外周性眩暈并發(fā)焦慮的神經(jīng)生物學(xué)機(jī)制

李非田　戴春富

外周性眩暈的年發(fā)病率約為8.4%[1]。部分患者除眩暈、平衡不穩(wěn)等前庭癥狀外，還易伴發(fā)情緒行為改變，臨床常見焦慮、抑郁、軀體形式障礙等，其中又以伴發(fā)焦慮最為常見，約占所有外周性眩暈患者的46%[2]。有學(xué)者報(bào)道焦慮患者發(fā)生良性陣發(fā)性位置性眩暈(benign paroxysmal positional vertigo, BPPV)的風(fēng)險(xiǎn)較正常人高[3]。另有報(bào)道對(duì)于BPPV成功復(fù)位后仍感到眩暈的患者使用抗焦慮藥依替唑倫后患者眩暈障礙評(píng)分顯著降低，眩暈癥狀得到改善[4]。我們的前期研究顯示伴發(fā)焦慮患者在改善前庭癥狀后，焦慮水平較治療前下降；焦慮患者繼發(fā)外周性眩暈的概率也較普通人高[5]。據(jù)此我們認(rèn)為大腦中的前庭神經(jīng)核及處理焦慮情緒相關(guān)核團(tuán)的活動(dòng)相互影響。

近年來，外周性眩暈與焦慮共病吸引了越來越多學(xué)者的關(guān)注?；A(chǔ)實(shí)驗(yàn)動(dòng)物主要采用Wistar大鼠、C57BL/6小鼠，研究內(nèi)容主要為干預(yù)中縫核、藍(lán)斑核、臂旁核、終紋床核、海馬等情緒相關(guān)核團(tuán)，觀察其與前庭神經(jīng)核之間的神經(jīng)纖維投射關(guān)系或功能聯(lián)系。核團(tuán)干預(yù)手段包括藥理遺傳學(xué)手段設(shè)計(jì)藥物特異性激活設(shè)計(jì)受體(designer receptors exclusively activated by designer drugs, DREADD)及光遺傳學(xué)技術(shù)(optogenetics)[6-7]。目前用于動(dòng)物行為檢測(cè)的方法主要有檢測(cè)焦慮水平的曠場(chǎng)實(shí)驗(yàn)(open field test，OFT)、高架十字(elevated plus maze, EPM)、黑白箱實(shí)驗(yàn)(light-dark test, LDT)[8-10]及檢測(cè)平衡功能的轉(zhuǎn)棒實(shí)驗(yàn)(rotarod test, RT)、水平梁實(shí)驗(yàn)(beam balance test, BBT)[11-12]等。而臨床研究主要通過采用眩暈及情緒調(diào)查問卷來探討眩暈與焦慮的相關(guān)性、疾病分布與焦慮程度[13-14]。另有學(xué)者使用磁共振技術(shù)識(shí)別可能參與外周性眩暈與焦慮共病發(fā)生的腦區(qū)。

1　外周性眩暈與焦慮共病的神經(jīng)生物學(xué)機(jī)制

現(xiàn)有研究認(rèn)為眩暈與焦慮共病是由于中樞神經(jīng)系統(tǒng)傳遞前庭及情緒信息的通路相互重疊所致。目前認(rèn)為與眩暈、焦慮共病關(guān)系密切的情緒相關(guān)中樞結(jié)構(gòu)有中縫背核、藍(lán)斑核及海馬、終紋床核等，這些核團(tuán)與前庭神經(jīng)核之間均有結(jié)構(gòu)或功能上的聯(lián)系[15-17]。

1.1中縫背核中縫背核(dorsal raphe nucleus,DRN)是腦內(nèi)5-羥色胺(5-hydroxytryptamine, 5-HT)的主要來源場(chǎng)所，而5-HT是最早研究與焦慮情緒產(chǎn)生有關(guān)的遞質(zhì)。Halberstadt等[18-19]將5-HT類似物5,7-雙羥色胺注射入大鼠DRN以損毀5-HT能神經(jīng)元，隨后行鼠腦切片染色發(fā)現(xiàn)來自DRN的5-HT能神經(jīng)纖維投射到前庭神經(jīng)核。其中細(xì)髓鞘5-HT能纖維投射部位主要在前庭內(nèi)側(cè)核室旁區(qū)，而粗髓鞘5-HT能纖維主要投射于前庭神經(jīng)核的外側(cè)。為觀察前庭神經(jīng)核向DRN的神經(jīng)投射分布，Cuccurazzu等[20]向前庭神經(jīng)核注射示蹤劑生物素化葡聚糖胺后發(fā)現(xiàn)，來自前庭神經(jīng)核的纖維投射在DRN腹內(nèi)側(cè)及外側(cè)。這些研究證實(shí)了DRN與前庭神經(jīng)核之間的雙向投射關(guān)系。

研究發(fā)現(xiàn)，當(dāng)動(dòng)物處于可引起其焦慮的環(huán)境下，DRN尾部及中上部的c-fos蛋白及色氨酸羥化酶表達(dá)增多；系統(tǒng)性應(yīng)用可產(chǎn)生焦慮癥狀的藥物(如腺苷受體拮抗劑咖啡因)也可導(dǎo)致DRN尾部及中上部5-HT能神經(jīng)元活動(dòng)增加，而電刺激DRN尾部及中上部可產(chǎn)生抗焦慮作用[21]。對(duì)前庭性眩暈伴發(fā)焦慮患者給予選擇性血清素再吸收抑制劑(selective serotonin reuptake inhibitors, SSIR)氟西汀可改善患者的眩暈及焦慮癥狀[22]。這些解剖及功能上的研究提示，外周前庭受到刺激后可能通過前庭神經(jīng)核向DRN傳遞信息而引起其5-HT能神經(jīng)元放電活動(dòng)增加，5-HT釋放增多而引起焦慮。

1.2藍(lán)斑核藍(lán)斑核(locus coeruleus, LC)是一個(gè)均質(zhì)性核團(tuán)，90%的神經(jīng)元為去甲腎上腺素能神經(jīng)元，為腦內(nèi)去甲腎上腺素的主要來源。已有研究[23]應(yīng)用化學(xué)遺傳技術(shù)證實(shí)前庭神經(jīng)核及LC之間具有雙向神經(jīng)纖維投射。LC向前庭神經(jīng)核的投射主要分布在前庭內(nèi)、外側(cè)核及前庭上核，而前庭神經(jīng)核主要投射于LC尾部[24]。

有研究[25-26]通過大鼠冷熱水試驗(yàn)觀察到大鼠前庭受刺激后LC放電活動(dòng)受抑制。Lai等[27]利用垂直軸旋轉(zhuǎn)的方法刺激大鼠橢圓囊，隨后觀察與前庭神經(jīng)核有關(guān)聯(lián)的各個(gè)核團(tuán)fos蛋白的表達(dá)密度，發(fā)現(xiàn)大鼠前庭受到刺激后LC與對(duì)照組相比fos蛋白表達(dá)增加。Baizer等[28]刺激貓及松鼠猴的前庭器官得到相似結(jié)果。McCall等[29]應(yīng)用光遺傳技術(shù)激活小鼠LC去甲腎上腺素能神經(jīng)元后，行為學(xué)檢測(cè)發(fā)現(xiàn)小鼠焦慮水平上升，而激活來自杏仁核中投射到LC兼具有分泌促腎上腺皮質(zhì)激素釋放激素(corticotropin releasing hormone, CRH)功能的神經(jīng)元后LC放電活動(dòng)增加，小鼠出現(xiàn)焦慮樣行為。這些研究提示LC與前庭神經(jīng)核存在功能上的聯(lián)系，前庭疾病導(dǎo)致的外周性眩暈可能通過前庭神經(jīng)核傳遞信息直接影響LC放電或作為一種應(yīng)激源促使機(jī)體CRH分泌增加，間接影響LC放電，從而導(dǎo)致焦慮樣行為的產(chǎn)生。

1.3海馬海馬(hippocampus)作為大腦邊緣系統(tǒng)的一部分，是中樞情緒處理的核心。目前關(guān)于海馬是否與前庭神經(jīng)核有直接投射關(guān)系尚無報(bào)道。大鼠實(shí)驗(yàn)證實(shí)腹側(cè)海馬-內(nèi)側(cè)前額葉通路介導(dǎo)焦慮的產(chǎn)生[30]。Zhao等[31]在研究中發(fā)現(xiàn)海馬JNK信號(hào)通路在中藥逍遙散改善大鼠焦慮癥狀中起介導(dǎo)作用。另有研究報(bào)道電刺激大鼠前庭可抑制海馬細(xì)胞增殖及神經(jīng)再生；雙側(cè)前庭受損后，海馬谷氨酸能神經(jīng)元細(xì)胞受體亞型表達(dá)發(fā)生變化[32-33]。海馬是否參與外周性眩暈與焦慮共病的發(fā)生尚缺乏明確證據(jù)，但根據(jù)現(xiàn)有研究，我們推斷前庭病變可能通過干擾海馬神經(jīng)元，尤其是谷氨酸能神經(jīng)元的正?；顒?dòng)而導(dǎo)致情緒障礙。

1.4終紋床核終紋床核(bed nucleus of stria terminalis, BST)被認(rèn)為是杏仁核周邊區(qū)的重要組成部分，它在應(yīng)激反應(yīng)發(fā)生時(shí)信息的整合、傳遞過程中起重要作用。但是Ni等[34]應(yīng)用熒光金逆行示蹤法對(duì)樹鼩BST進(jìn)行全腦投射分析發(fā)現(xiàn)，BST與前庭神經(jīng)核之間并沒有直接投射關(guān)系。Luyck等[35]研究發(fā)現(xiàn)，條件反射焦慮大鼠模型BST受到電刺激后，曠場(chǎng)實(shí)驗(yàn)示中央?yún)^(qū)域活動(dòng)時(shí)間增加，焦慮水平下降；與損毀BST效果類似。BST是近年來焦慮研究的熱點(diǎn)核團(tuán)，上述解剖學(xué)研究顯示樹鼩BST與前庭核沒有結(jié)構(gòu)上的聯(lián)系，這可能存在種屬上的差異，期待未來有更多的大、小鼠神經(jīng)解剖學(xué)研究來明確BST與前庭神經(jīng)核之間的結(jié)構(gòu)聯(lián)系。BST與前庭神經(jīng)核之間的功能聯(lián)系也不明確，這給我們提供了新的研究方向。

2　外周性眩暈與焦慮共病的臨床研究

外周性眩暈患者可發(fā)生多種情緒障礙及認(rèn)知功能損害，目前臨床上常采用調(diào)查問卷的形式來了解情緒障礙的分布特征。Eckhardt-Henn等[36]利用結(jié)構(gòu)化訪談(structured interviews)、癥狀自評(píng)量表(SCL90R)、焦慮狀態(tài)/特性詢問表(state-trait anxiety inventory)對(duì)189例外周性眩暈患者進(jìn)行調(diào)查發(fā)現(xiàn)，16.8%的患者并發(fā)情緒障礙，常見的有焦慮、抑郁、體感形式障礙，其中又以焦慮最多見。Zhai等[5]利用醫(yī)院焦慮抑郁量表(hospital anxiety and depression scale)、焦慮自評(píng)量表(self-rating anxiety scale)、抑郁自評(píng)量表(self-rating depression scale)、癥狀自評(píng)量表(SCL90R)對(duì)26例難治性外周性眩暈患者(其中梅尼埃病24例、遲發(fā)型膜迷路積水2例)分別進(jìn)行治療前、后問卷調(diào)查，結(jié)果顯示外周性眩暈患者焦慮、抑郁水平較正常人高，而治療后焦慮、抑郁水平較之前下降；其中梅尼埃病A、B級(jí)的患者經(jīng)過治療后焦慮、抑郁癥狀改善更顯著，提示盡早干預(yù)，眩暈癥狀療效更佳。Balaban等[37]采用眩暈障礙量表(dizziness handicap inventory, DHI)、貝克抑郁量表(Beck depression inventory, BDI)、Spielberger焦慮狀態(tài)/特性詢問表(Spielberger state-trait anxiety inventory, STAI)對(duì)544例眩暈患者進(jìn)行調(diào)查顯示，20%的眩暈患者同時(shí)患有情緒障礙。上述研究提示，長時(shí)間眩暈患者應(yīng)排除焦慮癥的可能，若同時(shí)合并焦慮應(yīng)在治療眩暈的同時(shí)對(duì)情緒障礙進(jìn)行干預(yù)。

1996年Vitte等[38]對(duì)10例健康受試者進(jìn)行單側(cè)冷熱水試驗(yàn)，結(jié)束后30 s內(nèi)立即使用血氧水平依賴(blood oxygenation level dependent, BOLD)功能磁共振成像技術(shù)行顱腦掃描，結(jié)果顯示與冷熱水試驗(yàn)同側(cè)的海馬活動(dòng)增強(qiáng)，并且這種現(xiàn)象可重復(fù)。Vita等[39]通過Meta分析認(rèn)為精神疾病患者海馬體積通常較正常人小。2012年Seo等[40]對(duì)20例精神分裂癥患者及其健康親屬行顱腦磁共振掃描發(fā)現(xiàn)，左側(cè)海馬體積較小者，情緒應(yīng)激反應(yīng)更加強(qiáng)烈。Seo等[41]應(yīng)用顱腦磁共振對(duì)38例梅尼埃病確診患者進(jìn)行檢查并與正常人的顱腦影像對(duì)比發(fā)現(xiàn)，梅尼埃病患者雙側(cè)海馬體積較正常人顯著減小，尤其是左側(cè)海馬體積縮小與聽力下降、受累側(cè)前庭功能損傷程度密切相關(guān)，這類患者也易患情緒障礙。因此海馬與前庭核之間存在功能上的聯(lián)系，且在外周性眩暈并發(fā)焦慮的發(fā)病過程中起一定的作用。結(jié)合既往研究可知，海馬參與外周性眩暈與焦慮共病的機(jī)制可能是當(dāng)發(fā)生前庭疾患時(shí)，傳入海馬的前庭信息減少，從而抑制海馬細(xì)胞增殖，隨后海馬體積縮小，功能發(fā)生變化，從而產(chǎn)生焦慮等情緒障礙。

3　展望

目前的基礎(chǔ)研究尚不能明確外周性眩暈與焦慮共病的發(fā)病機(jī)制，有許多問題亟待解決。前庭損傷是否通過已知的與焦慮相關(guān)的神經(jīng)核團(tuán)介導(dǎo)而導(dǎo)致動(dòng)物焦慮水平上升，這些核團(tuán)之間的聯(lián)系，發(fā)揮作用的主次，通過什么遞質(zhì)發(fā)揮作用，核團(tuán)通過哪些信號(hào)通路參與前庭損傷與焦慮的共病都給我們提供了新的研究思路。隨著光遺傳技術(shù)及不同轉(zhuǎn)基因動(dòng)物等的開發(fā)，精確干預(yù)目標(biāo)核團(tuán)，從而探索核團(tuán)之間聯(lián)系成為可能。隨著核團(tuán)之間關(guān)系的揭示，有望從中樞層面干預(yù)，從而阻斷眩暈、焦慮之間的惡性循環(huán)。

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