下回和初级体感皮质也观察到BOLD信号降低（经Bonferroni校正，P < 0.001）。在神经化学测量期间，在NAc中记录到刺激锁时的多巴胺释放变化，证实中脑边缘多巴胺能神经元受到DBS刺激。在参数研究中，BOLD信号变化与刺激幅度呈正相关。在本研究中，在大型动物中对与VTA-DBS相关的神经回路调节进行了表征。我们的研究结果表明，VTA-DBS可能会影响与奖赏、情绪调节以及MDD病理生理学相关的神经系统和脑区的活动。此外，我们表明，fMRI与基于电化学的神经化学检测平台相结合是阐明VTA-DBS所涉及神经回路的有效研究工具。
