首发重性抑郁症患者脑功能和脑结构的磁共振研究
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摘要
目的：结合血氧依赖水平的功能磁共振(BOLD—fMRI)，三维结构磁共振(3D)以及弥散张量成像(DTI)三种不同的磁共振技术，探讨首发重性抑郁症患者可能的脑功能和脑结构病理机制。
方法：对27例首发未治疗过的年轻成年重性抑郁症患者(同时符合CCMD-3抑郁发作和DSM-Ⅳ重性抑郁症的诊断标准)和28例正常人，使用汉密尔顿抑郁量表(HAMD)、汉密尔顿焦虑量表(HAMA)、生活事件量表(LES)，以及韦氏记忆量表的理解和再认分测验进行测评，要求HAMD评分患者≥24分，正常人≤7分。研究对象在入组后进行核磁共振检查，依次为BOLD-fMRI(包括情绪计数Stroop(ecStroop)任务、情绪面孔任务、情绪图片任务和情绪图片短时记忆提取任务)，3D和DTI。扫描后患者给予文拉法辛治疗并进行半年随访观察，随访结束时再次进行上述量表评定和记忆测验以及核磁共振检查，顺序同前。
结果：共22例患者和24例正常人完成了MRI扫描，16例患者完成随访并复查了MRI。排除头动导致的数据质量问题，进入统计分析的fMRI部分治疗前18例(14女4男)，治疗后16例(14女4男)；3D部分治疗前20例(16女4男)，治疗后13例(9女4男)；DTI部分治疗前19例(15女4男)，治疗后13例(9女4男)。对完成随访的16例患者和16例年龄、性别匹配的正常人进行fMRI比较；3D和DTI部分则对治疗前后都包括的13例患者和13例年龄、性别匹配的正常人进行比较，结果发现。1．抑郁症患者的HAMD和HAMA评分治疗后较治疗前明显下降(P=0.000)，但未达正常人水平(P=0.01)；患者组治疗前的理解和再认测验分数低于正常人(P=0.001，P=0.04)，治疗后接近正常人水平(P＞0.05)；患者和正常人两组的LES负性分和总分之间差异显著(P=0.000)。2．fMRI(1)ecStroop任务：抑郁症患者负性词汇对双侧扣带回和前额叶、颞叶、顶叶多个区域的激活较中性词汇低，和正常人正相反；两组对双侧小脑的激活都降低。发作期患者右侧扣带回和左侧颞中回激活较正常人低，左侧小脑激活较后者高；患者治疗前后比较，以及治疗后和正常人之间比较未见激活差异显著性的脑区。(2)情绪面孔任务：与高兴面孔比较，抑郁症患者和正常人面对悲伤面孔时视皮层和海马旁回的激活都高，右侧前额叶激活都低；抑郁症患者在悲伤面孔刺激时尾状核激活高，和正常人相反。发作期患者右侧后扣带回和左侧岛叶的激活较正常人高，双侧前额叶，左侧顶下小叶和梭状回，右侧钩回和海马旁回激活较正常人低；治疗后右侧前额叶和左侧颞叶，双侧视皮层，左侧基底神经节的激活较治疗前增高；治疗后双侧前额叶，右侧扣带回以及颞叶区域的激活较正常人高。(3)情绪图片任务：负性图片对抑郁症患者和正常人双侧视皮层的激活都较正性图片高；患者负性图片较正性图片对双侧杏仁核和左侧钩回激活高，而对左侧额中回，右侧扣带回前部和后部，同侧颞上回和顶叶，双侧岛叶的激活低；正常人负性和正性图片对前额叶均有激活高的区域。发作期患者双侧前额叶和左侧钩回的激活较正常人低；治疗后右侧额中回和同侧后扣带回，双侧颞叶，左侧丘脑的激活较治疗前增高；治疗后右侧额中回和顶下小叶、左侧楔前叶的激活较正常人低。(4)情绪图片短时记忆提取任务：抑郁症患者负性图片较正性图片对双侧前额叶和左侧顶叶，左侧前扣带回和同侧海马、基底神经节以及枕中回激活高，对左侧尾状核头部和双侧岛叶的激活低；正常人仅左侧前扣带回和右侧额内侧回在负性图片时激活稍低；发作期患者双侧前额叶和顶叶，右侧颞中回，双侧枕中回的激活较正常人高；治疗后双侧前额叶，颞叶和视皮层的激活较治疗前降低；治疗后双侧前额叶，右侧角回和同侧视皮层的激活较正常人高。(5)应激性事件和抑郁症脑功能改变的关系：ecStroop任务中，应激组和非应激组对前额叶都有多个区域的激活，应激组右侧岛叶和左侧颞下回的激活较非应激组低。面孔任务中，应激组对前额叶、右侧海马旁回和尾状核体部、双侧丘脑的激活高，左侧前扣带回的激活较非应激组低。图片任务中，两组对前额叶、右侧颞叶和左侧壳核都有激活，应激组右侧扣带回激活高，非应激组双侧顶叶和枕中回、左侧尾状核体部激活高。提取任务中，应激组左侧中央前回和顶叶，双侧颞叶的激活较非应激组低。(6)症状严重程度和抑郁症脑功能改变的关系：ecStroop任务中，HAMD高分组对双侧额中回、左侧颞上回和同侧岛叶的激活比低分组低。面孔任务中，高分组对前额叶、右侧扣带回、丘脑和尾状核体部的激活比低分组高，两组左侧视皮层均有激活。图片任务中，高分组对左侧钩回、右侧海马旁回和壳核、双侧岛叶的激活高，对前额叶和左侧海马的激活较低分组低。提取任务中，高分组对双侧前额叶和前扣带回，左侧岛叶，右侧楔叶和海马旁回的激活比低分组高。(7)病程和抑郁症脑功能改变的关系：ecStroop任务中，长病程组对右侧额中回、顶下小叶和枕上回的激活比短病程组高，而双侧颞叶、左侧顶上小叶和岛叶的激活低。面孔任务中，长病程组对右侧额上回，同侧丘脑、屏状核和视皮层，左侧楔前叶的激活比短病程组低。图片任务中，长病程组对左侧钩回和尾状核尾部、右侧丘脑的激活高，对前额叶、双侧顶叶和视皮层的激活低。提取任务中，长病程组对双侧前额叶BA10区，右侧枕中回和海马旁回的激活比短病程组高。(8)短时记忆功能(理解测验分数)和抑郁症脑功能改变的关系：ecStroop任务中，理解测验高分组对右侧前额叶，左侧前扣带回和颞中回，顶叶，双侧视皮层，左侧丘脑和尾状核体部的激活比低分组高。面孔任务中，高分组对双侧前额叶、颞叶和视皮层，左侧扣带回，右侧顶叶和岛叶及尾状核体部，及双侧小脑的激活高；对左侧杏仁核和海马旁回，右侧钩回，双侧尾状核的激活低。图片任务中，高分组对双侧前额叶、颞上回和顶叶，左侧岛叶的激活高；对双侧海马旁回，左侧胼胝下回，右侧额内侧回和尾状核及小脑的激活低。提取任务中，高分组对左侧前扣带回，双侧颞上回和右侧枕中回的激活比低分组低。3．3D：发作期抑郁症患者右侧额内侧回和同侧颞极、双侧壳核／苍白球和双侧小脑的灰质密度较正常人低；治疗后右侧额上回、双侧中央前回、双侧颞极、双侧壳核／苍白球和双侧小脑的灰质密度仍较正常人低，未见治疗前后差异有显著性的脑区。4．DTI：发作期抑郁症患者左侧额上回，双侧额中回和双侧前扣带回白质的分数各向异性(FA)值较正常人低；治疗后双侧额上回和额中回，右侧额下回白质FA值较治疗前增高，左侧额中回白质FA值仍较正常人低，而右侧颞中回和颞上回白质FA值高于正常人。5．长病程组和短病程组之间，HAMD高分组和低分组之间，应激组和非应激之间均未见灰质密度和白质FA值差异显著性的脑区。
结论：1．右侧额内侧回和颞极，双侧壳核／苍白球和小脑的灰质密度降低可能是抑郁症发生的神经病理基础，而非抑郁症的后果。2．首次报道首发未治疗的年轻成年MDD患者存在前额叶和前扣带回白质纤维整合性失常，提示白质病变在抑郁症发病的早期即已存在。3．双侧前额叶和扣带回，顶叶和视皮层功能异常可能是抑郁症患者认知功能损害的脑功能病理基础。4．边缘叶功能异常增强和额顶叶功能减退可能是抑郁症患者负性情绪的脑功能病理基础。5．脑功能异常和白质微结构失常是一种可逆性变化，在药物有效治疗，临床症状缓解后部分恢复。6．发病前存在应激性生活事件的患者对难过刺激的感知判断可能存在更大的偏差；应激事件的存在对抑郁症的注意力和执行功能无明显影响，对记忆功能的损害可能较轻。7．抑郁症患者的记忆功能和对情绪性刺激的反应能力可能和症状的严重程度以及病程呈负相关；执行功能和注意力可能与症状的严重程度呈负相关。8．灰质密度下降和白质微结构异常增加抑郁发生的风险，但可能与病程及症状严重程度无关，应激性生活事件在抑郁症的灰质密度下降和白质微结构改变中可能不发挥作用。
Object The aim of this study was to explore the brain functional and structuralpathological mechanism in first-episode major depressive disorder (MDD), by bloodoxygenation level dependent functional magnetic resonance imaging (BOLD-fMRI),three dimension MRI (3D), and diffusion tensor imaging (DTI) techniques.
Methods Twenty seven first-episode treatment-naive young adult with MDD(according to the diagnosis critietia of CCMD-Ⅲand DSM-Ⅳ) and twenty eight ageand gender-matched healthy controls were assessed using 17-item HamiltonDepression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA), LifeEvent Scale (LES), and Understanding and recognition test of Wechsler MemoryScale (WMS). HAMD sorces were requested≥24 in patients and≤7 in controls. Then,MRI scan were obtained ordering to BOLD-fMRI (including four task, emotionalcount Stroop, emotional face, emotional picture and the recall of short-term memory),3D, DTI. We assessed patients like above again after six months antidepressant(Venlafaxine) treatment.
Results Twenty two patients and 24 controls finished MRI scan. 16 patientswere followed. Some data were excluded because of head movement. Data could beanalyzed finally including 18 pre-treatment patients (4 males) and 16 post-treatmentpatients (4 males) in fMRI, 20 pre- patients (4 males) and post- patients (4 males) in3D; 19 pre- patients (4 males) and 13 post- patients (4 males) in DTI. Data of sixteenpatients and sixteen age and gender-matched healthy controls were analyzed in fMRIpart, and 13 patients and 13 age and gender-matched healthy controls were analyzedin 3D and DTI part. 1. HAMD and HAMA scores in post-treatment patients weresignificantly lower than those in pre-treatment (P=0.000), however still higher thanthose in healthy controls (P=0.01). Understanding and recognition tests scores werelower significantly in pre-treatment patients compared with healthy controls (P=0.001, P=0.04), and were similar between post-treatment patients and controls(P＞0.05). LES total scores and negative scores were different between pre-treatmentpatients and controls (P=0.000). 2. fMRI(1) ecStroop task The bilateral cingulategyfi, several regions of prefrontal lobe, temporal and parietal lobe had increasedactivation in negative words compared with neutral words in patients, which isconverse in controls. And bilateral cerebellum had decreased activation in negativewords than neutral words both in patients and controls. Pre-treatment patients showed decreased activation in right cingulate and left middle temporal gyrus, increasedactivation in left cerebellum compared with controls. No areas with significantlydifferent activation were found between pre- and post-treatment patients and betweenpost-treatment patients and controls. (2) Emotional face task There were increasedvisual cortex and parahippocampal gyrus activation and decreased right prefrontalcortex activation in sad face compared with happy face in both patients and controls.The caudate nucleus activation increased in sad face than happy face in patients,which is converse in controls. Compared with healthy controls, MDD patients showedincreased activation in right posterior cingulated and left insula, decreased activationin bilateral prefrontal, left inferior parietal lobule, left fusiform gyrus, right uncus andright parahippocampal gyrus. Post-treatment patients showed increased activation inright prefrontal cortex, left temporal lobe, bilateral visual cortex and left basal gangliathan pre-treatment, and increased activation in bilateral prefrontal lobe, right cingulategyrus and right temporal lobe than controls. (3) Emotional picture Both patientsand controls showed increased activation in bilateral visual cortex in negative picturecompared with positive picture. Compared with positive picture, negative pictureincreased bilateral amygdala and left uncus activation, and decreased activation in leftmiddle frontal gyrus, right anterior and posterior cingulate, right superior temporalgyrus, right parietal lobe and bilateral insula in MDD patients. Both negative andpositive picture activated prefrontal lobe in controls. Patients showed decreasedactivation in several areas of bilateral prefrontal lobe and left uncus compared withcontrols. Right middle frontal gyrus, right posterior cingulate, bilateral temporal lobeand left thalamus activation increased in post-treatment patient than pre-treatment.However, the right middle frontal gyrus, right inferior parietal lobule and leftprecuneus showed lower activation than controls yet. (4) Recall of short-termmemory task Compared with positive picture, negative picture increased theactivation in bilateral prefrontal and left parietal lobe, left anterior cingulate, lefthippocampus, left basal ganglia and left middle occipital lobe, and decreasedactivation in left caudate head and bilateral insula in MDD patients. Controlsshowed smaller decreased activation of left anterior cingulate and right medial frontalgyrus in negative picture than positive picture. Compared with controls, MDDpatients showed increased activation in several regions of bilateral prefrontal andparietal lobe, right middle temporal gyrus, bilateral middle occipital gyrus. Aftertreatment, the bilateral prefrontal lobe, temporal lobe and visual cortex activation decreased than pre-treatment patients. However, the bilateral prefrontal lobe, rightangular gyrus and right visual cortex still showed increased activation than controls.(5) Stressful life event (SLE) Patients with and without SLE also showed increasedactivation in prefrontal lobe in ecStroop task, and patients with SLE showeddecreased activation in right insula and left inferior temporal lobe than those withoutSLE. Compared with those without SLE, patients with SLE showed increasedactivation in prefrontal lobe, right parahippocampal gyrus, right caudate body,bilateral thalamus in face task, right anterior cingulate in picture task, whereas,decreased activation in left anterior cingulate in face task, and bilateral parietal lobeand middle occipital gyrus and left canduate body in picture task, and left precentralgyrus, left parietal lobe and bilateral temporal lobe in recall task. Furthermore, inpicture task, both patients with and without SLE showed increased activation inseveral areas of prefrontal lobe, right temporal lobe and left putamen. (6) SeverityCompared with patients with lower HAMD scores, those patients with high HAMDscores showed decreased activation in many regions, including bilateral middlefrontal gyrus, left superior temporal lobe and left insula in ecStroop task, bilateralprefrontal lobe, right cingulate, right thalamus and right caudate body in face task, leftuncus, right pamhippocampal gyrus, right putamen and bilateral insula in picture task,and bilateral prefrontal lobe and anterior cingulate, left insula, right cuneus and rightparahippocampal gyrus in recall task. Moreover, patients with higher HAMD scoresshowed decreased activation in several areas in frontal lobe and left hippocampus inpicture task than those with lower HAMD scores. (7) Course of disease Comparedwith patients with short course, the patients with long course showed increasedactivation in right middle frontal gyrus, right inferior parietal lobule and right superioroccipital gyrus in ecStroop task, in left uncus, left caudate tail and right thalamus inpicture task, bilateral prefrontal lobe (BA10), right middle occipital and rightparahippocampal gyrus in recall task. However, patients with long duration showeddecreased activation in some other regions than those patients with long duration,including bilateral temporal lobe, left superior parietal lobule and left insula inecStroop task, right superior frontal gyrus, right thalamus, right claustrum, right visualcortex and left precuneus in face task, several areas of prefrontal lobe, bilateralparietal lobe and visual cortex in picture task. (8) Short-time memory (WMSUnderstanding score) Compared with patients with lower Understanding scores, thepatients with higher Understanding scores showed increased activation in right prefrontal lobe, left anterior cingulated and middle temporal gyrus, parietal cortex,bilateral visual cortex, left thalamus and caudate body in ecStroop task, in bilateralprefrontal, temporal and visual cortex, left cingulate, right parietal cortex and insula,and bilateral cerebellum in face task, in bilateral prefrontal cortex, superior temporalgyri and parietal cortex, left insula in picture task. However, patients with highUnderstanding scores showed decreased activation in some other regions than thosepatients with lower Understanding scores, including left amygdala andparahippocampal gyrus, right uncus, bilateral caudate in face task, and bilateralparahippocampal gyri, left subcallosal gyrus, right medial frontal gyrus, right caudateand cerebellum in picture task, and left anterior cingulate, bilateral superior temporalgyri and right middle occipital gyrus in recall task. 3. 3D MDD patients showedsignificantly lower gray matter density than healthy controls in right medial frontalgyrus, right temporal pole, bilateral putamen and globus pallidus, bilateral cerebellum.After treatment, the gray matter density in right superior frontal gyrus, bilateralprecentral gyrus, temporal pole, putamen and globus pallidus, and cerebellum inpatients were still significantly lower than controls. 4. DTI Compared with controls,MDD patients exhibited significant decreased fractional anisotropy (FA) values in leftsuperior frontal gyrus, bilateral middle frontal gyrus and bilateral anterior cingnlate.FA values in bilateral superior and middle gyrus, right inferior frontal gyrus increasedafter treatment. However, FA values in left middle gyrus in post-treatment patientswere still lower than controls. Furthermore, FA values in right middle and superiortemporal gyrus were significantly higher than controls. 5. There were no regionswith significant different gray matter density and white matter FA values were foundbetween patient with long and short duration, between patients with high and lowHAMD scores, and between patients with or without SLE.
Conclusions 1. Decreased gray matter density in right medial frontal gyrus, righttemporal pole, bilateral putamen and globus pallidus, bilateral cerebellum may be theneuropathological substrate of MDD rather than a result. 2. This is the first study toreport that white matter microstructure abnormalities of prefrontal lobe and anteriorcingulate in first-episode, treatment-naive young adult MDD, suggesting thatabnormalities of brain white matter may be present early in the course of MDD. 3.Dysfunction in bilateral prefrontal lobe, cingulate, parietal and visual cortex maycontribute to the neuropathology of cognitive impairments in MDD. 4. Abnormalhyperfunction in limbic system and hypofunction in prefrontal and parietal lobe may contribute to neuropathology of mood processing bias in MDD. 5. Functional andwhite matter microstructure abnormalities could be improved by effectiveantidepressant treatment. 6. Occurring of SLE may induce greater bias to perceive sadstimuli in MDD, but no impairment to attention and execution function. And patientswith SLE may have little memory impairment than those without SLE. 7. Memoryand the ability to response to emotional stimuli may be negative correlation withsymptoms severity and illness course of MDD. Execution function and attention maybe negative correlation with symptoms severity of depression. 8. Lower gray matterdensity and FA values may increase the risk of MDD episode, however, no correlationwith the course, severity and the occurring of SLE.
方法：对27例首发未治疗过的年轻成年重性抑郁症患者(同时符合CCMD-3抑郁发作和DSM-Ⅳ重性抑郁症的诊断标准)和28例正常人，使用汉密尔顿抑郁量表(HAMD)、汉密尔顿焦虑量表(HAMA)、生活事件量表(LES)，以及韦氏记忆量表的理解和再认分测验进行测评，要求HAMD评分患者≥24分，正常人≤7分。研究对象在入组后进行核磁共振检查，依次为BOLD-fMRI(包括情绪计数Stroop(ecStroop)任务、情绪面孔任务、情绪图片任务和情绪图片短时记忆提取任务)，3D和DTI。扫描后患者给予文拉法辛治疗并进行半年随访观察，随访结束时再次进行上述量表评定和记忆测验以及核磁共振检查，顺序同前。
结果：共22例患者和24例正常人完成了MRI扫描，16例患者完成随访并复查了MRI。排除头动导致的数据质量问题，进入统计分析的fMRI部分治疗前18例(14女4男)，治疗后16例(14女4男)；3D部分治疗前20例(16女4男)，治疗后13例(9女4男)；DTI部分治疗前19例(15女4男)，治疗后13例(9女4男)。对完成随访的16例患者和16例年龄、性别匹配的正常人进行fMRI比较；3D和DTI部分则对治疗前后都包括的13例患者和13例年龄、性别匹配的正常人进行比较，结果发现。1．抑郁症患者的HAMD和HAMA评分治疗后较治疗前明显下降(P=0.000)，但未达正常人水平(P=0.01)；患者组治疗前的理解和再认测验分数低于正常人(P=0.001，P=0.04)，治疗后接近正常人水平(P＞0.05)；患者和正常人两组的LES负性分和总分之间差异显著(P=0.000)。2．fMRI(1)ecStroop任务：抑郁症患者负性词汇对双侧扣带回和前额叶、颞叶、顶叶多个区域的激活较中性词汇低，和正常人正相反；两组对双侧小脑的激活都降低。发作期患者右侧扣带回和左侧颞中回激活较正常人低，左侧小脑激活较后者高；患者治疗前后比较，以及治疗后和正常人之间比较未见激活差异显著性的脑区。(2)情绪面孔任务：与高兴面孔比较，抑郁症患者和正常人面对悲伤面孔时视皮层和海马旁回的激活都高，右侧前额叶激活都低；抑郁症患者在悲伤面孔刺激时尾状核激活高，和正常人相反。发作期患者右侧后扣带回和左侧岛叶的激活较正常人高，双侧前额叶，左侧顶下小叶和梭状回，右侧钩回和海马旁回激活较正常人低；治疗后右侧前额叶和左侧颞叶，双侧视皮层，左侧基底神经节的激活较治疗前增高；治疗后双侧前额叶，右侧扣带回以及颞叶区域的激活较正常人高。(3)情绪图片任务：负性图片对抑郁症患者和正常人双侧视皮层的激活都较正性图片高；患者负性图片较正性图片对双侧杏仁核和左侧钩回激活高，而对左侧额中回，右侧扣带回前部和后部，同侧颞上回和顶叶，双侧岛叶的激活低；正常人负性和正性图片对前额叶均有激活高的区域。发作期患者双侧前额叶和左侧钩回的激活较正常人低；治疗后右侧额中回和同侧后扣带回，双侧颞叶，左侧丘脑的激活较治疗前增高；治疗后右侧额中回和顶下小叶、左侧楔前叶的激活较正常人低。(4)情绪图片短时记忆提取任务：抑郁症患者负性图片较正性图片对双侧前额叶和左侧顶叶，左侧前扣带回和同侧海马、基底神经节以及枕中回激活高，对左侧尾状核头部和双侧岛叶的激活低；正常人仅左侧前扣带回和右侧额内侧回在负性图片时激活稍低；发作期患者双侧前额叶和顶叶，右侧颞中回，双侧枕中回的激活较正常人高；治疗后双侧前额叶，颞叶和视皮层的激活较治疗前降低；治疗后双侧前额叶，右侧角回和同侧视皮层的激活较正常人高。(5)应激性事件和抑郁症脑功能改变的关系：ecStroop任务中，应激组和非应激组对前额叶都有多个区域的激活，应激组右侧岛叶和左侧颞下回的激活较非应激组低。面孔任务中，应激组对前额叶、右侧海马旁回和尾状核体部、双侧丘脑的激活高，左侧前扣带回的激活较非应激组低。图片任务中，两组对前额叶、右侧颞叶和左侧壳核都有激活，应激组右侧扣带回激活高，非应激组双侧顶叶和枕中回、左侧尾状核体部激活高。提取任务中，应激组左侧中央前回和顶叶，双侧颞叶的激活较非应激组低。(6)症状严重程度和抑郁症脑功能改变的关系：ecStroop任务中，HAMD高分组对双侧额中回、左侧颞上回和同侧岛叶的激活比低分组低。面孔任务中，高分组对前额叶、右侧扣带回、丘脑和尾状核体部的激活比低分组高，两组左侧视皮层均有激活。图片任务中，高分组对左侧钩回、右侧海马旁回和壳核、双侧岛叶的激活高，对前额叶和左侧海马的激活较低分组低。提取任务中，高分组对双侧前额叶和前扣带回，左侧岛叶，右侧楔叶和海马旁回的激活比低分组高。(7)病程和抑郁症脑功能改变的关系：ecStroop任务中，长病程组对右侧额中回、顶下小叶和枕上回的激活比短病程组高，而双侧颞叶、左侧顶上小叶和岛叶的激活低。面孔任务中，长病程组对右侧额上回，同侧丘脑、屏状核和视皮层，左侧楔前叶的激活比短病程组低。图片任务中，长病程组对左侧钩回和尾状核尾部、右侧丘脑的激活高，对前额叶、双侧顶叶和视皮层的激活低。提取任务中，长病程组对双侧前额叶BA10区，右侧枕中回和海马旁回的激活比短病程组高。(8)短时记忆功能(理解测验分数)和抑郁症脑功能改变的关系：ecStroop任务中，理解测验高分组对右侧前额叶，左侧前扣带回和颞中回，顶叶，双侧视皮层，左侧丘脑和尾状核体部的激活比低分组高。面孔任务中，高分组对双侧前额叶、颞叶和视皮层，左侧扣带回，右侧顶叶和岛叶及尾状核体部，及双侧小脑的激活高；对左侧杏仁核和海马旁回，右侧钩回，双侧尾状核的激活低。图片任务中，高分组对双侧前额叶、颞上回和顶叶，左侧岛叶的激活高；对双侧海马旁回，左侧胼胝下回，右侧额内侧回和尾状核及小脑的激活低。提取任务中，高分组对左侧前扣带回，双侧颞上回和右侧枕中回的激活比低分组低。3．3D：发作期抑郁症患者右侧额内侧回和同侧颞极、双侧壳核／苍白球和双侧小脑的灰质密度较正常人低；治疗后右侧额上回、双侧中央前回、双侧颞极、双侧壳核／苍白球和双侧小脑的灰质密度仍较正常人低，未见治疗前后差异有显著性的脑区。4．DTI：发作期抑郁症患者左侧额上回，双侧额中回和双侧前扣带回白质的分数各向异性(FA)值较正常人低；治疗后双侧额上回和额中回，右侧额下回白质FA值较治疗前增高，左侧额中回白质FA值仍较正常人低，而右侧颞中回和颞上回白质FA值高于正常人。5．长病程组和短病程组之间，HAMD高分组和低分组之间，应激组和非应激之间均未见灰质密度和白质FA值差异显著性的脑区。
结论：1．右侧额内侧回和颞极，双侧壳核／苍白球和小脑的灰质密度降低可能是抑郁症发生的神经病理基础，而非抑郁症的后果。2．首次报道首发未治疗的年轻成年MDD患者存在前额叶和前扣带回白质纤维整合性失常，提示白质病变在抑郁症发病的早期即已存在。3．双侧前额叶和扣带回，顶叶和视皮层功能异常可能是抑郁症患者认知功能损害的脑功能病理基础。4．边缘叶功能异常增强和额顶叶功能减退可能是抑郁症患者负性情绪的脑功能病理基础。5．脑功能异常和白质微结构失常是一种可逆性变化，在药物有效治疗，临床症状缓解后部分恢复。6．发病前存在应激性生活事件的患者对难过刺激的感知判断可能存在更大的偏差；应激事件的存在对抑郁症的注意力和执行功能无明显影响，对记忆功能的损害可能较轻。7．抑郁症患者的记忆功能和对情绪性刺激的反应能力可能和症状的严重程度以及病程呈负相关；执行功能和注意力可能与症状的严重程度呈负相关。8．灰质密度下降和白质微结构异常增加抑郁发生的风险，但可能与病程及症状严重程度无关，应激性生活事件在抑郁症的灰质密度下降和白质微结构改变中可能不发挥作用。
Object The aim of this study was to explore the brain functional and structuralpathological mechanism in first-episode major depressive disorder (MDD), by bloodoxygenation level dependent functional magnetic resonance imaging (BOLD-fMRI),three dimension MRI (3D), and diffusion tensor imaging (DTI) techniques.
Methods Twenty seven first-episode treatment-naive young adult with MDD(according to the diagnosis critietia of CCMD-Ⅲand DSM-Ⅳ) and twenty eight ageand gender-matched healthy controls were assessed using 17-item HamiltonDepression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA), LifeEvent Scale (LES), and Understanding and recognition test of Wechsler MemoryScale (WMS). HAMD sorces were requested≥24 in patients and≤7 in controls. Then,MRI scan were obtained ordering to BOLD-fMRI (including four task, emotionalcount Stroop, emotional face, emotional picture and the recall of short-term memory),3D, DTI. We assessed patients like above again after six months antidepressant(Venlafaxine) treatment.
Results Twenty two patients and 24 controls finished MRI scan. 16 patientswere followed. Some data were excluded because of head movement. Data could beanalyzed finally including 18 pre-treatment patients (4 males) and 16 post-treatmentpatients (4 males) in fMRI, 20 pre- patients (4 males) and post- patients (4 males) in3D; 19 pre- patients (4 males) and 13 post- patients (4 males) in DTI. Data of sixteenpatients and sixteen age and gender-matched healthy controls were analyzed in fMRIpart, and 13 patients and 13 age and gender-matched healthy controls were analyzedin 3D and DTI part. 1. HAMD and HAMA scores in post-treatment patients weresignificantly lower than those in pre-treatment (P=0.000), however still higher thanthose in healthy controls (P=0.01). Understanding and recognition tests scores werelower significantly in pre-treatment patients compared with healthy controls (P=0.001, P=0.04), and were similar between post-treatment patients and controls(P＞0.05). LES total scores and negative scores were different between pre-treatmentpatients and controls (P=0.000). 2. fMRI(1) ecStroop task The bilateral cingulategyfi, several regions of prefrontal lobe, temporal and parietal lobe had increasedactivation in negative words compared with neutral words in patients, which isconverse in controls. And bilateral cerebellum had decreased activation in negativewords than neutral words both in patients and controls. Pre-treatment patients showed decreased activation in right cingulate and left middle temporal gyrus, increasedactivation in left cerebellum compared with controls. No areas with significantlydifferent activation were found between pre- and post-treatment patients and betweenpost-treatment patients and controls. (2) Emotional face task There were increasedvisual cortex and parahippocampal gyrus activation and decreased right prefrontalcortex activation in sad face compared with happy face in both patients and controls.The caudate nucleus activation increased in sad face than happy face in patients,which is converse in controls. Compared with healthy controls, MDD patients showedincreased activation in right posterior cingulated and left insula, decreased activationin bilateral prefrontal, left inferior parietal lobule, left fusiform gyrus, right uncus andright parahippocampal gyrus. Post-treatment patients showed increased activation inright prefrontal cortex, left temporal lobe, bilateral visual cortex and left basal gangliathan pre-treatment, and increased activation in bilateral prefrontal lobe, right cingulategyrus and right temporal lobe than controls. (3) Emotional picture Both patientsand controls showed increased activation in bilateral visual cortex in negative picturecompared with positive picture. Compared with positive picture, negative pictureincreased bilateral amygdala and left uncus activation, and decreased activation in leftmiddle frontal gyrus, right anterior and posterior cingulate, right superior temporalgyrus, right parietal lobe and bilateral insula in MDD patients. Both negative andpositive picture activated prefrontal lobe in controls. Patients showed decreasedactivation in several areas of bilateral prefrontal lobe and left uncus compared withcontrols. Right middle frontal gyrus, right posterior cingulate, bilateral temporal lobeand left thalamus activation increased in post-treatment patient than pre-treatment.However, the right middle frontal gyrus, right inferior parietal lobule and leftprecuneus showed lower activation than controls yet. (4) Recall of short-termmemory task Compared with positive picture, negative picture increased theactivation in bilateral prefrontal and left parietal lobe, left anterior cingulate, lefthippocampus, left basal ganglia and left middle occipital lobe, and decreasedactivation in left caudate head and bilateral insula in MDD patients. Controlsshowed smaller decreased activation of left anterior cingulate and right medial frontalgyrus in negative picture than positive picture. Compared with controls, MDDpatients showed increased activation in several regions of bilateral prefrontal andparietal lobe, right middle temporal gyrus, bilateral middle occipital gyrus. Aftertreatment, the bilateral prefrontal lobe, temporal lobe and visual cortex activation decreased than pre-treatment patients. However, the bilateral prefrontal lobe, rightangular gyrus and right visual cortex still showed increased activation than controls.(5) Stressful life event (SLE) Patients with and without SLE also showed increasedactivation in prefrontal lobe in ecStroop task, and patients with SLE showeddecreased activation in right insula and left inferior temporal lobe than those withoutSLE. Compared with those without SLE, patients with SLE showed increasedactivation in prefrontal lobe, right parahippocampal gyrus, right caudate body,bilateral thalamus in face task, right anterior cingulate in picture task, whereas,decreased activation in left anterior cingulate in face task, and bilateral parietal lobeand middle occipital gyrus and left canduate body in picture task, and left precentralgyrus, left parietal lobe and bilateral temporal lobe in recall task. Furthermore, inpicture task, both patients with and without SLE showed increased activation inseveral areas of prefrontal lobe, right temporal lobe and left putamen. (6) SeverityCompared with patients with lower HAMD scores, those patients with high HAMDscores showed decreased activation in many regions, including bilateral middlefrontal gyrus, left superior temporal lobe and left insula in ecStroop task, bilateralprefrontal lobe, right cingulate, right thalamus and right caudate body in face task, leftuncus, right pamhippocampal gyrus, right putamen and bilateral insula in picture task,and bilateral prefrontal lobe and anterior cingulate, left insula, right cuneus and rightparahippocampal gyrus in recall task. Moreover, patients with higher HAMD scoresshowed decreased activation in several areas in frontal lobe and left hippocampus inpicture task than those with lower HAMD scores. (7) Course of disease Comparedwith patients with short course, the patients with long course showed increasedactivation in right middle frontal gyrus, right inferior parietal lobule and right superioroccipital gyrus in ecStroop task, in left uncus, left caudate tail and right thalamus inpicture task, bilateral prefrontal lobe (BA10), right middle occipital and rightparahippocampal gyrus in recall task. However, patients with long duration showeddecreased activation in some other regions than those patients with long duration,including bilateral temporal lobe, left superior parietal lobule and left insula inecStroop task, right superior frontal gyrus, right thalamus, right claustrum, right visualcortex and left precuneus in face task, several areas of prefrontal lobe, bilateralparietal lobe and visual cortex in picture task. (8) Short-time memory (WMSUnderstanding score) Compared with patients with lower Understanding scores, thepatients with higher Understanding scores showed increased activation in right prefrontal lobe, left anterior cingulated and middle temporal gyrus, parietal cortex,bilateral visual cortex, left thalamus and caudate body in ecStroop task, in bilateralprefrontal, temporal and visual cortex, left cingulate, right parietal cortex and insula,and bilateral cerebellum in face task, in bilateral prefrontal cortex, superior temporalgyri and parietal cortex, left insula in picture task. However, patients with highUnderstanding scores showed decreased activation in some other regions than thosepatients with lower Understanding scores, including left amygdala andparahippocampal gyrus, right uncus, bilateral caudate in face task, and bilateralparahippocampal gyri, left subcallosal gyrus, right medial frontal gyrus, right caudateand cerebellum in picture task, and left anterior cingulate, bilateral superior temporalgyri and right middle occipital gyrus in recall task. 3. 3D MDD patients showedsignificantly lower gray matter density than healthy controls in right medial frontalgyrus, right temporal pole, bilateral putamen and globus pallidus, bilateral cerebellum.After treatment, the gray matter density in right superior frontal gyrus, bilateralprecentral gyrus, temporal pole, putamen and globus pallidus, and cerebellum inpatients were still significantly lower than controls. 4. DTI Compared with controls,MDD patients exhibited significant decreased fractional anisotropy (FA) values in leftsuperior frontal gyrus, bilateral middle frontal gyrus and bilateral anterior cingnlate.FA values in bilateral superior and middle gyrus, right inferior frontal gyrus increasedafter treatment. However, FA values in left middle gyrus in post-treatment patientswere still lower than controls. Furthermore, FA values in right middle and superiortemporal gyrus were significantly higher than controls. 5. There were no regionswith significant different gray matter density and white matter FA values were foundbetween patient with long and short duration, between patients with high and lowHAMD scores, and between patients with or without SLE.
Conclusions 1. Decreased gray matter density in right medial frontal gyrus, righttemporal pole, bilateral putamen and globus pallidus, bilateral cerebellum may be theneuropathological substrate of MDD rather than a result. 2. This is the first study toreport that white matter microstructure abnormalities of prefrontal lobe and anteriorcingulate in first-episode, treatment-naive young adult MDD, suggesting thatabnormalities of brain white matter may be present early in the course of MDD. 3.Dysfunction in bilateral prefrontal lobe, cingulate, parietal and visual cortex maycontribute to the neuropathology of cognitive impairments in MDD. 4. Abnormalhyperfunction in limbic system and hypofunction in prefrontal and parietal lobe may contribute to neuropathology of mood processing bias in MDD. 5. Functional andwhite matter microstructure abnormalities could be improved by effectiveantidepressant treatment. 6. Occurring of SLE may induce greater bias to perceive sadstimuli in MDD, but no impairment to attention and execution function. And patientswith SLE may have little memory impairment than those without SLE. 7. Memoryand the ability to response to emotional stimuli may be negative correlation withsymptoms severity and illness course of MDD. Execution function and attention maybe negative correlation with symptoms severity of depression. 8. Lower gray matterdensity and FA values may increase the risk of MDD episode, however, no correlationwith the course, severity and the occurring of SLE.
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