武文佼 張 鵬

(1山西省朔州師范高等專科學(xué)校教育系, 山西朔州 036000) (2北京師范大學(xué)心理學(xué)院, 北京 100875)

1 引言

自閉癥譜系障礙(Autism Spectrum Disorders,ASD), 又稱孤獨(dú)癥, 是一組常見的, 多發(fā)病于嬰幼兒時(shí)期的神經(jīng)發(fā)育障礙(Neurodevelopmental Disorders, ND)?；颊咧饕憩F(xiàn)為社會(huì)交往和溝通能力嚴(yán)重受損, 以及重復(fù)、刻板的興趣、行為或動(dòng)作(American Psychiatric Association, 2013)。

Kanner (1943)報(bào)告了 11例早期嬰兒自閉(early infantile autism)患者, 揭開了有關(guān)自閉癥研究的序幕。隨著對(duì)自閉癥的進(jìn)一步認(rèn)識(shí), 研究者對(duì)自閉癥的歸類發(fā)生了一系列演變。上世紀(jì)50年代以來(lái), 美國(guó)心理學(xué)會(huì)相繼頒布的 DSM-I和 DSM-II均將自閉癥收錄為兒童精神分裂的一種。1980年頒布的 DSM-III將自閉癥區(qū)分出一般的精神病,命名為自閉癥譜系障礙, 并作為一般發(fā)育障礙的一種(Pervasive Developmental Disorders, PDD)。之后的DSM-IV以及最近的 DSM-V均將自閉癥譜系障礙列為一組神經(jīng)發(fā)育障礙, 并認(rèn)為自閉癥譜系障礙以早發(fā)的社會(huì)交往與溝通損傷為核心癥狀,包含Kanner自閉癥、阿斯伯格綜合征、非典型性自閉癥和其他未注名普遍發(fā)育障礙等亞型。

自閉癥譜系障礙的發(fā)病率在近半個(gè)世紀(jì)以來(lái)快速增長(zhǎng)(Weintraub, 2011)。1976年的一項(xiàng)調(diào)查顯示自閉癥譜系障礙的發(fā)病率為0.4‰ (Wing, Yeates,Brierley, & Gould, 1976), 至2009年已上漲至為11‰～15.7‰ (Baron-Cohen et al., 2009; Kogan et al., 2009)。最近報(bào)告于 NHSR (National Health Statistics Reports)的學(xué)齡兒童ASD發(fā)病率則高達(dá)2.00% (Blumberg et al., 2013)。持續(xù)攀升的發(fā)病率引起了人們的普遍關(guān)注, 有學(xué)者認(rèn)為一方面隨著心理、生理環(huán)境的日益復(fù)雜, 的確有更多兒童罹患ASD, 另一方面ASD識(shí)別能力的提升、診斷內(nèi)涵和外延的擴(kuò)充以及診斷加積(diagnosis accretion)(包含了同一個(gè)體在不同生長(zhǎng)階段的診斷數(shù)據(jù), 導(dǎo)致統(tǒng)計(jì)患病人數(shù)高于實(shí)際人數(shù))等亦有可能導(dǎo)致ASD的發(fā)病率上升(Boyd, Odom, Humphreys, &Sam, 2010)。

ASD發(fā)病率的節(jié)節(jié)攀升, 意味著更多的患者和家庭經(jīng)受著自閉癥譜系障礙帶來(lái)的痛苦(Bradley& Corwyn, 2002; Lord & Cook, 2013; Shaw, Keenan,Vondra, Delliquardi, & Giovannelli, 1997)。自閉癥譜系障礙兒童語(yǔ)言發(fā)展遲滯, 缺乏眼神交流、角色游戲、身體語(yǔ)言等基本的社交技能, 這使其社會(huì)功能嚴(yán)重受損(Filipek et al., 1999; Manning-Courtney et al., 2013)。同時(shí), 自閉癥譜系障礙兒童多并發(fā)智力缺陷、注意缺陷綜合征(ADHD)、X綜合癥、腸胃功能紊亂(Buie, Campbell, et al., 2010;Buie, Fuchs et al., 2010; Ibrahim, Voigt, Katusic,Weaver, & Barbaresi, 2009)、睡眠障礙(Malow &McGrew, 2008)和癲癇(Turk et al., 2009)等一系列身心疾患(Turk, 2011)。這導(dǎo)致自閉癥患者本人和家庭成員經(jīng)受巨大的痛苦和頻繁的家庭沖突(Bradley & Corwyn, 2002; Lord & Cook, 2013;Shaw et al., 1997)。

然而, 由于ASD病因的復(fù)雜性, 目前尚沒有直接、有效的辦法來(lái)治愈ASD?；颊叨嗖捎眯袨榭祻?fù)訓(xùn)練配合一定藥物來(lái)進(jìn)行長(zhǎng)期治療。研究者們也未能解釋自閉癥譜系障礙的發(fā)病機(jī)制, 這使得盡快明確ASD發(fā)病的生物基礎(chǔ)尤為重要。雖然,目前研究積累了大量有關(guān) ASD生物基礎(chǔ)的證據(jù),但是研究者們并沒有一致的結(jié)論, 筆者將從遺傳、腦神經(jīng)結(jié)構(gòu)、營(yíng)養(yǎng)素等方面對(duì)現(xiàn)有成果加以簡(jiǎn)略的總結(jié), 以期為自閉癥譜系障礙生物基礎(chǔ)的研究提供一些新的思路。

2 遺傳因素

2.1 家族與雙生子研究

研究者對(duì)自閉癥譜系障礙患者的家族進(jìn)行調(diào)查, 發(fā)現(xiàn)其直系親屬表現(xiàn)出社交缺陷、語(yǔ)言障礙和親密關(guān)系缺失等類自閉癥狀(Main, Angley, Thomas,O'Doherty, & Fenech, 2010; Malhotra & Sebat,2012), 進(jìn)一步對(duì)社交缺陷和語(yǔ)言障礙進(jìn)行定量分析發(fā)現(xiàn), 約 20%～25%的兄弟姐妹存在語(yǔ)言缺陷(Lindgren, Folstein, Tomblin, & Tager-Flusberg,2009)。同時(shí), 在同一個(gè)家族中, 自閉癥譜系障礙的復(fù)發(fā)率為10%～35% (Constantino, Zhang, Frazier,Abbacchi, & Law, 2010; Freeman, 1989), 已育有自閉癥譜系障礙患者的父母再育時(shí), 其孩子患自閉癥譜系障礙的概率要高出發(fā)病基準(zhǔn)率20～50倍(O'Roak & State, 2008)。這一系列研究表明ASD具有明顯的家族遺傳性。

此外, 雙生子研究是遺傳研究的重要方法,通過(guò)比較同卵雙生子和異卵雙生子的相關(guān)指標(biāo),能夠很好的反映遺傳和環(huán)境對(duì)個(gè)體成長(zhǎng)發(fā)育的影響。有研究者報(bào)告自閉癥譜系障礙同卵雙生子(monozygotic)的共患率遠(yuǎn)高于異卵雙生子(dizygotic) (Ozonoff et al., 2011)。早期對(duì)異卵雙生子的研究發(fā)現(xiàn)他們的一致性為10%～15%, 隨后更大樣本的雙生子研究發(fā)現(xiàn)異卵雙生子的一致性為21%～36% (Hallmayer et al., 2011; Weintraub,2011)。而整合3個(gè)主要雙生子研究, 同卵雙生子的一致性高達(dá)60% (Bailey et al., 1995, Hallmayer et al., 2011; Rosenberg et al., 2009)。家族成員的高遺傳性和復(fù)發(fā)率以及同卵雙生子的高一致性意味著自閉癥譜系障礙具有遺傳特性, 這促使研究者們開始關(guān)注ASD的遺傳過(guò)程。

2.2 基因變異研究

目前, 有關(guān)自閉癥譜系障礙遺傳因素的研究主要集中在基因變異領(lǐng)域, 因?yàn)檎{(diào)查研究雖能表明ASD具有遺傳特性, 但其在進(jìn)一步了解遺傳機(jī)制、基因變異以及預(yù)防和治療ASD方面顯得十分乏力。自 2003年以來(lái), 研究者們對(duì) ASD遺傳機(jī)制的理解發(fā)生了根本性變化, 之前普遍認(rèn)可的常見變異(disorder-common)模型(該模型認(rèn)為 ASD受某一確定的, 能夠在多數(shù)患者身上發(fā)現(xiàn)的基因變異的影響)受到質(zhì)疑(Cook & Sherer, 2008)。研究者們通過(guò)全組基因測(cè)序(entire genome)、基因組從頭測(cè)序(de novo mutations)等方法對(duì)可能與 ASD有關(guān)的基因進(jìn)行了探索, 提出了ASD受多組基因變異影響的微廣(small-to-moderate)模型(該模型認(rèn)為ASD受微弱的、廣域基因變異的影響), 并發(fā)現(xiàn)一部分可能參與 ASD遺傳的候補(bǔ)基因(Parellada et al., 2014)。

2.2.1 常見變異基因

一般認(rèn)為, 全基因組測(cè)序技術(shù)可以測(cè)定DNA中的單核苷酸多態(tài)性(single-nucleotide polymorphisms,SNP)和其它常見基因變異, 從而明確某基因位點(diǎn)對(duì)個(gè)體疾病或者特質(zhì)的影響。全基因組關(guān)聯(lián)(Genome-wide association, GWA)研究通過(guò)大樣本的基因組測(cè)序來(lái)探索某一基因突變和 ASD是否具有關(guān)聯(lián), 從而確定ASD的致病基因。自閉癥基因組計(jì)劃發(fā)現(xiàn)大約100個(gè)變異基因和40個(gè)基因組可能與自閉癥譜系障礙有關(guān), 但單個(gè)基因?qū)?ASD的貢獻(xiàn)并不明顯。隨后研究者收集了 2700多個(gè)ASD患者的 DNA, 測(cè)定了超過(guò) 1000000個(gè) SNP位點(diǎn), 結(jié)果發(fā)現(xiàn)并結(jié)果發(fā)現(xiàn)沒有某個(gè)確定的 SNP位點(diǎn)是ASD發(fā)病的高危因素(OR < 3,P> 5×10-8**: OR (Odds Ration)是指全基因組關(guān)聯(lián)分析研究中的優(yōu)勢(shì)比, P是OR的統(tǒng)計(jì)檢驗(yàn)力。對(duì)基因芯片檢測(cè)的SNP位點(diǎn)數(shù)量進(jìn)行Bonferroni校正即可計(jì)算出P值。一般情況下, 當(dāng)OR>3, P<5*10-8時(shí), 可以認(rèn)為該SNP位點(diǎn)是某一疾病的高危因素。)(Anney et al., 2012)。同時(shí), 有調(diào)查發(fā)現(xiàn)由單一基因誘發(fā)ASD的情況僅占1%, 這提示ASD可能并不存在特定的致病基因(State & ?estan, 2012)。研究者認(rèn)為, ASD的發(fā)病更多源于數(shù)種常見變異的共同表達(dá), 從而表現(xiàn)出社交受損、刻板行為、智力障礙等癥狀(Levy, Mandell, & Schultz, 2009)。而常見的基因變異對(duì)個(gè)體的影響通常比較溫和, 加之多個(gè)基因變異之間的相互作用尚難以明確, 這解釋了為何沒有確定的SNP位點(diǎn)是ASD的高危因素。

但是, 常見基因變異與自閉癥譜系障礙的密切關(guān)聯(lián)不容忽視。GWA的研究將有助于ASD更深入的病理機(jī)制的探索。例如, 自閉癥基因組計(jì)劃研究發(fā)現(xiàn), 與ASD關(guān)系最為密切的SNP編碼為rs1718101, 這個(gè)基因位于 CNTNAP2, 而CNTNAP2是七號(hào)染色體上負(fù)責(zé)蛋白質(zhì)編碼的重要基因組, 其參與神經(jīng)細(xì)胞軸突的分化和發(fā)育(Anney et al., 2012)。更多的關(guān)聯(lián)研究發(fā)現(xiàn), 部分ASD兒童的脆性 X智力低下一號(hào)基因(fragile mental retardation 1 gene, FMR1)發(fā)生了突變, 而位于X染色體q27.3處的FMR1發(fā)生突變是導(dǎo)致先天性智力低下的主要原因, 這解釋了多數(shù) ASD患者并發(fā)先天性智力低下(Ramocki & Zoghbi,2008)。同時(shí), 研究發(fā)現(xiàn)位于X染色體的NLGN4X和 NLGN3發(fā)生變異與自閉癥狀關(guān)系密切, 而這兩個(gè)基因?qū)ι窠?jīng)細(xì)胞粘附和突觸的發(fā)育作用重大(El-Fishawy & State, 2010; Tabuchi et al., 2007)。研究者們還發(fā)現(xiàn) ASD患者基因中能夠引起免疫系統(tǒng)異常的MECP2 (影響γ-干擾素的合成)發(fā)生突變(Ramocki & Zoghbi, 2008)。綜上所述, 不同的常見基因變異導(dǎo)致不同的臨床癥狀, 最終以多樣化的形式表征于ASD患者。

2.2.2 罕見變異基因

相對(duì)于常見基因變異與 ASD風(fēng)險(xiǎn)之間的微弱關(guān)聯(lián), 罕見基因變異的發(fā)生對(duì)ASD的貢獻(xiàn)率更高?；谌旧w核型分析技術(shù)的細(xì)胞遺傳異常檢測(cè)發(fā)現(xiàn), 基因組拷貝數(shù)變異(基因組拷貝數(shù)變異是基因組變異的一種形式, 通常使基因組中大片段的DNA形成非正常的拷貝數(shù)量。例如人類正常染色體拷貝數(shù)是2, 有些染色體區(qū)域拷貝數(shù)變成1或3, 這樣該區(qū)域發(fā)生拷貝數(shù)缺失或增加, 位于該區(qū)域內(nèi)的基因表達(dá)便會(huì)受到影響)能夠解釋 5%的ASD, 而對(duì)于并發(fā)有智力障礙的 ASD患者, 解釋率高達(dá)22%(Miles, 2011; Shen et al., 2010)。基因組從頭測(cè)序研究進(jìn)一步探討了CNVs對(duì)ASD的影響。結(jié)果發(fā)現(xiàn) ASD與脆性 X染色體綜合征與結(jié)節(jié)性硬化綜合征表現(xiàn)出部分相同的 CNVs, 而這種變異抑制了谷氨酸的合成, 進(jìn)一步導(dǎo)致突觸發(fā)育不良, 從而表征出一些神經(jīng)活動(dòng)異常癥狀(Auerbach, Osterweil & Bear, 2011)。另外一些研究發(fā)現(xiàn)ASD患者16p11.2, 7q11.23和15q11.2基因組復(fù)制異常, 但未能發(fā)現(xiàn)這一異常是否與臨床癥狀有關(guān)(Levy et al., 2011)?？傊? 大量研究發(fā)現(xiàn)CNVs與ASD關(guān)系密切(Marshall et al., 2008; Neale et al.,2012; O’Roak et al., 2012a; Sanders et al., 2012;Sebat et al., 2007), 但由于缺乏CNVs的人口基線數(shù)據(jù), 我們無(wú)法進(jìn)一步確認(rèn)自閉癥譜系障礙與基因組拷貝數(shù)變異之間的明確關(guān)聯(lián), 不過(guò)這不失為一個(gè)值得努力的研究方向。

2.2.3 候選基因

當(dāng)前研究確定了一些與 ASD有關(guān)的候選基因, 但其對(duì)ASD發(fā)病的具體作用仍不清楚。這些基因主要涉及突觸蛋白的合成和轉(zhuǎn)運(yùn), 如NRXNs、NLNGs、CNTN3/4、CNTNAP2 和SHANK3 (Gilman et al., 2011; Kumar et al., 2011;Pe?a et al., 2011); 神經(jīng)細(xì)胞的遷移、生長(zhǎng)和分化異常, 如 EN2、MET、PTEN、TSC1/2和 FMR1(Eagleson, Campbell, Thompson, Bergman, & Levitt,2011; Pe?agarikano & Geschwind, 2012); 神經(jīng)遞質(zhì)的合成, 如控制 γ-氨基丁酸(γ－aminobutyric acid, GABA, 一種非蛋白質(zhì)氨基酸, 是人體中樞神經(jīng)系統(tǒng)重要的抑制性神經(jīng)遞質(zhì), 約 50%的中樞神經(jīng)突觸部位以 GABA為遞質(zhì))和谷氨酸受體合成的 GRIN2B; 細(xì)胞膜離子通透性, 如 SCN2A(Sanders et al., 2011)。此外, 研究還發(fā)現(xiàn)個(gè)別基因變異參與細(xì)胞分化和細(xì)胞結(jié)構(gòu)的形成, 如DYRK1A和KANTAL2, 并作用于細(xì)胞核, 如控制 DNA結(jié)合蛋白的 POGZ和參與染色體修復(fù)的 CHD8(O’Roak et al., 2012b)。這些基因不僅與自閉癥譜系障礙有關(guān), 而且與其他神經(jīng)發(fā)育障礙也有密切的聯(lián)系(Bozdagi et al., 2010; Campbell, Li, Sutcliffe,Persico, & Levitt, 2008; Hussman et al., 2011)。

研究還發(fā)現(xiàn), 主要參與細(xì)胞生長(zhǎng)與分化的受體酪氨酸激酶受MET基因控制, 這個(gè)基因片段位于7q31, 而這是GAW研究列出的候選基因區(qū)域。研究者認(rèn)為MET是ASD很明顯的候選基因。MET在皮質(zhì)和小腦的發(fā)展中發(fā)揮重要作用, 并且調(diào)控免疫系統(tǒng), 這與ASD患者的功能性障礙有很大關(guān)系, 家族研究亦發(fā)現(xiàn)MET與ASD有關(guān)聯(lián)(Campbell et al., 2006; Heuer, Braunschweig, Ashwood, van de Water, & Campbell, 2011)。

3 腦神經(jīng)異常

3.1 區(qū)域性腦發(fā)育異常

ASD患者存在時(shí)間和空間進(jìn)程上的腦發(fā)育異常。相比于正常兒童, 大約 25%～30%的 ASD兒童在 1～2歲時(shí)大腦體積過(guò)度增加, 并因此罹患巨頭癥(Macrocephaly)。在隨后的1～2年內(nèi), 他們出現(xiàn)自閉癥譜系障礙的核心癥狀, 并持續(xù)加重(Minshew & Williams, 2007; Stanfield et al., 2008)。跟蹤調(diào)查發(fā)現(xiàn), ASD患者的大腦在青春期的時(shí)候發(fā)育不完全 (Courchesne, Redcay, & Kennedy, 2004)。同時(shí), 神經(jīng)影像學(xué)的研究表明患者大腦的額葉、顳葉過(guò)度發(fā)育, 主要集中在皮質(zhì)白質(zhì)(cortical white matter)和邊緣結(jié)構(gòu)(limbic structures) (Pardo& Eberhart, 2007)。而這些區(qū)域在社會(huì)交往、運(yùn)動(dòng)等方面發(fā)揮著重要作用。同時(shí), 患者的皮質(zhì)微柱體(cortical minicolumn)、梭狀回面孔區(qū)(fusiform face area)和顳上溝(superior temporal sulcus)也發(fā)現(xiàn)了明顯的異常, 這使得他們?cè)诿婵椎母兄c識(shí)別上存在缺陷(DiCicco-Bloom et al., 2006; Schultz,2005), 另外一個(gè)過(guò)度發(fā)育的則是杏仁核(Amaral,Schumann & Nordahl, 2008; Courchesne, Campbell& Solso, 2011; Herbert, 2009), 而杏仁核對(duì)社交威脅信息的識(shí)別與處理十分關(guān)鍵(Zhao, Zhang, Chen,& Zhou, 2014)。還有研究證實(shí)尾狀核(caudate)的體積與患者的刻板行為有關(guān)(Hollander et al.,2005)。研究亦發(fā)現(xiàn) ASD患者小腦半球過(guò)度發(fā)育以及胼胝體(corpus callosum volume, CCV)萎縮(Frazier & Hardan, 2009, Stanfield et al., 2008)。小腦的發(fā)育異常還包括小腦蚓體浦肯野細(xì)胞(purkinje cells) (小腦皮層中唯一的傳出神經(jīng)元)活動(dòng)數(shù)量與規(guī)模減小(Schultz, 2005)。近年來(lái)形態(tài)測(cè)量學(xué)研究者還檢測(cè)了ASD患者大腦皮層的厚度、表面積和曲率, 以探索其與ASD的關(guān)系。有研究報(bào)告了相對(duì)于正常兒童而言, ASD兒童的大腦頂葉皮層過(guò)度折疊(Kates, Ikuta, & Burnette, 2009),并且厚度增加(Ecker et al., 2013), 但是, 目前并沒有太多研究證實(shí)大腦皮層體積和形態(tài)的異常與ASD患者的臨床癥狀有關(guān)。

總之, 研究者們發(fā)現(xiàn)了ASD患者存在一系列的大腦發(fā)育異常, 但無(wú)論是神經(jīng)影像研究、形態(tài)研究或者解剖研究, 我們依然無(wú)法了解到大腦神經(jīng)膠質(zhì)細(xì)胞的大小與規(guī)模、髓鞘的含量、神經(jīng)元樹突, 軸突的發(fā)育程度以及神經(jīng)炎性反應(yīng)等更為細(xì)微的變化(Courchesne & Pierce, 2005; DiCicco-Bloom et al., 2006; Vargas, Nascimbene, Krishnan,Zimmerman, & Pardo, 2005)。這使得我們?cè)谶M(jìn)一步定論相關(guān)區(qū)域的發(fā)育異常對(duì) ASD的影響時(shí)需要更加謹(jǐn)慎。

3.2 功能性聯(lián)結(jié)障礙

近期的研究更多關(guān)注大腦區(qū)域之間的功能性聯(lián)結(jié), 而非某個(gè)特定的區(qū)域, 因?yàn)檠芯堪l(fā)現(xiàn), ASD通常與大腦區(qū)域之間的聯(lián)結(jié)異常聯(lián)系比較密切,而非解剖學(xué)上的缺陷(Pina-Camacho et al., 2012)。如此, 功能核磁共振成像(Functional Magnetic Resonance Imaging, fMRI) (依賴任務(wù)、非依賴任務(wù)和靜息狀態(tài)下的 fMRI)和擴(kuò)散張量成像(Diffusion Tensor Tmaging, DTI)為研究大腦結(jié)構(gòu)之間的功能性關(guān)聯(lián)做出了巨大貢獻(xiàn)。fMRI關(guān)注解剖意義上完整大腦的功能性變化、區(qū)域性腦活動(dòng)異常及各個(gè)異?；顒?dòng)區(qū)域之間的關(guān)聯(lián)。DTI則通過(guò)測(cè)定水分子沿軸突擴(kuò)散的情況來(lái)評(píng)估某區(qū)域活動(dòng)的完整性。DTI和fMRI研究發(fā)現(xiàn), 與正常人相比, ASD患者及其兄弟姐妹后額葉皮層、杏仁核等區(qū)域功能聯(lián)結(jié)顯示出激活與連通的異常, 但我們無(wú)法明確這些異常是如何與自閉癥臨床癥狀相關(guān)聯(lián)(例如社交困難、語(yǔ)言障礙和刻板行為到底對(duì)應(yīng)哪個(gè)區(qū)域的聯(lián)結(jié)異常) (Barnea-Goraly, Lotspeich, &Reiss, 2010; Pina-Camacho et al., 2012; Schipul,Keller, & Just, 2011; Wass, 2011)。神經(jīng)生理學(xué)的研究使用腦電圖(electroencephalography, EEG)和腦磁圖(magnetoencephalography, MEG)發(fā)現(xiàn)ASD患者存在廣域的功能整合障礙, 主要表現(xiàn)在信號(hào)激活的不同步(Gandal et al., 2010; Kenet et al., 2012;Neumann et al., 2011; Oberman et al., 2013), 但是這種非連通性的模型并不是總與 ASD的嚴(yán)重程度相關(guān)聯(lián), 這可能是因?yàn)檫@些研究的被試多來(lái)自高功能和成人ASD患者(Philip et al., 2012)。研究者據(jù)此提出了 ASD 患者大腦功能性聯(lián)結(jié)異常的廣域鏈接模型(long-distance)和區(qū)域鏈接模型(local and short-range)。廣域鏈接模型是指在整個(gè)大腦產(chǎn)生的聯(lián)結(jié)異常, 諸如信號(hào)活動(dòng)不同步。區(qū)域連接模型是指在某一區(qū)域或針對(duì)某一活動(dòng)產(chǎn)生的活動(dòng)異常, 諸如視覺控制區(qū)的活動(dòng)異常。這種“非連通性(disconnectivity)”的模式導(dǎo)致ASD患者大腦各區(qū)域無(wú)法有效的整合, 在接受刺激后無(wú)法有效的調(diào)節(jié)各區(qū)域間的功能性連結(jié), 并由此產(chǎn)生復(fù)雜而無(wú)效的神經(jīng)活動(dòng)(Philip et al., 2012)。

因此, 這種大腦各區(qū)域間功能整合(激活、定時(shí)、同步)異常被認(rèn)為是 ASD患者腦神經(jīng)活動(dòng)的主要缺陷。研究者認(rèn)為細(xì)胞級(jí)的活動(dòng)異常, 諸如神經(jīng)元連接異常, 浦肯野細(xì)胞減少、突觸功能受損以及神經(jīng)膠質(zhì)細(xì)胞活動(dòng)的異常可能是 ASD患者大腦皮層活動(dòng)紊亂和信息整合加工能力受損的元兇(Parellada et al., 2014)。

3.3 生物化學(xué)因素

核磁共振光譜(Magnetic Resonance Spectroscopy,MRS)研究發(fā)現(xiàn)ASD患者大腦中的N-乙酰天冬氨酸(N-acetylaspartate, NAA)含量低于正常人, 而這被認(rèn)為是神經(jīng)元損傷嚴(yán)重程度的一項(xiàng)重要生化指標(biāo), 腦組織 NAA含量降低表明神經(jīng)元代謝紊亂(Anagnostou & Taylor, 2011; Fujii et al., 2010)。近期研究還探索了促進(jìn)腦細(xì)胞生長(zhǎng)的谷氨酸酯(glutamate, Glu)和谷氨酰胺(glutamine, Gln), 有學(xué)者報(bào)告 ASD患者前扣帶回(Anterior Cingular Cortex, ACC)的Glu和Gln濃度以及左顳頂聯(lián)結(jié)區(qū)(temporoparietal junction, TPJ)的肌醇(inositol)濃度均要低于正常人(Bernardi et al., 2011)。研究發(fā)現(xiàn)ASD患者前額葉、頂葉和小腦中GABA的含量顯著低于正常人(Fatemi, Folsom, Reutiman & Thuras,2009)。這很好的解釋了 ASD兒童多伴有智力發(fā)育障礙和癲癇(Amaral et al., 2008)。不過(guò), 目前有關(guān)MRS的研究十分有限, 且不夠深入, 今后的研究可以進(jìn)一步探討ASD患者的腦生化機(jī)制。

4 營(yíng)養(yǎng)素因素

4.1 谷蛋白和酪蛋白

研究發(fā)現(xiàn), 自閉癥譜系障礙患者的尿液中存在未經(jīng)分解的谷蛋白和酪蛋白。這提示了自閉癥譜系障礙患者可能存在分解谷蛋白和酪蛋白障礙。隨后研究者們開始嘗試給予自閉癥譜系障礙患者不含谷蛋白和酪蛋白的結(jié)構(gòu)化飲食(gluten-free,casein-free diet, GFCFD), 以明確谷蛋白和酪蛋白是否與自閉癥譜系障礙有關(guān)。Knivsberg, Reichelt,H?ien和 N?dland (2002)將 20名自閉癥譜系障礙兒童隨機(jī)分為實(shí)驗(yàn)組和控制組, 分別給予他們GFCFD和普通飲食, 1年后, 實(shí)驗(yàn)組兒童的刻板行為減少, 非言語(yǔ)認(rèn)知水平及運(yùn)動(dòng)障礙明顯改善。Niederhofer (2007)研究發(fā)現(xiàn), 自閉癥譜系障礙兒童口服鹽酸美金剛(memantine, 一種代謝型氨基酸拮抗劑, 可以促進(jìn)谷蛋白和酪蛋白的分解,常被用來(lái)治療阿爾茨海默型癡呆)4周(20 mg/d)后,其應(yīng)激水平顯著降低, 過(guò)度興奮和不準(zhǔn)確言語(yǔ)得到明顯的改善。Whiteley等(2010)以55名自閉癥譜系障礙兒童為研究對(duì)象, 26名兒童參與實(shí)驗(yàn)組給予為期一年的GFCFD, 29名兒童參與對(duì)照組給予為期一年的普通飲食, 結(jié)果發(fā)現(xiàn)實(shí)驗(yàn)組兒童在自閉癥診斷觀察量表(Autism Diagnostic Observation Schedule, ADOS)、自閉癥行為評(píng)定量表(Gilliam Autism Rating Scale, GARS)和注意缺陷綜合征診斷標(biāo)準(zhǔn)第四版(Attention-Deficit Hyperactivity Disorder-IV scale, ADHD-IV)上的得分均顯著降低。

研究表明 GFCFD對(duì)自閉癥譜系障礙有一定治療作用(Arnold, Hyman, Mooney, & Kirby, 2003;Elder, 2013), 這說(shuō)明谷蛋白和酪蛋白未能正常分解與自閉癥譜系障礙關(guān)系密切。其背后的生理途徑可能有以下兩條：第一, 谷蛋白和酪蛋白具有阿片活性, 它們會(huì)通過(guò)消化道吸收進(jìn)入血液, 并穿過(guò)血腦屏障進(jìn)入大腦, 進(jìn)而影響中樞神經(jīng)功能。第二, 谷蛋白和酪蛋白還能引起自身免疫反應(yīng), 對(duì)大腦造成直接損傷。這兩方面的作用導(dǎo)致自閉癥譜系障礙患者的大腦功能失調(diào), 并表現(xiàn)出對(duì)應(yīng)的臨床癥狀。但亦有研究未能發(fā)現(xiàn) GFCFD與自閉癥譜系障礙之間存在關(guān)聯(lián)(Elder et al.,2006; Johnson, Handen, Zimmer, Sacco, & Turner,2011), Elder等(2006)選取15名自閉癥譜系障礙兒童給予GFCFD, 沒有發(fā)現(xiàn)這些兒童的臨床癥狀在實(shí)驗(yàn)后有明顯的緩解。因此, 有關(guān)這方面的研究尚不夠完善, 研究者們也沒有提出明確的結(jié)論。今后的研究需要進(jìn)一步確認(rèn)谷蛋白和酪蛋白在自閉癥譜系障礙發(fā)病中的具體作用。

4.2 多聚不飽和脂肪酸

當(dāng)前有關(guān)多聚不飽和脂肪酸(Polyunsaturated Fatty Acid, PUFA)對(duì)自閉癥譜系障礙影響的研究主要集中在ω?3。它是一組含有3個(gè)或3個(gè)以上雙鍵的多聚不飽和脂肪酸。ω?3的主要成分為α-亞麻酸(α-linolenic acid, ALA, )、二十二碳六烯酸(docosahexaenoic acid, DHA)和二十碳五烯酸(eicosapentaenoic acid, EPA)。Amminger等(2007)選取 13名接受常規(guī)治療的自閉癥譜系障礙兒童,并隨機(jī)分為實(shí)驗(yàn)組(n=7)和控制組(n=6)。要求實(shí)驗(yàn)組被試每天口服700 mg DHA和840 mg EPA, 控制組每天口服安慰劑藥片(無(wú)實(shí)際有效成分), 持續(xù) 6周后發(fā)現(xiàn), 隨著時(shí)間的推移, 實(shí)驗(yàn)組兒童的治療效果顯著好于控制組(p<0.05)。

雖然暫時(shí)沒有更多有關(guān)食物供給ω?3的干預(yù)研究, 但上述結(jié)果提示了 ω?3的攝入增加伴隨著自閉癥譜系障礙患者臨床癥狀的緩解。這種關(guān)系的生理機(jī)制可能與ω?3參與腦細(xì)胞的磷脂代謝有關(guān)。一般認(rèn)為, 磷脂代謝與腦神經(jīng)活動(dòng)關(guān)系密切,異常的磷脂代謝會(huì)降低細(xì)胞膜的流動(dòng)性, 從而導(dǎo)致神經(jīng)活動(dòng)異常。ω?3可以有效的參與并改善磷脂酰肌醇、花生四烯酸等物質(zhì)的代謝, 而它們是磷脂代謝的重要參與成分。如果個(gè)體缺乏足夠的PUFA來(lái)參與磷脂代謝, 那么腦細(xì)胞的磷脂代謝就會(huì)發(fā)生異常。當(dāng)個(gè)體自身不能產(chǎn)生足夠的PUFA來(lái)維持腦組織的磷脂代謝時(shí), 機(jī)體會(huì)增加食物中的必需脂肪酸(Essential Fatty Acid, EFA)和PUFA的吸收來(lái)代替, 諸如 ω?3。這意味著, 食物供給PUFA可以通過(guò)維持腦細(xì)胞磷脂代謝平衡, 進(jìn)而改善神經(jīng)細(xì)胞膜的流動(dòng)性和信號(hào)傳遞, 以緩解自閉癥譜系障礙患者的臨床癥狀。

5 其它生理途徑

5.1 氧化還原反應(yīng)異常和線粒體功能紊亂

研究者認(rèn)為 ASD患者可能存在氧化還原反應(yīng)(redox system)異常, 并因此導(dǎo)致慢性氧化應(yīng)激(chronic oxidative stress) (James et al., 2008)。研究發(fā)現(xiàn), 相比于正常人, ASD兒童的活性氧族(Reactive Oxygen Species, ROS)和抗氧化劑(antioxidant)的活動(dòng)并不穩(wěn)定, 主要體現(xiàn)在谷胱甘肽(glutathione)較常人水平偏高, 半胱氨酸(cysteine), S-腺苷甲硫胺酸(S-adenosylmethionine), s-腺苷高半胱氨酸(S-adenosylhomocysteine)較常人水平偏低(James et al., 2004; Parellada et al., 2012; S??üt et al., 2003;Zoroglu et al., 2004)。同時(shí), 研究發(fā)現(xiàn)ASD患者和其父母的蛋氨酸(methionine)和谷胱甘肽的代謝異常保持高度的一致性, 這表明遺傳因素可能在氧化還原異常中起重要作用(James et al., 2008)。

大多數(shù)情況下, 氧化還原反應(yīng)異常與能量轉(zhuǎn)化關(guān)系密切。在ASD患者身上發(fā)現(xiàn)乳酸酸性中毒(lactic acidosis)、左旋肉堿(carnitine, 即卡尼丁)缺乏和一系列β-氧化異常的跡象(Palmieri & Persico,2010), 這進(jìn)一步證實(shí)了氧化還原反應(yīng)的異常導(dǎo)致了個(gè)體有氧呼吸、脂肪吸收等生理活動(dòng)難以正常進(jìn)行。另外有關(guān)高半胱氨酸(homocysteine, Hcy)的酶代謝(這是維持細(xì)胞正常甲基化和體內(nèi)氧化還原平衡的一個(gè)重要路徑)研究發(fā)現(xiàn), ASD患者在抗氧化能力和甲基化作用均顯著弱于正常兒童(Deth & Muratone, 2010)。與之一致的是, 基因多態(tài)性的研究發(fā)現(xiàn)這種異常的代謝途徑減弱了患者甲基化能力, 而在其父母身上也發(fā)現(xiàn)了同樣的異常(James et al., 2006, 2008)。

線粒體是個(gè)體細(xì)胞內(nèi)活性氧族電子轉(zhuǎn)移鏈(electron transport chain, ETC)活動(dòng)的主要能量來(lái)源(Gandal et al., 2010), 這提示線粒體功能紊亂可能與ASD患者氧化還原反應(yīng)異常關(guān)系密切。研究發(fā)現(xiàn)眾多ASD患者存在線粒體功能障礙, 而線粒體功能障礙不僅與個(gè)體的細(xì)胞功能紊亂和神經(jīng)衰弱有關(guān), 而且對(duì)突觸發(fā)育、學(xué)習(xí)和記憶也有重要影響(Manji et al., 2012; Nissenkorn et al., 2000)。研究發(fā)現(xiàn), Ca2+濃度對(duì)線粒體的功能產(chǎn)生重要的作用。線粒體的谷氨酸轉(zhuǎn)運(yùn)蛋白(aspartate/glutamate carrier, AGC)受Ca2+濃度的調(diào)控, 而ASD患者腦組織的AGC和Ca2+濃度均要高于正常人, 這增加了細(xì)胞內(nèi)的 Ca2+濃度, 進(jìn)一步導(dǎo)致異常的氧化還原反應(yīng)并影響突觸的功能和神經(jīng)細(xì)胞間的連通性(Palmieri et al., 2010)。但是, 目前的研究尚不能明確線粒體功能紊亂與氧化還原反應(yīng)異常是否存在因果關(guān)系, 還需要研究者進(jìn)一步探索。

5.2 免疫系統(tǒng)異常

一些研究發(fā)現(xiàn) ASD患者血液中部分免疫因子, 如腫瘤壞死因子(Tumor Necrosis Factor, TNF)、干擾素(interferon)和白細(xì)胞介素(interleukin, IL)含量上升(Ashwood et al., 2011a; Molloy et al., 2006;Zimmerman et al., 2005)。腦脊髓液(cerebral spinal fluid, CSF)中的促炎細(xì)胞因子(Pro-inflammatory cytokines)也有所上漲(Chez, Dowling, Patel, Khanna,& Kominsky, 2007; Vargas et al., 2005)。有研究者通過(guò)對(duì)死亡 ASD患者的大腦進(jìn)行蛋白質(zhì)陣列(protein arrays)分析發(fā)現(xiàn), 其存在過(guò)度促炎的現(xiàn)象(Li et al., 2009)。免疫物質(zhì)的含量在各個(gè)組織不明原因的上漲以及腦組織過(guò)度的炎性反應(yīng)提示著ASD患者免疫系統(tǒng)異常。流行病學(xué)的研究發(fā)現(xiàn),多半 ASD兒童和發(fā)育障礙兒童伴有自身免疫系統(tǒng)障礙(Ashwood et al., 2011b; Atladóttir et al.,2009; Keil et al., 2010)。與正常兒童相比, ASD兒童中樞神經(jīng)系統(tǒng)存在過(guò)度的炎性反應(yīng), 這一結(jié)果很好的解釋了為何 ASD兒童多伴有自身免疫系統(tǒng)障礙(Mostafa & Al-Ayadhi, 2011; Mostafa &Kitchener, 2009; Singh, 2009)。研究發(fā)現(xiàn)小神經(jīng)膠質(zhì)細(xì)胞活動(dòng)異常與類精神疾病性的臨床癥狀關(guān)系密切(Giaume, Kirchhoff, Matute, Reichenbach, &Verkhratsky, 2007; Marín, 2012)。研究者認(rèn)為小神經(jīng)膠質(zhì)細(xì)胞可能是免疫反應(yīng)與ASD的中間樞紐。小神經(jīng)膠質(zhì)細(xì)胞是定居在腦組織的吞噬細(xì)胞, 在炎性刺激下抗原性增強(qiáng)并殺死神經(jīng)細(xì)胞, 過(guò)度的炎性反應(yīng)導(dǎo)致小神經(jīng)膠質(zhì)細(xì)胞異?；钴S, 大量正常腦細(xì)胞受到攻擊和吞噬, 進(jìn)而影響到個(gè)體的神經(jīng)活動(dòng)(Schafer et al., 2012)。

5.3 環(huán)境毒素

研究發(fā)現(xiàn), 孕期婦女暴露在某些環(huán)境下會(huì)提升孩子患ASD的概率。諸如產(chǎn)前服用帝拔顛、反應(yīng)停等藥物, 以及早產(chǎn)和低齡生育(Croen, Najjar,Fireman, & Grether, 2007; Reichenberg, 2006)。同時(shí), 研究發(fā)現(xiàn), 在懷孕早期的化學(xué)毒素暴露(沙利度胺, 米索前列醇, 丙戊酸)、感染風(fēng)疹, 有機(jī)磷殺蟲劑, 毒死蜱和自閉癥都有特殊的聯(lián)系(Landrigan, 2010)。這些環(huán)境因素在非常有限的情況下解釋了外部效應(yīng)如何在產(chǎn)前和產(chǎn)后造成自閉癥的生理病理現(xiàn)象(有時(shí)在其他人身體上沒有明顯的異常) (Rossignol & Frye, 2012)。

然而, 難以明確這些化合物對(duì)自閉癥風(fēng)險(xiǎn)的具體作用。隨著社會(huì)環(huán)境的日益復(fù)雜, 大量化學(xué)物質(zhì), 空氣污染和其他有毒物質(zhì)對(duì)人的暴露程度持續(xù)增強(qiáng), 這些物質(zhì)會(huì)影響大腦發(fā)育。已知一些殺蟲劑會(huì)對(duì)懷孕母體的甲狀腺功能造成損害, 還有一些會(huì)改變大腦平衡的興奮/抑制, 另外一些會(huì)影響線粒體的功能, 導(dǎo)致神經(jīng)炎癥或氧化應(yīng)激壓力。在發(fā)展的敏感時(shí)期, 這些機(jī)制全部或部分觸發(fā)都可能導(dǎo)致自閉癥。然而, 很少有人知道這些環(huán)境毒素的潛在閾值。而且, 暴露的化學(xué)物質(zhì)很容易與其他的因素相結(jié)合, 這使得環(huán)境毒素對(duì)ASD影響過(guò)程更加復(fù)雜。因此, 有關(guān)環(huán)境毒素的研究是非常困難的, 需要巨大的樣本, 并且目前的研究技術(shù)也不是很成熟。

5.4 激素類物質(zhì)

有關(guān)催產(chǎn)素的動(dòng)物模型研究發(fā)現(xiàn)催產(chǎn)素和加壓素與社交行為關(guān)系密切, 這引發(fā)了人們對(duì)于ASD患者社交異常的思考。有研究顯示催產(chǎn)素和加壓素對(duì)大腦肽受體產(chǎn)生兩種截然相反的影響,具體表現(xiàn)為注射催產(chǎn)素的田鼠活動(dòng)頻繁、社交活躍, 而注射加壓素的田鼠冷漠自閉(Hammock &Young, 2005; Young, Nilsen, Waymire, Macgregor,& Insel, 1999)。有關(guān)ASD患者的研究亦得出了同樣的結(jié)果, 這說(shuō)明低水平的催產(chǎn)素可能是ASD發(fā)病的重要因素(Modahl et al., 1998)。而大樣本的調(diào)查顯示這與催產(chǎn)素受體基因的SNP有關(guān)(Jacob et al., 2007; Wu et al., 2005)。同時(shí), 一些臨床研究發(fā)現(xiàn), 催產(chǎn)素可以提升心理治療干預(yù)ASD患者的效果(Yamasue et al., 2012)。這意味著激素類物質(zhì)可能對(duì)自閉癥譜系障礙的發(fā)病有一定作用, 目前尚沒有研究探討直接供給催產(chǎn)素能否緩解 ASD, 但上述邊緣證據(jù)提示我們存在這一可能性。

6 總結(jié)與展望

6.1 現(xiàn)有結(jié)論的不足

目前, 我們從遺傳、腦神經(jīng)、營(yíng)養(yǎng)素、環(huán)境毒素以及免疫反應(yīng)、氧化還原反應(yīng)等方面獲得了大量有關(guān)ASD生物基礎(chǔ)的證據(jù), 幾乎包含了可以引起個(gè)體疾患的生物因素的各個(gè)方面。但當(dāng)我們進(jìn)一步探討其與臨床癥狀的關(guān)系和作用于發(fā)病的機(jī)制時(shí), 卻難以得出明確的結(jié)論。

第一, ASD難以簡(jiǎn)單劃分為遺傳疾病, 基因變異解釋ASD發(fā)病并不具有普適性。首先, 很多ASD患者并未表現(xiàn)出任何遺傳跡象。其次, 雖然研究發(fā)現(xiàn)了一些確定位點(diǎn)的罕見基因變異, 但它們只是出現(xiàn)在部分患者的身上。這表明ASD并不具有遺傳疾病的特性。常見的基因變異只能解釋ASD的部分癥狀, 而其他一些罕見變異如基因拷貝數(shù)變異(CNVs)也被證明與 ASD有很大的關(guān)聯(lián),尤其在解釋智力障礙方面(Auerbach et al., 2011)。大量不同的基因變異均與ASD有關(guān), 而某一種變異會(huì)導(dǎo)致對(duì)應(yīng)的臨床癥狀。不同基因和基因組在時(shí)間和空間上的規(guī)律性和共表現(xiàn)性, 是導(dǎo)致基因變異不同而臨床表現(xiàn)相同的重要因素。

第二, 腦神經(jīng)發(fā)育異常只是下游癥狀, 不能解釋 ASD發(fā)病的機(jī)制。神經(jīng)病理學(xué)的研究發(fā)現(xiàn),ASD患者的發(fā)病受腦發(fā)育異常、功能連通性異常、腦化學(xué)物質(zhì)水平異常、浦肯野細(xì)胞數(shù)量減少和大腦皮層的活動(dòng)異常等一系列腦神經(jīng)相關(guān)的致病因素影響。但是, 上述異常和ASD并沒有特異性的聯(lián)系。諸如, 浦肯野細(xì)胞是小腦皮層中的唯一傳出神經(jīng)元, 其對(duì)小腦功能的影響十分巨大; 大腦皮層是人神經(jīng)活動(dòng)的主要集中區(qū)域(Schultz,2005)。這兩個(gè)重要腦結(jié)構(gòu)的異常必然導(dǎo)致腦神經(jīng)功能的紊亂, 在其它精神疾病和神經(jīng)發(fā)育障礙患者身上也是同樣的情況。因此, 這些發(fā)現(xiàn)只能作為ASD患者發(fā)病的下游癥狀, 而不是最初的發(fā)病機(jī)制。

第三, 有關(guān)營(yíng)養(yǎng)素、環(huán)境毒素等與ASD發(fā)病的研究數(shù)量少而且觀點(diǎn)不一致, 結(jié)論難以推廣。谷蛋白和酪蛋白過(guò)剩、不飽和脂肪酸和激素類物質(zhì)的缺失均能提升ASD的患病幾率, 孕期攝入環(huán)境毒素也會(huì)增加罹患ASD的風(fēng)險(xiǎn)。這一系列生理過(guò)程均與ASD有關(guān), 但其背后的生理機(jī)制并不清楚。研究者們?cè)趫?bào)告這些異常與ASD有關(guān)時(shí), 只是簡(jiǎn)單的說(shuō)明了一種統(tǒng)計(jì)學(xué)意義上的聯(lián)系, 并不能解釋因果關(guān)系以及背后的生理原理。而且, 這些關(guān)系并不穩(wěn)固, 其受到個(gè)體差異和環(huán)境交互的巨大影響(Elder et al., 2006; Johnson et al., 2011)。因此, 我們無(wú)法證明某營(yíng)養(yǎng)物質(zhì)或毒素是導(dǎo)致ASD發(fā)病的罪魁禍?zhǔn)住?/p>

綜上所述, 研究發(fā)現(xiàn)了大量異常的存在, 但沒有一種是普遍性的。存在同樣異常的個(gè)體, 部分罹患了自閉癥譜系障礙, 而部分罹患了其它疾病, 還有少部分個(gè)體沒有觀察到明顯的病變。因此研究者們難以提出明確的結(jié)論與模型。

6.2 自閉癥譜系障礙生物基礎(chǔ)的孕期異常模型

當(dāng)前研究大多先入為主, 努力探索某種確定因素與 ASD的關(guān)聯(lián), 往往會(huì)忽略許多無(wú)關(guān)變量,難以得出更為普遍的結(jié)論。眾多生物因素交叉出現(xiàn)提示了 ASD并未存在與一般疾患類似的模式,即在發(fā)育過(guò)程中不由明確的致病因子誘發(fā)。

自閉癥譜系障礙一般發(fā)病于生命早期, 但在生命早期, 環(huán)境對(duì)個(gè)體生理、心理的影響十分有限, 且需要一個(gè)過(guò)程。而當(dāng)前研究亦未能發(fā)現(xiàn)自閉癥個(gè)體各種生理異常的明確致病因子, 這意味著致病因素要追溯到孕期。在個(gè)體出生之前, 胎兒的大腦和機(jī)體會(huì)不可避免的受到影響, 這種影響在生育后的成長(zhǎng)過(guò)程中也必然表達(dá)出來(lái)。雖然沒有研究直接探討這一問(wèn)題, 但是有關(guān)大小鼠孕期異常導(dǎo)致自閉癥幼鼠的研究佐證了我們的假設(shè)。研究證實(shí), 孕期大小鼠注射丙戊酸(Valproic Acid, VPA)可以導(dǎo)致其生產(chǎn)的幼鼠出現(xiàn)類自閉癥狀和腦神經(jīng)解剖異常(Favre et al., 2015; Olexová,Senko, ?tefánik, Talarovi?ová, & Kr?ková, 2013)。因此, VPA被認(rèn)為是導(dǎo)致自閉癥的高危險(xiǎn)因素,眾多研究者們使用孕期注射 VPA的大小鼠的后代來(lái)作為自閉癥幼鼠開展研究(Banerjee et al.,2014; Cusmano & Mong, 2014; Mehta, Gandal, &Siegel,2011)。

這說(shuō)明孕期異常的表達(dá)是自閉癥發(fā)病的重要因素。當(dāng)然, 這種表達(dá)同樣受到個(gè)體閾限和嬰幼兒期外界環(huán)境的調(diào)控, 這解釋了為什么同卵雙生子的基因和孕期環(huán)境具有很高的一致性, 但仍表現(xiàn)出個(gè)體差異。如此, 研究搜集到的腦發(fā)育異常、神經(jīng)活動(dòng)紊亂、免疫反應(yīng)異常、過(guò)度促炎和營(yíng)養(yǎng)素缺失等一系列生物線索都可能成為自閉癥譜系障礙的下游癥狀, 而非原始的致病因子。這些下游癥狀的表達(dá), 在某種程度上可能進(jìn)一步促進(jìn)了自閉癥的發(fā)展, 而通過(guò)行為干預(yù)以及藥物干預(yù)的對(duì)抗, 自閉癥患者亦表現(xiàn)出部分癥狀和生理指標(biāo)的可逆性, 這表明個(gè)體對(duì)已有的生理異常具有抵抗能力, 該能力在外源性行為和藥物干預(yù)的促進(jìn)下進(jìn)行機(jī)體的自我修復(fù)。這為自閉癥譜系障礙的可治愈性提供了理論依據(jù)。

綜上所述, 我們認(rèn)為動(dòng)物孕期異常模型可以進(jìn)一步拓展至人類, 來(lái)解釋自閉癥譜系障礙發(fā)病機(jī)制。首先, 受基因變異和孕期環(huán)境(諸如胚胎暴露于VPA)的影響, 個(gè)體在孕期形成大腦和機(jī)體異常; 其次, 這種異常通過(guò)大腦發(fā)育、神經(jīng)活動(dòng)、免疫系統(tǒng)等生理途徑在出生后的發(fā)育中表現(xiàn)出來(lái);最后, 表現(xiàn)途徑受到出生后環(huán)境和個(gè)體閾限的共同調(diào)節(jié), 最終表現(xiàn)為以社交困難和刻板行為為核心的癥狀群。

當(dāng)然, ASD發(fā)病的生物機(jī)制尚不能一概而論。是否存在更為切貼的理論和臨床模型來(lái)解釋ASD的生物機(jī)制呢？這一問(wèn)題還需要研究者們進(jìn)一步探索。

6.3 今后的研究方向

雖然我們更新和拓展了現(xiàn)有的孕期異常模型,并在有限范圍內(nèi)解釋了 ASD患者復(fù)雜生物異常的機(jī)制, 但并不全面。今后的研究可以從以下方向探索：第一, 進(jìn)一步細(xì)化ASD及其亞型的分類以及明確 ASD概念的內(nèi)涵和外延可能會(huì)對(duì)理清這些繁多的生物線索有所幫助。第二, 生物影響的動(dòng)態(tài)性提示我們, 今后可以開展橫跨不同 ASD亞型、年齡、發(fā)育階段、性別的大范圍、橫向與縱向相結(jié)合的研究。第三, 大多研究集中在 ASD臨床群體, 并與正常人進(jìn)行比較, 鮮有研究將其與其他精神障礙類型比較。這亦是ASD病理機(jī)制研究的短板。第四, 開展不同學(xué)科的交叉研究是值得探索的方向。不同學(xué)科理論和方法的差異將有助于我們更好的排除無(wú)關(guān)變量, 提升研究的可信度。

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