WHITE MATTER TRACT DISRUPTION BY DTI IN PEDIATRIC FAMILIAL BIPOLAR DISORDER

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。在许多（但不是全部）双相情感障碍（BD）患者（包括成人和儿童）的研究中都报道了t2加权MRI图像上白质高强度（WMH）的增加（Lyoo等人，2002；Strakowski等人，2000；Sassi等人，2003）。这些发现提出了白质破坏与双相障碍病因有关的可能性。然而，也有可能成年双相障碍患者有更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，研究患有双相障碍的儿童，他们可能很少有机会发生这些事件，将有助于阐明WMH在双相障碍中的作用。迄今为止，很少有这样的研究受到样本量小、方法不一致或精神病学样本组合的影响。另一种评估白质完整性的方法是通过弥散张量成像（DTI） （Taylor et al., 2004），它可以测量双相障碍患者白质各向异性的相对程度。然而，尚未有关于双相障碍的DTI研究发表。我们试图通过DTI和MRI评估家族性儿童双相障碍患者来检查可能的双相障碍白质破坏。方法与材料研究对象为13名经WASH-U-KSADS诊断为双相I型障碍的双相子代和12名健康对照者。双相情感障碍后代的父母都被SCID诊断为双相情感障碍I或II。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扫描仪获取磁共振图像。DTI序列基于单次自旋回波，回波平面成像（EPI）序列，在180°再聚焦脉冲的两侧施加扩散敏化梯度。成像参数为：视场(FOV)= 24 cm，矩阵尺寸128 × 128， TE/TR=106/6000 ms， 19片轴斜切片，切片厚度5 mm/跳片1.5 mm。扫描从大脑顶部开始，只包括小脑的最上面部分。扩散梯度持续时间d = 32 ms，扩散权重b = 900 s/mm2。此外，通过去除扩散增感梯度获得T2加权图像。沿六个非共线方向：XY， XZ， YZ, -XY， -XZ和-YZ测量扩散。这种模式被重复四次，每片与所有扩散梯度的符号倒转奇数次重复。根据Basser和Pierpaoli （Basser & Pierpaoli, 1996）计算每个体素的分数各向异性（FA），生成FA图像。使用统计参数映射软件（SPM99; Wellcome， UK）对FA图像进行进一步处理。在图像上使用白质掩模来消除噪声和边缘影响。使用体素双尾t检验比较对照组和BD患者的平滑图像，并将结果归一化为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分数高度和程度的联合期望概率分布来判断是否存在显著的差异聚类，并校正数据中的空间相关性。其他地方描述了进一步的方法（Barnea-Goraly et al., 2004）。结论：这是我们所知的第一份关于儿童双相情感障碍患者白质各向异性的报告。值得注意的是，与对照组相比，双相障碍受试者中没有FA增加的区域。因此，DTI发现各组之间的所有差异都是由于双相受试者FA减少，这表明儿科家族性双相障碍患者可能出现相对白质破坏。据报道，与对照组相比，双相障碍患者中白质高信号的数量更多。这些WMH，主要在心室周围和深部白质，也可能表明白质破坏的区域。正如假设的那样，我们发现前额皮质区域FA减少，特别是腹内侧区域。前额叶白质破坏可能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颞下区域的白质，包括杏仁核，我们在本研究中也发现了异常。然而，我们也发现双相受试者胼胝体、顶叶和枕叶白质中的FA减少。顶叶白质破坏可能与双相障碍中观察到的认知缺陷有关，包括视觉空间记忆下降（Dickstein等人，2004；Quraishi和Frangou等人，2002）。然而，枕部白质FA减少与双相障碍病理生理的相关性尚不清楚。同样，尽管在双相障碍受试者中发现了广泛的胼胝体破坏，但半球间通讯破坏的神经功能相关性尚不清楚，值得进一步研究。本研究的局限性包括样本量相对较小，双相障碍患者存在精神药物暴露。虽然需要更多的进一步研究，但本研究表明双相障碍儿童患者有明显的白质破坏。引用1。张建军，张建军，张建军，张建军（2004）：自闭症患者脑白质结构的研究进展。生物精神病学55:32 -6。2. 陈志强，陈志强，陈志强，等（1996）：磁共振定量扩散张量成像的研究进展。[J]中国医学杂志[B](1): 59 - 61。3. Blumberg HP, Martin A， Kaufman J等（2003）：双相情感障碍青少年额纹状体异常：功能性MRI的初步观察。精神病学杂志160:1345-7。4. Dickstein DP, Treland JE, Snow J，等（2004）：儿童双相情感障碍的神经心理表现。精神病学，55:32-9。5. 刘志强，李洪，郑建辉，Noam GG, Renshaw PF(2002)：儿童精神疾病的脑白质高磁共振成像。《精神病学比较》43:361-8。6. 陈志强，陈志强（2002）：双相情感障碍的神经心理学研究进展。[J]情感障碍72:209-26。7. Sassi RB, Brambilla P， Nicoletti M等（2003）：相对轻至中度疾病严重程度的双相和单极患者的白质高强度。J情感障碍77:237-45。8. 张晓明，张晓明，张晓明（2000）：双相情感障碍的神经影像学诊断。躁郁症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、潜力和效用。生物精神病学55:201-7。

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.