Functional & Structural Connectivity of Alcohol Use Disorders

功能性

• 批准号: 9559242
• 负责人: Abdolreza Momenan
• 金额: $ 111.5万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9559242
• 关键词: Acute; Alcohol consumption; Alcohol dependence; Alcohols; Alleles; Amnesia; Anger; Anterior; Autistic Disorder; Basal Ganglia; Behavior Therapy; Behavioral; Biological Psychiatry; Collaborations; Compulsive Behavior; Corpus striatum structure; Data; Data Analyses; Data Set; Dopamine; Dorsal; Emotional; Ethanol; Fright; Functional Magnetic Resonance Imaging; Genes; Genetic Polymorphism; Image; Immune response; Impairment; Individual; Intravenous; Laboratories; Left; Manuscripts; Mediating; Metabolic; Minor; National Institute on Alcohol Abuse and Alcoholism; Network-based; Neurons; Neurosciences; Nicotine Dependence; Nicotinic Receptors; Participant; Pathway Analysis; Patients; Positron-Emission Tomography; Process; Publications; Rest; Rewards; Risk; Role; Seeds; Signal Pathway; Signal Transduction; Statistical Data Interpretation; Structure of subthalamic nucleus; Substantia nigra structure; Synapses; Variant; Ventral Striatum; addiction; alcohol effect; alcohol use disorder; base; cingulate cortex; dopamine system; dopamine transporter; endophenotype; executive function; genetic variant; neuroimaging; putamen; response; reward processing; social; volunteer; white matter

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.

摘要：fMRI网络分析和静息状态研究 a. 静息状态连接和酒精使用障碍域 我们一直在分析主要的网络，如显着性，默认模式和执行控制网络，以及它们与Koob et al（2010）定义的成瘾循环中所涉及的回路的关系。目前，我们已经收集并正在处理健康对照志愿者和酒精依赖患者的静息状态数据。初步结果表明，酒精依赖的个人有较少的默认模式网络中的网络连接，与健康对照组相比。此外，我们还确定了这些相同网络的组之间的光谱差异。 B.静息态连通性与遗传变异 在与各种NIAAA部分的合作中，我们目前正在研究与非依赖性对照相比，几种基因对酒精依赖患者静息状态连接的调节作用。这些基因包括： CD 38 CD 38功能的丧失与免疫应答受损、代谢紊乱和行为改变相关，包括可能与自闭症相关的社交健忘症。在与玛丽李博士（博士Leggios CPN）合作，我们分析了种子为基础的静息状态功能连接在健康对照个体与次要和主要等位基因的CD 38基因rs3796863。与主要等位基因的个体相比，次要等位基因的个体显示出左腹侧纹状体和前扣带皮层之间的功能连接增加。这些结果与其他成像（PET）和非成像行为数据相结合，以研究该基因对健康个体奖励处理的影响。本研究的手稿：CD 38 rs3796863多态性在酒精和金钱奖励中的作用：可能参与多巴胺信号传导已提交给生物精神病学出版。 多巴胺能信号通路的改变和腹侧纹状体（VS）对成瘾中奖励的反应的激活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取决于突触中多巴胺的存在，而突触中多巴胺的存在又与多巴胺转运蛋白（DAT）的活性相关。DAT的表达受DAT基因多态性的影响。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影像学内表型，即与具有10个重复等位基因的个体相比，具有9个重复等位基因的个体具有更高的VS-多巴胺可用性，反映为更高的VS反应性。与Lohoffs CGET博士合作，我们目前正在进行静息状态分析，以确定健康对照和具有9个重复等位基因的酒精使用障碍患者与具有10个重复等位基因的患者相比是否具有更高的VS连接性。我们也在研究这些变异对恐惧和愤怒情绪处理的影响。 CRHNA 5我们已经向Ramchandanis博士的HP部门提供了一百多个静息数据集，以分析CHRNA 5变体对酒精依赖和健康对照受试者静息状态的影响。烟碱乙酰胆碱受体（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博士的合作，我们将评估与CHRNA 5相关的功能连接改变是否介导过度饮酒的风险。 C.急性酒精管理下的静息状态连接 由Lovinger博士的综合神经科学实验室进行的研究已经证明了对与背侧纹状体具有特定连接的外部苍白球（GPe）神经元的选择性急性乙醇作用（Abrahao等人_ 2016年）。基于这一发现和已知的作用，基底神经节的习惯性和强迫性行为中看到的成瘾，我们调查了功能的静息态连接的变化GPe和基底神经节的25个健康的社会饮酒者之前和之后静脉注射乙醇。使用基于网络的统计分析，我们的初步结果表明，急性乙醇管理后，静息态连接的GPe与尾状核和壳核显着改变。我们还发现了黑质，丘脑底核和GPi和其他皮质区域的连接变化。对这些数据及其翻译影响的进一步分析正在进行中。