本文選題：阿片類物質(zhì)使用障礙 + 阿片類處方藥�。� 參考：《廣州醫(yī)科大學(xué)》2017年碩士論文

【摘要】：阿片類物質(zhì)依賴一直是最嚴(yán)重的世界性社會、經(jīng)濟(jì)和公共衛(wèi)生問題之一,近十多年來阿片類處方藥的濫用和依賴急劇增長,其引起的成癮和依賴問題逐漸成為關(guān)注的焦點(diǎn)。濫用阿片類處方藥者可嘗試通過藥物治療劑量以外的方式強(qiáng)化欣快感和愉悅感,進(jìn)而引發(fā)強(qiáng)烈的藥物渴求和強(qiáng)迫性覓藥行為。對于阿片類物質(zhì)依賴的診斷,臨床上以癥狀評定量表為主的主觀判斷,尚未明確客觀的神經(jīng)生物學(xué)指標(biāo)。尋求客觀的神經(jīng)生物學(xué)指標(biāo)以協(xié)助阿片類處方藥依賴的診斷、監(jiān)測病情變化和療效反應(yīng)是有必要的。磁共振波譜(magnetic resonance spectroscopy,MRS)以無創(chuàng)性的方式定量檢測活體組織內(nèi)局部的代謝物水平的變化,有望為阿片類處方藥依賴診斷提供定量檢測的技術(shù)手段。獎賞環(huán)路是阿片類物質(zhì)獎賞效應(yīng)產(chǎn)生的神經(jīng)解剖學(xué)基礎(chǔ),前額皮層作為獎賞通路關(guān)鍵區(qū)域,參與高級執(zhí)行功能,被認(rèn)為與物質(zhì)成癮密切相關(guān)。γ-氨基丁酸(γ-aminobutyric acid,GABA)和谷氨酸Glu(glutamate,Glu)分別為獎賞環(huán)路中主要的抑制性和興奮性神經(jīng)遞質(zhì),阿片類藥物依賴與前額皮層中的神經(jīng)遞質(zhì)GABA和Glu水平有關(guān),其可能參與依賴的形成,但其長期依賴效應(yīng)的機(jī)制仍然不十分清楚。因此,本研究擬在3.0 T磁共振掃描儀上利用MEGA-PRESS和Optimal TE波譜編輯技術(shù)檢測GABA和Glu的絕對濃度,分析在大孔徑3.0 T MR掃描儀上定量檢測活體人腦前額皮層內(nèi)GABA絕對濃度的可行性和可重復(fù)性,檢測阿片類處方藥依賴者腦內(nèi)前額皮層GABA和Glu的絕對濃度,探討阿片類處方藥依賴者前額皮層內(nèi)GABA和Glu絕對濃度與神經(jīng)心理學(xué)指標(biāo)的關(guān)系,旨在為評估阿片類處方藥依賴提供可能的生物學(xué)標(biāo)記物。論文分三個部分,摘要如下:第一部分在70 cm大孔徑臨床3.0 T磁共振系統(tǒng)上定量檢測活體人腦前額皮層GABA絕對濃度的可行性目的:探討在70 cm大孔徑臨床3.0 T MRI系統(tǒng)上使用MEGA-PRESS波譜編輯技術(shù)定量檢測活體人腦前額皮層GABA絕對濃度的可行性。材料與方法:研究對象包括32名健康志愿者(男性25名,女性7名,年齡18~33歲,平均22.6±3.0歲),均為右利手,無頭部外傷史和神經(jīng)精神疾病史,無磁共振掃描禁忌癥。所有掃描均在Siemens MAGNETOM SKyra 3.0 T磁共振成像儀上完成。首先采用MEGA-PRESS序列對志愿者大腦腹內(nèi)側(cè)前額皮層進(jìn)行1H-MRS信號采集;另外使用同樣的掃描序列進(jìn)行水模實(shí)驗,將一個裝有濃度為50 m M的GABA溶液水模進(jìn)行定位掃描,感興趣區(qū)位于與人腦相對應(yīng)位置,掃描結(jié)果作為定量分析的外部參考標(biāo)準(zhǔn)。應(yīng)用jMRUI v5.0軟件對1H-MRS波譜數(shù)據(jù)進(jìn)行后處理,計算出腹內(nèi)側(cè)前額皮層GABA的絕對濃度(Mean±SD)及其變異系數(shù)。結(jié)果:利用MEGA-PRESS序列成功采集了32名志愿者的GABA波譜數(shù)據(jù),經(jīng)jMRUI v5.0軟件后處理均可清晰地顯示GABA譜峰,測得的GABA絕對濃度為1.58±0.26 mM,變異系數(shù)為16.2%。結(jié)論:使用MEGA-PRESS波譜編輯法在70 cm大孔徑臨床3.0 T MRI系統(tǒng)上定量檢測活體人腦前額皮層的GABA信號是可行的,所采集的GABA譜線具有較高的穩(wěn)定性。第二部分在70 cm大孔徑臨床3.0 T磁共振系統(tǒng)上定量檢測活體人腦前額皮層GABA絕對濃度的可重復(fù)性目的:在70 cm大孔徑臨床3.0 T磁共振成像儀上采用MEGA-PRESS編輯技術(shù)檢測健康志愿者的GABA波譜,探討活體人腦內(nèi)GABA絕對量化方法的可重復(fù)性。材料與方法:研究對象包括16名健康志愿者(男性10名,女性6名,年齡19~28歲,平均23.1±2.3歲),均為右利手,無頭部外傷史和神經(jīng)精神疾病史,無磁共振掃描禁忌癥。所有掃描均在Siemens MAGNETOM Skyra 3.0 T磁共振成像儀上完成。所有志愿者至少進(jìn)行2次磁共振掃描,另外再抽取6名進(jìn)行第3、4次磁共振掃描。所有掃描2次的志愿者重復(fù)掃描時間間隔大于5天,重復(fù)掃描4次的志愿者間隔時間超過1星期以上。應(yīng)用jMRUI v5.0軟件進(jìn)行波譜數(shù)據(jù)后處理,并對GABA含量進(jìn)行相對量化(GABA/NAA)和絕對量化(|GABA|),計算出相應(yīng)的平均值、標(biāo)準(zhǔn)差和變異系數(shù)。結(jié)果:前后多次掃描均成功采集到16名志愿者的GABA波譜數(shù)據(jù),經(jīng)jMRUI v5.0軟件處理后均可良好顯示GABA譜峰。多次重復(fù)測量的相對量化和絕對量化變異系數(shù)均小于20%,且無統(tǒng)計學(xué)差異(P0.05)。無論是組內(nèi)還是組間可重復(fù)性,絕對量化組內(nèi)和組間的變異系數(shù)均小于相對量化,即絕對量化的可重復(fù)性優(yōu)于相對量化。男女組間GABA相對含量平均值無統(tǒng)計學(xué)差異(P0.05);但男女組間GABA絕對含量平均值有統(tǒng)計學(xué)差異(P0.05)。結(jié)論:在大孔徑短磁體磁共振掃描儀采用MEGA-PRESS波譜編輯法測量GABA絕對濃度具有較好的組內(nèi)和組間可重復(fù)性,且GABA絕對量化整體上優(yōu)于相對量化。同時,GABA絕對量化具有性別特異性,且具有良好的組間可重復(fù)性。結(jié)果表明,該技術(shù)可在大孔徑臨床MRI系統(tǒng)上用來研究正常和異常大腦的GABA水平改變。第三部分阿片類處方藥依賴者前額皮層中GABA和Glu絕對濃度的靜息態(tài)磁共振波譜測定及其臨床意義目的:利用MRS測量阿片類處方藥依賴患者腹內(nèi)側(cè)前額皮層的GABA和Glu絕對濃度的變化,并探究GABA和Glu絕對濃度的變化與行為心理學(xué)改變之間的相關(guān)性。材料與方法:研究對象包括31名阿片類處方藥依賴患者(男29名,女2名,年齡18~35歲,平均24.94±4.19歲)和32名相匹配的健康對照者(男25名,女7名,年齡18~33歲,平均22.6±3.0歲)。所有研究對象均為右利手。使用Siemens MAGNETOM Skyra 3.0 T磁共振成像儀進(jìn)行人體頭部掃描,采用MEGA-PRESS序列采集所有受試者腹內(nèi)側(cè)前額皮層的GABA波譜數(shù)據(jù),采用Optimal TE方法采集Glu波譜數(shù)據(jù)。將分別裝有50 mM的GABA水溶液和肌酸水溶液的水模進(jìn)行磁共振掃描,作為定量的外部參考標(biāo)準(zhǔn)。應(yīng)用jMRUI v5.0軟件對所采集的波譜數(shù)據(jù)進(jìn)行后處理和量化。采用阿片成癮嚴(yán)重指數(shù)來評估成癮的嚴(yán)重程度,采用Barratt沖動性量表(BIS-11)來評估受試者的沖動性,焦慮自評量表(SAS)、抑郁自評量表(SDS)、蒙特利爾認(rèn)知評估量表(MOCA)分別來評估受試者的沖動性、焦慮、抑郁和認(rèn)知狀態(tài)。采用兩獨(dú)立樣本t檢驗比較兩組GABA和谷氨酸絕對濃度的差異,應(yīng)用Spearman相關(guān)分析評價阿片類處方藥依賴者前額皮層與神經(jīng)心理學(xué)指標(biāo)之間的相關(guān)性。結(jié)果:阿片類處方藥依賴者前額皮層中|GABA|濃度低于對照組,而|Glu|濃度高于對照組,且兩組之間具有顯著性差異(P0.001)。依賴者的BIS-11總評分比對照組高,MOCA總評分比對照組低(低于26分),兩組間存在統(tǒng)計學(xué)差異(P0.05),其他量表總分在兩組之間無統(tǒng)計學(xué)差異(P0.05)。阿片類處方藥依賴者前額皮層內(nèi)GABA絕對濃度與谷氨酸絕對濃度、BIS-11、SAS呈負(fù)相關(guān)、與MOCA評分呈正相關(guān);而谷氨酸絕對濃度與BIS-11呈正相關(guān)、與MOCA評分呈負(fù)相關(guān)。結(jié)論:本研究表明GABA和Glu水平異常與覓藥沖動性、焦慮狀態(tài)、認(rèn)知功能受損有關(guān)。因此,抑制性GABA能和興奮性Glu能神經(jīng)遞質(zhì)系統(tǒng)的失調(diào)可能是阿片類處方藥依賴者渴求和復(fù)吸的一個重要的病理生理學(xué)機(jī)制。通過MRS定量檢測前額皮層中GABA和Glu的絕對濃度有望成為臨床上的一個預(yù)測性指標(biāo),以利于客觀地評估阿片類處方藥依賴者的成癮嚴(yán)重程度、心理狀態(tài)、病情變化和治療效果。
[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.

【學(xué)位授予單位】：廣州醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R445.2;R749.6

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