Alteration of gray matter microstructure in schizophrenia
- 230 Downloads
Neuroimaging studies demonstrate gray matter (GM) macrostructural abnormalities in patients with schizophrenia (SCZ). While ex-vivo and genetic studies suggest cellular pathology associated with abnormal neurodevelopmental processes in SCZ, few in-vivo measures have been proposed to target microstructural GM organization. Here, we use diffusion heterogeneity- to study GM microstructure in SCZ. Structural and diffusion magnetic resonance imaging (MRI) were acquired on a 3 Tesla scanner in 46 patients with SCZ and 37 matched healthy controls (HC). After correction for free water, diffusion heterogeneity as well as commonly used diffusion measures FA and MD and volume were calculated for the four cortical lobes on each hemisphere, and compared between groups. Patients with early course SCZ exhibited higher diffusion heterogeneity in the GM of the frontal lobes compared to controls. Diffusion heterogeneity of the frontal lobe showed excellent discrimination between patients and HC, while none of the commonly used diffusion measures such as FA or MD did. Higher diffusion heterogeneity in the frontal lobes in early SCZ may be due to abnormal brain maturation (migration, pruning) before and during adolescence and early adulthood. Further studies are needed to investigate the role of heterogeneity as potential biomarker for SCZ risk.
KeywordsDiffusion MRI Heterogeneity Schizophrenia Neurodevelopment Gray matter
This study was part of the doctoral thesis of Johanna Seitz. We thank all subjects for their participation. We also thank the clinical, research assistant, and data management staff from the Boston CIDAR study, including Bryant C, Cousin A, Francis G, Franz M, Friedman-Yakoobian M, Gibson L, Gnong-Granato A, Hiraldo M, Hornbach S, Klein K, Min G, Pilo C, Rodenhiser-Hill J, Schutt J, Sorenson S, Szent-Imry R, Thomas A, Tucker L, Wakeham C, Woodberry K. We are grateful for the hard work of many research volunteers, including Donodoe D, Feder Z, Khromina S, Molokotos E, Oldershaw A, Reading J, Piazza E, and Schanz O. Finally, we would like to thank Zuo A and Eckbo R for their support with data processing.
Compliance with ethical standards
This work was supported by the National Institutes of Health (grant number P50MH080272 (to MN, LJS, TP, RM, JW, RM, MES, MK), R01 MH102377 (to MK), T32MH016259–35 (to AL), K05MH070047 (to MES)); the Veterans Affairs Merit Awards (to RM, MES); R01MH074794; P41EB015902; NARSAD young investigator award (to OP); by the Else Kroener-Fresenius Stiftung, Deutschland (to IK); by the Commonwealth Research Center (SCDMH82101008006 (to RM, JW, LJS)); and by a Clinical Translational Science Award (UL1RR025758 to Harvard University and Beth Israel Deaconess Medical Center from the National Center for Research Resources (to LJS)).
Disclosure of potential conflicts of interest
The Authors Seitz Johanna, Rathi Yogesh, Lyall Amanda, Pasternak Ofer, del Re Elisabetta C, Niznikiewicz Margaret, Nestor Paul, Seidman Larry J, Petryshen Tracey L, Mesholam-Gately Raquelle I, Wojcik Joanne, McCarley Robert W, Shenton Martha E, Koerte Inga K, and Kubicki Marek have declared that there are no conflicts of interest in relation to the subject of this study.
Research involving human participants and/or animals
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.
Informed consent was obtained from all individual participants included in the study.
- Anderson, D., Ardekani, B. A., Burdick, K. E., Robinson, D. G., John, M., Malhotra, A. K., & Szeszko, P. R. (2013). Overlapping and distinct gray and white matter abnormalities in schizophrenia and bipolar I disorder. Bipolar Disorders, 15(6), 680–693. doi: 10.1111/bdi.12096.CrossRefPubMedPubMedCentralGoogle Scholar
- Andreasen, N. C. (1984a). The scale for the assessment of negative symptoms (SANS). Iowa City: University of Iowa.Google Scholar
- Andreasen, N. C. (1984b). The scale for the assessment of positive symptoms (SAPS). Iowa City: University of Iowa.Google Scholar
- Assunção Leme, I. B., Gadelha, A., Sato, J. R., Ota, V. K., Mari, J., Melaragno, M. I.,… Jackowski, A. P. (2013). Is there an association between cortical thickness, age of onset, and duration of illness in schizophrenia? CNS Spectr, 18(6), 315–321.Google Scholar
- Basser, P. J., Matielo, B., & Bihan, D. L. (1996). MR diffusion tensor spectroscopy and imaging. Biophs, 66, 259–267.Google Scholar
- First, M. B., Spitzer, R. L., Gibbon, M., & Williams, J. B. W. (2002a). Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Non-patient Edition. (SCID-I/NP). In N. Y. S. P. Institute (Ed.), Biometrics Research. New York.Google Scholar
- First, M. B., Spitzer, R. L., Gibbon, M., & Williams, J. B. W. (2002b). Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition. (SCID-I/P) Biometrics Research. New York: New York State Psychiatric Institute.Google Scholar
- Fjell, A. M., Westlye, L. T., Greve, D. N., Fischl, B., Benner, T., van der Kouwe, A. J., et al. (2008). The relationship between diffusion tensor imaging and volumetry as measures of white matter properties. NeuroImage, 42(4), 1654–1668. doi: 10.1016/j.neuroimage.2008.06.005.CrossRefPubMedPubMedCentralGoogle Scholar
- Gogtay, N., Giedd, J. N., Lusk, L., Hayashi, K. M., Greenstein, D., Vaituzis, A. C., et al. (2004). Dynamic mapping of human cortical development during childhood through early adulthood. Proceedings of the National Academy of Sciences of the United States of America, 101(21), 8174–8179.CrossRefPubMedPubMedCentralGoogle Scholar
- GraphPadSoftware. (2014). GraphPad Prism version 6.00 for Windows. San Diego California USA GraphPadSoftware. Retrieved from www.graphpad.com
- Hien, D., Matzner, F. J., First, M. B., Spitzer, R. L., Gibbon, M., & Williams, J. B. W. (1994). Structured clinical interview for DSM-IV-child edition (1.0 ed.). New York: Columbia University.Google Scholar
- Hosmer, D. W., & Lemeshow, S. (2000). Applied logistic regression (Wiley Ed.). Hoboken, NJ.Google Scholar
- IBMCorp (2013). IBM SPSS statistics for windows, version 22.0. Armonk: IBMCorp.Google Scholar
- Jouan, L., Girard, S. L., Dobrzeniecka, S., Ambalavanan, A., Krebs, M. O., Joober, R., … Rouleau, G. A. (2013). Investigation of rare variants in LRP1, KPNA1, ALS2CL and ZNF480 genes in schizophrenia patients reflects genetic heterogeneity of the disease. Behav Brain Funct, 9, 9. doi: 10.1186/1744-9081-9-9
- Kochunov, P., Chiappelli, J., Wright, S. N., Rowland, L. M., Patel, B., Wijtenburg, S. A., et al. (2014). Multimodal white matter imaging to investigate reduced fractional anisotropy and its age-related decline in schizophrenia. Psychiatry Research, 223(2), 148–156. doi: 10.1016/j.pscychresns.2014.05.004.CrossRefPubMedPubMedCentralGoogle Scholar
- Mills, R. (1973). Self-Diffusion in Normal and Heavy Water. The Journal of Physical Chemistry, 77(5).Google Scholar
- Pasternak, O., Koerte, I. K., Bouix, S., Fredman, E., Sasaki, T., Mayinger, M., et al. (2014). Hockey Concussion Education Project, Part 2. Microstructural white matter alterations in acutely concussed ice hockey players: a longitudinal free-water MRI study. Journal of Neurosurgery, 120(4), 873–881. doi: 10.3171/2013.12.JNS132090.CrossRefPubMedPubMedCentralGoogle Scholar
- Petanjek, Z., Judas, M., Simic, G., Rasin, M. R., Uylings, H. B., Rakic, P., & Kostovic, I. (2011). Extraordinary neoteny of synaptic spines in the human prefrontal cortex. Proceedings of the National Academy of Sciences of the United States of America, 108(32), 13281–13286.CrossRefPubMedPubMedCentralGoogle Scholar
- (2011) Progressive brain change in schizophrenia: a prospective longitudinal study of first-episode schizophrenia, 7, 70 Cong. Rec. 672–679.Google Scholar
- Roberts, G., & Harrison, B. J. (2000). Gliosis and its implications for the disease process. In B. J. Harrison & G. Roberts (Eds.), The neuropathology of schizophrenia: Progress and interpretation (pp. 137–150). New York: Oxford Univ. Press.Google Scholar
- Roberts, R. C., Barksdale, K. A., Roche, J. K., & Lahti, A. C. (2015). Decreased synaptic and mitochondrial density in the postmortem anterior cingulate cortex in schizophrenia. Schizophr Res.Google Scholar
- Rössler, W., Salize, H. J., van Os, J., & Riecher-Rössler, A. (2005). Size of burden of schizophrenia and psychotic disorders. European Neuropsychopharmacology: The Journal of the Eurpoean College of Neuropsychopharmacology, 15(4), 399–400. doi: 10.1016/j.euroneuro.2005.04.009.CrossRefGoogle Scholar
- Spoletini, I., Cherubini, A., Banfi, G., Rubino, I. A., Peran, P., Caltagirone, C., & Spalletta, G. (2011). Hippocampi, thalami, and accumbens microstructural damage in schizophrenia: a volumetry, diffusivity, and neuropsychological study. Schizophrenia Bulletin, 37(1), 118–130.CrossRefPubMedGoogle Scholar
- TheMathWorks. MATLAB and Statistics Toolbox Release 2012b. Natick, Massachusetts, United States: TheMathWorks.Google Scholar
- Thermenos, H. W., Keshavan, M. S., Juelich, R. J., Molokotos, E., Whitfield-Gabrieli, S., Brent, B. K., et al. (2013). A review of neuroimaging studies of young relatives of individuals with schizophrenia: a developmental perspective from schizotaxia to schizophrenia. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 162B(7), 604–635. doi: 10.1002/ajmg.b.32170.CrossRefGoogle Scholar
- van Haren, N. E. M., Hulshoff Pol, H. E., Schnack, H. G., Cahn, W., Brans, R., Carati, I., et al. (2008). Progressive brain volume loss in schizophrenia over the course of the illness: evidence of maturational abnormalities in early adulthood. Biological Psychiatry, 63(1), 106–113.CrossRefPubMedGoogle Scholar
- Vollmar, C., O'Muircheartaigh, J., Barker, G. J., Symms, M. R., Thompson, P., Kumari, V., et al. (2010). Identical, but not the same: intra-site and inter-site reproducibility of fractional anisotropy measures on two 3.0 T scanners. NeuroImage, 51(4), 1384–1394.CrossRefPubMedPubMedCentralGoogle Scholar
- Whiteford, H. A., Degenhardt, L., Rehm, J., Baxter, A. J., Ferrari, A. J., Erskine, H. E., et al. (2013). Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet, 382(9904), 1575–1586. doi: 10.1016/S0140-6736(13)61611-6.CrossRefPubMedGoogle Scholar
- Wilkinson, G. (1993). The wide range achievement test- revision 3. Wilmington: Jastak Association.Google Scholar
- Zhu, J., Zhuo, C., Qin, W., Wang, D., Ma, X., Zhou, Y., & Yu, C. (2014). Performances of diffusion kurtosis imaging and diffusion tensor imaging in detecting white matter abnormality in schizophrenia. Neurologic Clinics, 7, 7170–7176.Google Scholar