【论文阅读笔记】精神分裂症的前额叶功能障碍——光脑功能成像的临床应用 | 【Paper Reading Note】Prefrontal Dysfunction in Schizophrenia——Clinical Application of Optical Brain Imaging

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1. 文献信息 | Literature Information

中文：

标题： 統合失調症の前頭葉機能障害——光脳機能イメージングの臨床応用 (精神分裂症的前额叶功能障碍——光脑功能成像的临床应用)[1]

年份： 2008

作者： 滝沢 龍，笠井 清登

引用： 滝沢, 龍., & 笠井, 清登. (2008). 統合失調症の前頭葉機能障害. 認知神経科学, 10(1), 15-18.

English:

Title: Prefrontal Dysfunction in Schizophrenia: Clinical Application of Optical Brain Function Imaging [1]

Year: 2008

Authors: Ryu Takizawa, Kiyoto Kasai

Citation: Takizawa, R., & Kasai, K. (2008). Prefrontal dysfunction in schizophrenia. Cognitive Neuroscience, 10(1), 15-18.

2. 重要术语 | Key Terms

2.1 近红外线光谱法 | Near-Infrared Spectroscopy (NIRS)

中文：

近红外线光谱法是一种利用近红外光进行脑功能测量的方法。

该方法通过测量大脑皮质中氧合血红蛋白与脱氧血红蛋白浓度相对于基线的变化，来反映脑功能活动状态。

其主要特点在于（1）能够在自然姿势下进行测量，（2）方法简便且非侵袭性，对受试者的身体负担较小，因此适合在临床现场反复实施。

其却显示该方法只能测量大脑皮质的功能活动，无法获取深部脑结构的信息；在时间分辨率方面较高，但空间分辨率相对有限。

English:

Near-infrared spectroscopy (NIRS) is a method for measuring brain function using near-infrared light.

This method reflects brain functional activity by measuring changes in oxygenated and deoxygenated hemoglobin concentrations in the cerebral cortex relative to baseline.

Its main characteristics include: (1) the ability to conduct measurements in natural postures, and (2) simplicity and non-invasiveness with minimal physical burden on subjects, making it suitable for repeated implementation in clinical settings.

However, this method can only measure functional activity in the cerebral cortex and cannot obtain information from deep brain structures; it has high temporal resolution but relatively limited spatial resolution.

2.2 内表型 | Endophenotype

中文：

内表型（endophenotype）是指一种可以被客观测量的生物学或功能性特征，它反映了遗传因素对脑功能或行为的影响，并与精神障碍的发生相关。

更正式地说，内表型是指受遗传变异影响、在个体中相对稳定存在，并用于连接遗传因素与临床症状的生物学或功能性表型。引入内表型概念的目的在于降低直接以临床诊断作为表型所带来的异质性，从而为精神障碍的遗传学与神经生物学研究提供更具机制指向性的研究对象。

在精神病学研究中，通常认为一个生物学或功能性指标若要被界定为内表型，需要满足以下六项基本标准[2]：

  1. 群体关联性： 该表型在群体水平上与疾病状态相关联
  2. 具有遗传性： 该表型在个体差异中具有可检测的遗传基础
  3. 状态独立性： 该表型不依赖于疾病的当前状态，在发病期与缓解期均可观察到
  4. 家系内伴随遗传： 在家系中，该表型与疾病倾向于共同遗传
  5. 家系富集性： 该表型在患者家系中的出现频率高于普通人群
  6. 可测量性： 该表型应能够被可靠测量，并与所研究的疾病相关

从概念关系上看，内表型可被视为生物标志物中的一种特定类型。与一般生物标志物相比，内表型对遗传性、稳定性以及其在”遗传因素—脑功能—临床症状”之间所处的连接作用提出了更为严格的要求。因此，并非所有生物标志物都符合内表型的判定标准。

通过引入内表型这一概念，精神障碍研究得以在遗传变异与临床表现之间建立更为清晰的功能与生物学联系，为后续探索具有遗传学意义的脑功能指标及其临床应用奠定了方法论基础。

English:

An endophenotype refers to an objectively measurable biological or functional characteristic that reflects the influence of genetic factors on brain function or behavior and is associated with the development of psychiatric disorders.

More formally, an endophenotype is a biological or functional phenotype that is influenced by genetic variation, exists relatively stably within individuals, and serves to connect genetic factors with clinical symptoms. The purpose of introducing the endophenotype concept is to reduce the heterogeneity associated with using clinical diagnoses directly as phenotypes, thereby providing more mechanistically-oriented research targets for genetic and neurobiological studies of psychiatric disorders.

In psychiatric research, a biological or functional indicator is generally considered an endophenotype if it meets the following six basic criteria [2]:

  1. Population association: The phenotype is associated with disease state at the population level
  2. Heritability: The phenotype has a detectable genetic basis underlying individual differences
  3. State independence: The phenotype does not depend on the current disease state and can be observed during both active and remission phases
  4. Familial co-segregation: Within families, the phenotype tends to be inherited together with the disease
  5. Familial enrichment: The phenotype appears more frequently in patient families than in the general population
  6. Measurability: The phenotype should be reliably measurable and relevant to the disease under study

Conceptually, endophenotypes can be viewed as a specific type of biomarker. Compared to general biomarkers, endophenotypes impose stricter requirements regarding heritability, stability, and their connecting role between “genetic factors—brain function—clinical symptoms.” Therefore, not all biomarkers meet the criteria for endophenotype designation.

By introducing the endophenotype concept, psychiatric disorder research can establish clearer functional and biological connections between genetic variation and clinical manifestations, laying a methodological foundation for subsequent exploration of genetically meaningful brain function indicators and their clinical applications.

2.3 COMT 遗传子多型 | COMT Genetic Polymorphism

中文：

COMT（儿茶酚-O-甲基转移酶）遗传子多型是指编码多巴胺代谢相关酶的基因在不同个体之间存在的变异。该多型会影响 COMT 酶活性，从而调节前头叶区域多巴胺水平，并被认为与前头叶功能效率及精神障碍风险有关。

English:

COMT (Catechol-O-Methyltransferase) genetic polymorphism refers to variations in the gene encoding enzymes related to dopamine metabolism across different individuals. This polymorphism affects COMT enzyme activity, thereby regulating dopamine levels in the prefrontal region, and is believed to be associated with prefrontal functional efficiency and psychiatric disorder risk.

2.4 GAF（全球功能评估量表）| GAF (Global Assessment of Functioning)

中文：

GAF 是一种用于评估个体整体生活功能水平的临床量表，用于反映个体在心理、社会及职业功能方面的综合状态，常作为精神疾病中症状严重程度和生活功能障碍程度的指标。

English:

GAF is a clinical scale used to assess an individual’s overall level of life functioning, reflecting their comprehensive status in psychological, social, and occupational functioning. It is commonly used as an indicator of symptom severity and degree of functional impairment in psychiatric disorders.

3. 研究目的 | Research Objectives

中文：

本研究为2008年滝沢龍等人的研究，其旨在探讨统合失调症（精神分裂症）中前头叶功能障碍的病态生理基础，并评估一种相对较新的非侵袭性脑功能测量方法——近红外线光谱法（NIRS，光脑功能成像）在精神科临床中的应用可能性。

English:

This 2008 study by Ryu Takizawa and colleagues aimed to investigate the pathophysiological basis of prefrontal dysfunction in schizophrenia and evaluate the clinical applicability of a relatively new non-invasive brain function measurement method—near-infrared spectroscopy (NIRS, optical brain imaging)—in psychiatric practice.

4. 研究内容 | Research Content

中文：

  1. 比较统合失调症患者与健康对照者在语流畅性任务过程中前头叶皮质血红蛋白浓度变化的差异
  2. 探讨前头叶功能指标与临床症状评价（GAF 等）之间的关系
  3. 从中间表型（endophenotype）的角度，检验NIRS信号的遗传学基础
  4. 分析与多巴胺代谢相关的COMT遗传子多型与前头叶功能指标之间的关联
  5. 以临床应用为目标，探索NIRS是否有可能发展为诊断补助、症状评估或药效预测的生物学指标

English:

  1. Compare differences in prefrontal cortical hemoglobin concentration changes between schizophrenia patients and healthy controls during verbal fluency tasks
  2. Explore relationships between prefrontal functional indicators and clinical symptom assessments (such as GAF)
  3. Examine the genetic basis of NIRS signals from an endophenotype perspective
  4. Analyze associations between COMT genetic polymorphisms related to dopamine metabolism and prefrontal functional indicators
  5. With clinical application as the goal, explore whether NIRS could potentially develop into a biological indicator for diagnostic assistance, symptom assessment, or drug efficacy prediction

5. 研究方法 | Research Methods

5.1 对象 | Subjects

中文：

  • 研究对象包括统合失调症患者与健康对照者；在部分分析中引入重性抑郁障碍患者作为比较对象；另包含双生子样本用于遗传率相关分析
  • 部分分析中进行了年龄、性别、任务成绩的匹配
  • 包含双生子样本用于遗传率分析

English:

  • Study subjects included schizophrenia patients and healthy controls; major depressive disorder patients were included as comparison subjects in some analyses; twin samples were included for heritability-related analyses
  • Age, sex, and task performance were matched in some analyses
  • Twin samples were included for heritability analysis

5.2 测量方法 | Measurement Methods

中文：

  • 使用多通道近红外光谱脑功能成像装置（ETG-4000）
  • 探头左右对称放置于前额部，覆盖前头前野，共 52 个通道
  • 测量指标主要为氧合血红蛋白（[oxy-Hb]）浓度相对于基线的变化，脱氧血红蛋白（[deoxy-Hb]）的变化用于辅助描述前头叶血流动力学反应特征

English:

  • Used a multi-channel near-infrared spectroscopy brain function imaging device (ETG-4000)
  • Probes were placed symmetrically on the forehead, covering the prefrontal cortex, with a total of 52 channels
  • Primary measurement indicator was changes in oxygenated hemoglobin ([oxy-Hb]) concentration relative to baseline; deoxygenated hemoglobin ([deoxy-Hb]) changes were used to assist in describing prefrontal hemodynamic response characteristics

5.3 认知任务 | Cognitive Tasks

中文：

  • 60秒语流畅性任务
  • 前后设置简单发音任务作为基线
  • 分析任务期间血红蛋白浓度的时间变化特征，如变化趋势及整体变化量

English:

  • 60-second verbal fluency task
  • Simple pronunciation tasks before and after served as baseline
  • Analyzed temporal change characteristics of hemoglobin concentration during tasks, such as change trends and overall magnitude of change

5.4 分析内容 | Analysis Content

中文：

  • 各组在前头叶血流动力学反应模式上的差异
  • 与临床指征（GAF、症状严重度）的相关分析
  • 采用双生子样本对 NIRS 信号的遗传相关性进行初步检讨
  • 探讨 COMT val158met 遗传子多型与前头叶 NIRS 信号模式之间的关系

English:

  • Differences in prefrontal hemodynamic response patterns among groups
  • Correlation analysis with clinical indicators (GAF, symptom severity)
  • Preliminary investigation of genetic correlations of NIRS signals using twin samples
  • Exploration of relationships between COMT val158met genetic polymorphism and prefrontal NIRS signal patterns

6. 结论与意义 | Conclusions and Significance

中文：

  1. 统合失调症患者在语流畅性任务中前头叶皮质的血红蛋白反应显著减弱，且其时间变化模式与健康对照者不同
  2. 前头极部通道中氧合血红蛋白变化量与社会功能水平（GAF）呈相关，提示其具有症状评估的潜在价值
  3. 不同精神障碍（统合失调症与抑郁障碍）呈现出不同的时间动态反应模式，显示出一定的疾病区分可能性
  4. 前头极部（BA10）通道表现出特别显著的差异，该区域被认为是高度进化且承担高级整合功能的前头叶区域
  5. NIRS 信号在双生子分析中显示出一定的遗传相关性，并与COMT遗传子多型呈现一致的变化模式，支持其作为中间表型的可能性
  6. 综合考虑其非侵袭性、简便性、可重复测量性，光脑功能成像有潜力发展为精神科临床中有实用价值的生物学指标
  7. 作者指出，尽管 NIRS 在信号准确性与解析方法上仍存在限制，但在2008年阶段的技术条件下，其在诊断补助、药效预测及病态生理理解方面具有现实且值得进一步验证的临床应用前景

English:

  1. Schizophrenia patients showed significantly weakened prefrontal cortical hemoglobin responses during verbal fluency tasks, with temporal change patterns different from healthy controls
  2. Changes in oxygenated hemoglobin in frontopolar channels correlated with social functioning level (GAF), suggesting potential value for symptom assessment
  3. Different psychiatric disorders (schizophrenia and depressive disorder) presented different temporal dynamic response patterns, indicating some potential for disease differentiation
  4. Frontopolar (BA10) channels showed particularly significant differences; this region is considered a highly evolved prefrontal area responsible for higher-order integrative functions
  5. NIRS signals showed genetic correlations in twin analyses and consistent change patterns with COMT genetic polymorphism, supporting their potential as endophenotypes
  6. Considering its non-invasiveness, simplicity, and repeatability, optical brain function imaging has potential to develop into a practically valuable biological indicator in psychiatric clinical practice
  7. The authors noted that despite limitations in signal accuracy and analysis methods, under 2008 technical conditions, NIRS showed realistic and worthy-of-further-validation clinical application prospects in diagnostic assistance, drug efficacy prediction, and understanding pathophysiology

参考文献 | References

[1] 滝沢, 龍., & 笠井, 清登. (2008). 統合失調症の前頭葉機能障害. 認知神経科学, 10(1), 15-18.

Takizawa, R., & Kasai, K. (2008). Prefrontal dysfunction in schizophrenia. Cognitive Neuroscience, 10(1), 15-18.

[2] “Endophenotype”, https://en.wikipedia.org/wiki/Endophenotype