王曉樂 王東林

(杭州師范大學(xué)認(rèn)知與腦疾病研究中心; 浙江省認(rèn)知障礙評(píng)估技術(shù)研究重點(diǎn)實(shí)驗(yàn)室, 杭州 311121)

1 引言

抑郁癥(major depressive disorder, MDD)是一種常見的情感性精神障礙, 主要表現(xiàn)為情緒低落、興趣喪失、精力減退、思維遲緩、自我價(jià)值感降低、內(nèi)疚自責(zé)、食欲不振、睡眠障礙等。這些癥狀可能會(huì)長期存在或反復(fù)發(fā)作, 嚴(yán)重者有自殺念頭甚至自殺行為。抑郁癥在一般人群中的終身患病率高達(dá)10%～20% (Kessler et al., 2005), 在內(nèi)科疾病中也很常見(Mitchell et al., 2011)。MDD給患者帶來社會(huì)功能損害(Sanderson, Tilse, Nicholson,Oldenburg, & Graves, 2007)和精神痛苦, 抑郁癥患者自殺給家庭和社會(huì)帶來巨大沖擊(Séguin et al.,2006)。對(duì)抑郁癥的發(fā)病機(jī)制已有大量探索, 其中,下丘腦在抑郁癥發(fā)生的作用近年來受到關(guān)注成為研究熱點(diǎn)。

下丘腦是調(diào)節(jié)情緒的關(guān)鍵腦區(qū)之一(Vandewalle et al., 2011), 又是連接應(yīng)激與抑郁的樞紐, 其功能異常與抑郁癥的發(fā)生有密切關(guān)系, 下丘腦及其下游神經(jīng)內(nèi)分泌系統(tǒng)的異常激活被普遍認(rèn)為是抑郁癥發(fā)病機(jī)制的最終共同通路(Bao & Swaab,2010)。下丘腦雖是人腦很小的一部分, 但卻對(duì)神經(jīng)內(nèi)分泌系統(tǒng)和人體多種生理活動(dòng)有重要而廣泛的調(diào)節(jié)作用, 進(jìn)而影響人的心身健康。已有的一些研究發(fā)現(xiàn), 情感性精神障礙與下丘腦對(duì)認(rèn)知、行為和內(nèi)臟活動(dòng)調(diào)節(jié)的異常有關(guān)聯(lián)(Cousins, Butts,& Young, 2009; Elizabeth Sublette, Oquendo, & John Mann, 2006; Price & Drevets, 2010; Strakowski,Delbello, & Adler, 2005)。本文擬對(duì)下丘腦與抑郁癥的發(fā)病機(jī)制方面的研究進(jìn)展進(jìn)行綜述。

2 下丘腦的解剖學(xué)與生理學(xué)概要

下丘腦是間腦的一部分, 位于下丘腦溝的腹側(cè), 構(gòu)成第三腦室側(cè)壁的下份和底壁, 其邊界不甚分明, 向下延伸與垂體柄相連(Collins, Neelin,Peters, & Evans, 1994), 人類下丘腦大小僅約4 cm3(Hofman & Swaab, 1992), 占人類腦容積的0.3% (Standring, 2008)。盡管下丘腦體積很小, 但卻有著復(fù)雜的分區(qū)(Sawchenko, 1998)。一般分為前、中、后三個(gè)部分。前部又稱視前上區(qū), 位于視交叉上方。中部又稱結(jié)節(jié)區(qū), 位于漏斗的后方。后部又稱乳頭體區(qū), 位于乳頭體。

下丘腦有許多細(xì)胞核團(tuán), 這些核團(tuán)的功能既有重疊, 又有區(qū)分(Nieuwenhuys, Voogd, & van Huijzen, 2007)。位于下丘腦前部的重要核團(tuán)有室旁核(paraventricular nucleus, PVN)和視上核(supraoptic nucleus, SON), 其神經(jīng)元可合成并分泌促腎上腺皮質(zhì)激素釋放因子/激素(corticotrophin-releasing factor/hormone, CRF/H)、抗利尿激素(antidiuretic hormone, ADH)和催產(chǎn)素(oxytocin,OXT), 它們發(fā)出纖維構(gòu)成下丘腦垂體束到達(dá)垂體后葉(神經(jīng)垂體), 兩核分泌的CRF、ADH、OXT沿此束流到神經(jīng)垂體內(nèi)貯存, 在神經(jīng)調(diào)節(jié)下釋放入血液循環(huán)。CRF刺激垂體促腎上腺皮質(zhì)激素(adrenocorticotropic hormone, ACTH)的釋放, 促進(jìn)腎上腺皮質(zhì)合成糖皮質(zhì)激素(主要是皮質(zhì)醇),調(diào)節(jié)應(yīng)激反應(yīng)和代謝過程等; ADH又稱精胺酸血管加壓素(arginine vasopressin, AVP), 主要調(diào)節(jié)水鹽平衡和血管收縮; OXT促進(jìn)子宮收縮和乳汁分泌。CRF、AVP、OXT都具有調(diào)節(jié)情緒的作用。來自下丘腦“促垂體區(qū)”正中隆起的激素可激發(fā)垂體前葉(腺垂體), 對(duì)腺垂體的分泌起特異性刺激作用, 稱為釋放激素(RH); 來自下丘腦其他部位的激素可抑制垂體前葉, 對(duì)腺垂體的分泌起特異性抑制作用, 稱為抑制激素(IH)。下丘腦中間基底部分布著大量的促甲狀腺激素釋放激素(thyrotrophinreleasing hormone, TRH)神經(jīng)元, 主要作用于腺垂體促進(jìn)促甲狀腺激素(thyrotropic- stimulating hormone,TSH)的釋放。下丘腦的弓狀核、內(nèi)側(cè)視前區(qū)和室旁核分泌促性腺激素釋放激素(gonadotropinreleasing hormone, GnRH), GnRH可促進(jìn)腺垂體合成與釋放促性腺激素, 進(jìn)而促進(jìn)性腺合成分泌性激素。下丘腦的外側(cè)區(qū)是攝食中樞, 調(diào)節(jié)攝食行為; 下丘腦的前部是溫度敏感神經(jīng)元所在的部位,下丘腦后部是體溫調(diào)節(jié)的整合部位, 能調(diào)整機(jī)體的產(chǎn)熱和散熱過程, 以保持體溫穩(wěn)定在一定水平。由下丘腦核發(fā)出的下行傳導(dǎo)束到達(dá)腦干和脊髓的植物神經(jīng)中樞, 支配植物神經(jīng)調(diào)節(jié)內(nèi)臟活動(dòng)。下丘腦通過上述途徑和機(jī)制, 調(diào)節(jié)體溫、攝食、睡眠﹑生殖、水鹽平衡、心血管活動(dòng)、內(nèi)分泌、免疫反應(yīng)、新陳代謝、應(yīng)激、情緒反應(yīng)、內(nèi)臟活動(dòng)等多種生理過程(Baroncini et al., 2012)。下丘腦不僅是生理調(diào)節(jié)的重要中樞, 而且是情緒調(diào)節(jié)的關(guān)鍵腦區(qū)之一(Vandewalle et al., 2011)。

3 下丘腦結(jié)構(gòu)的改變與抑郁癥

下丘腦結(jié)構(gòu)的改變, 無論發(fā)生在宏觀水平或微觀水平, 都可能關(guān)系到抑郁癥的發(fā)生。Bielau等人(2005)對(duì)心境障礙的患者(9個(gè)抑郁癥和11個(gè)Ⅰ型躁郁癥患者)進(jìn)行死后尸檢發(fā)現(xiàn), 與沒有神經(jīng)精神疾病的控制組相比, Ⅰ型躁郁癥患者的下丘腦體積明顯減小, 而抑郁癥患者的下丘腦體積也有減小的趨勢(shì), 但是并沒有達(dá)到顯著水平。Schindler等人(2012)總結(jié)已有的使用死后尸檢和活體人形態(tài)學(xué)測(cè)定的方法對(duì)心境障礙病人的下丘腦和鄰近的第三腦室進(jìn)行研究的結(jié)果, 認(rèn)為心境障礙(單相和雙相)病人下丘腦的體積減小, 而下丘腦視上核的體積卻增大; 這與Bao, Hestiantoro,van Someren, Swaab和Zhou (2005)的發(fā)現(xiàn)相似,他們?cè)谛木痴系K患者(8個(gè)抑郁癥和5個(gè)雙相情感障礙的患者)死后對(duì)其大腦進(jìn)行免疫細(xì)胞化學(xué)的研究, 發(fā)現(xiàn)心境障礙患者的PVN體積顯著大于控制組的。此外, 有動(dòng)物研究發(fā)現(xiàn), 與控制組相比,下丘腦腹內(nèi)側(cè)核損傷的大鼠表現(xiàn)出更強(qiáng)的應(yīng)激逃避行為, 而PVN損傷的大鼠有更多的抑郁樣行為(Aou, 2006)。也有研究發(fā)現(xiàn)抑郁癥患者下丘腦某些核團(tuán)內(nèi)神經(jīng)元的異常變化, 如Purba, Hoogendijk,Hofman和Swaab (1996)對(duì)抑郁癥患者死后腦組織的尸檢研究發(fā)現(xiàn)抑郁癥患者下丘腦的PVN內(nèi)表達(dá)AVP的神經(jīng)元數(shù)目增加了56%, 表達(dá)OXT的神經(jīng)元數(shù)量增加了23%, 并認(rèn)為抑郁癥或躁郁癥患者的PVN內(nèi)的這兩種神經(jīng)元的活動(dòng)性增加可能與這些患者的下丘腦-垂體-腎上腺皮質(zhì)(hypothalamicpituitary-adrenal, HPA)軸功能亢進(jìn)有關(guān); Zhou等人(2001)的研究有類似的發(fā)現(xiàn), 即抑郁癥患者下丘腦視交叉上核(suprachiasmatic nucleus, SCN)內(nèi)AVP神經(jīng)元數(shù)量增加, 而AVP的信使核糖核酸(messenger ribonucleic acid, mRNA)的數(shù)量卻減少,這提示抑郁癥患者的SCN內(nèi)AVP的合成、釋放與轉(zhuǎn)運(yùn)之間的平衡發(fā)生了改變。有研究發(fā)現(xiàn)抑郁癥和躁郁癥患者組下丘腦PVN內(nèi)的總的神經(jīng)元數(shù)目與年齡匹配控制組的相比, 表現(xiàn)出選擇性穩(wěn)定的減少約50%, 這提示PVN內(nèi)選擇性的神經(jīng)元減少可能是抑郁癥臨床行為表現(xiàn)的一個(gè)重要的神經(jīng)生物學(xué)基礎(chǔ)(Manaye et al., 2005)。研究者觀測(cè)慢性不可預(yù)見性溫和應(yīng)激(chronic unpredictable mild stress, CUMS)下的抑郁模型組的大鼠, 發(fā)現(xiàn)其下丘腦PVN和杏仁核CRF陽性神經(jīng)元及神經(jīng)纖維密度顯著高于對(duì)照組, 提示下丘腦PVN和杏仁核的CRF神經(jīng)元可能對(duì)動(dòng)物抑郁樣行為的形成起著重要作用(Wang, Yan, Hofman, Swaab, &Zhou, 2010)。

4 下丘腦有關(guān)功能軸的改變與抑郁癥

下丘腦有關(guān)功能軸, 除了上文提到的HPA軸,還有下丘腦-垂體-甲狀腺(hypothalamic-pituitarythyroid, HPT)軸和下丘腦-垂體-性腺(hypothalamicpituitary-gonadal, HPG)軸等。研究顯示, 這些功能軸的活動(dòng)異常與抑郁癥的關(guān)系較為密切。

4.1 HP A軸的改變與抑郁癥

已知正常情況下, 作為HPA軸的軸心下丘腦,其PVN分泌CRF和AVP刺激腺垂體分泌ACTH,進(jìn)而促進(jìn)腎上腺分泌糖皮質(zhì)激素(主要是皮質(zhì)醇),而皮質(zhì)醇、ACTH的增多會(huì)負(fù)反饋抑制CRF和AVP的合成和釋放, 從而確保各激素保持在適度水平。然而, 患抑郁癥時(shí)下丘腦活動(dòng)異常增加,PVN分泌過多的CRF, CRF刺激垂體分泌過多的ACTH, ACTH刺激腎上腺皮質(zhì)分泌過多的皮質(zhì)激素, 因而, 患抑郁癥時(shí)整個(gè)HPA軸處于活動(dòng)過度的狀態(tài)。研究認(rèn)為調(diào)節(jié)應(yīng)激反應(yīng)的HPA軸功能系統(tǒng)是形成抑郁癥癥狀的一個(gè)主要通路(Bao, Meynen,& Swaab, 2008; Drevets, Price, & Furey, 2008;Price & Drevets, 2010), 而且HPA軸活動(dòng)過度是抑郁癥研究中最一致的生物學(xué)發(fā)現(xiàn)之一(Pariante& Lightman, 2008)。下丘腦是HPA軸的軸心, 其主要核團(tuán)PVN分泌CRF, CRF可增加皮質(zhì)醇的水平, 促使抑郁癥的癥狀和體征的形成(Bao & Swaab,2010)。在抑郁或焦慮狀態(tài)的動(dòng)物, 下丘腦PVN中內(nèi)分泌細(xì)胞的CRF免疫反應(yīng)性增加(Mironova,Rybnikova, & Pivina, 2013)。

許多研究顯示, HPA軸過度活動(dòng)很可能決定了抑郁癥的形成和發(fā)展(Barden, 2004; Holsboer,1999; Holsboer & Ising, 2008; Kathol, Jaeckle,Lopez, & Meller, 1989; Schatzberg & Kraemer,2000)。HPA軸功能異常是抑郁相關(guān)認(rèn)知損害的神經(jīng)生物學(xué)決定因素(Schlosser, Wolf, & Wingenfeld,2011)。抑郁癥患者的唾液、血漿及尿液中皮質(zhì)激素水平增高, 垂體和腎上腺的體積增大(Nemeroff &Vale, 2005; Rubin, Phillips, McCracken, & Sadow,1996)、海馬的體積縮小(Colla et al., 2007); 大多伴有HPA軸亢進(jìn)的抑郁癥患者的地塞米松抑制試驗(yàn)表現(xiàn)為陽性, 尤其是在兒童期受過心理創(chuàng)傷的患者(Heim, Mletzko, Purselle, Musselman, & Nemeroff,2008); 有研究資料提示, HPA軸功能亢進(jìn)不是抑郁癥本身的結(jié)果, 而是患抑郁癥之前就已存在的持久神經(jīng)生物學(xué)異常, 與個(gè)體的幼年不良遭遇有關(guān)(Heim & Nemeroff, 2002; Sánchez, Ladd, &Plotsky, 2001)。動(dòng)物實(shí)驗(yàn)不僅發(fā)現(xiàn)CUMS可使大鼠產(chǎn)生抑郁樣行為并伴有HPA軸過度活動(dòng), 而且發(fā)現(xiàn)抑郁的大鼠下丘腦突觸可塑性的變化(Ge, Qi,& Zhou, 2013)。O'Toole, Sekula和Rubin (1997)研究發(fā)現(xiàn), 抑郁癥患者ACTH基礎(chǔ)水平升高, 其24 h分泌節(jié)律也出現(xiàn)了異常, 垂體體積也增大。Rubin等人(1996)的研究發(fā)現(xiàn), 抑郁癥患者垂體和腎上腺體積增大, 與正常對(duì)照比較, 抑郁癥患者腎上腺皮質(zhì)增生約38%, 增生程度與皮質(zhì)醇的濃度相關(guān), 隨著抑郁癥的恢復(fù), 增生也隨著皮質(zhì)醇濃度下降而恢復(fù)。但是, Bhagwagar, Hafizi和Cowen(2003)臨床研究顯示, 抑郁癥患者存在HPA軸功能亢進(jìn)或高反應(yīng)狀態(tài), 甚至在抑郁緩解之后仍然存在; 他們對(duì)已處于完全康復(fù)期的31例重性抑郁癥患者進(jìn)行了研究, 結(jié)果發(fā)現(xiàn), 與31例健康對(duì)照相比, 康復(fù)期患者晨醒時(shí)唾液皮質(zhì)醇濃度顯著高于健康者, 提示重性抑郁癥患者即使在疾病的臨床康復(fù)期仍然存在HPA軸功能亢進(jìn), 使患者處于復(fù)發(fā)的風(fēng)險(xiǎn)之中; 對(duì)反復(fù)發(fā)作的MDD患者的縱向隨訪研究發(fā)現(xiàn), 皮質(zhì)醇濃度增加是患者的一種持久的特質(zhì), 與抑郁發(fā)作或緩解無關(guān)(Lok et al.,2012)。對(duì)老年抑郁癥患者在晨醒時(shí)(T1), 晨醒后30分鐘(T2)、45分鐘(T3)、60分鐘(T4)及晚上10點(diǎn)(T5)等幾個(gè)時(shí)點(diǎn)留取唾液標(biāo)本檢測(cè), 發(fā)現(xiàn)其在晨醒時(shí)有較高的皮質(zhì)醇水平, 但皮質(zhì)醇晨醒反應(yīng)(cortisol awakening response)較弱, 說明老年抑郁患者處于高皮質(zhì)醇狀態(tài), 且對(duì)晨醒應(yīng)激的反應(yīng)能力減弱, 提示老年人的HPA軸對(duì)應(yīng)激變得不敏感,在長期乃至終身處于高皮質(zhì)醇狀態(tài)的基礎(chǔ)上, 最終導(dǎo)致皮質(zhì)醇晝夜節(jié)律性失調(diào)進(jìn)一步加重(Rhebergen et al., 2015)。近來又發(fā)現(xiàn)伴有精神病性癥狀的抑郁患者也存在HPA功能軸的活動(dòng)顯著增加(Schatzberg,2015)。此外, Baeken等人(2009)對(duì)抑郁癥的研究發(fā)現(xiàn), 高頻重復(fù)經(jīng)顱磁刺激(high frequency repetitive transcranial magnetic stimulation, HF-rTMS)治療后病人唾液皮質(zhì)醇濃度顯著下降, 提示HF-rTMS對(duì)治療抑郁癥有效可能是通過抑制HPA軸活動(dòng)而取得的, 這從治療角度反證了下丘腦神經(jīng)內(nèi)分泌功能異常在抑郁癥發(fā)病中的作用。

4.2 HPT軸的改變與抑郁癥

通常, TRH主要作用于腺垂體促進(jìn)TSH的釋放, TSH刺激甲狀腺分泌甲狀腺激素, 導(dǎo)致血中游離甲狀腺激素濃度升高, 而TSH和游離甲狀腺激素的增多又反饋抑制TRH的活性, 從而調(diào)控機(jī)體代謝, 維持神經(jīng)系統(tǒng)、循環(huán)系統(tǒng)等的正常興奮性。研究顯示, HPT軸功能紊亂可能與抑郁的相關(guān)癥狀有關(guān)。最早在1972年有研究首次報(bào)告抑郁癥患者在TRH刺激試驗(yàn)中表現(xiàn)出TSH對(duì)TRH反應(yīng)減弱(Kastin, Ehrensing, Schalch, & Anderson, 1972;Prange, Lara, Wilson, Alltop, & Breese, 1972), 而且約有25% ～ 30%的抑郁癥患者表現(xiàn)出TSH對(duì)TRH反應(yīng)遲鈍(Loosen, 1985; Loosen & Prange,1982)。一些研究已發(fā)現(xiàn)甲狀腺功能標(biāo)記物的變化與產(chǎn)后抑郁癥相關(guān)(Harris et al., 1992; Kuijpens et al., 2001; McCoy et al., 2008; Plaza et al., 2010)。還有研究發(fā)現(xiàn)沒有自殺史的抑郁癥患者在早上8點(diǎn)和晚上23點(diǎn)TRH刺激試驗(yàn)表現(xiàn)出TSH對(duì)TRH反應(yīng)遲鈍, 而且不論是否有自殺史的抑郁癥患者這兩個(gè)時(shí)點(diǎn)TSH含量的差值均顯著降低(Duval et al., 2010)。目前研究者更進(jìn)一步認(rèn)識(shí)到甲狀腺功能和抑郁癥之間的關(guān)系, 發(fā)現(xiàn)患有甲狀腺功能減退的患者通常表現(xiàn)出抑郁癥狀, 如與TSH水平正常或升高的個(gè)體相比, TSH抑制的個(gè)體產(chǎn)生亞臨床抑郁癥的可能性更大(Kvetny, Ellervik, & Bech,2015), 反之亦然, 抑郁癥可能伴隨各種輕微的甲狀腺功能異常, 而且通常也記錄到TSH對(duì)TRH反應(yīng)遲鈍和腦脊液中TRH濃度升高(Hage & Azar,2011)。還有研究顯示, 與單純卒中亞組(漢密爾頓抑郁量表得分＜8分)相比, 卒中后抑郁亞組(漢密爾頓抑郁量表得分≥8分) 0～21天的血TSH水平較低, 在3個(gè)月時(shí)兩亞組間血TSH無顯著性差異,而且在第7天TRH刺激試驗(yàn)顯示, 卒中后抑郁亞組的TSH反應(yīng)明顯比單純卒中亞組的弱; 還有相關(guān)分析顯示卒中后抑郁亞組患者血TSH水平與漢密爾頓抑郁量表得分之間有顯著的負(fù)相關(guān), 這些表明與普通腦卒中患者比較, 卒中后抑郁患者HPT功能軸的改變時(shí)間久、程度重, 這可能是出現(xiàn)卒中后抑郁的重要機(jī)制(蔡永良等, 2012)。也有研究發(fā)現(xiàn), 產(chǎn)前血清游離甲狀腺素3(free thyroxine 3,FT3)和游離甲狀腺素4(free thyroxine 4, FT4)水平較低的婦女在產(chǎn)后第4天的抑郁得分較高, 并認(rèn)為產(chǎn)后情緒障礙的發(fā)生與產(chǎn)前甲狀腺功能相關(guān), 且在正常情況下, 產(chǎn)前低水平的FT3和FT4與產(chǎn)后第一周情緒障礙的發(fā)病率增加有關(guān)(Lambrinoudaki et al., 2010)。雖然分娩后立即測(cè)量TSH的水平與產(chǎn)后5天或6周時(shí)自我報(bào)告的產(chǎn)后抑郁沒有顯著相關(guān), 但是卻與6個(gè)月時(shí)自我報(bào)告的抑郁癥狀有顯著正相關(guān), 同時(shí)還發(fā)現(xiàn)分娩時(shí)測(cè)得的游離甲狀腺激素水平與產(chǎn)后5天自我報(bào)告的抑郁癥狀之間存在顯著的負(fù)相關(guān)(Sylvén et al., 2013)。研究也發(fā)現(xiàn)甲狀腺過氧化物酶自身抗體(thyroid peroxidase autoantibody, TPO-Ab)與抑郁癥的特征標(biāo)記(如艾森克人格問卷中神經(jīng)質(zhì)得分)存在正相關(guān), TPO-Ab的出現(xiàn)可能是抑郁癥易感性的標(biāo)志物(van de Ven et al., 2012)。另外臨床研究提示, 與患有其他精神疾病和軀體疾病的人相比, 雙相情感障礙的患者特別是正在服用鋰鹽的患者有較高的TSH異常比率(?zerdem, Tunca, ??mr?n, H?d?ro?lu, & Erg?r, 2014),通過檢測(cè)TSH水平, Wysokiński和K?oszewska(2014)確認(rèn)心境障礙(單相或雙相抑郁)患者可能有更高的甲狀腺功能紊亂的患病率。

4.3 HPG軸的改變與抑郁癥

健康人GnRH促進(jìn)性腺、垂體合成和釋放促性腺激素, 進(jìn)而促進(jìn)機(jī)體性激素的釋放, 以促進(jìn)性器官的發(fā)育、維持正常的生理周期以及生殖活動(dòng)。而當(dāng)HPG功能軸紊亂時(shí), 性激素水平下降,可致機(jī)體生理周期紊亂, 性欲減退, 甚至產(chǎn)生焦慮、抑郁等癥狀。Bloch等人(2011)的研究發(fā)現(xiàn), 對(duì)處在體外受精轉(zhuǎn)移周期的女性使用GnRH受體激動(dòng)劑可以導(dǎo)致她們產(chǎn)生抑郁和焦慮癥狀; 這與Warnock, Bundren和Morris (1998)的研究結(jié)果類似, 他們發(fā)現(xiàn)應(yīng)用GnRH受體激動(dòng)劑治療女性子宮內(nèi)膜異位癥時(shí), 患者的抑郁癥狀增加, 且這種抑郁癥狀又可以通過服用舍曲林而得到有效的控制。此外, 低水平的睪丸酮(testosterone, T)與抑郁癥間的因果關(guān)系本質(zhì)雖然不確定, 但是許多性腺機(jī)能減退的男性患有抑郁癥, 反之有些抑郁癥病人同時(shí)患有性腺機(jī)能減退(Amore et al., 2012)。之前也有研究顯示, 男性抑郁癥患者的T水平下降(Margolese, 2000), 女性抑郁癥患者血清雌二醇(estradiol, E2)水平顯著低于正常對(duì)照組(Rasgon,Altshuler, & Fairbanks, 2001)。還有研究提示, 對(duì)某些圍絕經(jīng)期的抑郁癥患者進(jìn)行抗抑郁藥治療,使用雌激素替代療法有抗抑郁的效果(Rasgon,Altshuler, Fairbanks, Dunkin, et al., 2001)。以上這些結(jié)果提示抑郁癥患者可能存在HPG功能軸紊亂。有研究表明補(bǔ)充T可以增加健康女性其皮質(zhì)-皮質(zhì)間抑郁神經(jīng)環(huán)路的功能連接(Schutter, Peper,Koppeschaar, Kahn, & van Honk, 2005) (所謂的“抑郁神經(jīng)環(huán)路”指左側(cè)前額葉皮層與右側(cè)頂葉皮層之間的神經(jīng)通路, 因有研究提示這一通路的功能連接降低可能是抑郁的敏感生理指標(biāo)而得名), 對(duì)于抑郁癥患者, 特別是伴有性腺機(jī)能減退或艾滋病的抑郁癥患者及老年抑郁癥患者, T可能有一定的抗抑郁作用(Zarrouf, Artz, Griffith,Sirbu, & Kommor, 2009)。由此可見, HPG軸的功能異常與抑郁癥有一定的聯(lián)系, 但目前的研究還不夠充分, 應(yīng)用性激素的抗抑郁治療方法還有待臨床更深入的研究。

5 下丘腦相關(guān)激素、受體及其基因、神經(jīng)肽的改變與抑郁癥

與抑郁癥關(guān)系比較密切而且研究較多的激素、受體及其基因主要是CRF、糖皮質(zhì)激素(glucocorticoids, GC)、糖皮質(zhì)激素受體(glucocorticoid receptor, GR)等。如果長期應(yīng)激使HPA軸功能持續(xù)亢進(jìn), 過量的GC不斷刺激GR使其受損。而受損的GR又不能有效抑制HPA軸亢進(jìn), 兩者互為因果, 形成惡性循環(huán), 損傷海馬神經(jīng)元, 導(dǎo)致以海馬為重要組成部分的情感調(diào)節(jié)中樞功能失常,就可能引發(fā)抑郁癥(Cowen, 2010)。早先Parker,Schatzberg和Lyons (2003)總結(jié)前人的研究提出,急性抑郁癥是以下丘腦CRF、垂體ACTH和腎上腺皮質(zhì)醇的分泌增多為主要特征, 而慢性抑郁癥由于加強(qiáng)腎上腺對(duì)ACTH的反應(yīng)和GC的負(fù)反饋?zhàn)饔眠@種補(bǔ)償機(jī)制, 反而當(dāng)ACTH水平下降時(shí)皮質(zhì)醇水平仍然較高。另外, 有動(dòng)物研究發(fā)現(xiàn)抑郁模型組的大鼠下丘腦的GR表達(dá)下調(diào), 且與控制組大鼠相比其下丘腦CRF水平增加(Raone et al.,2007); 對(duì)老年無自殺病史的抑郁癥患者死后尸檢發(fā)現(xiàn), 前扣帶回和背外側(cè)前額葉選擇性的出現(xiàn)鹽皮質(zhì)激素受體(mineralocorticoid receptor, MR)含量和GRα受體與MR比率紊亂, 且在背外側(cè)前額葉和下丘腦PVN內(nèi)MR-mRNA水平和GRα/MR的比率成負(fù)相關(guān), 這些改變可能導(dǎo)致了HPA軸過度活動(dòng), 因此成為抑郁癥的病因(Qi et al., 2013)。臨床研究表明, GR下調(diào)與抑郁癥的發(fā)生密切相關(guān);正常受試者口服單劑量地塞米松(dexamethasone,DEX)后激活GR, 負(fù)反饋抑制HPA軸活性, ACTH和皮質(zhì)醇的分泌減少; 然而, 20%～50%抑郁癥患者服用DEX后, ACTH和皮質(zhì)醇的分泌沒有變化(劉金梅, 史芳, 呂永寧, 2013), 這表明部分抑郁癥患者的GR下調(diào), 負(fù)反饋抑制作用減弱, 從而不能抑制HPA軸的活動(dòng)。對(duì)精神病性的抑郁癥研究發(fā)現(xiàn)GR和CRF1型受體都對(duì)精神病性癥狀的測(cè)量有重要作用, 而且CRF1型受體對(duì)抑郁癥嚴(yán)重程度等級(jí)也有重要作用(Schatzberg et al., 2014)。對(duì)大鼠慢性給藥全反式視黃酸(all-trans retinoic acid, ATRA)可導(dǎo)致下丘腦PVN內(nèi)的AVP和CRF表達(dá)顯著增加, 并促使下丘腦內(nèi)CRF1型受體、雌激素β受體和MR轉(zhuǎn)錄水平顯著增加, 而且這些受CRF控制的受體與大鼠抑郁有關(guān)的行為(如強(qiáng)迫游泳測(cè)驗(yàn))高度相關(guān)(Cai, Li, & Zhou, 2015)。

此外, 抑郁癥患者死后尸檢證實(shí), 抑郁癥患者PVN中CRF mRNA水平明顯增加, 而抑制CRF神經(jīng)元活性的雄激素受體mRNA的表達(dá)卻有明顯減少, 這表明受體含量的不平衡可能導(dǎo)致了抑郁癥的HPA軸的功能亢進(jìn)(Wang, Kamphuis,Huitinga, Zhou, & Swaab, 2008); 而且患者下丘腦SON內(nèi)的AVP基因的表達(dá)增加達(dá)60%, 這可能部分解釋抑郁癥患者的AVP水平增加的原因(Meynen et al., 2006)。Meynen, Unmehopa, Hofman,Swaab和Hoogendijk (2007)進(jìn)一步研究發(fā)現(xiàn)與非憂郁型抑郁癥患者相比, 憂郁型的患者下丘腦PVN內(nèi)的OXT mRNA和SON內(nèi)的AVP mRNA表達(dá)都顯著增加; 且與健康控制組相比, 整個(gè)抑郁癥組患者下丘腦SON內(nèi)的AVP mRNA表達(dá)顯著增加。還有實(shí)驗(yàn)表明, CRF和AVP受體的基因的單核苷酸多態(tài)性與抑郁癥的危險(xiǎn)因子相關(guān), 而且性激素對(duì)CRF基因的表達(dá)有關(guān)鍵作用(Bao &Swaab, 2010)。近來有研究者認(rèn)為, 依據(jù)CRF和AVP的致抑郁作用, 部分拮抗CRF和AVP的受體的藥物可以用于抑郁癥的治療(Beurel & Nemeroff,2014), 使用AVP受體拮抗劑的實(shí)驗(yàn)已發(fā)現(xiàn)其有一定的抗焦慮作用而沒有抗抑郁作用(Hodgson et al., 2014), 也有實(shí)驗(yàn)發(fā)現(xiàn)GR拮抗劑米非司酮可改善雙相抑郁癥患者的空間工作記憶(Watson et al., 2012)。另一方面, 對(duì)抑郁癥模型大鼠下丘腦PVN的研究結(jié)果提示抑郁癥不僅與雌激素減少有關(guān), 且可能與其受體表達(dá)減少有關(guān)(林圣彬, 唐曉偉, 李偉, 魯亞平, 2011)。然而, 也有研究發(fā)現(xiàn)抑郁癥病人下丘腦PVN的CRF神經(jīng)元上雌激素和雄激素受體表達(dá)增加, 而且其下丘腦內(nèi)調(diào)控CRF神經(jīng)元活性的許多其他受體也表現(xiàn)為平衡紊亂(周江寧, 閆雪波, 2008)。已知γ-氨基丁酸(Gamma-aminobutyric, GABA)是一種主要的抑制性神經(jīng)遞質(zhì), 由谷氨酸經(jīng)谷氨酸脫羧酶催化而成,可減弱HPA軸的活性, 在抑郁癥的發(fā)病機(jī)制中發(fā)揮著重要作用。對(duì)抑郁癥患者死后尸檢的研究發(fā)現(xiàn), 生前患抑郁癥的人腦PVN內(nèi)的谷氨酸脫羧酶(65/67)免疫反應(yīng)性細(xì)胞密度與控制組的相比顯著減少達(dá)43%, 還發(fā)現(xiàn)抑郁癥組的PVN內(nèi)的谷氨酸脫羧酶(65/67)免疫反應(yīng)性細(xì)胞密度和CRF神經(jīng)元的數(shù)量呈顯著的負(fù)相關(guān), 而在控制組卻沒有發(fā)現(xiàn)這樣的關(guān)系(Gao, Klomp, Wu, Swaab, & Bao,2013)。這樣抑郁癥的CRF神經(jīng)元增多, CRF的合成和釋放增多, 而同時(shí)抑制CRF活性的谷氨酸脫羧酶、雄激素受體、GR等受體的減少, 使得CRF進(jìn)一步增多, 最終導(dǎo)致血液維持過高的皮質(zhì)醇含量, 使HPA軸功能亢進(jìn)。另外, 研究顯示CRFR1基因單核苷酸多態(tài)性rs110402影響大腦對(duì)負(fù)性情緒刺激的反應(yīng), 這提示易于發(fā)展重度抑郁癥的潛在機(jī)制(Hsu et al., 2012)。也有動(dòng)物實(shí)驗(yàn)發(fā)現(xiàn)抑郁模型組的動(dòng)物下丘腦內(nèi)食欲肽和強(qiáng)啡肽含量減少(Nocjar, Zhang, Feng, & Panksepp, 2012), 以及食欲肽2型受體表達(dá)減少(Nollet et al., 2011), 這可能與抑郁癥患者的食欲不振、睡眠障礙等癥狀有關(guān)。

6 下丘腦與其他腦區(qū)功能聯(lián)系的改變與抑郁癥

研究者不僅關(guān)注下丘腦在抑郁癥的神經(jīng)機(jī)制中的重要作用, 而且關(guān)注下丘腦與其他腦區(qū)的聯(lián)系, 并嘗試從整體的角度去闡釋抑郁癥的病理生理學(xué)機(jī)制。下丘腦與前額邊緣網(wǎng)絡(luò)(The Prefrontal-Limbic Network, PLN)聯(lián)系密切(Bennett, 2011),主要接受來自該網(wǎng)絡(luò)內(nèi)的海馬、杏仁核和前扣帶回皮質(zhì)(anterior cingulate cortex, ACC)喙部等腦結(jié)構(gòu)的神經(jīng)投射, 功能上也受這些腦結(jié)構(gòu)的調(diào)節(jié)(Feldman, Conforti, & Weidenfeld, 1995)。在正常情況下, 海馬和ACC喙部對(duì)下丘腦的凈效應(yīng)都是抑制下丘腦分泌CRF, 而杏仁核對(duì)下丘腦的凈效應(yīng)是促進(jìn)下丘腦分泌CRF (Herman, Ostrander,Mueller, & Figueiredo, 2005)?；家钟舭Y時(shí), PLN內(nèi)一些腦區(qū)活動(dòng)減弱, 而杏仁核和膝下ACC活動(dòng)增強(qiáng)(Taylor & Liberzon, 2007)。有自殺企圖的抑郁癥患者的ACC灰質(zhì)體積明顯減少, 而杏仁核灰質(zhì)體積則明顯增加(Drevets, 2007; Drevets et al.,1997)。患抑郁癥時(shí)糖皮質(zhì)激素分泌增多, 可使杏仁核活動(dòng)增強(qiáng), 但可導(dǎo)致海馬、前扣帶回皮質(zhì)喙部、腹內(nèi)側(cè)前額葉皮質(zhì)(ventromedial prefrontal cortex,vmPFC)及眶額葉皮質(zhì)(orbital frontal cortex, OFC)等腦區(qū)活動(dòng)減弱(Dedovic, Duchesne, Andrews,Engert, & Pruessner, 2009)?？傊? 在患抑郁癥和糖皮質(zhì)激素增多的情況下, 正常時(shí)對(duì)下丘腦有抑制作用的腦區(qū)活動(dòng)減弱, 而正常時(shí)對(duì)下丘腦有促進(jìn)作用的腦區(qū)則活動(dòng)增強(qiáng), 形成惡性循環(huán), 結(jié)果導(dǎo)致下丘腦功能活動(dòng)異?？哼M(jìn)。Price和Drevets(2012)也認(rèn)為重度抑郁癥和雙相情感障礙與一個(gè)擴(kuò)展的網(wǎng)絡(luò)有密切關(guān)系, 該網(wǎng)絡(luò)包括內(nèi)側(cè)前額葉和邊緣系統(tǒng)、紋狀體、丘腦和前腦基底部等結(jié)構(gòu)。近來有功能磁共振成像研究發(fā)現(xiàn), 伴有精神病性癥狀的抑郁癥患者的下丘腦與膝下皮層(subgenual cortex)之間的功能連接下降, 且這兩個(gè)腦區(qū)間的連接下降及皮質(zhì)醇升高都與精神病性癥狀的嚴(yán)重程度關(guān)聯(lián), 提示此類型的抑郁癥患者的下丘腦和膝下皮層之間的連接受到破壞, 這可能是皮質(zhì)醇紊亂的原因, 也可能是結(jié)果(Sudheimer et al.,2015)。

7 小結(jié)與展望

以上研究提供了眾多證據(jù), 從不同角度說明了下丘腦與抑郁癥的發(fā)生發(fā)展有密切關(guān)系。然而,下丘腦與抑郁癥關(guān)系的研究仍存在一些不足。例如, 不少研究是以動(dòng)物為研究對(duì)象, 通過動(dòng)物抑郁模型來探討下丘腦異常與抑郁癥的關(guān)系, 因而這些結(jié)果不能直接反應(yīng)病人的病理變化, 更不能直接應(yīng)用于臨床; 在以人為研究對(duì)象的研究中,大多是通過測(cè)量反映下丘腦功能的間接指標(biāo)(如外周血相關(guān)激素等神經(jīng)內(nèi)分泌指標(biāo))來考察下丘腦與抑郁癥的關(guān)系; 雖然也有研究對(duì)抑郁癥患者下丘腦進(jìn)行直接觀察, 但使用的方法是對(duì)患者死后進(jìn)行腦組織尸檢, 所獲得的證據(jù)尚不能反映患者活體狀態(tài)下的病理生理變化。雖然確有一些研究使用了神經(jīng)影像學(xué)手段研究抑郁癥, 但未見以下丘腦為主要考察腦區(qū)、以探測(cè)下丘腦異常為主要研究目的的深入系統(tǒng)研究?？梢? 以活體人為研究對(duì)象直接探索下丘腦功能異常與抑郁癥關(guān)系的研究目前還比較缺乏。

使用功能磁共振成像技術(shù)對(duì)活體人的下丘腦功能的研究可能是理解抑郁癥的病理生理機(jī)制的一個(gè)突破口。盡管由于下丘腦體積較小、位置較深, 其磁共振信號(hào)的信噪比相對(duì)較差等原因, 對(duì)其進(jìn)行磁共振研究在技術(shù)上存在一定的難度, 但近年來已有研究證實(shí)人類活體下丘腦及其亞結(jié)構(gòu)如PVN、下丘腦的腹內(nèi)側(cè)核、纖維等在磁共振上是可以識(shí)別的, 且已經(jīng)將這些可以識(shí)別的下丘腦區(qū)域、核團(tuán)和白質(zhì)纖維束的精確位置標(biāo)準(zhǔn)化到蒙特利爾神經(jīng)病學(xué)研究所(Montreal Neurological Institute, MNI)開發(fā)的解剖學(xué)坐標(biāo)空間(MNI space)(Baroncini et al., 2012; Lemaire et al., 2011), 這為后續(xù)研究提供了可供參考的坐標(biāo)位點(diǎn)。近來有研究者首次嘗試通過聚類彌散加權(quán)成像數(shù)據(jù)描繪出健康人的下丘腦亞區(qū)的輪廓取得成功(Sch?nknecht et al., 2013)。有研究表明, 臨床常規(guī)磁共振頭顱掃描序列可發(fā)現(xiàn)下丘腦區(qū)的部分核團(tuán),如穹窿及前聯(lián)合在T1W1及T2W1中均顯示為結(jié)構(gòu)清晰的低信號(hào)結(jié)構(gòu), 定位后發(fā)現(xiàn)室旁核在T1和T2的掃描中邊界清晰; 而乳頭體核只在T1W1中呈等信號(hào), 邊界清晰; 視上核在T1W1中呈等信號(hào)與周圍核團(tuán)分界欠清, 且在T2W1圖像上顯示為與周圍灰質(zhì)相同的等信號(hào)區(qū)(張銳等, 2013)。最近利用靜息態(tài)功能磁共振來研究偏頭痛, 發(fā)現(xiàn)與健康控制組相比, 偏頭痛患者的下丘腦功能連接發(fā)生改變(Yang et al., 2015); 還有利用該技術(shù)研究肥胖或體重超重者的發(fā)現(xiàn), 與健康正常體重的控制組相比, 肥胖或體重超重組的被試其OFC和伏隔閡與下丘腦內(nèi)側(cè)網(wǎng)絡(luò)的功能連接更強(qiáng)(Kullmann et al., 2014)。這些研究表明, 以下丘腦為切入點(diǎn), 利用功能磁共振成像技術(shù)研究活體人下丘腦在方法學(xué)上是可行的。

對(duì)抑郁癥下丘腦的少量影像學(xué)研究已展示誘人的初步結(jié)果, 如Pinilla (2009)運(yùn)用基于體素的形態(tài)學(xué)測(cè)量的磁共振技術(shù)研究急性期抑郁癥患者,發(fā)現(xiàn)與健康組相比, 其下丘腦的體積顯著減小;張婧、盧青、劉海燕、滕皋軍和姚志劍(2011)在研究基因多態(tài)性對(duì)重性抑郁癥患者全腦灰質(zhì)密度的影響時(shí), 將抑郁癥患者和健康對(duì)照分為低、高活性基因型組, 經(jīng)結(jié)構(gòu)磁共振頭部掃描, 發(fā)現(xiàn)重性抑郁癥患者右側(cè)下丘腦灰質(zhì)密度顯著降低。最近有研究發(fā)現(xiàn), 給抑郁癥患者服用抗抑郁藥舍曲林8周后, 其下丘腦與某些腦區(qū)(前額葉背外側(cè)、OFC、ACC、腦島葉、殼核、尾狀核和屏狀核)的靜息態(tài)功能連接比服藥前顯著增加, 而與另外一些腦區(qū)(額下回、額內(nèi)側(cè)回、扣帶回、楔前葉、丘腦和小腦)的靜息態(tài)功能連接則出現(xiàn)顯著下降, 這提示抗抑郁治療可能是通過改變下丘腦靜息態(tài)的功能連接而達(dá)到治療效果的(Yang et al., 2014),故而從治療角度反證了下丘腦功能連接與抑郁癥的關(guān)系。但總的來說, 目前國內(nèi)外對(duì)抑郁癥下丘腦的零散影像學(xué)研究尚不夠系統(tǒng)、深入, 沒有使用多模態(tài)影像學(xué)手段對(duì)下丘腦的結(jié)構(gòu)和功能指標(biāo)進(jìn)行詳細(xì)考察, 沒有取得一致而清晰的結(jié)果。

顯然, 對(duì)抑郁癥下丘腦的影像學(xué)研究才剛剛起步, 存在大量空白未知地帶, 現(xiàn)有的少數(shù)零星研究無法完整而系統(tǒng)地闡明下丘腦在抑郁癥中有何特征性異常模式。歸納來看, 目前需要解決的問題有：下丘腦在抑郁癥中的異常神經(jīng)影像學(xué)征象到底是怎樣的？抑郁癥下丘腦異常神經(jīng)影像學(xué)征象與其它相關(guān)腦區(qū)有何關(guān)聯(lián)？抑郁癥下丘腦異常神經(jīng)影像學(xué)征象的穩(wěn)定性如何？抑郁癥下丘腦異常神經(jīng)影像學(xué)征象與應(yīng)激有何關(guān)系？未來研究可考慮從以下幾個(gè)方面探討下丘腦在抑郁癥的發(fā)病中的作用：(1)運(yùn)用多模態(tài)神經(jīng)影像學(xué)手段系統(tǒng)地探討抑郁癥患者下丘腦結(jié)構(gòu)特征和功能特征,尋找抑郁癥下丘腦神經(jīng)活動(dòng)的異常模式; (2)探討抑郁癥患者下丘腦異常功能活動(dòng)與其它腦區(qū)功能活動(dòng)的聯(lián)系; (3)探討抑郁癥下丘腦異常神經(jīng)影像學(xué)征象的穩(wěn)定性; (4)探討抑郁癥下丘腦異常神經(jīng)影像學(xué)征象與應(yīng)激因素及應(yīng)激反應(yīng)的關(guān)系。可以預(yù)期, 對(duì)抑郁癥下丘腦活體結(jié)構(gòu)和功能的系統(tǒng)探索如取得進(jìn)展, 將會(huì)為抑郁癥的早期識(shí)別和客觀診斷提供依據(jù), 為抑郁癥病理機(jī)制的探討提供重要線索。

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