【作者】 彭雪华；

【导师】 蒋莉；

【作者基本信息】 重庆医科大学 ， 儿科学， 2014， 博士

【摘要】 第一部分儿童语言障碍的临床表现及常规MRI研究目的：探讨儿童语言障碍病因或相关因素和临床特征，结合常规MRI影像表现，为临床早期诊治提供依据。方法：收集本院243例以语言障碍就诊的病例，进行常规神经病学及MRI检查，针对不同年龄采用《早期语言发育进程量表》及《汉语沟通发展量表普通话版（短表）》即PCDI，《精神障碍诊断与统计手册4版修订版》（Diagnostic and Statistical Manual of Mental Disorders-IV-TR，DSM-IV-TR）进行语言评估；采用不同年龄段韦氏儿童智力量表（Wechsler Intelligence Scale forChildren,WISC）或Gesell量表测定智商。结果：就诊年龄范围1.5岁-14岁,163例母孕史、生产史及生长史正常，5例缺乏语言环境的刺激，1例听力障碍，1例舌头活动障碍，HIE(包括宫内窘迫史)17例、早产11例、胆红素脑病5例、宫内感染2例及母亲妊娠高血压2例；癫痫史2例，1例其父有语言延迟病史，初诊孤独症12例，病史不详21例。排除听力障碍1例，舌头活动障碍1例，孤独症8例，癫痫2例。231例不同年龄段构成比：1.5-2岁6例（2.6%）、2.1-3岁71例（29.4%）、3.1-4岁53（21.6%）、4.1-5岁41例（17.3%）、5.1-6岁24例（10%），>6岁47（19%）,其中男178例（77.1%），女性53（22.9%）。语言障碍伴运动障碍78例（33.8%），智低45例（18.5%），二者均有38例（16.5%），语言障碍无或伴智低（智力≥70分），无特殊病史，常规神经病学检查无明显异常113例（48.9%），学龄前（≤6岁）92例（81.4%）,6岁以后21例（18.6%）。常规MRI表现：双侧额颞脑萎缩68例（29.4%）、大脑萎缩10例（4.3%）、小脑萎缩6例（2.6%）、胼胝体发育不良例12（5.2%）、脑白质髓鞘化异常8例（3.5%）、其它异常14（6.1%）、正常113例（48.9%）。分别对各组数据进行统计学分析，P﹤0.05有统计学意义。结论：(1)儿童语言障碍病因或相关因素复杂呈多样性,部分原因不明。(2)学龄前儿童是语言障碍高发年龄段，尤其是2-4岁之间，男性多见，也体现在各年龄组。（3）常伴随运动障碍和智低，发育性语言障碍比例较高，尤其在学龄前儿童明显。（4）常规MRI示儿童语言障碍发育性和继发性脑结构异常，双侧额颞叶萎缩明显多见，提示发育期语言障碍主要是语言中枢异常，还有大部分常规MRI显示阴性。第二部分VBM对学龄前儿童发育性语言障碍脑结构研究目的：用VBM研究学龄前儿童发育性语言障碍与正常配对组儿童脑结构的差别，进一步探寻语言障碍的神经机制。方法：21例发育性语言障碍学龄前男孩（年龄2.0-6.2岁，平均4.4岁）和20例正常配对组男孩（年龄2-6.4岁，平均4岁）纳入研究。均为右利手，常规检查没有神经病学症状和体征。诊断为发育性语言障碍满足如下：《精神障碍诊断与统计手册4版修订版》（Diagnosticand Statistical Manual of Mental Disorders-IV-TR，DSM-IV-TR）诊断语言障碍；采用韦氏儿童智力量表（Wechsler Intelligence Scale for Children,WISC）或Gesell量表测定智商（IQ≥70分），没有听力损害、基本的社会或情感障碍、环境剥夺、孤独症或其它特殊神经病学诊断。对照组为正常发育儿童，韦氏儿童智商评定IQ≥85，据标准测试语言在正常范围。两组均行常规和高分辨率3D-T1WI磁共振扫描，将所有被试资料在MatlabR2010a平台上采用SPM8软件包，利用DARTEL对全脑结构进行VBM分析，包括标准化、分割、调制、平滑等，所得图像数据利用SPM自带统计软件包进行统计分析，比较两组之间的脑灰质体积、密度和白质体积的差异。经FWE校正后p<0.05,体素大于50认为差异有统计学意义。结果：与对照组比较，发育性语言障碍组结果如下：（1）脑灰质体积减少的脑区左侧楔前叶、左侧角回及左侧颞中回；灰质密度减少的脑区包括左侧角回、左侧楔前叶、左侧海马、左侧海马旁回、左侧梭状回、左侧杏仁核、左侧前扣带回、左侧中扣带回、左侧补充运动区和右侧枕中回、右侧梭状回及右侧中央前回、右侧小脑-Crus1和左侧小脑-4-5；灰质密度增加的脑区包括右侧背外侧额上回、右侧颞中回、右侧额上回眶部、右侧中央沟盖、右侧颞下回、右侧内侧额上回和左侧额下回岛盖部、左侧岛叶及左侧背外侧额上回、右侧小脑-8（.2）脑白质体积增加脑区包括左颞中回、左侧角回、左侧楔前叶及右侧颞上回；白质体积减少脑区包括左侧额中下回交界处、左侧背外侧额上回、右侧背外侧额上回和右额上回眶部。结论：（1）发育性语言障碍儿童脑结构异常范围较广，以左脑灰质密度及体积减少明显，验证了右利手儿童语言优势半球在左侧。（2）灰质密度增加的区域主要在右侧大脑，提示右侧大脑代偿功能，部分与左脑非语言同源区，可能经其它神经回路进行调制，也提示脑的可塑性能力。（3）小脑参与语言调节，右侧小脑与左侧大脑额叶呈交叉共变关系。（4）双侧大脑灰质密度异常主要累及位于额颞叶的边缘系统，边缘系统是调节情绪的主要中枢，同时额颞叶也是语言中枢所在区域，提示情绪和语言调节有潜在共同神经解剖基础。本文从脑结构影像研究中提出新的语言障碍神经机制，即边缘系统脑结构异常，使学龄前儿童正负性情绪失调，儿童以消极情绪为主，影响了正常语言发育健康心理及精神状态，是学龄前儿童DLD原因之一。同时语言障碍影响情绪调节，导致情绪调节中枢结构异常甚至引起精神或神经疾病。（5）左侧裂周后部及多个颞叶脑回存在广泛灰质密度下降，尤其角回灰质密度和体积均明显下降，即左侧Wernicke区语言感觉中枢异常，提示语言感知及习得能力下降，同时左侧角回综合语言的能力下降，导致学龄前儿童DLD。（6）双侧运动语言中枢额下回三角部灰白质体积及密度均未见异常，且左侧岛盖部灰质密度增加，提示学龄前儿童表达性语言未受损，有潜在的恢复能力。临床观察也证实部分语言障碍儿童经干预治疗后显示出一个明显的追赶效应，干预年龄越早，将明显降低语言障碍的短期或长期的影响。更多还原

【Abstract】 PART Ⅰ CLINIC MANIFESTATIONS AND GENERALMRI PROFILES OF CHILDREN WITH LANGUAGEDISORDERObjective: To explore the pathogenesis or relevant factors andclinical charecteristics of children language disorder, combining withgeneral MRI profiles to provide the bases for early diagnosis andtreatment.Methods: A total of243children who saw a doctor for languagedisorder were collected from our hospital. All children have undergoneroutine neurological examination and MRI. Every one’s Language levelwas assessed by 《Early Language Milestone Scale》, PCDI, DSM-IV-TR,and IQ by WISC or Gesell according to different ages.Results: Ages were from1.5to14years. The medical histories werenegative history（163cases）,absence of language environment （5cases）,hearing deficits（1case）,tongue movement impairment（1case）, HIE（17cases）, preterm birth（11cases）, bilirubin encephalopathy（5cases）,intrauterine infection（2cases）,hypertension of pregnancy （2cases）, epilepsy（2cases）, father having language delay （1case）, autism diagnosisedfirstly（12cases）,unknown history（21cases）.Excluding hearing deficits（1case）,tongue movement impairment（1case）, autism（8cases） andepilepsy（2cases）, the percentage ratios of different age range childrenamonge231were2.6%（1.5-2years,6case）,29.4%（2.1-3years,71case）,1.6%（3.1-4years,53cases）,17.3%（4.1-5yeas,41cases）,10%（5.1-6years,24cases）,9%（>6years,47cases）, male77.1%（178cases）, female22.9%（53cases）. Themain comorbidity are dyskinesia（78cases,33.8%）, mental retardation（45cases,18.5%）, both of them（38cases,16.5%）. The others are113cases（48.9%）without or with mental retardation（IQ≥70）,no special history andnegative neurological profiles,among them92cases（81.4%）preschoolchildren（≤6years） and21cases（18.6%）children（﹥6years）。General MRIshowed frontal and temporal lobe atrophy bilaterally（68case,29.4%）,cerebral atrophy （10cases,4.3%）,cerebellar atrophy(6cases,2.6%, corpuscallosum dysgenesis （12cases,5.2%）, abnormal white matter myelination（8cases,3.5%）,others（14cases,6.1%）, negative MRI（113,48.9%）. All datawere analyzed by SAS9.13software, stastistical significance was set atp<0.05.Conclusion:（1）The pathogenesis or relevant factors of childrenlanguage disorder presented complexity and diversity,including unknownaetiology.（2）Language disorder in preschool children was the mostcommon among the children, especially between2to4years，also the high ratio of male children reflected in every age range.（3） The maincomorbidity were dyskinesia and mental retardation, while developmentallanguage disorder also accounted for higher percentage, particularly inpreschool children.（4）General MRI revealed the abnormal structural brainfrom developmental and secondary factors in children with languagedisorder. Obvious findings were frontal and temporal atrophy bilaterally,suggesting that language disorder during the growth period was mainlyduo to language areas dysfunction. But negative MRI in most childrenwith language disorder were also observed。 PART Ⅱ A voxel-based morphometry study of brainstructure in preschool children with developmental languagedisorder（DLD）Objective: To study the difference of the brain structure between thepreschool children with DLD and the typically developing age-matchedcontrol children by VBM, and further to explore the neural bases oflanguage disorder.Methods:21preschool boys with DLD（age range2-6.2years,average4.4years） and20age-matched control boys （age range2-6.4years,average4years）participated in the study.all of them wereright-handed without neurological symptoms and signs by routine examination. A diagnosis of DLD was according to the DSM-IV-TR,and intelligence quotient≥70by WISC or Gesell，and the absence ofhearing loss, primary social or emotional problems, environmentaldeprivation, autism, or other specific neurological diagnoses.Controlchildren were typically developing children who had normal IQ（IQ≥85）and normal language scores on standardized tests. All children haveundergone routine and high-resolution3D-T1WI MRI examination. Thedata were assessed using the optimized VBM with DARTEL.The datapreprocessing was conducted with Statiscal Parametric Mapping （SPM8）software package on a Matlab R2010a platform, including normalizing,segmenting, modulating and smoothing. All these images-processed werestatistically analyzed automatically by SPM. We compared the differencesof the brain structure in gray density, gray and white matter volume ofwhole brain between2groups. Statistical parametric maps werethresholded at an FDR-corrected voxel-wise threshold of p<0.05, andonly the clusters with no less than50voxels were reported.Results: Relative to controls, The DLD group showed thoses, asfollows:（1）decreased gray matter volume in the Precuneus_L, Angular_Land Temporal_Mid_L, also density in Angular_L, Occipital_Mid_R,Precuneus_L, Hippocampus_L, Cingulum_Mid_L, Supp_Motor_Area_L,Cingulum_Ant_L, Fusiform_L, Parahippocampus_L, Amygdala_L,Fusiform_R, Precentral_R, Cerebelum_Crus1_R, Cerebelum_45L, and increased gray matter density in Frontal_Sup_R, Temporal_Mid_R,Frontal_Sup_Orb_R, Rolandic_Oper_R, Insular_L, Frontal_Inf_Oper_L,Temporal_Inf_R,Frontal_Sup_Medial_R,Frontal_Sup_L, Cerebelum_8R.（2）decreased white matter volume in Frontal_Sup_R,Frontal_Mid/Inf_L,Frontal_Sup_L, Frontal_Sup_Orb_R, and increased inTemporal_Mid_L, Angular_L,Temporal_Sup_R,Precuneus_L.Conclusion:（1） The preschool children with DLD had wide range ofbrain structural abnormality, which presented obviously decreased graymatter density and volume in the left cerebral hemisphere conforming tohemispheric language dominance in children with right-handness.（2） Theincreased gray matter density mainly in the right cerebral hemispheresuggested the right compensatory function, part of which was not the lefthomologous region. Perhaps, the compensation was regulated via otherneural circuit, also declaring the brain plasticity.（3） The cerebelparticipated in the language adjustment, and the cross covariantrelationship between the right cerebel and the left front lobe was alsodemonstrated.（4） Abnormal bilateral hemispheric gray matter densityprevailingly involved the limbic system located in the frontal and temporallobe which were just the language areas，while the limbic system primarilyregulates the emotion, hinting that there is a potential commonneuroanatomical basis between emotion and language adjustment. A newneural basis was put forward from the study of brain structure by imaging. Namely, abnomal limbic brain structure resulted in positive and negativeemotion disorders in preschool children having negative mood chiefly,affecting healthy mood and mental state for normal language development,which may be the one of the reasons leading to DLD in preschool children.Meanwhile, language disorder influenced emotion adjustment, whichpossiblely induced the structural abnormality in the areas of emotionadjustment, and even contributing to psychiatric and neurologicaldisorders.（5） Wide range of decreased gray matter density in the lefthemisphere of the posterior peri-Sylvian areas and multi-gyrus located intemporal lobe, especially the Angular gyrus complicated by decreasedgray matter density and volume evidently, which meaned that the leftWernicke areas abnormality leading to language perception andacquisition ablity down, together with the Angular gyrus of comprehensivelanguage ability down caused the DLD in preschool children.（6） Normalinferior frontal gyrus of pars triangularis bilaterally which was the motorspeech area，and increased gray matter density in the left pars opercularisimplied the expressive language unimpaired，likely being of the potentialrecovery capability. Clinic observation also affirmed that part of childrenwith language disorder displayed obvious catching-up effect viaintervention, and early intervention will evidently reduce the short andlong-term effect because of language disorder.更多还原