基于ABIDE数据库的孤独症谱系障碍小脑形态自动分割与多中心验证

doi:10.3877/cma.j.issn.2095-655X.2026.01.003

目的

基于多中心脑结构磁共振成像数据，探讨孤独症谱系障碍(ASD)患者与典型发育(TD)个体之间的小脑形态学差异，并验证结果的跨站点稳健性。

方法

共纳入来自28个站点的2 147名被试(6~35岁，ASD组1 030人，TD组1 117人)。首先通过线性回归去除颅内总体积影响，获得小脑残差体积。随后建立线性混合效应(LME)模型，以组别、性别、年龄为固定效应，扫描站点为随机效应，分析组间估计边际均值(EMMeans)差异。进一步采用随机效应荟萃分析整合各站点效应量，评估结果一致性。

结果

在控制年龄、性别及站点变异后，LME模型显示TD组左侧小脑残差体积显著大于ASD组(β＝0.515，P＝0.0345)，右小脑无显著组间差异(β＝0.368，P＝0.1280)。年龄对左侧(β＝－0.094)和右侧(β＝－0.091)小脑体积均呈显著负向影响(均P<0.01)；女性左右两侧体积均显著小于男性(β＝－0.959，－0.925；均P<0.01)。边际均值比较进一步证实，左侧小脑中ASD组较TD组体积显著减小(EMMeans＝－0.515，95%CI：－0.992~－0.037，P＝0.0346)，而右侧小脑差异不显著(EMMeans＝－0.368，95%CI：－0.842~0.106，P＝0.1277)。荟萃分析显示，左右小脑跨站点异质性均为0%(I²＝0%)，合并效应量分别为左小脑－0.06(95%CI：－0.14~0.03)和右小脑－0.03(95%CI：－0.12~0.05)，左小脑差异具有良好的一致性。

结论

ASD患者存在左侧小脑结构的特异性异常，该发现在多中心数据中具有稳健性。左小脑形态学改变可能为理解ASD的神经病理机制提供影像学依据。

关键词: 孤独症谱系障碍, 小脑, 脑体积, 结构磁共振成像, 多中心研究

Objective

To examine cerebellar morphological differences between individuals with autism spectrum disorder (ASD) and typically developing (TD) controls using multicenter structural MRI data and validate the cross-site robustness of the results.

Methods

This study included 2 147 participants (aged 6-35 years; 1 030 cases of ASD, 1 117 cases of TD) from 28 sites. Intracranial volume effects were regressed out to obtain residual cerebellar volumes. A linear mixed-effects (LME) model was applied with group, sex, and age as fixed effects and scanning sites as random effects. Estimated marginal means (EMMeans) were derived from the LME model for group comparisons. Cross-site consistency was further evaluated using random-effects meta-analysis of effect sizes (Hedges′g).

Results

After controlling for age, sex, and site, the LME model revealed that the residual volume of the left cerebellum in the TD group was significantly larger than that in the ASD group (β=0.515, P=0.0345), while no significant intergroup difference was observed in the right cerebellum (β=0.368, P=0.1280). Age was negatively associated with bilateral cerebellar volumes (β=-0.094, -0.091, P<0.01), and females exhibited smaller volumes than males (β=-0.959, -0.925, P<0.01). The estimated marginal mean comparison further confirmed that the volume of the left cerebellum was significantly reduced in the ASD group compared to the TD group (EMMeans=-0.515, 95%CI: -0.992 to -0.037, P=0.0346), whereas no significant difference in the right cerebellum (EMMeans=-0.368, 95%CI: -0.842 to 0.106, P=0.1277). Meta-analysis demonstrated minimal cross-site heterogeneity (I²=0%) for both hemispheres, with pooled effect sizes of -0.06 (95%CI: -0.14 to 0.03) for the left cerebellum and -0.03 (95%CI: -0.12 to 0.05) for the right cerebellum, indicating the left cerebellar differences have good consistency.

Conclusions

Individuals with ASD exhibit specific reductions in the structure of the left cerebellum, a finding that is robust across multi-center data. These morphdogical changes in the left cerebellum may provide imaging evidence contributing to the understanding of neuropathological mechanisms in ASD.

Key words: Autism spectrum disorder, Cerebellum, Brain volume, Structural magnetic resonance imaging, Multicenter study

表1 ABIDE数据库各站点样本量分布(例)

站点名称	ASD	TD	合计
California Institute of Technology(Caltech)	15	16	31
Carnegie Mellon University(CMU)	11	11	22
Kennedy Krieger Institute (KKI)	77	187	264
Ludwig Maximilians University Munich(LMU)	23	33	56
NYU Langone Medical Center(NYU)	151	132	283
Institute of Living at Hartford Hospital(Olin)	19	16	35
Oregon Health and Science University(OHSU)	47	56	103
San Diego State University(SDSU)	47	47	94
Social Brain Lab(SBL)	15	15	30
Stanford University(Stanford)	40	37	77
Trinity Centre for Health Sciences(TCD)	20	21	41
University of California，Los Angeles(UCLA_1)	41	32	73
University of California，Los Angeles(UCLA_2)	13	13	26
University of Leuven(Leuven_1)	14	15	29
University of Leuven(Leuven_2)	15	20	35
University of Michigan(UM_1)	47	53	100
University of Michigan(UM_2)	12	22	34
University of Pittsburgh School of Medicine(Pitt)	35	31	66
University of Utah School of Medicine(USM)	71	54	125
Yale Child Study Center(Yale)	27	25	52
Barrow Neurological Institute(BNI)	28	27	55
Erasmus University Medical Center Rotterdam(EMC)	26	27	53
ETH Zürich(ETH)	13	23	36
Georgetown University(GU)	50	52	102
Indiana University(IU)	20	20	40
Institut Pasteur and Robert Debré Hospital(IP)	21	34	55
Katholieke Universiteit Leuven(KUL)	28	0	28
Olin Neuropsychiatry Research Center(ONRC)	23	29	52
Trinity Centre for Health Sciences(TCD_2)	21	20	41
University of California Davis(UCD)	18	13	31
University of California Los Angeles(UCLA)	29	21	50
University of Miami(UM)	13	15	28
总计	1 030	1 117	2 147

表1 ABIDE数据库各站点样本量分布(例)

站点名称	ASD	TD	合计
California Institute of Technology(Caltech)	15	16	31
Carnegie Mellon University(CMU)	11	11	22
Kennedy Krieger Institute (KKI)	77	187	264
Ludwig Maximilians University Munich(LMU)	23	33	56
NYU Langone Medical Center(NYU)	151	132	283
Institute of Living at Hartford Hospital(Olin)	19	16	35
Oregon Health and Science University(OHSU)	47	56	103
San Diego State University(SDSU)	47	47	94
Social Brain Lab(SBL)	15	15	30
Stanford University(Stanford)	40	37	77
Trinity Centre for Health Sciences(TCD)	20	21	41
University of California，Los Angeles(UCLA_1)	41	32	73
University of California，Los Angeles(UCLA_2)	13	13	26
University of Leuven(Leuven_1)	14	15	29
University of Leuven(Leuven_2)	15	20	35
University of Michigan(UM_1)	47	53	100
University of Michigan(UM_2)	12	22	34
University of Pittsburgh School of Medicine(Pitt)	35	31	66
University of Utah School of Medicine(USM)	71	54	125
Yale Child Study Center(Yale)	27	25	52
Barrow Neurological Institute(BNI)	28	27	55
Erasmus University Medical Center Rotterdam(EMC)	26	27	53
ETH Zürich(ETH)	13	23	36
Georgetown University(GU)	50	52	102
Indiana University(IU)	20	20	40
Institut Pasteur and Robert Debré Hospital(IP)	21	34	55
Katholieke Universiteit Leuven(KUL)	28	0	28
Olin Neuropsychiatry Research Center(ONRC)	23	29	52
Trinity Centre for Health Sciences(TCD_2)	21	20	41
University of California Davis(UCD)	18	13	31
University of California Los Angeles(UCLA)	29	21	50
University of Miami(UM)	13	15	28
总计	1 030	1 117	2 147

表2 ASD与TD组的人口学特征

组别	例数	年龄(岁，±s)	FIQ(±s)	男性[例(%)]
ASD组	1 030	15.77±8.71	106.04±16.83	892(86.60)
TD组	1 117	15.94±8.55	113.05±12.70	852(76.28)
统计量		t＝－0.44	t＝－10.43	χ²＝36.80
P值		0.662	<0.01	<0.01

表2 ASD与TD组的人口学特征

组别	例数	年龄(岁，±s)	FIQ(±s)	男性[例(%)]
ASD组	1 030	15.77±8.71	106.04±16.83	892(86.60)
TD组	1 117	15.94±8.55	113.05±12.70	852(76.28)
统计量		t＝－0.44	t＝－10.43	χ²＝36.80
P值		0.662	<0.01	<0.01

表3 ASD与TD小脑残差体积的线性混合效应模型结果

脑区	固定效应	估计值	标准误	自由度	t值	P值
左侧	截距	2.078	0.540	86.40	3.849	0.0002
	诊断(TD vs ASD)	0.515	0.243	2125.41	2.115	0.0345
	性别(女vs男)	－0.959	0.318	2138.02	－3.014	0.0026
	年龄	－0.094	0.020	1078.44	－4.673	<0.0001
右侧	截距	2.111	0.500	95.35	4.226	<0.0001
	诊断(TD vs ASD)	0.368	0.242	2128.73	1.524	0.1280
	性别(女vs男)	－0.925	0.316	2141.46	－2.932	0.0034
	年龄	－0.091	0.020	834.83	－4.641	<0.0001

表3 ASD与TD小脑残差体积的线性混合效应模型结果

脑区	固定效应	估计值	标准误	自由度	t值	P值
左侧	截距	2.078	0.540	86.40	3.849	0.0002
	诊断(TD vs ASD)	0.515	0.243	2125.41	2.115	0.0345
	性别(女vs男)	－0.959	0.318	2138.02	－3.014	0.0026
	年龄	－0.094	0.020	1078.44	－4.673	<0.0001
右侧	截距	2.111	0.500	95.35	4.226	<0.0001
	诊断(TD vs ASD)	0.368	0.242	2128.73	1.524	0.1280
	性别(女vs男)	－0.925	0.316	2141.46	－2.932	0.0034
	年龄	－0.091	0.020	834.83	－4.641	<0.0001

表4 左右侧小脑估计边际均值与组间比较

区域	组别	EMMeans	标准误	自由度	t值	P值	EMMeans(95%CI)
左侧	ASD	0.116	0.432	45.7			－0.755~0.987
	TD	0.630	0.427	43.2			－0.231~1.491
	ASD-TD	－0.515	0.243	2126.3	－2.115	0.0346	－0.992~－0.037
右侧	ASD	0.212	0.388	49.3			－0.568~0.993
	TD	0.580	0.382	45.8			－0.189~1.350
	ASD-TD	－0.368	0.242	2129.5	－1.524	0.1277	－0.842~0.106

表4 左右侧小脑估计边际均值与组间比较

区域	组别	EMMeans	标准误	自由度	t值	P值	EMMeans(95%CI)
左侧	ASD	0.116	0.432	45.7			－0.755~0.987
	TD	0.630	0.427	43.2			－0.231~1.491
	ASD-TD	－0.515	0.243	2126.3	－2.115	0.0346	－0.992~－0.037
右侧	ASD	0.212	0.388	49.3			－0.568~0.993
	TD	0.580	0.382	45.8			－0.189~1.350
	ASD-TD	－0.368	0.242	2129.5	－1.524	0.1277	－0.842~0.106

图1 左右侧小脑体积的站点级效应量森林图注：a图、b图分别为基于荟萃分析的右侧、左侧小脑残差体积在ASD与TD组间差异的多站点森林图。每条线代表一个扫描站点，方形点为效应量，横线为其95%CI，底部菱形为随机效应模型的合并效应量。结果显示跨站点异质性几乎为0(I²＝0%)；ASD为孤独症谱系障碍；TD为典型发育；SMD为标准化均数差

表5 小脑左右半球的荟萃分析站点级效应整合结果

小脑区域(K)	样本量(例)		效应量大小	异质性
小脑区域(K)	ASD	TD	SMD(95%CI)	I²	τ²	P值
左侧(33)	1 002	1 117	－0.06(－0.14，0.03)	0.0%	0	0.6211
右侧(33)	1 002	1 117	－0.03(－0.12，0.05)	0.0%	0	0.5448

表5 小脑左右半球的荟萃分析站点级效应整合结果

小脑区域(K)	样本量(例)		效应量大小	异质性
小脑区域(K)	ASD	TD	SMD(95%CI)	I²	τ²	P值
左侧(33)	1 002	1 117	－0.06(－0.14，0.03)	0.0%	0	0.6211
右侧(33)	1 002	1 117	－0.03(－0.12，0.05)	0.0%	0	0.5448

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Automated segmentation of cerebellar morphology in autism spectrum disorder and multi-center validation based on the ABIDE database

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Automated segmentation of cerebellar morphology in autism spectrum disorder and multi-center validation based on the ABIDE database