This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.INTRODUCTIONIncreased 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 MATERIALSSubjects 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).CONCLUSIONSThis 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.REFERENCES1. 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.
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