Abstract
The neurobiology of adolescent depression remains poorly understood. Initial studies suggested impaired white matter microstructure in adults and adolescents, but findings have not been consistent. Challenges in this literature have included small samples, medication confounds and inconsistent correction for type I error. This study addressed these issues in a new examination of fractional anisotropy (FA) in adolescents with major depressive disorder (MDD) using diffusion tensor imaging. We examined FA in 81 adolescents aged 12–19 (44 MDD [all unmedicated], 37 controls). We conducted logistic regression analyses to examine the odds of MDD versus control based on FA within standard white matter tracts that were delineated by probabilistic tractography. We also examined relationships between FA and disease severity (overall depression and dimensions of illness). Finally, we conducted a voxel-wise group comparison of FA. All analyses covaried for age, sex and socioeconomic status, and applied rigorous corrections for multiple testing. Logistic regression did not reveal significant associations between diagnosis and FA within white matter tracts defined by probabilistic tractography. Dimensional analyses revealed that greater lassitude was associated with higher FA in right cingulum bundle and bilateral corticospinal tracts, but with lower FA in right anterior thalamic radiation. Voxel-wise group comparisons of FA did not reveal significant group differences. The current findings do not support low FA as a neurobiological marker of adolescent depression. Dimensional results suggest that FA relates to lassitude but not overall depression. Given the clinical and neurobiological heterogeneity of depression, future work utilizing dimensional approaches may help elucidate the role of white matter microstructure in adolescent depression neurobiology.
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Abe, O., Yamasue, H., Kasai, K., Yamada, H., Aoki, S., Inoue, H., Takei, K., Suga, M., Matsuo, K., Kato, T., Masutani, Y., & Ohtomo, K. (2010). Voxel-based analyses of gray/white matter volume and diffusion tensor data in major depression. Psychiatry Research, 181(1), 64–70.
Aghajani, M., I. M. Veer, N. D. J. van Lang, P. H. F. Meens, B. G. van den Bulk, S. A. R. B. Rombouts, R. R. J. M. Vermeiren, and N. J. van der Wee. (2013). “Altered white-matter architecture in treatment-naive adolescents with clinical depression. Psychological Medicine, December, 1–12.
Barnea-Goraly, N., Menon, V., Eckert, M., Tamm, L., Bammer, R., Karchemskiy, A., Dant, C. C., & Reiss, A. L. (2005). White matter development during childhood and adolescence: A cross-sectional diffusion tensor imaging study. Cerebral Cortex, 15(12), 1848–1854.
Beck, Aaron T., Robert A. Steer, Gregory K. Brown, and Others. (1996). “Beck Depression Inventory”. http://www.nctsnet.org/content/beck-depression-inventory-second-edition.
Bessette, K. L., Nave, A. M., Caprihan, A., & Stevens, M. C. (2013). White matter abnormalities in adolescents with major depressive disorder. Brain Imaging and Behavior, November., 8, 531–541. https://doi.org/10.1007/s11682-013-9274-8.
Blood, A. J., Iosifescu, D. V., Makris, N., Perlis, R. H., Kennedy, D. N., Dougherty, D. D., Kim, B. W., Lee, M. J., Wu, S., Lee, S., Calhoun, J., Hodge, S. M., Fava, M., Rosen, B. R., Smoller, J. W., Gasic, G. P., Breiter, H. C., & for the Phenotype Genotype Project on Addiction and Mood Disorders. (2010). Microstructural abnormalities in subcortical reward circuitry of subjects with major depressive disorder. PLoS One, 5(11), e13945.
Bracht, T., Linden, D., & Keedwell, P. (2015). A review of white matter microstructure alterations of pathways of the reward circuit in depression. Journal of Affective Disorders, 187(November), 45–53.
Bürgel, U., Amunts, K., Hoemke, L., Mohlberg, H., Gilsbach, J. M., & Zilles, K. (2006). White matter Fiber tracts of the human brain: Three-dimensional mapping at microscopic resolution, topography and Intersubject variability. NeuroImage, 29(4), 1092–1105.
Buysse, D. J., C. F. Reynolds 3rd, T. H. Monk, S. R. Berman, and D. J. Kupfer. (1989). “The Pittsburgh sleep quality index: A new instrument for psychiatric practice and research. Psychiatry Research 28 (2): 193–213.
Chen, N. K., Chou Y. H., Sundman, M., Hickey P., Kasoff W. S,. Bernstein A, Trouard, T. P, Lin T, Rapcsak S. Z, Sherman, S. J. (2018). Weingarten CPAlteration of Diffusion-Tensor Magnetic Resonance Imaging Measures in Brain Regions Involved in Early Stages of Parkinson's Disease. Brain Connect, 8(6):343–349.
Cheng, Y., Xu, J., Yu, H., Nie, B., Li, N., Luo, C., Li, H., Liu, F., Bai, Y., Shan, B., Xu, L., & Xu, X. (2014). Delineation of early and later adult onset depression by diffusion tensor imaging. PLoS One, 9(11), e112307.
Choi, K. S., Holtzheimer, P. E., Franco, A. R., Kelley, M. E., Dunlop, B. W., Hu, X. P., & Mayberg, H. S. (2014). Reconciling variable findings of white matter integrity in major depressive disorder. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, 39(6), 1332–1339.
Connolly, C. G., Wu, J., Ho, T. C., Hoeft, F., Wolkowitz, O., Eisendrath, S., Frank, G., Hendren, R., Max, J. E., Paulus, M. P., Tapert, S. F., Banerjee, D., Simmons, A. N., & Yang, T. T. (2013). Resting-state functional connectivity of Subgenual anterior cingulate cortex in depressed adolescents. Biological Psychiatry, 74(12), 898–907.
Cullen, K. R., Gee, D. G., Klimes-Dougan, B., Gabbay, V., Hulvershorn, L., Mueller, B. a., Camchong, J., et al. (2009). A preliminary study of functional connectivity in comorbid adolescent depression. Neuroscience Letters, 460(3), 227–231.
Cullen, K. R., Klimes-Dougan, B., Muetzel, R., Mueller, B. A., Camchong, J., Houri, A., Kurma, S., & Lim, K. O. (2010). Altered white matter microstructure in adolescents with major depression: A preliminary study. Journal of the American Academy of Child and Adolescent Psychiatry, 49(2), 173–83.e1.
Cullen, Kathryn R., Melinda K. Westlund, Bonnie Klimes-Dougan, Bryon A. Mueller, Alaa Houri, Lynn E. Eberly, and Kelvin O. Lim. (2014). “Abnormal amygdala resting-state functional connectivity in adolescent depression. JAMA Psychiatry, August. https://doi.org/10.1001/jamapsychiatry.2014.1087, 71, 1138, 1147.
Cuthbert, B. N. (2005). Dimensional models of psychopathology: Research agenda and clinical utility. Journal of Abnormal Psychology, 114(4), 565–569.
Friedman, J. H., Brown, R. G., Comella, C., Garber, C. E., Krupp, L. B., Lou, J. S., Marsh, L., Nail, L., Shulman, L., Taylor, C.B. (2007). Working Group on Fatigue in Parkinson's Disease. Fatigue in Parkinson's disease: a review. Mov Disord, 22(3):297–308.
Gabbay, V., Ely, B. A., Li, Q., Bangaru, S. D., Panzer, A. M., Alonso, C. M., Xavier Castellanos, F., & Milham, M. P. (2013). Striatum-based circuitry of adolescent depression and anhedonia. Journal of the American Academy of Child and Adolescent Psychiatry, 52(6), 628–41.e13.
Ghashghaei, H. T., & Barbas, H. (2002). Pathways for emotion: Interactions of prefrontal and anterior temporal pathways in the amygdala of the rhesus monkey. Neuroscience, 115(4), 1261–1279.
Giedd, J. N., Blumenthal, J., Jeffries, N. O., Castellanos, F. X., Liu, H., Zijdenbos, A., Paus, T., Evans, a. C., & Rapoport, J. L. (1999). Brain development during childhood and adolescence: A longitudinal MRI study. Nature Neuroscience, 2(10), 861–863.
Giorgio, A., Watkins, K. E., Douaud, G., James, a. C., James, S., De Stefano, N., Matthews, P. M., Smith, S. M., & Johansen-Berg, H. (2008). Changes in white matter microstructure during adolescence. NeuroImage, 39(1), 52–61.
Henderson, S. E., Johnson, A. R., Vallejo, A. I., Katz, L., Wong, E., & Gabbay, V. (2013). A preliminary study of white matter in adolescent depression: Relationships with illness severity, anhedonia, and irritability. Frontiers in Psychiatry / Frontiers Research Foundation, 4(January), 152.
Henje, B. E., Connolly, C. G., Ho, T. C., LeWinn, K. Z., Mobayed, N., Han, L., Paulus, M. P., Jing, W., Simmons, A. N., & Yang, T. T. (2015). Altered insular activation and increased insular functional connectivity during sad and happy face processing in adolescent major depressive disorder. Journal of Affective Disorders, 178(June), 215–223.
Hollingshead, A. B. (1975). “Four Factor Index of Social Status. In. New Haven: Yale University Department of Sociology.
Huang, H., Fan, X., Williamson, D. E., & Rao, U. (2011). White matter changes in healthy adolescents at familial risk for unipolar depression: A diffusion tensor imaging study. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, 36(3), 684–691.
Kaufman, J., Birmaher, B., Brent, D., Rao, U., Flynn, C., Moreci, P., Williamson, D., & Ryan, N. (1997). Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): Initial reliability and validity data. Journal of the American Academy of Child and Adolescent Psychiatry, 36(7), 980–988.
Kieseppä, T., Eerola, M., Mäntylä, R., Neuvonen, T., Poutanen, V.-P., Luoma, K., Tuulio-Henriksson, A., Jylhä, P., Mantere, O., Melartin, T., Rytsälä, H., Vuorilehto, M., & Isometsä, E. (2010). Major depressive disorder and white matter abnormalities: A diffusion tensor imaging study with tract-based spatial statistics. Journal of Affective Disorders, 120(1–3), 240–244.
Lebel, C., Gee, M., Camicioli, R., Wieler, M., Martin, W., & Beaulieu, C. (2012). Diffusion tensor imaging of white matter tract evolution over the lifespan. NeuroImage, 60(1), 340–352.
LeWinn, K. Z., Connolly, C. G., Wu, J., Drahos, M., Hoeft, F., Ho, T. C., Simmons, A. N., & Yang, T. T. (2014). White matter correlates of adolescent depression: Structural evidence for Frontolimbic Disconnectivity. Journal of the American Academy of Child and Adolescent Psychiatry, 53(8), 899–909.e7.
Ma, N., Li, L., Shu, N., Liu, J., Gong, G., He, Z., Li, Z., et al. (2007). White matter abnormalities in first-episode, treatment-naive young adults with major depressive disorder. The American Journal of Psychiatry, 164(5), 823–826.
Marsh L. (2013) Depression and Parkinson's disease: current knowledge. Curr Neurol Neurosci Rep 13(12):409.
Morey, Leslie C. (2007). “Personality Assessment Inventory. Lutz, FL: Psychological Assessment Resources.
Mulders, P. C., van Eijndhoven, P. F., Schene, A. H., Beckmann, C. F., & Tendolkar, I. (2015). Resting-state functional connectivity in major depressive disorder: A review. Neuroscience and Biobehavioral Reviews, 56(September), 330–344.
Osoba, A., Hänggi, J., Li, M., Horn, D. I., Metzger, C., Eckert, U., Kaufmann, J., Zierhut, K., Steiner, J., Schiltz, K., Heinze, H.-J., Bogerts, B., & Walter, M. (2013). Disease severity is correlated to tract specific changes of fractional anisotropy in MD and CM thalamus--a DTI study in major depressive disorder. Journal of Affective Disorders, 149(1–3), 116–128.
Paus, T., Keshavan, M., & Giedd, J. N. (2008). Why do many psychiatric disorders emerge during adolescence? Nature Reviews. Neuroscience, 9(12), 947–957.
Poznanski, E. O., Freman, L. N., & Mokros, H. B. (1985). Children’s depression rating scale-revised. Psychopharmacology Bulletin, 21, 979–989.
Sexton, C. E., Mackay, C. E., & Ebmeier, K. P. (2009). A systematic review of diffusion tensor imaging studies in affective disorders. Biological Psychiatry, 66(9), 814–823.
Smith, S. M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T. E., Mackay, C. E., Watkins, K. E., Ciccarelli, O., Cader, M. Z., Matthews, P. M., & Behrens, T. E. J. (2006). Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data. NeuroImage, 31(4), 1487–1505.
Thomason, M. E., & Thompson, P. M. (2011). Diffusion imaging, white matter, and psychopathology. Annual Review of Clinical Psychology, 7(January), 63–85.
Uğurbil, K., Xu, J., Auerbach, E. J., Moeller, S., Vu, A. T., Duarte-Carvajalino, J. M., Lenglet, C., Wu, X., Schmitter, S., van de Moortele, P. F., Strupp, J., Sapiro, G., de Martino, F., Wang, D., Harel, N., Garwood, M., Chen, L., Feinberg, D. A., Smith, S. M., Miller, K. L., Sotiropoulos, S. N., Jbabdi, S., Andersson, J. L., Behrens, T. E., Glasser, M. F., van Essen, D. C., Yacoub, E., & WU-Minn HCP Consortium. (2013). Pushing spatial and temporal resolution for functional and diffusion MRI in the human connectome project. NeuroImage, 80(October), 80–104.
Wager, T. D., Davidson, M. L., Hughes, B. L., Lindquist, M. A., & Ochsner, K. N. (2008). Prefrontal-subcortical pathways mediating successful emotion regulation. Neuron, 59(6), 1037–1050.
Watson, D., O’Hara, M. W., Simms, L. J., Kotov, R., Chmielewski, M., McDade-Montez, E. a., Gamez, W., & Stuart, S. (2007). Development and validation of the inventory of depression and anxiety symptoms (IDAS). Psychological Assessment, 19(3), 253–268.
Watson, D., O’Hara, M. W., Naragon-Gainey, K., Koffel, E., Chmielewski, M., Kotov, R., Stasik, S. M., & Ruggero, C. J. (2012). Development and validation of new anxiety and bipolar symptom scales for an expanded version of the IDAS (the IDAS-II). Assessment, 19(4), 399–420.
Wechsler, D. (1999). Wechsler abbreviated scale of intelligence (WASI). San Antonio, Texas: American Psychological Association.
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This study was funded by the National Institute of Mental Health (K23MH090421) and the National Alliance for Research on Depression.
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The research was approved and monitored by the University of Minnesota Institutional Review Board, Human Research Protection Program. The informed consent process was completed with all participants before participation in the study. For those 18–19 years, participants completed consent on their own. For those 17 years of age and younger, participants provided assent while parents completed the consent. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Cullen, K.R., Brown, R., Schreiner, M.W. et al. White matter microstructure relates to lassitude but not diagnosis in adolescents with depression. Brain Imaging and Behavior 14, 1507–1520 (2020). https://doi.org/10.1007/s11682-019-00078-8
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DOI: https://doi.org/10.1007/s11682-019-00078-8