Functional & Structural Connectivity of Alcohol Use Disorders

功能磁共振网络分析与静息状态研究综述 A.静息状态连接性和酒精使用障碍域 我们一直在分析主要的网络，如显著、默认模式和执行控制网络，以及它们与Koob等人(2010)定义的成瘾周期中涉及的电路的关系。目前，我们已经收集了健康对照志愿者和酒精依赖患者的静息状态数据，并正在进行处理。初步结果表明，与健康对照组相比，酒精依赖者在默认模式网络中的网络连接性较少。此外，我们还确定了这些相同网络的不同基团之间的光谱差异。 B.休眠状态连通性和遗传变异 在与NIAAA不同部门的合作中，我们目前正在研究几个基因对酒精依赖患者静息状态连通性的调制作用，并与非依赖对照进行比较。这些基因包括： CD38功能的丧失与免疫反应受损、代谢紊乱和行为改变有关，包括可能与自闭症有关的社交健忘症。与Mary Lee博士(Dr.Leggios CPN)合作，我们分析了具有CD38基因rs3796863的次要等位基因和主要等位基因的健康对照个体基于种子的静息状态功能连接。与携带主要等位基因的个体相比，携带次要等位基因的个体在左侧腹侧纹状体和前扣带皮质之间的功能连接性增强。这些结果已经与其他成像(PET)和非成像行为数据相结合，来研究这种基因对健康个体奖励处理的影响。这项研究的手稿：CD38 rs3796863多态在酒精和金钱奖励中的作用：可能涉及多巴胺信号已提交给生物精神病学发表。 DAT改变的多巴胺能信号通路和对成瘾奖赏反应的腹侧纹状体(VS)激活增强与多巴胺系统的功能多态性有关。多巴胺相关的突触后活动依赖于突触中多巴胺的存在，而突触中的多巴胺又与多巴胺转运体(DAT)的活性有关。DAT基因的多态影响DAT的表达。有证据表明，9-重复与DAT水平降低有关。这可能代表了一种可能的神经成像内表型，即与携带10重复等位基因的个体相比，携带9重复等位基因的个体具有更高的VS-多巴胺利用率，反映为VS反应活性更高。与Lohoff CGET博士合作，我们目前正在进行休息状态分析，以确定携带9重复等位基因的健康对照组和酒精使用障碍患者是否比携带10重复等位基因的患者具有更高的VS连接性。我们还在研究这些变异对恐惧和愤怒情绪处理的影响。 我们已经向Ramchandanis HP研究组提供了100多个静息数据集，以分析CHRNA5变异对酒精依赖和健康对照组受试者静息状态的影响。烟碱型乙酰胆碱受体(NAChR)已被证明与尼古丁成瘾和潜在的酒精使用障碍有关。通过与Ramchandanis博士部门的合作，我们将评估与CHRNA5相关的功能连接改变是否介导了过度饮酒的风险。 C.急性酒精摄入下的静息态连接 洛文格博士的整合神经科学实验室进行的研究表明，急性乙醇对与背侧纹状体有特定连接的外脑苍白球(GPE)神经元具有选择性的急性酒精效应(Abraho等人，2016)。基于这一发现和已知的基底神经节在成瘾习惯性和强迫行为中的作用，我们研究了25名健康社交饮酒者静脉注射酒精前后GPE和基底神经节功能静息态连接性的变化。使用基于网络的统计分析，我们的初步结果显示，在急性乙醇给药后，GPE与尾状核和壳核的静息状态连接性显著改变。我们还发现黑质、丘脑底核和GPI等皮质区域的连通性发生了变化。对这些数据及其翻译影响的进一步分析正在进行中。

Summary: fMRI Network Analysis and Resting State Studies a. Resting state Connectivity and alcohol use disorder domains We have been in the process of analyzing major networks such as Salience, Default Mode, and Executive Control networks and their relationship with the circuits involved in addiction cycle as defined by Koob et al (2010). Currently we have collected and are processing the resting state data of healthy control volunteers and alcohol dependent patients. Preliminary results indicate that alcohol dependent individuals have less within network connectivity in the Default Mode Network, when compared to healthy controls. Furthermore, we have identified differences in spectra between groups for these same networks. b. Resting State Connectivity and Genetic Variants In collaborations with various NIAAA sections, we are currently investigating the modulatory effects of several genes on resting state connectivity of alcohol dependent patients in comparison to non-dependent controls. Amongst these genes are: CD38 The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications including social amnesia possibly related to autism. In collaboration with Dr. Mary Lee (Dr. Leggios CPN) we have analyzed seed-based resting state functional connectivity in healthy control individuals with the minor and major allele of the CD38 gene rs3796863. Individuals with the minor allele showed increased functional connectivity between the left ventral striatum and the anterior cingulate cortex compared to individuals with the major allele. These results have been combined with other imaging (PET) and non-imaging behavioral data to investigate this genes effect on reward processing in healthy individuals. The manuscript for this study: A role for the CD38 rs3796863 polymorphism in alcohol and monetary reward: possible involvement of dopamine signaling has been submitted to Biological Psychiatry for publication. DAT - Altered dopaminergic signaling pathways and heightened ventral striatum (VS) activation in response to reward in addiction has been related to functional polymorphisms of the dopamine system. Dopamine related post-synaptic activity depends on the presence of dopamine in the synapse, which in turn is related to the activity of the dopamine transporter (DAT). Expression of DAT is influenced by a polymorphism of the DAT gene. There is evidence that the 9-repeat is associated with decreased DAT levels. This could represent a possible neuroimaging endophenotype of higher VS-dopamine availability reflected as higher VS reactivity in individuals with the 9-repeat allele when compared to individuals with the 10-repeat allele. In collaboration with Dr. Lohoffs CGET, we are currently conducting resting state analyses to determine whether healthy controls and patients with alcohol use disorder with the 9-repeat allele had higher VS-connectivity compared to those with the 10-repeat allele. We are also investigating the effects of these variants on emotional processing of fear and and anger. CRHNA5 We have provided over a hundred resting data sets to Dr. Ramchandanis HP section to analyze the effects of CHRNA5 variants on the resting state of alcohol dependent and healthy control subjects. The nicotinic acetylcholine receptor (nAChR) has been shown to be associated with nicotine addiction, and potentially alcohol use disorders. Through a collaboration with Dr. Ramchandanis section, we will be assessing whether altered functional connectivity related to CHRNA5 mediates the risk for excessive alcohol use. c. Resting State Connectivity under acute alcohol administration Studies conducted by Dr. Lovinger's Laboratory for Integrative Neuroscience have demonstrated a selective acute ethanol effect on external globus palidus (GPe) neurons that have a specific connectivity with the dorsal striatum (Abrahao et al._2016). Based on this finding and the known role of the basal ganglia in habitual and compulsive behaviors seen in addiction, we investigated the functional resting-state connectivity changes of the GPe and basal ganglia of 25 healthy social drinkers before and after intravenous ethanol administration. Using a network based statistical analysis, our preliminary results show that after acute ethanol administration resting-state connectivity of the GPe with the caudate and putamen is significantly altered. We also found changes in the connectivity of the substantia nigra, subthalamic nucleus and GPi and other cortical regions. Further analysis of this data and its translational implications is underway.