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Articles   |    
Reduced White Matter Integrity in Sibling Pairs Discordant for Bipolar Disorder
Emma Sprooten, Ph.D.; Margaret S. Brumbaugh, B.S.; Emma E.M. Knowles, Ph.D.; D. Reese McKay, Ph.D.; John Lewis, Ph.D.; Jennifer Barrett, B.A.; Stefanie Landau, B.A.; Lindsay Cyr, B.A.; Peter Kochunov, Ph.D.; Anderson M. Winkler, M.D.; Godfrey D. Pearlson, M.D.; David C. Glahn, Ph.D.
Am J Psychiatry 2013;170:1317-1325. doi:10.1176/appi.ajp.2013.12111462
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Dr. Winkler has received a doctoral scholarship from GlaxoSmithKline. Dr. Pearlson has received consulting fees from Bristol-Myers Squibb. The other authors report no financial relationships with commercial interests.

Supported by grant RO1 MH080912 (D.C.G., principal investigator).

From the Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Hartford, Conn.; the Departments of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Conn.; McConnell Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, Canada; and the Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore.

Address correspondence to Dr. Sprooten (emma.sprooten@yale.edu).

Copyright © 2013 by the American Psychiatric Association

Received November 24, 2012; Revised February 27, 2013; Revised March 29, 2013; Accepted April 11, 2013.

Abstract

Objective  Several lines of evidence indicate that white matter integrity is compromised in bipolar disorder, but the nature, extent, and biological causes remain elusive. To determine the extent to which white matter deficits in bipolar disorder are familial, the authors investigated white matter integrity in a large sample of bipolar patients, unaffected siblings, and healthy comparison subjects.

Method  The authors collected diffusion imaging data for 64 adult bipolar patients, 60 unaffected siblings (including 54 discordant sibling pairs), and 46 demographically matched comparison subjects. Fractional anisotropy was compared between the groups using voxel-wise tract-based spatial statistics and by extracting mean fractional anisotropy from 10 regions of interest. Additionally, intraclass correlation coefficients were calculated between the sibling pairs as an index of familiality.

Results  Widespread fractional anisotropy reductions in bipolar patients (>40,000 voxels) and more subtle reductions in their siblings, mainly restricted to the corpus callosum, posterior thalamic radiations, and left superior longitudinal fasciculus (>2,000 voxels) were observed. Similarly, region-of-interest analysis revealed significant reductions in most white matter regions in patients. In siblings, fractional anisotropy in the posterior thalamic radiation and the forceps was nominally reduced. Significant between-sibling correlations were found for mean fractional anisotropy across the tract-based spatial statistic skeleton, within significant clusters, and within nearly all regions of interest.

Conclusions  These findings emphasize the relevance of white matter to neuropathology and familiality of bipolar disorder and encourage further use of white matter integrity markers as endophenotypes in genetic studies.

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FIGURE 1. Voxel-Wise Comparisons in a Study of White Matter Integrity in Bipolar Disordera

a Panel A depicts voxel-wise analysis showing reduced fractional anisotropy in bipolar patients relative to healthy comparison subjects (p<0.05, family-wise error corrected; tract-based spatial statistics filled). Panel B depicts a histogram of raw t statistics of all voxels in the skeleton mask. Panel C depicts extracted mean fractional anisotropy within the significant cluster per individual.

FIGURE 2. Voxel-Wise Comparisons in a Study of White Matter Integrity in Bipolar Disordera

a Panel A depicts voxel-wise analysis showing reduced fractional anisotropy in unaffected siblings (p<0.05, family-wise error corrected, within the above patient < comparison cluster mask; tract-based spatial statistics filled). Panel B depicts a histogram of raw t statistics of all voxels in significant case-comparison cluster. Panel C depicts extracted mean fractional anisotropy within the significant cluster per individual.

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TABLE 1.Demographic and Clinical Sample Characteristics in a Study of White Matter Integrity in Bipolar Disordera
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a IQR=interquartile range; LDPS=Lifetime Dimension of Psychotic Symptoms Scale (this composite score was calculated by summing the scores of the positive psychotic symptoms subscale and the schizophrenia subscale).

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b Full IQ according to WAIS.

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c Data are not normally distributed and IQR is reported instead of SD and, where applicable, Kruskal-Wallis test with chi-square.

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d Age at onset and duration of illness are calculated since the first manic episode.

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e As a result of small numbers per cell, Fisher’s exact tests were performed instead of chi-square tests.

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f None of the patients were treated with typical antipsychotics.

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g Past history of abuse of or dependence on cannabis, cocaine, amphetamines, hallucinogens, opiates, sedatives, or anxiolytics.

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TABLE 2.Between-Group Differences on Mean Fractional Anisotropy Within Atlas-Based Regions-Of-Interesta
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a FDR=false-discovery rate.

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TABLE 3.Intraclass Correlation Coefficients Between Siblings in a Study of White Matter Integrity in Bipolar Disordera
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a FDR=false-discovery rate.

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* pFDR<0.05. ** pFDR<0.01.

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