Functional & Structural Connectivity in Alcohol Use Disorder

1.功能互联互通 A.AUD受试者功能连接的纵向变化--成瘾神经回路模型描述了几个大脑回路(药物奖励、负面情绪和渴望/执行控制)在酒精使用和随后发生的酒精使用障碍(AUD)中的作用。需要使用静息状态功能磁共振成像(rs-fMRI)检查纵向变化的人体研究，以了解这些回路的功能变化是如何由持续的AUD引起的或有助于持续的AUD。为了表征持续的AUD对内在功能连接性的影响，我们分析了从2012-2020年间，作为NIAAA内科项目各种研究的一部分，来自AUD患者(n=18；寻求治疗和未寻求治疗)和没有AUD(n=21)的患者的rS-fMRI数据。种子相关分析的结果表明，随着时间的推移，AUD患者在情绪性和渴望神经回路之间的功能连接性增加，在执行控制和奖励网络之间的连接性减少。对AUD严重程度和两次扫描之间饮酒的后调查显示，这些AUD特征在许多回路中具有相加效应，因此饮酒越多或AUD越严重，同步性变化就越明显。这些发现表明，情绪性和饮酒冲动背后的网络一致性增加，而网络连接性也减少，这与成瘾神经回路模型一致。此外，他们还表明，持续大量饮酒对神经回路中的这些脆弱性有复杂的影响。有必要进行更多的纵向研究，以了解在这项研究中没有充分代表的AUD患者的轨迹，以及这是否可以为有效的减少伤害战略提供信息(Fede等人。2022年)。 B.创伤计时负荷(TTL)和功能连接性-创伤的计时和类型已被证明影响涉及情绪处理、自上而下抑制控制和认知功能的大脑回路的发育、功能和连接性。在酒精使用障碍(AUD)患者中，通常可以观察到这些过程及其潜在的大脑回路功能障碍。此外，AUD和创伤后应激障碍的高发病率表明，成年期间的创伤暴露也在增加AUD的风险和严重程度方面发挥着关键作用。在这一证据的基础上，本研究的目标是调查创伤的时机(童年和成人)是否会对AUD患者的行为和回路水平的表型产生不同的影响。我们的初步数据分析表明，酒精使用障碍在与滥用经历相关的区域的静息状态连接改变方面的影响远远比滥用令人印象深刻。这项研究中的数据分析继续进一步证实了这些影响。 C.PAG功能连接-中脑导水管周围灰质(PAG)是一个广泛涉及疼痛、抑郁、负性情绪性和睡眠研究的区域，其中大多数也与物质使用障碍(SUDS)相关(Le等人。2020年；George等人。2019年)。尽管PAG明显地参与了行为精神障碍，但一直有有限的神经影像研究探讨该区域在SUD维持和复发中所起的调节作用。与Spagnolo博士合作，我们对AUD和功能性PAG连接之间的关联进行了初步研究。在这一分析中，我们发现左右头侧前额叶皮质(RPFC)、左RPFC与前扣带回(ACC)、左缘上回与右RPFC、ACC与左前岛(ANS)以及左右ANS之间的突起网络连接发生了变化。由于其他优先事项，该项目已被搁置。我们将在不久的将来总结这项研究的结果。 D.高血糖素样多肽-1受体(GLP-1R)基因变异和脑功能连通性-酒精使用严重程度与GLP-1R基因变异之间的关联研究，以及人脑的功能连通性是由CNIRC与Leggio博士的临床精神神经内分泌学小组和神经精神药理学分部合作进行的。在这项研究中，我们发现GLP-1R变体之一与前突起网络、背侧默认模式网络和基底节网络的网络连通性之间存在显著的交互作用。我们还发现，在其中一些网络(Farokhnia、Fede等人，2022)中，高与低的审核分数与更强的网络连接相关。 E.酒精使用严重程度和休息状态--在另一项合作中，我们为酒精使用障碍和大脑功能连接性之间的关系研究做出了贡献。这项研究由沃尔科博士的神经成像实验室(LNI)进行，重点是女性比男性更容易受到酒精对情绪和睡眠的不利影响。这项研究得出的结论是，患有酒精使用障碍的男性和女性参与者比健康对照组都有更严重的睡眠和情绪问题，酒精使用对性行为的影响因严重程度而异。这项研究的结果还表明，静息状态功能连接性的变化可能是酒精使用障碍女性睡眠和情绪障碍的原因(Zhang等人，2022)。

1. Functional Connectivity a. Longitudinal alterations in functional connectivity of AUD subjects - The addiction neurocircuitry model describes the role of several brain circuits (drug reward, negative emotionality, and craving/executive control) in alcohol use and subsequent development of alcohol use disorder (AUD). Human studies examining longitudinal change using resting-state functional magnetic resonance imaging (rs-fMRI) are needed to understand how functional changes to these circuits are caused by or contribute to continued AUD. In order to characterize how intrinsic functional connectivity changes with sustained AUD, we analyzed rs-fMRI data from individuals with (n = 18; treatment seeking and non-treatment seeking) and without (n = 21) AUD collected on multiple visits as part of various research studies at the NIAAA intramural program from 2012-2020. Results of the seed correlation analysis showed that individuals with AUD had an increase in functional connectivity over time between emotionality and craving neurocircuits, and a decrease between executive control and reward networks. Posthoc investigations of AUD severity and alcohol consumption between scans revealed an additive effect of these AUD features in many of the circuits, such that more alcohol consumption or more severe AUD was associated with more pronounced changes to synchronicity. These findings suggest an increased concordance of networks underlying emotionality and compulsions towards drinking while also a reduction in network connectivity, consistent with the addiction neurocircuitry model. Further, they suggest a compounding effect of continued heavy drinking on these vulnerabilities in neurocircuitry. More longitudinal research is necessary to understand the trajectories of individuals with AUD not adequately represented in this study, as well as whether this can inform effective harm reduction strategies (Fede et al. 2022). b. Trauma Timing Load (TTL) and functional connectivity - Timing and type of trauma have been shown to impact on the development, function and connectivity of brain circuits implicated in emotion processing, top-down inhibitory control, and cognitive functions. Dysfunctions in these processes and their underlying brain circuits are commonly observed in patients with alcohol use disorder (AUD). Furthermore, the high comorbidity between AUD and PTSD suggests that trauma exposure during adulthood also plays a critical role in increasing the risk and severity of AUD. Building on this body of evidence, the goal of this study is to investigate whether timing of trauma (childhood vs. adulthood) differentially affect the behavioral and circuit-level phenotype of individuals with AUD. Our preliminary data analysis indicates that the effect of alcohol use disorder is far more impressive than that of abuse on alteration of resting state connectivity in regions associated with abuse experiences. The analysis of data in this study continues to further confirm these effects. c. PAG functional connectivity - The Periaqueductal gray (PAG) is a region widely implicated in pain, depression, negative emotionality, and sleep studies, most of which are also comorbidities associated with substance use disorders (SUDs) (Le, et al. 2020; George, et al. 2019). Despite the apparent prominent involvement of PAG in behavioral psychiatric disorders there have been limited neuroimaging studies investigating the modulatory role that this region plays in SUD maintenance and relapse. In collaboration with Dr. Spagnolo, we have conducted a preliminary study of the association between AUD and functional PAG connectivity. In this analysis we have found that there are alterations in salience network connectivity between left and right rostral prefrontal cortex (RPFC), left RPFC and anterior cingulate (ACC), left supramarginal gyrus and right RPFC, ACC and left anterior insula (AIns), and between the right and left AIns. This project has been on hold due to other priorities. We will summarize the results from this study in the near future. d. Glucagon Like Peptide-1 Receptor (GLP-1R) gene variants and brain functional connectivity - A study of the association between alcohol use severity and GLP-1R gene variants, and the functional connectivity of human brain was conducted in collaboration between CNIRC and Dr. Leggio's Clinical Psychoneuroendocrinology group and Neuropsychopharmacology Section. In this study we found there was a significant interaction effect between one of the GLP-1R variants and network connectivity of the anterior salience network, the dorsal default mode network, and the basal ganglia network. We also found that high versus low AUDIT scores were associated with stronger within-network connectivity in some of these networks (Farokhnia, Fede, et al., 2022) e. Alcohol use severity and resting state - In another collaboration, we contributed to the study of association between alcohol use disorder and brain functional connectivity. This study, conducted by Dr. Volkow's Laboratory of Neuroimaging (LNI), was focused on greater vulnerability of women than men to the adverse effects of alcohol on mood and sleep. This study concluded that both men and women participants with alcohol use disorder had greater sleep and mood problems than healthy control, with sex by alcohol use effect varying by severity. The results of this study also suggested that changes in resting state functional connectivity may account for sleep and mood impairments in females with alcohol use disorder (Zhang et al., 2022).