中国科学院自动化研究所机构知识库

人类的小脑位于大脑半球后方，颅后窝、脑桥和延髓的后上方。整个小脑的 体积约占脑组织的 10%，但它却拥有全脑 80%的脑神经元。小脑被普遍认为是 一个与运动相关的脑结构，通过它与大脑的、脑干和脊髓之间的传入和传出联系， 参与躯体平衡和肌肉紧张的调节。然而近年来，大量来自解剖、临床与神经影像 学等方面的证据，表明小脑参与了人类的高级功能，如认知、情感、社交等过程。 当病变区域局限于小脑时，患者将表现出一系列认知转移、情感丧失以及社交淡 漠等高级功能障碍。

精神分裂症是一种遗传度高，一旦发病可能会严重影响患者日常工作生活的 精神障碍。多项研究已经发现，精神分裂症会对患者脑组织及功能产生广泛影响 且存在着高度异质性，不同症状的患者间可能表现出不同位置以及程度的损伤。 精神分裂症患者的结构影像学特征表现为严重的脑灰质体积萎缩，如小脑、额叶、 丘脑等脑组织的灰质体积会出现明显下降。认知障碍假说指出参与协调运动与 认知功能的大脑皮层-小脑-丘脑-大脑皮层神经环路(Cortico-Cerebellar-Thalamo- Cortical Circuitry，CCTCC)产生异常，可能导致患者出现幻觉、幻听等极具有代 表性的精神分裂症症状。因此，探究精神分裂症发病机制以及探讨小脑在脑认知 过程中所扮演的角色，对制定有效、稳定的个体化治疗方案具有很高的临床价值。 本文从以下三个方面展开工作:

1.精神分裂症小脑灰质体积异常改变:本章利用正常被试的小脑灰质结构 信息建立标准化模型，并对比了三种常用的建立标准化模型的方法的拟合结果。 标准化模型能够给出可接受变化范围，将疾病异质性考虑在模型中。基于实验结 果，我们选定了高斯过程回归作为后续标准化模型回归方式，并在个体层面以及 位置分布上分别验证了精神分裂症患者间存在的高度异质性。这项工作也分别 在发现集以及验证集中独立完成，证明了所得结论的稳定性。

2.精神分裂症大脑形态学测量异常改变:本章利用正常被试的大脑皮层厚

度与表面积信息建立标准化模型，模型利用高斯过程回归实现。此外，我们利用 双因子模型在 PANSS 症状量表中提取得到了可更好地刻画数据潜在结构的一般 化因子与三个症状特异性公共因子。基于精神分裂症患者得到个体化结构偏移 水平，我们探究了影像学改变与症状因子之间的关系，进一步验证了精神分裂症 内部异质性。总体来看，皮层厚度与表面积分别与一般化因子呈正、负相关。此 外，中央前回区域、腹侧枕叶等区域与阴性症状相关，可能预示着形态学改变与 情感障碍、运动控制等功能的联系。

3.精神分裂症结构功能损伤:本章将精神分裂症患者小脑灰质体积萎缩区 域的功能改变作为研究起点，提取结构受损区域的功能连接建立损伤网络，并结 合其临床症状表现分析这种功能异常是否导致了某种特异性临床症状表现。具 体而言，我们借鉴损伤网络映射的方法定义了小脑结构-功能正、负向损伤环路。 利用偏最小二乘回归在发现集与验证集中定义并筛选了环路内与功能改变稳定 相关的临床症状。我们发现阴性症状与小脑-额、顶叶-丘脑环路功能连接变化呈 正相关，与认知障碍假说所提到功能环路吻合。此外，我们发现精神分裂症患者 小脑 VisPeri 网络与大脑外侧枕叶复合体的连接变化可能直接导致了患者出现妄 想、幻觉等阳性症状。这提示我们，小脑-外侧枕叶复合体-额、顶叶环路的耦合 改变可能是这一改变的深层诱因。

The human cerebellum is located behind the cerebral hemispheres, the posterior cranial fossa, pons, and medulla oblongata. The volume of the entire cerebellum accounts for about 10% of the brain tissue, but it has 80% of the brain neurons of the whole brain. The cerebellum is generally considered a motor-related brain structure involved in regulating somatic balance and muscle tone through its afferent and efferent connections to the cerebrum, brain stem, and spinal cord. However, recently, a large amount of evidence from anatomical, clinical, neuroimaging, etc., has shown that the cerebellum is involved in high-level mental processes, such as cognitive, emotional, social, and other functions. When the lesion area is limited to the cerebellum, patients will show a series of high-level dysfunctions such as cognitive transfer, blunted effect, poor attention, etc.

Schizophrenia is a highly heritable mental disorder that may seriously affect the patient's daily work and life once it develops. Several studies have found that schizophrenia has a wide range of effects on brain tissue and function and is highly heterogeneous. Patients with different symptoms may show different locations and extents of damage. Patients with schizophrenia may suffer from severe gray matter volume atrophy in the cerebellum, frontal lobe, thalamus, and other brain tissues. The cognitive dysmetria hypothesis points out that while the cerebral cortex-cerebellar- thalamo-cerebral cortical circuit (CCTCC) involved in coordinating movement and cognitive function shows abnormal changes, it may lead to representative symptoms schizophrenia, such as hallucinations, auditory hallucinations, etc. Therefore, exploring the pathogenesis of schizophrenia and the cerebellum's role in the cognitive process is highly valuable for formulating an effective and stable individualized treatment plan. This paper works from the following three aspects:

1. Abnormal changes of cerebellar gray matter volume in schizophrenia:

We use healthy controls' cerebellar gray matter volumes to establish a normative model and compare the fitting degrees of three commonly used methods for building normative models. Normative models can provide acceptable ranges of variation,

taking heterogeneity into hypothesis account. Based on the experimental results, we chose Gaussian process regression as the subsequent regression method and validated the great extent of heterogeneity among schizophrenia patients, both individual-wise and location-wise. This work is also independently implemented in the discovery dataset and the validation dataset, respectively, proving the stability of the current conclusions.

2. Abnormal changes in brain morphological measurements in schizophrenia:

We use cortical thickness and surface area of healthy controls to establish a normative model, which is implemented using Gaussian process regression. In addition, we extracted generalized factors and three symptom-specific common factors that could better describe the underlying data structure of the PANSS symptom scale using a bi-factor mod el. Based on the ind ivid ual-wise morphological d eviations of schizophrenia patients, we explored the relationship between MRI images and symptom factors, further validated the strong heterogeneity in schizophrenia. Overall, cortical thickness was positively correlated with generalization factors, and surface areas were negatively correlated with generalization factors, respectively. In addition, we found that the region of the precentral gyrus and the ventral medial occipital cortex show strong correlations with N-factor, characterized by expanded surface area and decreased thickness. It links up the primary motor cortex and disorders of affection and motion controls in schizophrenia patients.

3. Cerebro-cerebellum functional lesion networks seeded of cerebellar atrophy in schizophrenia:

Here, we explore the relationship between functional connectivity, abnormal changes in cerebellar gray matter atrophy areas, and clinical symptoms in schizophrenia. Specifically, we extract the functional connectivity of cerebellar atrophy areas to establish a functional lesion circuit following the pipeline of lesion network mapping. We introduced label permutation tests to ensure the structural-lesion specificity of our functional circuit. Clinical symptoms associated with stable, functional changes within the circuit were defined and validated in discovery and validation datasets using partial least squares regression. We found that negativesymptoms were positively associated with functional connectivity changes of the cerebellar-frontal and parietal-thalamic circuits, consistent with CCTCC in the cognitive dysmetria hypothesis. In addition, we found that functional connectivities between the VisPeri network in the cerebellum and the lateral occipital lobe complex may directly lead to positive symptoms such as delusions and hallucinations in patients with schizophrenia. These findings suggest that the coupling of the cerebellum-lateral occipital complex-frontal and parietal circuits may lead to functional abnormalities in this circuit.