阿片类处方药依赖者前额皮层中γ-氨基丁酸和谷氨酸绝对浓度的静息态磁共振波谱测定及其临床意义

发布时间：2018-05-15 18:21

本文选题：阿片类物质使用障碍 + 阿片类处方药　；参考：《广州医科大学》2017年硕士论文

【摘要】：阿片类物质依赖一直是最严重的世界性社会、经济和公共卫生问题之一,近十多年来阿片类处方药的滥用和依赖急剧增长,其引起的成瘾和依赖问题逐渐成为关注的焦点。滥用阿片类处方药者可尝试通过药物治疗剂量以外的方式强化欣快感和愉悦感,进而引发强烈的药物渴求和强迫性觅药行为。对于阿片类物质依赖的诊断,临床上以症状评定量表为主的主观判断,尚未明确客观的神经生物学指标。寻求客观的神经生物学指标以协助阿片类处方药依赖的诊断、监测病情变化和疗效反应是有必要的。磁共振波谱(magnetic resonance spectroscopy,MRS)以无创性的方式定量检测活体组织内局部的代谢物水平的变化,有望为阿片类处方药依赖诊断提供定量检测的技术手段。奖赏环路是阿片类物质奖赏效应产生的神经解剖学基础,前额皮层作为奖赏通路关键区域,参与高级执行功能,被认为与物质成瘾密切相关。γ-氨基丁酸(γ-aminobutyric acid,GABA)和谷氨酸Glu(glutamate,Glu)分别为奖赏环路中主要的抑制性和兴奋性神经递质,阿片类药物依赖与前额皮层中的神经递质GABA和Glu水平有关,其可能参与依赖的形成,但其长期依赖效应的机制仍然不十分清楚。因此,本研究拟在3.0 T磁共振扫描仪上利用MEGA-PRESS和Optimal TE波谱编辑技术检测GABA和Glu的绝对浓度,分析在大孔径3.0 T MR扫描仪上定量检测活体人脑前额皮层内GABA绝对浓度的可行性和可重复性,检测阿片类处方药依赖者脑内前额皮层GABA和Glu的绝对浓度,探讨阿片类处方药依赖者前额皮层内GABA和Glu绝对浓度与神经心理学指标的关系,旨在为评估阿片类处方药依赖提供可能的生物学标记物。论文分三个部分,摘要如下:第一部分在70 cm大孔径临床3.0 T磁共振系统上定量检测活体人脑前额皮层GABA绝对浓度的可行性目的:探讨在70 cm大孔径临床3.0 T MRI系统上使用MEGA-PRESS波谱编辑技术定量检测活体人脑前额皮层GABA绝对浓度的可行性。材料与方法:研究对象包括32名健康志愿者(男性25名,女性7名,年龄18~33岁,平均22.6±3.0岁),均为右利手,无头部外伤史和神经精神疾病史,无磁共振扫描禁忌症。所有扫描均在Siemens MAGNETOM SKyra 3.0 T磁共振成像仪上完成。首先采用MEGA-PRESS序列对志愿者大脑腹内侧前额皮层进行1H-MRS信号采集;另外使用同样的扫描序列进行水模实验,将一个装有浓度为50 m M的GABA溶液水模进行定位扫描,感兴趣区位于与人脑相对应位置,扫描结果作为定量分析的外部参考标准。应用jMRUI v5.0软件对1H-MRS波谱数据进行后处理,计算出腹内侧前额皮层GABA的绝对浓度(Mean±SD)及其变异系数。结果:利用MEGA-PRESS序列成功采集了32名志愿者的GABA波谱数据,经jMRUI v5.0软件后处理均可清晰地显示GABA谱峰,测得的GABA绝对浓度为1.58±0.26 mM,变异系数为16.2%。结论:使用MEGA-PRESS波谱编辑法在70 cm大孔径临床3.0 T MRI系统上定量检测活体人脑前额皮层的GABA信号是可行的,所采集的GABA谱线具有较高的稳定性。第二部分在70 cm大孔径临床3.0 T磁共振系统上定量检测活体人脑前额皮层GABA绝对浓度的可重复性目的:在70 cm大孔径临床3.0 T磁共振成像仪上采用MEGA-PRESS编辑技术检测健康志愿者的GABA波谱,探讨活体人脑内GABA绝对量化方法的可重复性。材料与方法:研究对象包括16名健康志愿者(男性10名,女性6名,年龄19~28岁,平均23.1±2.3岁),均为右利手,无头部外伤史和神经精神疾病史,无磁共振扫描禁忌症。所有扫描均在Siemens MAGNETOM Skyra 3.0 T磁共振成像仪上完成。所有志愿者至少进行2次磁共振扫描,另外再抽取6名进行第3、4次磁共振扫描。所有扫描2次的志愿者重复扫描时间间隔大于5天,重复扫描4次的志愿者间隔时间超过1星期以上。应用jMRUI v5.0软件进行波谱数据后处理,并对GABA含量进行相对量化(GABA/NAA)和绝对量化(|GABA|),计算出相应的平均值、标准差和变异系数。结果:前后多次扫描均成功采集到16名志愿者的GABA波谱数据,经jMRUI v5.0软件处理后均可良好显示GABA谱峰。多次重复测量的相对量化和绝对量化变异系数均小于20%,且无统计学差异(P0.05)。无论是组内还是组间可重复性,绝对量化组内和组间的变异系数均小于相对量化,即绝对量化的可重复性优于相对量化。男女组间GABA相对含量平均值无统计学差异(P0.05);但男女组间GABA绝对含量平均值有统计学差异(P0.05)。结论:在大孔径短磁体磁共振扫描仪采用MEGA-PRESS波谱编辑法测量GABA绝对浓度具有较好的组内和组间可重复性,且GABA绝对量化整体上优于相对量化。同时,GABA绝对量化具有性别特异性,且具有良好的组间可重复性。结果表明,该技术可在大孔径临床MRI系统上用来研究正常和异常大脑的GABA水平改变。第三部分阿片类处方药依赖者前额皮层中GABA和Glu绝对浓度的静息态磁共振波谱测定及其临床意义目的:利用MRS测量阿片类处方药依赖患者腹内侧前额皮层的GABA和Glu绝对浓度的变化,并探究GABA和Glu绝对浓度的变化与行为心理学改变之间的相关性。材料与方法:研究对象包括31名阿片类处方药依赖患者(男29名,女2名,年龄18~35岁,平均24.94±4.19岁)和32名相匹配的健康对照者(男25名,女7名,年龄18~33岁,平均22.6±3.0岁)。所有研究对象均为右利手。使用Siemens MAGNETOM Skyra 3.0 T磁共振成像仪进行人体头部扫描,采用MEGA-PRESS序列采集所有受试者腹内侧前额皮层的GABA波谱数据,采用Optimal TE方法采集Glu波谱数据。将分别装有50 mM的GABA水溶液和肌酸水溶液的水模进行磁共振扫描,作为定量的外部参考标准。应用jMRUI v5.0软件对所采集的波谱数据进行后处理和量化。采用阿片成瘾严重指数来评估成瘾的严重程度,采用Barratt冲动性量表(BIS-11)来评估受试者的冲动性,焦虑自评量表(SAS)、抑郁自评量表(SDS)、蒙特利尔认知评估量表(MOCA)分别来评估受试者的冲动性、焦虑、抑郁和认知状态。采用两独立样本t检验比较两组GABA和谷氨酸绝对浓度的差异,应用Spearman相关分析评价阿片类处方药依赖者前额皮层与神经心理学指标之间的相关性。结果:阿片类处方药依赖者前额皮层中|GABA|浓度低于对照组,而|Glu|浓度高于对照组,且两组之间具有显著性差异(P0.001)。依赖者的BIS-11总评分比对照组高,MOCA总评分比对照组低(低于26分),两组间存在统计学差异(P0.05),其他量表总分在两组之间无统计学差异(P0.05)。阿片类处方药依赖者前额皮层内GABA绝对浓度与谷氨酸绝对浓度、BIS-11、SAS呈负相关、与MOCA评分呈正相关;而谷氨酸绝对浓度与BIS-11呈正相关、与MOCA评分呈负相关。结论:本研究表明GABA和Glu水平异常与觅药冲动性、焦虑状态、认知功能受损有关。因此,抑制性GABA能和兴奋性Glu能神经递质系统的失调可能是阿片类处方药依赖者渴求和复吸的一个重要的病理生理学机制。通过MRS定量检测前额皮层中GABA和Glu的绝对浓度有望成为临床上的一个预测性指标,以利于客观地评估阿片类处方药依赖者的成瘾严重程度、心理状态、病情变化和治疗效果。
[Abstract]:Opioid substance dependence has been one of the most serious world society, economic and public health problems. The abuse and dependence of opioid prescriptions have increased rapidly in the past more than 10 years. The addiction and dependence problems caused by opioids have gradually become the focus of attention. Euphoria and pleasure, which lead to strong drug craving and compulsive drug seeking behavior. For the diagnosis of opioid dependence, the subjective judgment based on the symptom assessment scale is not clear and objective. Objective neurobiological indicators are sought to assist in the diagnosis of opioid prescription dependence. The change of the disease and the response to the curative effect are necessary. The magnetic resonance spectroscopy (MRS) is used to quantify the changes in the level of local metabolites in the living tissue in a noninvasive way, which is expected to provide a quantitative test for the opioid prescription dependence diagnosis. The reward loop is the reward effect of opioid substances. The neuroanatomical basis, the prefrontal cortex, as the key area of the reward pathway, participates in the advanced executive function, and is considered to be closely related to substance addiction. Gamma aminobutyric acid (gamma -aminobutyric acid, GABA) and glutamate Glu (glutamate, Glu) are the main inhibitory and excitatory neurotransmitters in the reward loop, opioid dependence and forehead The neurotransmitters in the cortex are related to the level of GABA and Glu, which may be involved in the formation of dependence, but the mechanism of its long-term dependence is still not very clear. Therefore, this study is intended to detect the absolute concentration of GABA and Glu using MEGA-PRESS and Optimal TE spectral editors on 3 T MRI scanners and analyzed on the large aperture 3 T MR scanner. The feasibility and repeatability of quantitative determination of the absolute concentration of GABA in the human brain prefrontal cortex were measured, and the absolute concentration of GABA and Glu in the frontal cortex of the opioid prescription drug addicts was detected. The relationship between the absolute concentration of GABA and Glu in the prefrontal cortex of opioid addicts and the relationship between the absolute concentration of the Glu and the neuropsychological index was discussed in order to evaluate opioid prescription drugs. The possible biological markers are provided. The paper is divided into three parts. The summary is as follows: the first part is the feasibility of quantitative determination of the absolute concentration of GABA in the human brain prefrontal cortex on the 70 cm large aperture clinical 3 T magnetic resonance system: the quantitative detection of the MEGA-PRESS wave editing technique on the 70 cm large aperture clinical 3 T MRI system The feasibility of the absolute concentration of GABA in human brain prefrontal cortex. Materials and methods: the subjects included 32 healthy volunteers (25 men, 7 women, 22.6 years old, 22.6 + 3 years old), all right hand, no history of head trauma and neuropsychiatric history, no contraindication of MRI. All the scans were in Siemens MAGNETOM SKyra 3 T The MEGA-PRESS sequence was used to collect the 1H-MRS signal of the ventral medial prefrontal cortex of the volunteers. In addition, the same scanning sequence was used to carry out the water model experiment. A GABA solution water model with a concentration of 50 m M was positioned and scanned, the region of interest was located at the corresponding position with the human brain, and the scanning result was made. For the external reference standard of quantitative analysis, the absolute concentration of GABA in the medial prefrontal cortex (Mean + SD) and its variation coefficient were calculated by using jMRUI V5.0 software after processing the 1H-MRS wave data. Results: the GABA wave data of 32 volunteers were collected successfully by MEGA-PRESS sequence, and the post-processing of jMRUI v5.0 software could be clearly displayed. The absolute concentration of GABA was 1.58 + 0.26 mM, and the coefficient of variation was 16.2%.. It was feasible to detect the GABA signal of the human brain prefrontal cortex on the 70 cm large aperture clinical 3 T MRI system using MEGA-PRESS spectrum editing method, and the collected GABA lines had high stability. The second part was in the 70 cm large aperture. The repeatability of quantitative determination of the absolute concentration of GABA in human brain prefrontal cortex on the bed 3 T magnetic resonance imaging system: the GABA spectrum of healthy volunteers was detected by MEGA-PRESS editing technique on the 70 cm large aperture clinical 3 T magnetic resonance imaging instrument, and the repeatability of GABA absolute quantification method in human brain was explored. Materials and methods: research object Including 16 healthy volunteers (10 men, 6 women, age 19~28 years, average 23.1 + 2.3 years old), all were right hand, no history of head trauma and neuropsychiatric history, no contraindication of MRI. All the scans were performed on the Siemens MAGNETOM Skyra 3 T magnetic resonance imaging instrument. All volunteers performed at least 2 MRI scans. 6 people were selected for the second magnetic resonance imaging (3,4). The time interval between the 2 volunteers was more than 5 days and the interval of the volunteers repeated for 4 times more than 1 weeks. The jMRUI V5.0 software was used to post the spectral data processing, and the GABA content was quantized (GABA/NAA) and the absolute quantization (|GABA|) was used to calculate the phase. Mean value, standard deviation and coefficient of variation. Results: the GABA spectrum data of 16 volunteers were collected successfully before and after multiple scans. The GABA spectrum peak could be displayed well after jMRUI V5.0 software. The relative quantization and absolute quantized coefficient of variation of repeated measurements were less than 20%, without statistical difference (P0.05). The variation coefficients between groups and between groups were less than relative quantization, that is, the repeatability of absolute quantization is better than that of relative quantization. The mean value of GABA in women and men has no statistical difference (P0.05), but the mean value of the absolute content of GABA between men and women has statistical difference (P0.05). Conclusion: in large aperture short magnets magnetic resonance The MEGA-PRESS spectrum editing method was used to measure the absolute concentration of GABA with better intra group and inter group repeatability, and the absolute quantification of GABA was superior to relative quantification. At the same time, the absolute quantification of GABA had sex specificity and had good reproducibility. The results showed that the technique could be used in the study of the large aperture clinical MRI system. The changes in the GABA level of normal and abnormal brain. Third partial opioid prescription drug addicts in the prefrontal cortex of the prefrontal cortex with the absolute concentration of GABA and Glu in resting state magnetic resonance spectroscopy (MRI) and its clinical significance Objective: to measure the changes in the absolute concentration of GABA and Glu in the ventral medial prefrontal cortex by MRS in opioid prescription drug dependence patients and to explore GABA and Glu. The correlation between the changes of absolute concentration and behavioral psychology. Materials and methods: the subjects included 31 opioid prescription addicts (29 men, 2 women, age 18~35 years, average 24.94 + 4.19 years old) and 32 healthy controls (25 men, 7 women, age 18~33 years, and average 22.6 + 3 years old). All the subjects were all The right hand. Using the Siemens MAGNETOM Skyra 3 T magnetic resonance imaging instrument for human head scan, the GABA spectrum data of the ventral prefrontal cortex of all the subjects were collected by MEGA-PRESS sequence, and the Glu wave data were collected by Optimal TE method. The magnetic resonance scanning of the GABA aqueous solution with 50 mM and the water model of the creatine water solution, respectively, was performed. As a quantitative external reference standard, the jMRUI V5.0 software was used to post and quantify the spectral data collected. The severity of addiction was assessed by the opioid addiction severity index, and the Barratt Impulsivity Scale (BIS-11) was used to assess the impulsivity of the subjects, the self rating Anxiety Scale (SAS), the self rating Depression Scale (SDS), Montreal, and the Depression Scale (SDS). The cognitive assessment scale (MOCA) was used to evaluate the subjects' impulsivity, anxiety, depression and cognitive state. The difference in the absolute concentration of GABA and glutamate in the two groups was compared by two independent sample t tests. The correlation between the prefrontal cortex and the psychological indicators of the opioid addicts was evaluated by Spearman correlation analysis. The concentration of |GABA| in the prefrontal cortex of the prescription drug addicts was lower than that in the control group, and the concentration of |Glu| was higher than that in the control group (P0.001). The total score of BIS-11 in the two groups was higher than that in the control group, and the total MOCA score was lower than the control group (lower than 26). The two groups had the difference of the total count (P0.05), and the total score of the other scales was in the two groups. P0.05. The absolute concentration of GABA in the prefrontal cortex of opioid prescription drug addicts was negatively correlated with the absolute concentration of glutamate, BIS-11, SAS, and positive correlation with the MOCA score; but the absolute concentration of glutamic acid was positively correlated with BIS-11, and was negatively correlated with the MOCA score. Conclusion: This study showed that the abnormal level of GABA and Glu and the state of drug seeking and anxiety were positively correlated with the MOCA score. Therefore, the maladjustment of the inhibitory GABA energy and the excitatory Glu neurotransmitter system may be an important pathophysiological mechanism for the thirst and relapse of opioid prescription addicts. The quantitative detection of the absolute concentration of GABA and Glu in the prefrontal cortex by MRS is expected to be a predictor of clinical use. Objective to assess the severity of addiction, psychological state, disease condition and therapeutic effect of opioid dependent drug addicts.

【学位授予单位】：广州医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R445.2;R749.6

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