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基础研究
初诊原发性甲减患者静息态脑功能的初步研究
秦瑞 赵莲萍 韩亚兰 邵菲菲 曹剑仓 郭茜 田利民

Cite this article as: Qin R, Zhao LP, Han YL, et al. A pilot study of resting-state brain function in naive patients with primary hypothyroidism[J]. Chin J Magn Reson Imaging, 2022, 13(1): 81-85.本文引用格式:秦瑞, 赵莲萍, 韩亚兰, 等. 初诊原发性甲减患者静息态脑功能的初步研究[J]. 磁共振成像, 2022, 13(1): 81-85. DOI:10.12015/issn.1674-8034.2022.01.016.


[摘要] 目的 利用静息态分数低频振幅(fractional amplitude of low-frequency fluctuations,fALFF)技术探讨初诊原发性甲状腺功能减退症(甲减)患者脑损害的神经病理生理机制。材料与方法 对25名初诊未治疗的甲减患者(甲减组)和19名健康对照(健康对照组)行认知心理量表评定和头颅MRI扫描,用两样本t检验比较全脑fALFF值的组间差异,并与临床变量及认知心理评分行Pearson相关分析。结果 甲减组蒙特利尔认知评估量表评分减低(P=0.009),汉密顿抑郁量表-24和汉密顿焦虑量表评分增高(P=0.013;P=0.041),其左侧枕下回、舌回和右侧梭状回、枕上回、脑岛、中央后回的fALFF值减低(GRF校正,体素水平P<0.005,团块水平P<0.05),其中左侧枕下回、舌回和右侧梭状回的fALFF值与认知评分呈正相关(r=0.514,P=0.009;r=0.468,P=0.018;r=0.400,P=0.048)。当体素水平阈值降至P<0.001时,左侧舌回fALFF仍显著减低,且与认知评分呈正相关(r=0.547,P=0.005),另外,甲减组甲状腺素与抑郁评分呈负相关(r=-0.363,P=0.005)。结论 甲减患者存在认知功能受损、抑郁及焦虑状态。静息状态下,多个与认知功能及情绪密切相关脑区的自发性神经元活动减低,可能是甲减患者认知功能受损及情绪异常的重要神经病理生理机制。
[Abstract] Objective To explore the neurophysiological mechanisms of the brain damage in naive patients with primary hypothyroidism by using the fractional amplitude of low-frequency fluctuations (fALFF) of the resting-state functional magnetic resonance imaging (rs-fMRI).Meterials and Methods: Twenty-five untreated patient with hypothyroidism (hypothyroidism group) and 19 healthy volunteers (healthy control group) were assessed with cognitive psychological scales and cranial rs-fMRI scan. The two-sample t test was used to compare the difference of whole brain fALFF value between groups and Pearson correlation analysis with clinical variables and cognitive psychological scores.Results In the hypothyroidism group, the cognitive scores of Montreal Cognitive Assessment (P=0.009), and the scores of Hamilton Depression Scale-24 and Hamilton Anxiety Scale increased (P=0.013; P=0.041). Compared to controls, the fALFF values in the hypothyroidism group were decreased in the left inferior occipital gyrus, lingual gyrus and right fusiform gyrus, superior occipital gyrus,insula, and central posterior gyrus (GRF correction, voxel level P<0.005, mass level P<0.05). Meanwhile, the fALFF values of left inferior occipital gyrus, lingual gyrus and right fusiform gyrus were positively correlated with cognitive scores (r=0.514, P=0.009; r=0.468, P=0.018; r=0.400, P=0.048). When the voxel decreased to P<0.001, the fALFF of the left lingual gyrus still decreased significantly and was positively correlated with Montreal Cognitive Assessment scores (r=0.547, P=0.005). Additionally, thyroxine was negatively correlated with depression scores in hypothyroidism group (r=-0.363, P=0.005).Conclusions Patients with hypothyroidism have cognitive impairment, depression and anxiety. In the resting state, the spontaneous neuronal activity is decreased in multiple brain regions closely related to cognitive function and emotion, which may be a crucially neurophysiological mechanism of cognitive impairment and emotional abnormality in patients with hypothyroidism.
[关键词] 甲状腺功能减退症;认知功能;静息态功能磁共振成像;分数低频振幅
[Keywords] hypothyroidism;cognition;resting-state functional magnetic resonance imaging;fractional amplitude of low-frequency fluctuations

秦瑞 1, 5   赵莲萍 1, 2   韩亚兰 1   邵菲菲 3, 5   曹剑仓 1   郭茜 3, 5   田利民 1, 4, 5*  

1 甘肃中医药大学第一临床医学院,兰州 730000

2 甘肃省人民医院放射科,兰州 730000

3 甘肃省人民医院干部内分泌科,兰州 730000

4 甘肃省人民医院内分泌科,兰州 730000

5 甘肃省代谢性疾病临床医学研究中心,730000 兰州

田利民,E-mail:tlm7066@sina.com

全体作者均声明无利益冲突。


基金项目: 国家自然科学基金 82060152
收稿日期:2021-08-08
接受日期:2021-11-09
中图分类号:R445.2  R581.2 
文献标识码:A
DOI: 10.12015/issn.1674-8034.2022.01.016
本文引用格式:秦瑞, 赵莲萍, 韩亚兰, 等. 初诊原发性甲减患者静息态脑功能的初步研究[J]. 磁共振成像, 2022, 13(1): 81-85. DOI:10.12015/issn.1674-8034.2022.01.016

       甲状腺功能减退症(甲减)是甲状腺素合成、分泌减少或组织作用减弱导致的全身低代谢综合征,2017年中国成人甲减诊治指南认为其发病率约5%,且发病隐匿,病程较长,患者多缺乏特异性症状和体征。甲状腺素对维持成人神经系统的功能具有重要作用[1],Bavarsad等[2]发现随着甲减病程的进展,患者可出现不同程度的认知障碍及异常情绪,甚至进展为痴呆[3],带来沉重的社会负担。因此,尽早识别甲减相关脑损害对该病的早期干预具有重要价值。然而,目前关于甲减所致脑损害的神经病理生理机制尚不明确。近年来,静息态功能磁共振成像技术(resting-state functional magnetic resonance imaging,rs-fMRI)以其简便、无创及较好的时间、空间分辨率的优势,被广泛应用于阿尔茨海默病[4]、帕金森病[5]及双相障碍[6]等神经心理疾病的神经病理生理机制研究。其中分数低频振幅(fractional amplitude of low-frequency fluctuations,fALFF)是反映大脑自发性神经活动强度的重要指标,因其有效抑制了rs-fMRI非特异性信号成分,具有更高的敏感度和特异度[7],但其在甲减脑损害的研究中尚不多见。因此,本研究拟采用rs-fMRI技术中的fALFF分析方法,结合临床变量及认知心理量表,探讨原发性甲减患者认知功能损害及情绪异常的自发性神经元活动异常,为阐明其神经病理机制提供客观神经影像学依据。

1 材料与方法

1.1 研究对象

       前瞻性连续收集2019年10月至2020年12月期间甘肃省人民医院内分泌科门诊初诊的28名未接受治疗的临床型原发性甲减患者(甲减组),纳入标准:(1)符合2017版中国《成人甲状腺功能减退症诊治指南》的原发性甲减患者且未行任何治疗;(2)年龄18~60岁;(3)小学及以上文化水平;(4)右利手。排除标准:(1)既往或现患精神病性障碍者;(2)近期有头部外伤、晕厥;(3)严重视力障碍(矫正后未达到正常视力);(4)合并糖尿病等其他内分泌疾病或自身免疫性疾病;(5)缺血性心肌病;(6)有酒精或精神活性物质滥用或者依赖史;(7)有脑器质性损伤或疾病;(8)孕期、哺乳期及服用避孕药的女性;(9)有磁共振检查禁忌证。

       同期招募居住在周边社区的24名健康志愿者(健康对照组)。纳入标准:(1)甲状腺功能正常;(2)无明确神经系统及其他躯体疾病;(3)年龄18~60岁;(4)小学及以上文化水平;(5)右利手。排除标准同甲减组。

       本研究经甘肃省人民医院医学伦理委员会批准通过(批准编号:2019-196),所有受试者均自愿参与,并签署知情同意书。

1.2 一般临床资料

       收集所有受试者的年龄、性别、受教育水平、甲状腺功能水平(促甲状腺激素—TSH、游离三碘甲状原氨酸—FT3、游离甲状腺素—FT4、甲状腺素—T4)、蒙特利尔认知评估量表(Montreal Cognitive Assessment,MoCA)、汉密尔顿抑郁量表-24 (Hamilton Rating Scale for Depression-24,HRSD-24)和汉密尔顿焦虑量表(Hamilton Anxiety Scale,HAMA),所有量表在做头颅rs-fMRI检查的当天完成。

1.3 影像学检查

       应用德国西门子Magnetom Skyra 3.0 T磁共振32通道头线圈采集影像数据。所有扫描由同一位操作熟练的放射科医生完成。在检查过程中,受试者平卧,固定头部,清醒闭眼,全身放松,尽量不做任何专注思维活动,平静呼吸并最大限度地减少主动或被动运动。先行常规结构像平扫,排除颅内器质性病变后采集rs-fMRI和三维颅脑容积T1WI结构像,扫描参数见表1

表1  rs-fMRI和3D-T1WI的数据采集扫描参数
Tab. 1  rs-fMRI and 3D-T1WI data acquisition scanning parameters

1.4 图像数据预处理

       采用基于Matlab 2018b的SPM12和DPIBA V4.2软件对图像数据行预处理。过程包括图像数据格式转换、剔除前10个时间点、层时间校正、头动校正(剔除头动平动>3.0 mm,或转动>3.0°的数据)、空间标准化(重采样为3 mm×3 mm×3 mm)、空间平滑(平滑核半高全宽为6 mm)、去线性漂移和回归去除协变量(头动、脑脊液、脑白质和全脑均值信号)。将性别、年龄、受教育程度及Friston 24个方向的头动参数作为协变量回归以减少其影响,提高结果的准确性。

1.5 计算fALFF

       采用DPARSF 4.2软件,预处理去线性漂移后,每个体素的时间序列不带通滤波直接转换为频域,计算功率谱每个频率的平方根,然后计算出低频和全频段范围的比值即为fALFF[8]。对fALFF进行空间标准化,以降低个体差异对结果的影响,再对个体数据进行Z转换提高数据的正态性后行统计分析。

1.6 统计学方法

       一般资料采用SPSS 24.0软件进行分析,服从正态分布的计量资料用(x¯±s)表示,组间比较采用两独立样本检验;不服从正态分布采用M (Qr)表示,组间比较采用秩和检验;计数资料组间比较采用卡方检验。fMRI数据采用DPABI软件中的两独立样本检验统计模块,多重比较校正采用高斯随机场(GRF)校正,分别在体素水平P<0.005、团块水平P<0.05和体素水平P<0.001、团块水平P<0.05两个水平分析fALFF组间差异,提取组间差异显著脑区的fALFF值与临床资料行Pearson相关分析,以P<0.05为差异有统计学意义。

2 结果

2.1 一般人口学及临床资料

       因头动等原因剔除3名甲减和5名健康受试者,最终入组25名甲减和19名健康受试者。两组性别、年龄、受教育年限差异无统计学意义,甲状腺激素水平及认知心理量表评分差异有统计学意义(表2)。

表2  人口学及临床资料
Tab. 2  Demographic and clinical data

2.2 fALFF的组间差异及相关分析

       基于GRF校正,在体素水平P<0.005、团块水平P<0.05时,甲减组左侧枕下回、舌回和右侧梭状回、枕上回、脑岛、中央后回的fALFF较健康对照组显著减低,且左侧枕下回、舌回及右侧梭状回fALFF值与MoCA评分均呈正相关(r=0.514,P=0.009;r=0.468,P=0.018;r=0.400,P=0.048) (表3图1),在体素水平P值降至<0.001时,左侧舌回fALFF仍显著减低(表3;图2),且与MoCA评分呈正相关(r=0.547,P=0.005)。此外,甲减组T4与HRSD-24评分呈负相关(r=-0.363,P=0.005;图3)。|r|表明两变量间相关的程度,越接近1,表明两变量相关程度越高,其关系越密切。

图1  甲减组与健康对照组全脑fALFF值组间差异及相关分析结果(GRF校正,体素水平P<0.005,团块水平P<0.05)。A~D中蓝绿色区域示甲减组左侧枕下回、舌回和右侧梭状回、枕上回、脑岛、中央后回fALFF较健康对照组显著减低。其中,左侧枕下回(B)、舌回(C)和右侧梭状回(D)的fALFF与MoCA评分呈正相关。fALFF:分数低频振幅;MoCA:蒙特利尔认知评估量表。
图2  甲减组与健康对照组全脑fALFF值组间差异及相关分析结果(GRF校正,体素水平P<0.001,团块水平P<0.05)。A~B蓝绿色区域为示甲减组左侧舌回fALFF较健康对照组显著减低。B:左侧舌回的fALFF与MoCA评分呈正相关。fALFF:分数低频振幅;MoCA:蒙特利尔认知评估量表。
图3  甲减患者HRSD-24评分与T4水平的相关分析。T4:甲状腺素;HRSD-24:汉密顿抑郁量表-24。
Fig. 1  The difference and correlation analysis of fALFF value between hypothyroidism group and healthy control group (GRF correction, voxel level P<0.005, mass level P<0.05). In A—D, the blue and green areas showed that fALFF value in the hypothyroidism group was significantly lower than that in the healthy control group in the left inferior occipital gyrus, lingual gyrus and right fusiform gyrus, superior occipital gyrus,insula, and central posterior gyrus. fALFF value was positively correlated with MoCA score in left inferior occipital gyrus (B), lingual gyrus (C) and right fusiform gyrus (D).
Fig. 2  The difference and correlation analysis of fALFF value between hypothyroidism group and healthy control group (GRF correction, voxel level P<0.001, mass level P<0.05). In A and B, the blue and green areas showed that fALFF value in the hypothyroidism group was significantly lower than that in the healthy control group in the left inferior occipital gyrus. In B,fALFF value was positively correlated with MoCA score in left inferior occipital gyrus.
Fig. 3  Correlation analysis between HRSD-24 score and T4 in patients with hypothyroidism.
表3  甲减组与健康对照组fALFF值比较
Tab. 3  Comparison of fALFF value between hypothyroidism group and healthy control group

3 讨论

       本研究采用静息态fALFF技术评价甲减患者的脑功能活动,发现甲减患者左侧舌回、枕下回和右侧梭状回、枕上回、脑岛、中央后回的fALFF值显著减低,尤其舌回是甲减较为稳定的受损脑区,其中,大部分fALFF减低脑区与MoCA评分存在显著正相关关系。据我们所知,尽管国内外有研究以rs-fMRI技术对亚临床甲减、实验性(亚)甲减、原发性甲减等进行过探讨,但本研究的优势是所有原发性甲减受试者均为初诊未治疗的患者,具有更好的同质性,且目前文献中尚未见关于fALFF技术在初诊未治疗原发性甲减中的应用报道。

3.1 甲减引起认知功能损害及情绪异常的可能机制

       脑是甲状腺激素(thyroid hormone,TH)作用的主要靶器官,成年后的甲减会导致类似抑郁、焦虑的症状及认知功能异常等,研究发现约60%的甲减患者存在一定程度的抑郁症状,约63%的患者出现一定程度的焦虑症状[9],这可能与TH缺乏引起多种神经递质的合成代谢紊乱[10]及相关功能脑区血液灌注不足[11]等有关。一方面,TH参与神经元的分化和迁移、髓磷脂的形成、突触的建立和树突的形成,多种神经递质都会受到TH的影响,从而影响神经功能的改变[12]。例如,谷氨酸是哺乳动物大脑的主要兴奋性神经递质,研究发现与健康对照相比,甲减患者的谷氨酸显著降低[13]。另一方面,脑血流灌注不足也是引起脑功能障碍的原因之一。一项大型队列研究发现脑血流量减少与死亡率和痴呆风险增加有关[14],而正电子发射断层扫描研究中发现甲减患者的全脑或部分脑区脑血流量低于健康受试者[15]。且已有荟萃分析证实,高血清TSH水平与抑郁患者整体和局部脑血流量的降低相关[16]。另有研究发现甲减患者大脑的糖代谢较正常人群有所下降[17],支持本结果。本研究发现甲减患者的焦虑与抑郁评分均明显高于正常对照,且抑郁评分与TH的水平呈负相关,焦虑评分与甲状腺功能的关系暂不显著可能是与样本量不足有关。

3.2 甲减组较对照组的差异脑区及与MoCA评分的关系

       本组结果中的fALFF差异脑区舌回、枕下回、枕上回、梭状回均位于枕叶。枕叶是重要的视觉中枢,不仅参与整合视觉信号,还负责介导言语、运动及空间工作记忆等认知功能[18]。枕叶视觉皮层损害将导致整体认知功能下降,这在帕金森患者中已被证实,其视觉皮层局部一致性广泛减低[19]。另有学者基于扩散张量成像发现重度先天性甲减患儿枕叶白质微观结构受损[20],支持本组结果。舌回位于枕叶内侧,参与视觉记忆加工、面部识别[21]、发散思维和逻辑分析[22],与邻近脑区协调发挥功能。本研究中,经过更严格的多重比较校正后,舌回的功能异常仍显著存在,提示舌回是甲减患者脑损害的重要神经影像学生物标记。研究已证实甲减患者的舌回脑血流减少,且舌回的表面积与焦虑-抑郁的严重程度相关[23]。另外,阿尔茨海默病伴抑郁患者的舌叶功能连接下降[24]、焦虑抑郁患者双侧舌回低频振幅降低[25],进一步提示舌回是参与认知功能障碍及情绪异常发生发展过程的重要脑区。枕下回和梭状回在人脸识别处理及情绪加工过程中起关键作用,枕下回属于默认网络,主要参与情绪加工及自我记忆提取的高级认知[26],梭状回属于边缘系统,主要参与认知功能[27]、面部识别和情绪变化[28]。本研究发现,甲减组左侧枕下回、舌回和右侧梭状回的fALFF值与MoCA评分呈中等程度的正相关关系,即相关程度较为密切。换言之,甲减患者左侧枕下回、舌回和右侧梭状回的fALFF值越低,其认知功能下降越严重,推测上述脑区神经元的自发性活动减低参与甲减患者认知功能受损的发生发展过程。

       脑岛同属边缘系统,在功能上与初级、次级运动皮质等相连,尤其与中央后回的大部分区域的连接较多[29],是目前认知神经科学领域中最受关注的脑区之一,是对认知起重要作用的高度发达脑区[30],也是参与情绪环路的重要脑区[31]。多项证据表明,脑岛的状态会影响认知功能和情绪反应,学者通过对创伤性脑损伤患者的功能网络分析,发现若去除脑岛,整个神经网络功能可能会出现“瘫痪”[32],认为脑岛具有“核心”脑区的功能。已有研究证实甲减患者中央后回的脑血流[33]和脑代谢[34]显著降低,进一步支持本研究结果。本研究中脑岛、中央后回的fALFF减低,提示脑岛和中央后回参与甲减脑损害的神经病理生理机制。

3.3 不足与展望

       本研究首次应用fALFF的分析方法探索了原发性甲减患者脑损害的神经机制,可为临床诊断及科研提供一定参考价值,但本研究属于横断面初步研究,样本量较小,尚不能对甲减组根据严重程度及是否合并认知功能损害和(或)情绪异常进行亚组分析,亦不能评价甲减患者治疗后的神经康复机制。因此,后续研究将扩大样本量,细化分组,密切随访,纵向对比,结合多模态神经影像学等手段,进一步阐明甲减脑损害的神经病理生理机制。

       综上,本研究基于fALFF技术的初步研究结果表明,甲减患者存在多个脑区的神经元自发性活动减低,尤其是舌回的fALFF异常可能是甲减患者脑损害的重要神经影像生物学标记。

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