WHITE MATTER TRACT DISRUPTION BY DTI IN PEDIATRIC FAMILIAL BIPOLAR DISORDER

DTI 对儿科家族性双相情感障碍患者白质束的破坏

• 批准号: 7722867
• 负责人: KIKI D CHANG
• 金额: $ 0.28万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7722867
• 关键词: Accounting; Adolescent; Adult; Affect; Amygdaloid structure; Anisotropy; Area; Autistic Disorder; Bipolar Disorder; Body of uterus; Brain; Cerebellum; Child; Childhood; Cognitive deficits; Communication; Computer Retrieval of Information on Scientific Projects Database; Computer software; Corpus Callosum; Data; Depth; Diagnosis; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Disruption; Echo-Planar Imaging; Etiology; Event; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Grant; Height; Hour; Image; Inferior; Institution; Joints; Magnetic Resonance Imaging; Maps; Masks; Measures; Memory; Mental disorders; Methodology; Methods; Neuropsychology; Noise; Numbers; Parents; Parietal; Patients; Pattern; Performance; Pharmaceutical Preparations; Physiologic pulse; Physiological; Prefrontal Cortex; Probability; Process; Psychiatry; Publishing; Pulse taking; Relative (related person); Reporting; Research; Research Personnel; Resources; Role; Sample Size; Sampling; Scanning; Score; Severity of illness; Side; Slice; Snow; Source; Structure; Tail; Test Result; Thick; Time; Tissues; United States National Institutes of Health; Visuospatial; Weight; base; cardiovascular risk factor; emotion regulation; human prostaglandin D2 receptor; neuroimaging; neuropsychological; size; white matter

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. INTRODUCTION Increased amounts of white matter hyperintensities (WMH) on T2-weighted MRI images have been reported in many, but not all, studies of patients with bipolar disorder (BD), both adult and pediatric (Lyoo et al., 2002; Strakowski et al., 2000; Sassi et al., 2003). These findings raise the possibility that disruption of white matter contributes to the etiology of BD. However, it is also possible that adults with BD have higher cardiovascular risk factors, which may account for micro CNS events leading to WMH. Therefore, studying children with BD, who presumably have had less chance to develop such events, would help clarify the role of WMH in BD. The few such studies as yet have suffered from either small sample size, inconsistent methodologies, or combination of psychiatric samples. Another way of assessing white matter integrity is through diffusion tensor imaging (DTI) (Taylor et al., 2004), which can measure the relative degree of white matter anisotropy in patients with BD. However, no DTI studies have yet been published in BD. We sought to examine possible white matter disruption in BD by assessing patients with familial pediatric BD by DTI and MRI. METHODS AND MATERIALS Subjects were 13 bipolar offspring diagnosed with bipolar I disorder by the WASH-U-KSADS and12 healthy controls. Parents of bipolar offspring all had a diagnosis of bipolar I or II disorder by the SCID. Subjects had stimulants discontinued for at least 24 hours; other medications were continued. Magnetic resonance images were acquired using a GE-Signa 3-Tesla scanner. A DTI sequence was based on a single-shot spin-echo, echo-planar imaging (EPI) sequence with diffusion sensitizing gradients applied on either side of the 180¿ refocusing pulse. Imaging parameters were: field of view (FOV)= 24 cm, matrix size 128x128, TE/TR=106/6000 ms, 19 axial-oblique slices, slice thickness 5 mm/skip 1.5 mm. The scan was prescribed from the top of the brain and included only the most superior part of the cerebellum. Diffusion gradient duration was d = 32 ms, diffusion weighting was b = 900 s/mm2. In addition, T2 weighted image were acquired by removing the diffusion sensitizing gradients. Diffusion was measured along six non-collinear directions: XY, XZ, YZ, -XY, -XZ and -YZ. This pattern was repeated four times for each slice with the sign of all diffusion gradients inverted for odd repetitions. Fractional anisotropy (FA) was calculated for each voxel according to Basser and Pierpaoli (Basser & Pierpaoli, 1996) to produce an FA image. FA images were further processed using Statistical Parametric Mapping software (SPM99; Wellcome, UK). A white matter mask was applied to the images to eliminate noise and edge effects. Smoothed images for controls and subjects with BD were compared using voxel-wise two-tailed t-tests and results were normalized to Z-scores. Finally, the joint expected probability distribution of the height and extent of Z-scores, with height (Z 1.67; p 0.05) and extent (p 0.01) thresholds, was used to determine the presence of significant clusters of difference and correct for spatial correlation in the data. Further methods have been described elsewhere (Barnea-Goraly et al., 2004). CONCLUSIONS This is the first report, of which we are aware, of white matter anisotropy in pediatric patients with bipolar disorder. Notably, there were no regions of increased FA in the subjects with BD compared to controls. Thus, all areas of differences between groups found by DTI were due to decreased FA in bipolar subjects, signifying possible relative white matter disruption in pediatric familial BD. White matter hyperintensities have been reported to be found in greater numbers in patients with BD compared to controls. These WMH, largely periventricular and in deep white matter, may also signify areas of white matter disruption. As hypothesized, we found decreased FA in areas of the prefrontal cortex, particularly ventromedial areas. Prefrontal white matter disruption may cause dysfunction of prefrontal-limbic circuitry involved in emotion regulation (Blumberg et al., 2003). These circuits may include white matter extending to inferior temporal regions, including amygdala, which we also found abnormal in this study. However, we also found decreased FA in corpus callosal, parietal, and occipital white matter of bipolar subjects. Parietal white matter disruption could be related to cognitive deficits observed in BD, including decreased visuospatial memory (Dickstein et al., 2004; Quraishi & Frangou et al., 2002). However, it is less clear what relevance decreased FA in occipital white matter has to the pathophysiology of BD. Similarly, although widespread disruption of corpus callosum was seen in bipolar subjects, the neurofunctional relevance of disruption of interhemispheric communication is unclear but deserves further study. Limitations of this study include a relatively small sample size and presence of psychotropic medication exposure in subjects with BD. While further studies with larger numbers are needed, this study suggests that pediatric subjects with bipolar disorder have significant white matter disruption. REFERENCES 1. Barnea-Goraly N, Kwon H, Menon V, Eliez S, Lotspeich L, Reiss AL (2004): White matter structure in autism: preliminary evidence from diffusion tensor imaging. Biol Psychiatry 55:323-6. 2. Basser PJ, Pierpaoli C (1996): Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. J Magn Reson B 111:209-19. 3. Blumberg HP, Martin A, Kaufman J, et al (2003): Frontostriatal abnormalities in adolescents with bipolar disorder: preliminary observations from functional MRI. Am J Psychiatry 160:1345-7. 4. Dickstein DP, Treland JE, Snow J, et al (2004): Neuropsychological performance in pediatric bipolar disorder. Biol Psychiatry 55:32-9. 5. Lyoo IK, Lee HK, Jung JH, Noam GG, Renshaw PF (2002): White matter hyperintensities on magnetic resonance imaging of the brain in children with psychiatric disorders. Compr Psychiatry 43:361-8. 6. Quraishi S, Frangou S (2002): Neuropsychology of bipolar disorder: a review. J Affect Disord 72:209-26. 7. Sassi RB, Brambilla P, Nicoletti M, et al (2003): White matter hyperintensities in bipolar and unipolar patients with relatively mild-to-moderate illness severity. J Affect Disord 77:237-45. 8. Strakowski SM, DelBello MP, Adler C, Cecil DM, Sax KW (2000): Neuroimaging in bipolar disorder. Bipolar Disord 2:148-64. 9. Taylor WD, Hsu E, Krishnan KR, MacFall JR (2004): Diffusion tensor imaging: background, potential, and utility in psychiatric research. Biol Psychiatry 55:201-7.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 介绍 许多（但不是全部）针对成人和儿童双相情感障碍（BD）患者的研究都报告了 T2 加权 MRI 图像上白质高信号（WMH）数量的增加（Lyoo 等人，2002 年；Strakowski 等人，2000 年；Sassi 等人，2003 年）。 这些发现提出了白质破坏导致双相情感障碍病因的可能性。 然而，患有双相情感障碍的成年人也可能具有较高的心血管危险因素，这可能是导致 WMH 的微中枢神经系统事件的原因。因此，研究患有 BD 的儿童（可能发生此类事件的机会较少）将有助于阐明 WMH 在 BD 中的作用。 迄今为止，此类研究为数不多，要么是样本量小，要么是方法不一致，要么是精神病学样本的组合。 评估白质完整性的另一种方法是通过弥散张量成像 (DTI)（Taylor 等，2004），它可以测量 BD 患者白质各向异性的相对程度。 然而，BD 上尚未发表任何 DTI 研究。 我们试图通过 DTI 和 MRI 评估患有家族性儿科 BD 的患者，来检查 BD 中可能存在的白质破坏。 方法和材料 受试者包括 13 名经 WASH-U-KSADS 诊断患有 I 型双相情感障碍的双相后代和 12 名健康对照。 双相情感障碍后代的父母均被 SCID 诊断为 I 型或 II 型双相情感障碍。受试者停用兴奋剂至少 24 小时；继续服用其他药物。使用 GE-Signa 3-Tesla 扫描仪采集磁共振图像。 DTI 序列基于单次自旋回波、平面回波成像 (EPI) 序列，并在 180° 重聚焦脉冲的两侧应用扩散敏化梯度。 成像参数为：视场（FOV）= 24 cm，矩阵尺寸128x128，TE/TR=106/6000 ms，19个轴向倾斜切片，切片厚度5 mm/跳过1.5 mm。扫描是从大脑顶部进行的，仅包括小脑的最上部。扩散梯度持续时间为 d = 32 ms，扩散权重为 b = 900 s/mm2。此外，通过去除扩散敏化梯度获得T2加权图像。 沿着六个非共线方向测量扩散：XY、XZ、YZ、-XY、-XZ 和-YZ。对于每个切片，该模式重复四次，所有扩散梯度的符号反转为奇数重复。根据 Basser 和 Pierpaoli（Basser & Pierpaoli，1996）计算每个体素的分数各向异性 (FA)，以生成 FA 图像。 使用统计参数制图软件（SPM99；Wellcome，英国）进一步处理 FA 图像。对图像应用白质掩模以消除噪声和边缘效应。使用体素双尾 t 检验比较对照组和 BD 受试者的平滑图像，并将结果标准化为 Z 分数。最后，使用 Z 分数高度和范围的联合预期概率分布以及高度 (Z 1.67；p < 0.05) 和范围 (p < 0.01) 阈值来确定是否存在显着差异簇并校正数据中的空间相关性。 其他方法已在其他地方描述过（Barnea-Goraly 等，2004）。 结论 据我们所知，这是第一份关于双相情感障碍儿科患者白质各向异性的报告。 值得注意的是，与对照组相比，BD 受试者中没有出现 FA 增加的区域。 因此，DTI 发现的各组之间的所有差异都是由于双相情感障碍受试者的 FA 减少所致，这表明儿科家族性 BD 可能存在相对的白质破坏。 据报道，与对照组相比，BD 患者中白质高信号的数量更多。 这些 WMH 主要位于脑室周围和深部白质中，也可能表示白质破坏的区域。 正如假设的那样，我们发现前额皮质区域，特别是腹内侧区域的 FA 减少。前额叶白质破坏可能会导致参与情绪调节的前额叶边缘回路功能障碍（Blumberg et al., 2003）。 这些回路可能包括延伸到下颞区的白质，包括杏仁核，我们在这项研究中也发现了异常。然而，我们还发现双相情感障碍受试者胼胝体、顶叶和枕叶白质的 FA 减少。 顶叶白质破坏可能与 BD 中观察到的认知缺陷有关，包括视觉空间记忆下降（Dickstein 等，2004；Quraishi 和 Frangou 等，2002）。 然而，枕叶白质 FA 减少与 BD 病理生理学有何相关性尚不清楚。 同样，尽管在双相情感障碍受试者中观察到胼胝体广泛受损，但半球间通讯受损的神经功能相关性尚不清楚，但值得进一步研究。 这项研究的局限性包括样本量相对较小以及双相情感障碍受试者存在精神药物暴露。 虽然需要进行更多的研究，但这项研究表明，患有双相情感障碍的儿科受试者有明显的白质破坏。 参考 1. Barnea-Goraly N、Kwon H、Menon V、Eliez S、Lotspeich L、Reiss AL (2004)：自闭症白质结构：来自弥散张量成像的初步证据。生物精神病学 55：323-6。 2. Basser PJ, Pierpaoli C (1996)：通过定量扩散张量 MRI 阐明组织的微观结构和生理特征。 J Magn Reson B 111：209-19。 3. Blumberg HP、Martin A、Kaufman J 等人 (2003)：双相情感障碍青少年的额纹状体异常：功能性 MRI 的初步观察。 《美国精神病学杂志》160：1345-7。 4. Dickstein DP、Treland JE、Snow J 等人 (2004)：儿科双相情感障碍的神经心理学表现。生物精神病学 55：32-9。 5. Lyoo IK、Lee HK、Jung JH、Noam GG、Renshaw PF (2002)：精神疾病儿童大脑磁共振成像白质高信号。 Compr 精神病学 43：361-8。 6. Quraishi S, Frangou S (2002)：双相情感障碍的神经心理学：综述。 J 情感障碍 72：209-26。 7. Sassi RB、Brambilla P、Nicoletti M 等人 (2003)：疾病严重程度相对轻至中度的双相和单相患者的白质高信号。 J 情感失调 77：237-45。 8. Strakowski SM、DelBello MP、Adler C、Cecil DM、Sax KW (2000)：双相情感障碍的神经影像学。双相情感障碍 2：148-64。 9. Taylor WD、Hsu E、Krishnan KR、MacFall JR (2004)：扩散张量成像：精神病学研究的背景、潜力和实用性。生物精神病学 55：201-7。