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; 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.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 介绍 在许多但不是全部，对双相情感障碍（BD）的研究（Lyoo等，2002; Strakowski et al。，2000; Sassi et al。，2003; Sassi et et and close）据报道，但不是全部，对T2加权MRI图像的白质高强度（WMH）的增加量增加了。这些发现增加了白质破坏有助于BD病因的可能性。但是，患有BD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的微型CNS事件。因此，研究BD的儿童大概有较少的发展此类事件的机会，将有助于阐明WMH在BD中的作用。少数此类研究还遭受了小样本量，不一致的方法或精神病样本的组合。评估白质完整性的另一种方法是通过扩散张量成像（DTI）（Taylor等，2004），该成像可以测量BD患者的白质各向异性相对程度。但是，尚未在BD中发表DTI研究。我们感觉到通过通过DTI和MRI评估家族小儿BD患者，可以检查BD中可能的白质破坏。 方法和材料 受试者是13个双极后代，被WASH-U-KADS诊断为双极I障碍和12个健康对照。双极后代的父母都通过SCID诊断为双极I或II障碍。受试者的兴奋剂至少停止24小时；继续其他药物。使用GE-Signa 3-Tesla扫描仪获取磁共振图像。 DTI序列基于单发旋转回声，回声 - 平面成像（EPI）序列，其扩散敏化梯度施加在180™重新聚焦脉冲的两侧。成像参数为：视场（FOV）= 24厘米，矩阵尺寸128x128，TE/TR = 106/6000 ms，19轴向粘合片，切片厚度为5 mm/skip 1.5 mm。扫描是从大脑顶部开出的，仅包括小脑中最优越的部分。扩散梯度持续时间为d = 32 ms，扩散加权为b = 900 s/mm2。另外，通过去除扩散敏化梯度来获得T2加权图像。沿六个非共线方向测量扩散：xy，xz，yz，-xy，-xz和-yz。对于每个切片，将这种模式重复四次，其符号的所有差异梯度倒置以进行奇数重复。根据Basser和Pierpaoli（Basser＆Pierpaoli，1996）计算每个体素的分数各向异性（FA），以产生FA图像。使用统计参数映射软件（SPM99； Wellcome，UK）进一步处理FA图像。将白色物质面膜应用于图像，以消除噪声和边缘效应。使用Voxel的两尾t检验比较了对照和BD受试者的平滑图像，并将结果标准化为Z分数。最后，使用高度（z 1.67; p 0.05）和程度（p 0.01）阈值的z得分的高度和程度的关节预期概率分布，用于确定存在显着的差异簇并正确地存在数据中的空间相关性。在其他地方已经描述了进一步的方法（Barnea-Goraly等，2004）。 结论 这是我们知道的第一份报告，关于双相情感障碍的小儿患者白质各向异性。值得注意的是，与对照组相比，BD受试者的FA没有增加的区域。这是DTI发现的组之间的所有差异领域都是由于双极受试者的FA降低，这表明小儿家族BD可能相对白质破坏。 据报道，与对照组相比，在BD患者中发现了白质高密度性。这些WMH在很大程度上是周期性的，在深层白质中也可能表示白质破坏区域。正如假设的那样，我们发现在前额叶皮层，尤其是腹侧区域的区域下降了FA。前额叶白质破坏可能会导致情绪调节中涉及的前额叶膜电路功能障碍（Blumberg等，2003）。这些电路可能包括延伸到临时区域的白质，包括杏仁核，我们在这项研究中也发现了异常。但是，我们还发现双极受试者的Calloss，顶叶和枕白质的FA下降。顶叶白质的破坏可能与BD中观察到的认知缺陷有关，包括视觉记忆的减少（Dickstein等，2004； Quaraishi＆Frangou等，2002）。但是，尚不清楚枕白质与BD的病理生理学中的相关性恶化。同样，尽管在双极受试者中看到了call体的广泛破坏，但尚不清楚骨膜间交流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相对较小的样本量和BD受试者中精神药物暴露的存在。尽管需要更多的研究，但这项研究表明，患有躁郁症的小儿受试者会严重破坏白质。 参考 1。Barnea-Goraly N，Kwon H，Menon V，Eliez S，Lotspeich L，Reiss AL（2004）：自闭症中的白质结构：扩散张量张量成像的初步证据。生物精神病学55：323-6。 2。BasserPJ，Pierpaoli C（1996）：通过定量扩散张量MRI阐明的组织的微结构和物理特征。 J Magn Reson B 111：209-19。 3。BlumbergHP，Martin A，Kaufman J等人（2003年）：双相情感障碍青少年的额叶异常：功能性MRI的初步观察。 Am J Psychiatry 160：1345-7。 4。DicksteinDP，Treland JE，Snow J等人（2004年）：小儿躁郁症的神经心理学表现。生物精神病学55：32-9。 5。Lyooik，Lee HK，Jung JH，Noam GG，Renshaw PF（2002）：精神疾病儿童中磁共振成像的白质超强度。综合精神病学43：361-8。 6. Quaraishi S，Frangou S（2002）：躁郁症的神经心理学：评论。 J影响疾病72：209-26。 7。SassiRB，Brambilla P，Nicoletti M等（2003年）：双极和单极患者的白质超强度，患有相对轻度至中度疾病的严重程度。 J影响疾病77：237-45。 8。StrakowskiSM，Delbello MP，Adler C，Cecil DM，Sax KW（2000）：双相情感障碍的神经影像学。躁郁症2：148-64。 9。TaylorWD，Hsu E，Krishnan KR，Macfall JR（2004）：扩散张量成像：精神病研究中的背景，潜力和效用。生物精神病学55：201-7。