Investigation of cerebellar involvement in AUD

最近的动物研究提供了新的证据，证明小脑可能与奖赏有更强的联系 比以前认识到的大脑系统。小脑深核（DN）向小脑顶核的直接投射 腹侧被盖区（VTA）已被确定，刺激这些小脑传入VTA的， 被发现是值得的。这些发现增加了小脑功能障碍可能导致 通过小脑对腹侧被盖区的影响而成瘾。与动物研究结果一致，我们发现， 人类功能磁共振成像初步数据显示，相对于非酒精刺激， 与对照组相比，酒精使用障碍（AUD）患者的酒精刺激，并观察到密切耦合 DN和VTA激活之间的关系。研究AUD和控制参与者，该项目将解决三个 重要的问题第一个问题是：小脑对腹侧被盖区的输入的性质是什么，它是如何被干扰的？ 澳元？许多研究表明，当刺激出现时，小脑会产生 基于先前的关联学习对接下来的事件进行预测，然后将预测的和 实际结果产生预测误差。我们假设这些功能在AUD中被破坏。我们 初步数据显示，当预期的刺激没有发生时， 观察到小脑与其投射靶点之间的功能连接（FC）增加， 我们发现，当酒精图片时， 指出了在目标1中，使用fMRI和金钱激励任务，我们将调查DN-VTA FC是否反映了 奖励预测和/或正或负奖励预测误差。第二个问题是： 大脑奖励中心的激活，这是由酒精刺激引起的，与大脑功能障碍的数量有关。 小脑？在目标2中，我们将研究小脑完整性的两种测量方法，以确定它们与 在小脑、腹侧被盖区和其他奖赏结构中与酒精线索相关的激活的程度， VTA FC：（1）小脑血流动力学反应功能（HRF）下冲的时间， 已被发现与一生的饮酒次数有关;（2）经典眨眼条件反射， 小脑是必要的。第三个问题是：小脑的异常激活能和FC以及酒精有关吗 非侵入性小脑刺激能减少食欲吗目的3：利用fMRI结合小脑 在线索反应性任务期间，我们假设在AUD中， 参与者小脑和VTA的激活将减少，DN-VTA FC将正常化，酒精渴望 将减少。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研究， tDCS对奖励系统重要结构间FC的影响以及对DN-VTA FC的影响。这些 调查将导致更好地了解小脑参与AUD，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.