基于体素分析方法的广泛性焦虑障碍患者脑白质弥散张量成像研究
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摘要
目的：利用弥散张量成像(diffusion tensor imaging,DTI)技术分析首次发病未经治疗的广泛性焦虑障碍(GAD)患者脑白质纤维微观结构的完整性,从神经影像学角度探讨GAD患者可能的脑功能病理机制。
方法：应用《DSM-Ⅳ-TR轴Ⅰ障碍定式临床检查病人版》(即SCID-I/P)诊断工具,筛选符合广泛性焦虑障碍的诊断标准且无共病、年龄在18-44岁之间、从未接受过临床治疗、首发患者22例(GAD患者组),按照年龄以及受教育程度匹配入组正常对照39例(正常对照组),两组均采用汉密尔顿焦虑量表(HAMA)、汉密尔顿抑郁量表(HAMD)、宾尼法尼亚担心状态问卷(PSWQ)、焦虑状态特质量表(STAI)进行评估,要求患者组HAMA评分患者≥18分,PSQW≥60分,HAMD评分≤12分；正常对照组HAMA评分<7分,HAMD<7分。研究对象入组后接受核磁共振检查,进行全脑的DTI扫描,对其中影像学数据良好的16例广泛性焦虑障碍患者和26例按照组内男女比例1：1再次匹配的正常对照进入影像学研究。应用DTI-Studio,SPM2等软件,使用基于体素的分析法(voxel-based analysis)比较两组脑白质的分数各向异性(fractional anisotropy, FA),以P<0.005并且连续50个以上的体素集合视为两组间差异有统计学意义的区域。将差异有统计学意义的脑区叠加到SPM2的标准脑上,使用本研究室自行开发,得到国际公认的软件,计算每个研究对象从VBA方法中得到的有差异的各个脑区FA绝对平均值。然后将每个有差异脑区的FA绝对值与病程、焦虑症状临床量表分(HAMA、PSWQ、STAI)分别做进一步的Spearman's相关分析。FA值来源于弥散张量成像,是常被用来研究脑白质纤维微观结构的影像学标记。FA值降低被认为反映的是脑组织微观完整性受损。
结果：完成MRI扫描的共有22例患者和39例正常人,因为头动等原因,进入统计分析的患者组16例(8女8男)及正常对照组26例(13女13男),结果显示：首发末经过治疗的GAD患者组左侧额叶内侧回、右侧岛叶脑白质FA值显著低于正常对照组(P<0.005)；GAD患者组右侧杏仁核脑白质FA值显著高于正常对照组(P<0.005)。Spearman's相关分析显示：GAD患者组右侧杏仁核FA绝对值同PSWQ、HAMA、状态焦虑问卷(S-AI)和特质焦虑问卷(T-AI)的评分存在显著正相关(P<0.05),而左侧额叶内侧回和右侧岛叶的FA绝对值与各项临床量表评分之间未发现有显著相关(P>0.05)；此外,GAD患者组的平均病程与其右侧杏仁核的FA绝对值呈正相关,与其他脑区FA绝对值无显著相关(P>0.05)。患者组病程与其各临床量表评分之间未见显著相关(P>0.05)。
结论1.本研究发现首发未经治疗的GAD患者组存在右侧杏仁核、左侧额叶内侧回和右侧岛叶FA值异常,提示GAD患者组脑白质纤维微观结构完整性异常,推测脑白质病变在广泛性焦虑患者发病的早期可能即已存在。2.GAD患者组右侧杏仁核FA值增高可能显示该部位与某些脑区之间的连接增强,提示焦虑障碍依赖的以杏仁核为核心的恐惧条件反射神经环路存在异常激活,个体对外界信息持续敏感性加工,导致机体自律反应和唤醒度增高,产生忐忑不安、警觉性增高和植物神经紊乱等临床症状。3.GAD患者组右侧杏仁核FA值增高可能提示杏仁核功能的偏侧化现象,右侧杏仁核无意识状态下对威胁信息进行优先加工。4.GAD患者组右侧杏仁核FA绝对值增高的程度与疾病的症状严重程度和病程慢性化相关,其左侧额叶内侧回和右侧岛叶的FA绝对值异常程度与疾病的症状严重程度和病程之间无显著相关。
Object To assess the microstructure integrity of brain white matter tracts in patients with first-episode treatment-naive general anxiety disorders (GAD) using diffusion tensor imaging (DTI) technique. To explore the possible pathological mechanism of brain function in GAD from neuroimaging field.
Methods Twenty two first-episode,treatment-naive and no comorbid patients with GAD,aged 18 to 44 years old (according to the diagnosis criteria of DSM-IV-TR Handbook of Differential Diagnosis, SCID-I/P) and thirty nine age-and educational level-matched healthy controls were enrolled. All subjects were assessed using Hamilton Anxiety Rating Scale (HAMA), Hamilton Depression Rating Scale (HAMD), Penn State Worry Questionnaire (PSWQ), and State-Trait Anxiety Inventory (STAI). HAMA scores≥18,PSQW scores≥60 and HAMD scores<12 were needed in patients, and both HAMA and HAMD scores≤7 were needed in controls.Then, all subjects accepted the MRI scans and DTI. Using software DTI-Studio and SPM2,the fractional anisotropy (FA) in brain white matter of the two groups were compared by voxel-based analysis. The areas with continous 50 voxels and above were considered be a significant different area (P<0.005).Then these areas were superimposed to the standard brain of SPM2.Using a self-develop software, the average FA in these significant different areas of each subject were calculated. Then Spearman's correlation analysis was carried to test the association among FA and disease course and clinical scales'scores (HAMA, PSWQ, STAI).
Results Twenty two patients with GAD and thirty nine healthy controls accepted MRI scan. Data could be analyzed finally including sixteen GAD patients (8 females and 8 males) and twenty six healthy controls(13 females and 13 males).The result showed that compared to healthy controls, FA significantly decreased in the left medial frontal and right insula white matter and increased in right amygdala in first-episode treatment-naive GAD patients (P<0.005).The Spearman correlation analysis showed a significant positive correlation between FA in amygdala white matter in GAD patients and the scores of PSWQ, HAMA and S-AI and T-AI (P<0.05).No significant correlation were found between FA in left medial frontal and insla white matter and scales'scores (P>0.05).Furthermore, a positive correlation existed between the average disease duration of GAD and FA in the right amygdale white matter (P> 0.05).And no significant correlation between duration of disease and scales'scores were found (P>0.05).
Conclusions 1.This study found that microstructure abnormalities in right amygdala, left medial frontal and right insula brain white matter tracts in first-episode treatment-naive GAD patients, which suggests brain white matter lesion has happened at the early period of GAD.2.FA increase in amygdala in GAD patients suggests that the connectivity among amygdala and some other brain areas maybe increase, which implys the activate of amygdala-based fear conditional reflex neural circuitry were abnormal.The individuals with GAD persistently process environmental information sensitively, which leads to the clinical symptoms, persistent restlessness, increased arousal,autonomic nerve dysfunction, and so on.3.FA increased in right amygdala in GAD patients reflects lateralization of amygdala function. The right amygdala unconsciously prior processes the threatening information.4.Abnormal activation degree of right amygdala white matter tracts is dose-reponse associated with the severity and disease duration, while, the white matter abnormalities degree in left medial frontal and right insula is not related to the severity and disease duration in GAD patients.
方法：应用《DSM-Ⅳ-TR轴Ⅰ障碍定式临床检查病人版》(即SCID-I/P)诊断工具,筛选符合广泛性焦虑障碍的诊断标准且无共病、年龄在18-44岁之间、从未接受过临床治疗、首发患者22例(GAD患者组),按照年龄以及受教育程度匹配入组正常对照39例(正常对照组),两组均采用汉密尔顿焦虑量表(HAMA)、汉密尔顿抑郁量表(HAMD)、宾尼法尼亚担心状态问卷(PSWQ)、焦虑状态特质量表(STAI)进行评估,要求患者组HAMA评分患者≥18分,PSQW≥60分,HAMD评分≤12分；正常对照组HAMA评分<7分,HAMD<7分。研究对象入组后接受核磁共振检查,进行全脑的DTI扫描,对其中影像学数据良好的16例广泛性焦虑障碍患者和26例按照组内男女比例1：1再次匹配的正常对照进入影像学研究。应用DTI-Studio,SPM2等软件,使用基于体素的分析法(voxel-based analysis)比较两组脑白质的分数各向异性(fractional anisotropy, FA),以P<0.005并且连续50个以上的体素集合视为两组间差异有统计学意义的区域。将差异有统计学意义的脑区叠加到SPM2的标准脑上,使用本研究室自行开发,得到国际公认的软件,计算每个研究对象从VBA方法中得到的有差异的各个脑区FA绝对平均值。然后将每个有差异脑区的FA绝对值与病程、焦虑症状临床量表分(HAMA、PSWQ、STAI)分别做进一步的Spearman's相关分析。FA值来源于弥散张量成像,是常被用来研究脑白质纤维微观结构的影像学标记。FA值降低被认为反映的是脑组织微观完整性受损。
结果：完成MRI扫描的共有22例患者和39例正常人,因为头动等原因,进入统计分析的患者组16例(8女8男)及正常对照组26例(13女13男),结果显示：首发末经过治疗的GAD患者组左侧额叶内侧回、右侧岛叶脑白质FA值显著低于正常对照组(P<0.005)；GAD患者组右侧杏仁核脑白质FA值显著高于正常对照组(P<0.005)。Spearman's相关分析显示：GAD患者组右侧杏仁核FA绝对值同PSWQ、HAMA、状态焦虑问卷(S-AI)和特质焦虑问卷(T-AI)的评分存在显著正相关(P<0.05),而左侧额叶内侧回和右侧岛叶的FA绝对值与各项临床量表评分之间未发现有显著相关(P>0.05)；此外,GAD患者组的平均病程与其右侧杏仁核的FA绝对值呈正相关,与其他脑区FA绝对值无显著相关(P>0.05)。患者组病程与其各临床量表评分之间未见显著相关(P>0.05)。
结论1.本研究发现首发未经治疗的GAD患者组存在右侧杏仁核、左侧额叶内侧回和右侧岛叶FA值异常,提示GAD患者组脑白质纤维微观结构完整性异常,推测脑白质病变在广泛性焦虑患者发病的早期可能即已存在。2.GAD患者组右侧杏仁核FA值增高可能显示该部位与某些脑区之间的连接增强,提示焦虑障碍依赖的以杏仁核为核心的恐惧条件反射神经环路存在异常激活,个体对外界信息持续敏感性加工,导致机体自律反应和唤醒度增高,产生忐忑不安、警觉性增高和植物神经紊乱等临床症状。3.GAD患者组右侧杏仁核FA值增高可能提示杏仁核功能的偏侧化现象,右侧杏仁核无意识状态下对威胁信息进行优先加工。4.GAD患者组右侧杏仁核FA绝对值增高的程度与疾病的症状严重程度和病程慢性化相关,其左侧额叶内侧回和右侧岛叶的FA绝对值异常程度与疾病的症状严重程度和病程之间无显著相关。
Object To assess the microstructure integrity of brain white matter tracts in patients with first-episode treatment-naive general anxiety disorders (GAD) using diffusion tensor imaging (DTI) technique. To explore the possible pathological mechanism of brain function in GAD from neuroimaging field.
Methods Twenty two first-episode,treatment-naive and no comorbid patients with GAD,aged 18 to 44 years old (according to the diagnosis criteria of DSM-IV-TR Handbook of Differential Diagnosis, SCID-I/P) and thirty nine age-and educational level-matched healthy controls were enrolled. All subjects were assessed using Hamilton Anxiety Rating Scale (HAMA), Hamilton Depression Rating Scale (HAMD), Penn State Worry Questionnaire (PSWQ), and State-Trait Anxiety Inventory (STAI). HAMA scores≥18,PSQW scores≥60 and HAMD scores<12 were needed in patients, and both HAMA and HAMD scores≤7 were needed in controls.Then, all subjects accepted the MRI scans and DTI. Using software DTI-Studio and SPM2,the fractional anisotropy (FA) in brain white matter of the two groups were compared by voxel-based analysis. The areas with continous 50 voxels and above were considered be a significant different area (P<0.005).Then these areas were superimposed to the standard brain of SPM2.Using a self-develop software, the average FA in these significant different areas of each subject were calculated. Then Spearman's correlation analysis was carried to test the association among FA and disease course and clinical scales'scores (HAMA, PSWQ, STAI).
Results Twenty two patients with GAD and thirty nine healthy controls accepted MRI scan. Data could be analyzed finally including sixteen GAD patients (8 females and 8 males) and twenty six healthy controls(13 females and 13 males).The result showed that compared to healthy controls, FA significantly decreased in the left medial frontal and right insula white matter and increased in right amygdala in first-episode treatment-naive GAD patients (P<0.005).The Spearman correlation analysis showed a significant positive correlation between FA in amygdala white matter in GAD patients and the scores of PSWQ, HAMA and S-AI and T-AI (P<0.05).No significant correlation were found between FA in left medial frontal and insla white matter and scales'scores (P>0.05).Furthermore, a positive correlation existed between the average disease duration of GAD and FA in the right amygdale white matter (P> 0.05).And no significant correlation between duration of disease and scales'scores were found (P>0.05).
Conclusions 1.This study found that microstructure abnormalities in right amygdala, left medial frontal and right insula brain white matter tracts in first-episode treatment-naive GAD patients, which suggests brain white matter lesion has happened at the early period of GAD.2.FA increase in amygdala in GAD patients suggests that the connectivity among amygdala and some other brain areas maybe increase, which implys the activate of amygdala-based fear conditional reflex neural circuitry were abnormal.The individuals with GAD persistently process environmental information sensitively, which leads to the clinical symptoms, persistent restlessness, increased arousal,autonomic nerve dysfunction, and so on.3.FA increased in right amygdala in GAD patients reflects lateralization of amygdala function. The right amygdala unconsciously prior processes the threatening information.4.Abnormal activation degree of right amygdala white matter tracts is dose-reponse associated with the severity and disease duration, while, the white matter abnormalities degree in left medial frontal and right insula is not related to the severity and disease duration in GAD patients.
引文
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[1]American Psychiatric Association.(2000), Diagnostic and statistical manual of mentaldisorders, Washington DC
[2]Buchel C, Dolan RJ. Classical fear conditioning in functional neuroimaging. Curr Opin Neurobiol 2000 Apr;10(2):219-23.
[3]Cannistraro PA, Rauch SL. Neural circuitry of anxiety:evidence from structural and functional neuroimaging studies. Psychopharmacol Bull 2003;37(4):8-25.
[4]LeDoux JE. Emotion circuits in the brain. Annu Rev Neurosci 2000;23:155-84.
[5]Buchel C, Dolan RJ. Classical fear conditioning in functional neuroimaging. Curr Opin Neurobiol 2000 Apr; 10(2):219-23.
[6]Charney DS. Neuroanatomical circuits modulating fear and anxiety behaviors. Acta Psychiatr Scand Suppl 2003;(417):38-50.
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[8]Cannistraro PA, Rauch SL. Neural circuitry of anxiety:evidence from structural and functional neuroimaging studies. Psychopharmacol Bull 2003;37(4):8-25.
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[11]Grillon C.Startle reactivity and anxiety disorders:aversive conditioning, context, and neurobiology. Biol Psychiatry 2002;52:958-75.
[12]Dugas MJ, Freeston MH, Ladouceur R, Rheaume J, Provencher M, Boisvert JM. Worry themes in primary GAD, secondary GAD,and other anxiety disorders. J Anxiety Disord 1998 May;12(3):253-61.
[13]Bhakoo KK, Pearce D. In vitro expression of N-acetyl aspartate by oligodendrocytes:implications for proton magnetic resonance spectroscopy signal in vivo. J Neurochem 2000 Jan;74(1):254-62.
[14]Baslow H. Functions of N-acety-L-aspartate and N-acetyl-L-aspartylglutamate in the vertebrate brain:role in glial cell-specific signaling. J Neurochem 2000 Aug;75(2):453-9.
[15]Sanjay J.Mathew, Xiangling Mao, Jeremy D.Coplan. Dorsolateral Prefrontal Cortical Pathology in Generalized Anxiety Disorder:A Proton Magnetic Resonance Spectroscopic Imaging Study. Am J Psychiatry 2004;(161):1119-21.
[16]Coplana b, Sanjay J.,Mathewc. Decreased choline and creatine concentrations in centrum semiovale in patients with generalized anxiety disorder: relationship to IQ and early trauma. Psychiatry Research:Neuroimaging 2006;9(173):13-7.
[17]Christopher S.Monk, Eva H.Telzer, Karin Mogg. Amygdala and ventrolateral prefrontal cortex activation to masked angry faces in children and adolescents with generalized anxiety disorde. Archives of General Psychiatry 2008;65(5):568-76.
[18]McClure EB, Monk CS, Nelson EE, et al. Abnormal attention modulation of fear circuit function in pediatric generalized anxiety disorder. Arch Gen Psychiatry 2007 Jan;64(l):97-106.
[19]De Bellis MD, Casey BJ, Dahl R BB.A pilot study of amygdala volumes in pediatric generalized anxiety disorder. Biol Psychiatry 2000;(48):51-7.
[20]Michael D, De Bellis, Superior Temporal Gyrus Volumes in Pediatric Gneralized Anxiety Disorder. BIOL PSYCHIATRY 2002;(51):553-62.
[21]Mamata Hea. High-resolution line scan diffusion tensor MR imaging of white matter fiber tract anatomy. AJNR Am J Neuroradiol 2002;23(1):67-75.
[22]Scheltens Peal. Histopathologic correlates of white matter changes on MRI in Alzheimer's disease and normal aging. Neurology 1995;45(5):883-8.