Investigation of cerebellar involvement in AUD

最近的动物研究提供了新的证据，表明小脑可能与奖赏有更强的联系 大脑的系统比之前所认识的要多。小脑深核(DN)向下丘脑的直接投射 腹侧被盖区(VTA)已被识别，这些小脑传入VTA的刺激是 发现是有回报的。这些发现增加了小脑功能障碍可能导致 实质上是通过小脑对VTA的影响而成瘾。与动物的发现一致，我们在 人类fMRI初步数据显示，与非酒精信号相比，酒精刺激对小脑和VTA有较强的激活作用 酒精使用障碍(AUD)患者的酒精刺激与对照组的比较，并密切耦合观察 在目录号码和VTA激活之间。研究AUD和对照参与者，本项目将解决三个问题 重要的问题。第一个问题是：小脑输入VTA的性质是什么，它是如何被干扰的？ 澳元？许多研究表明，当提供刺激时，小脑产生 根据先前的联想学习对随后发生的事件进行预测，然后将预测和 实际结果会产生预测误差。我们假设这些功能在澳元病中被破坏。我们的 初步数据显示，当预期的刺激没有出现时，市场中的强烈预测误差信号 观察到小脑和其投射靶点之间的功能连接(FC)增加的形式，以及 我们发现，当酒精图片出现时，AUD患者的DN-VTA FC也有类似的增加，这在正常情况下是不正常的 提出了一种新的解决方案。在目标1中，使用fMRI和货币激励任务，我们将调查dN-VTA fc是否反映 奖励预测和/或正或负奖励预测误差。第二个问题是： 酒精刺激引起的大脑奖赏中心的激活与脑功能障碍的数量有关 小脑？在目标2中，我们将调查小脑完整性的两个指标，以确定它们与 在小脑、VTA和其他奖赏结构中与酒精线索相关的激活的幅度，并与DN- VTA Fc：(1)小脑血流动力学反应功能(HRF)下降的时间，具有 被发现与终生饮酒的次数有关；以及(2)经典的眨眼条件作用，对于这种情况 小脑是必需的。第三个问题是：小脑异常激活和Fc，以及酒精 渴望，可以通过非侵入性小脑刺激来减少吗？在目标3中，使用功能磁共振结合小脑 经颅直流电刺激(TDC)在线索反应任务中，我们假设在AUD 参与者小脑和VTA的激活将减少，DN-VTA Fc将正常化，酒精渴求 将会减少。我们将使用静息状态功能磁共振成像和心理生理相互作用分析来检验， 在奖励系统的重要结构中，tdcs对fc的影响以及对dn-vta fc的影响。这些 研究将有助于更好地了解小脑在AUD中的参与，以及 小脑调节的治疗潜力。

Recent animal studies have provided new evidence that the cerebellum may have a stronger link to the reward system of the brain than was previously recognized. Direct projections from cerebellar deep nuclei (DN) to the ventral tegmental area (VTA) have been identified, and stimulation of these cerebellar afferents to the VTA was found to be rewarding. Such findings raise the possibility that cerebellar dysfunction could contribute substantially to addiction via a cerebellar influence over VTA. Consistent with animal findings, we have found in human fMRI preliminary data strong cerebellar and VTA activation in response to alcohol cues relative to non- alcohol stimuli in patients with alcohol use disorder (AUD) compared to controls, and close coupling observed between DN and VTA activation. Studying AUD and control participants, this project will address three important questions. The first is: What is the nature of cerebellar input to the VTA, and how is it perturbed in AUD? A number of investigations have suggested that when a stimulus is presented, the cerebellum generates a prediction of events that will follow based on prior associative learning, and then compares predicted and actual outcomes to generate a prediction error. We hypothesize that these functions are disrupted in AUD. Our preliminary data show that when an expected stimulus does not occur, a strong prediction error signal in the form of increased functional connectivity (FC) between cerebellum and its projection target is observed, and we found an analogous increase in DN-VTA FC, that was abnormal in AUD patients, when alcohol pictures were presented. In Aim 1, using fMRI and a monetary incentive task, we will investigate if DN-VTA FC reflects reward prediction and/or positive or negative reward prediction error. The second question is: Is the amount of activation in brain reward centers that is elicited by alcohol stimuli related to the amount of dysfunction in the cerebellum? In Aim 2 we will investigate 2 measures of cerebellar integrity to determine their relationship with the magnitude of alcohol cue related activation in cerebellar, VTA, and other reward structures, and with DN- VTA FC: (1) The timing of the undershoot of the cerebellar hemodynamic response function (HRF), which has been found to be correlated with number of lifetime drinks; and (2) classical eyeblink conditioning, for which the cerebellum is necessary. The third question is: Can abnormal cerebellar activation and FC, as well as alcohol craving, be reduced by non-invasive cerebellar stimulation? In Aim 3, Using fMRI combined with cerebellar transcranial direct current stimulation (tDCS) during a cue reactivity task, we hypothesize that in AUD participants cerebellar and VTA activation will be reduced, DN-VTA FC will be normalized, and alcohol craving will be reduced. We will examine, using both resting state fMRI and psychophysiological interaction analysis, the effects of tDCS on FC among important structures of the reward system as well as on DN-VTA FC. These investigations will lead to a better understanding of the involvement of the cerebellum in AUD, as well as the therapeutic potential of cerebellar modulation.