Cerebral Structural and Metabolic Correlates of Aggressive or Addictive Behavior

攻击性或成瘾行为的大脑结构和代谢相关性

• 批准号: 8746456
• 负责人: Markus Heilig
• 金额: $ 87.79万
• 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/8746456
• 关键词: Accounting; Acute; Addictive Behavior; Affect; Age-Years; Aggressive behavior; Alcohol consumption; Alcohol dependence; Alcohol or Other Drugs use; Alcoholic beverage heavy drinker; Alcoholism; Alcohols; Amygdaloid structure; Anisotropy; Anterior; Area; Atrophic; Autopsy; Brain; Brain imaging; Cerebral cortex; Cerebrospinal Fluid; Cerebrum; DSM-IV; Data; Data Set; Dependence; Diagnosis; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Drug abuse; Drug usage; Education; Emotions; Ethanol; Exhibits; Family; Family history of; Fathers; Functional disorder; Genetic; Genetic Predisposition to Disease; Glutamates; Growth; Heavy Drinking; Human; Image Analysis; Impulsive Behavior; Infusion procedures; Inpatients; Insula of Reil; Left; Light; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Manuscripts; Measurement; Measures; Medical; Mental disorders; Metabolic; Mothers; Neurocognitive; Neurons; Nucleus Accumbens; Pathway interactions; Patients; Pattern; Population; Post-Traumatic Stress Disorders; Preparation; Psychopharmacology; Recording of previous events; Relative (related person); Research; Research Personnel; Rewards; Risk; Scanning; Structure; Substance abuse problem; Temporal Lobe; Testing; Thalamic structure; Thick; Tissues; Weight; Wernicke-Korsakoff Syndrome; Woman; alcohol effect; alcohol seeking behavior; base; brain size; brain volume; design; drug craving; early onset; early-onset alcoholic; executive function; frontal lobe; gray matter; healthy volunteer; human subject; interest; liver function; men; mind control; morphometry; neurochemistry; non-alcoholic; nutrition; offspring; polysubstance abuse; problem drinker; sexual dimorphism; social stress; white matter

MR Volumetric Measurements: We have collected full, volumetric T-1 weighted MR images to measure intracranial volumes several hundred alcoholics and healthy, non-alcoholic subjects. Alcoholics show greater brain degeneration than non-alcoholics. In addition, alcoholics have smaller ICVs than controls suggesting that pre-morbid differences in brain size may contribute to the risk for alcoholism. Despite the significant difference in ICV, degeneration accounts for a greater amount of the difference in brain volume between alcoholics and controls than brain growth does. We have examined how a family history (FH) of heavy drinking affects both brain shrinkage as measured by the ratio of brain volumes to ICV as well as maximal brain growth as measured by ICV in early-onset and late-onset alcoholics. FH positive alcoholic patients have significantly smaller ICVs than FH negative patients, suggesting smaller premorbid brain growth among alcoholics with a heavy drinking mother or father. Brain shrinkage was not affected by FH. Late-onset alcoholics show a greater difference in ICV between FH positive and FH negative patients than early-onset alcoholics. These data provide evidence that heavy parental alcohol use may increase risk for alcoholism in offspring in part by a genetic and/or environmental effect resulting in reduced brain growth. Insula Morphometry: The insula, a structure involved in higher order representation of interoceptive states, has recently been implicated in drug craving and social stress. Here, we performed brain MRI to measure volumes of the insula and subcortical regions with direct insular connections in 26 alcohol dependent patients (ADPs) and 26 healthy volunteers (HVs). In ADPs, anterior insula volumes were bilaterally reduced compared with controls. This reduction was selective, as neither posterior insula nor total brain gray matter volumes differed between groups. In ADPs, we also found increased volume of several subcortical structures that have direct afferent, efferent or reciprocal connections with the insula. Specifically, left and right amygdala, left and right thalami, and the right nucleus accumbens were larger in ADPs than HVs. The amygdala, which demonstrated the greatest volume increase in the alcoholics, has strong reciprocal connections with the insula. Postmortem studies of the anterior insula showed that decrease in the volume of the anterior insula was associated with a diminished population of Von Economo neurons in the subjects with a history of alcoholism (n=6) as compared with the subjects without a history of alcoholism (n=6). The pattern of neuroanatomical change observed in our alcohol dependent patients might result in a loss of top-down control of amygdala function, potentially contributing to an inability to control negatively reinforced alcohol seeking and use (Senatorov et al., manuscript in preparation). MR Diffusion Tensor Measurements: Many brain imaging studies have demonstrated reductions in gray and white matter volumes in alcoholism, with fewer investigators using diffusion tensor imaging (DTI) to examine the integrity of white matter pathways. Among various medical conditions, alcoholism and post-traumatic stress disorder (PTSD) are two comorbid diseases that have similar degenerative effects on the white matter integrity. It is widely believed that these types of abnormalities in both alcoholism and PTSD are related to fronto-limbic dysfunction. DTI was used to measure white matter fractional anisotropy (FA), which provides information about tissue microstructure. We quantitatively investigated the microstructure of white matter through whole brain DTI analysis in 19 healthy volunteers (HV) and 19 alcohol dependent subjects without PTSD (ALC) and with 17 PTSD (ALC+PTSD). These data show significant differences in FA between alcoholics and non-alcoholic HVs, with no significant differences in FA between ALC and ALC+PTSD in any white matter structure. We performed a post-hoc region of interest analysis that allowed us to incorporate multiple covariates into the analysis and found similar results. Relative to all alcoholics, HV had higher FA in several areas implicated in the reward circuit, emotion, and executive functioning, suggesting that there may be microstructural abnormalities in white matter pathways that contribute to neurocognitive and executive functioning deficits observed in alcoholics. Furthermore, our data do not reveal any differences between ALC and ALC+PTSD, suggesting that the effect of alcohol on white matter microstructure may be more significant than any effect caused by PTSD (Durkee et al., manuscript in review). Morphometric Measures: Alcoholism has been associated with a widespread pattern of gray matter atrophy. We sought to investigate the spectrum of volume alterations in a population of alcoholics with only alcohol dependence, polysubstance abusing alcoholics, and a comparison population of healthy controls. Thirty-seven pure alcoholics, 93 polysubstance abusing alcoholics, and 69 healthy controls underwent structural T1 MRI scans. Voxel-based morphometry was performed to investigate gray matter alterations. Alcoholic dependent inpatients (both with and without a history of DSM-IV substance abuse/dependence diagnosis) displayed significant gray matter differences in the mesial region of the frontal lobe and right temporal lobe. Pure alcoholics exhibited a pattern of subcortical changes similar to that seen in Wernicke-Korsakoff Syndrome when compared to polysubstance abusing alcoholics. Pure alcoholics and polysubstance abusing alcoholics did not differ significantly in measures of cortical gray matter, liver function, or nutrition. This study calls for additional research in order to investigate the spectrum from uncomplicated alcoholism to Wernicke-Korsakoff Syndrome (Grodin et al., 2013). Cortical Thickness: Alterations of brain structures have been seen in patients suffering from drug abuse or mental disorders. Similar changes in volume of brain structures have been observed in both alcoholic men and women. We examined the thickness of gray matter in the cerebral cortex in control men and women (n=69, 47 men) and alcohol dependent subjects (n=130, 83 men) to test the hypothesis that alcoholic inpatients would have more cortical damage than controls. Covarying for age and years of education, we confirmed significant differences between alcoholics and healthy controls in cortical thickness in both the left and right hemispheres. Significant differences in cortical thickness between control men and women were also observed. These differences may reflect sexual dimorphisms in the human brain, a genetic predisposition to alcoholism and comorbid drug use, and the extent of gray matter damage in alcoholism and substance use (Momenan et al., 2013). MR Spectroscopy of acute alcohol infusion: We are collaborating with Section on Human Psychopharmacology (Dr. Ramchandani) to measure the effect of acute alcohol infusion on brain metabolites, particularly glutamate, in heavy and light drinkers. We bring human subjects to a steady state BAC of 0.08 g/dl while using MRS scans to measure the concentrations of alcohol, glutamate and other brain metabolites in the subject's brain. Our preliminary results not surprisingly indicate significant differences between brain Ethanol/NAA concentration ratio before and after infusion. However, there was no difference in pre- and post-infusion Glutamate/NAA ratio. When separating the only two Heavy Drinkers in current data set, the Light Drinkers had higher Glutamate/NAA ratio than Heavy Drinkers both before and after the infusion. Interestingly, the Light Drinkers had higher Glutamate/NAA ratio after the infusion. But, the Heavy Drinker subjects had decreased Glutamate/NAA ratio after the infusion.

MR 体积测量： 我们收集了完整的体积 T-1 加权 MR 图像，以测量数百名酗酒者和健康的非酒精受试者的颅内体积。酗酒者比不酗酒者表现出更严重的大脑退化。此外，酗酒者的 ICV 比对照组小，这表明病前大脑大小的差异可能会增加酗酒的风险。尽管 ICV 存在显着差异，但与大脑生长相比，退化对酗酒者和对照组之间大脑体积差异的影响更大。 我们研究了重度饮酒家族史 (FH) 如何影响早发性和晚发性酗酒者的大脑萎缩（通过脑容量与 ICV 的比率测量）以及最大大脑生长（通过 ICV 测量）。 FH 阳性酗酒患者的 ICV 明显小于 FH 阴性患者，这表明母亲或父亲酗酒的酗酒者病前大脑生长较小。大脑萎缩不受 FH 影响。与早发性酗酒者相比，晚发性酗酒者在 FH 阳性和 FH 阴性患者之间的 ICV 差异更大。这些数据提供的证据表明，父母大量饮酒可能会增加后代酗酒的风险，部分原因是遗传和/或环境影响导致大脑生长减缓。 岛叶形态测量： 岛叶是一种参与内感受状态高级表征的结构，最近与药物渴望和社会压力有关。在这里，我们对 26 名酒精依赖患者 (ADP) 和 26 名健康志愿者 (HV) 进行了脑部 MRI 测量，以测量岛叶和与岛叶直接连接的皮质下区域的体积。在 ADP 中，与对照组相比，双侧前岛叶体积减少。这种减少是有选择性的，因为组间后岛叶和总脑灰质体积都没有差异。在 ADP 中，我们还发现与岛叶有直接传入、传出或相互连接的几个皮质下结构的体积增加。具体来说，ADP 中的左右杏仁核、左右丘脑以及右侧伏核比 HV 中的更大。杏仁核在酗酒者中表现出最大的体积增加，与岛叶有很强的相互联系。对前岛叶的尸检研究表明，与无酗酒史的受试者 (n=6) 相比，有酗酒史的受试者 (n=6) 前岛叶体积的减小与 Von Economo 神经元数量的减少有关。在我们的酒精依赖患者中观察到的神经解剖学变化模式可能会导致杏仁核功能自上而下的控制丧失，从而可能导致无法控制负强化的酒精寻求和使用（Senatorov等人，手稿正在准备中）。 MR 扩散张量测量： 许多脑成像研究表明，酗酒时灰质和白质体积会减少，但很少有研究人员使用扩散张量成像 (DTI) 来检查白质通路的完整性。在各种医疗状况中，酗酒和创伤后应激障碍（PTSD）是两种共存疾病，它们对白质完整性具有类似的退化影响。人们普遍认为，酗酒和创伤后应激障碍的这些类型的异常都与额叶边缘功能障碍有关。 DTI 用于测量白质各向异性分数 (FA)，提供有关组织微观结构的信息。我们通过全脑 DTI 分析对 19 名健康志愿者 (HV) 和 19 名没有 PTSD 的酒精依赖受试者 (ALC) 和 17 名患有 PTSD (ALC+PTSD) 的酒精依赖受试者的白质微观结构进行了定量研究。这些数据显示，酗酒者和非酒精性 HV 之间的 FA 存在显着差异，而 ALC 和 ALC+PTSD 之间的 FA 在任何白质结构中均无显着差异。我们进行了事后感兴趣区域分析，使我们能够将多个协变量纳入分析中，并发现了类似的结果。相对于所有酗酒者，HV 在与奖赏回路、情绪和执行功能有关的几个领域具有更高的 FA，这表明白质通路中可能存在微观结构异常，从而导致酗酒者中观察到的神经认知和执行功能缺陷。此外，我们的数据没有揭示 ALC 和 ALC+PTSD 之间的任何差异，这表明酒精对白质微结构的影响可能比 PTSD 引起的任何影响更显着（Durkee 等人，审稿中的手稿）。 形态测量： 酗酒与广泛的灰质萎缩有关。我们试图调查仅有酒精依赖的酗酒者群体、滥用多种物质的酗酒者以及健康对照群体的体积变化范围。 37 名纯酗酒者、93 名滥用多种物质的酗酒者和 69 名健康对照者接受了结构 T1 MRI 扫描。进行基于体素的形态测量来研究灰质改变。 酒精依赖住院患者（无论是否有 DSM-IV 药物滥用/依赖诊断史）在额叶和右颞叶的内侧区域表现出显着的灰质差异。与滥用多种物质的酗酒者相比，纯粹的酗酒者表现出类似于韦尼克-科萨科夫综合症的皮质下变化模式。纯粹的酗酒者和滥用多种物质的酗酒者在皮质灰质、肝功能或营养方面没有显着差异。这项研究需要进行额外的研究，以调查从简单的酗酒到韦尼克-科尔萨科夫综合症的范围（Grodin 等，2013）。 皮质厚度： 在患有药物滥用或精神障碍的患者中已经发现了大脑结构的改变。在酗酒的男性和女性中都观察到大脑结构体积的类似变化。我们检查了对照组男性和女性（n = 69、47 名男性）和酒精依赖受试者（n = 130、83 名男性）的大脑皮层灰质厚度，以检验酒精住院患者比对照组有更多皮质损伤的假设。随着年龄和受教育年限的变化，我们证实酗酒者和健康对照者的左半球和右半球皮质厚度存在显着差异。还观察到对照男性和女性之间的皮质厚度存在显着差异。这些差异可能反映了人类大脑中的性别二态性、酗酒和共病吸毒的遗传倾向，以及酗酒和药物滥用对灰质的损害程度（Momenan 等，2013）。 急性酒精输注的磁共振波谱分析： 我们正在与人类精神药理学部门（Ramchandani 博士）合作，测量急性酒精输注对重度和轻度饮酒者大脑代谢物（特别是谷氨酸）的影响。我们使人类受试者的 BAC 达到 0.08 g/dl 的稳态，同时使用 MRS 扫描来测量受试者大脑中酒精、谷氨酸和其他脑代谢物的浓度。我们的初步结果毫不奇怪地表明输注前后脑乙醇/NAA浓度比存在显着差异。然而，输注前和输注后谷氨酸/NAA 比率没有差异。当分离当前数据集中仅有的两名重度饮酒者时，在输注之前和之后，轻量饮酒者的谷氨酸/NAA比率高于重度饮酒者。有趣的是，少量饮酒者在输注后具有更高的谷氨酸/NAA 比率。但是，酗酒者受试者在输注后谷氨酸/NAA 比率降低。