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Altered intracortical myelin staining in the dorsolateral prefrontal cortex in severe mental illness

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European Archives of Psychiatry and Clinical Neuroscience Aims and scope Submit manuscript

Abstract

Imaging and postmortem studies into the severe mental illnesses of major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) have revealed deficiencies in the myelination of deep white matter tracts of the brain. Recent studies have further suggested that deficits could extend to myelinated fibers running through the cortex in those illnesses. Disruptions in this intracortical myelin may underlie functional symptomology in MDD, BD, and SZ; thus, in this study, we hypothesized that individuals with these illnesses may have reduced myelin staining relative to controls in the cerebral cortex. We stained 60 sections of dorsolateral prefrontal cortex for myelin with Luxol® fast blue in four groups: 15 BD, 15 MDD, 15 SZ, and 15 controls with no psychiatric illness. We digitally measured optical tissue attenuation reflecting the amount of myelin staining across six cortical depths in the middle frontal gyrus (MFG), in superficial white matter in the crown of the MFG, and in deep white matter. We found that a diagnosis of MDD or SZ meant that optical tissue attenuation was significantly reduced in the shallowest depths of the cortex. Furthermore, there was a trend toward reduced optical tissue attenuation in all illnesses across all myelinated regions we studied. These results encourage future studies into potential reductions in intracortical myelin in severe mental illness.

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References

  1. Nortje G, Stein DJ, Radua J, Mataix-Cols D, Horn N (2013) Systematic review and voxel-based meta-analysis of diffusion tensor imaging studies in bipolar disorder. J Affect Disord 150(2):192–200. doi:10.1016/j.jad.2013.05.034

    Article  PubMed  Google Scholar 

  2. Wheeler AL, Voineskos AN (2014) A review of structural neuroimaging in schizophrenia: from connectivity to connectomics. Front Human Neurosci 8:653. doi:10.3389/fnhum.2014.00653

    Article  Google Scholar 

  3. Sexton CE, Mackay CE, Ebmeier KP (2009) A systematic review of diffusion tensor imaging studies in affective disorders. Biol Psychiatry 66(9):814–823. doi:10.1016/j.biopsych.2009.05.024

    Article  PubMed  Google Scholar 

  4. Murphy ML, Frodl T (2011) Meta-analysis of diffusion tensor imaging studies shows altered fractional anisotropy occurring in distinct brain areas in association with depression. Biol Mood Anxiety Disord 1(1):3. doi:10.1186/2045-5380-1-3

    Article  PubMed  PubMed Central  Google Scholar 

  5. Thomas AJ, Perry R, Kalaria RN, Oakley A, McMeekin W, O’Brien JT (2003) Neuropathological evidence for ischemia in the white matter of the dorsolateral prefrontal cortex in late-life depression. Int J Geriatr Psychiatry 18(1):7–13. doi:10.1002/gps.720

    Article  PubMed  Google Scholar 

  6. Marlinge E, Bellivier F, Houenou J (2014) White matter alterations in bipolar disorder: potential for drug discovery and development. Bipolar Disord 16(2):97–112. doi:10.1111/bdi.12135

    Article  CAS  PubMed  Google Scholar 

  7. Regenold WT, Phatak P, Marano CM, Gearhart L, Viens CH, Hisley KC (2007) Myelin staining of deep white matter in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and unipolar major depression. Psychiatry Res 151(3):179–188. doi:10.1016/j.psychres.2006.12.019

    Article  CAS  PubMed  Google Scholar 

  8. Rajkowska G, Mahajan G, Maciag D, Sathyanesan M, Iyo AH, Moulana M, Kyle PB, Woolverton WL, Miguel-Hidalgo JJ, Stockmeier CA, Newton SS (2015) Oligodendrocyte morphometry and expression of myelin—related mRNA in ventral prefrontal white matter in major depressive disorder. J Psychiatr Res 65:53–62. doi:10.1016/j.jpsychires.2015.04.010

    Article  PubMed  PubMed Central  Google Scholar 

  9. Haroutunian V, Katsel P, Roussos P, Davis KL, Altshuler LL, Bartzokis G (2014) Myelination, oligodendrocytes, and serious mental illness. Glia 62(11):1856–1877. doi:10.1002/glia.22716

    Article  CAS  PubMed  Google Scholar 

  10. Bartzokis G, Lu PH, Stewart SB, Oluwadara B, Lucas AJ, Pantages J, Pratt E, Sherin JE, Altshuler LL, Mintz J, Gitlin MJ, Subotnik KL, Nuechterlein KH (2009) In vivo evidence of differential impact of typical and atypical antipsychotics on intracortical myelin in adults with schizophrenia. Schizophr Res 113(2–3):322–331. doi:10.1016/j.schres.2009.06.014

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bartzokis G, Lu PH, Raven EP, Amar CP, Detore NR, Couvrette AJ, Mintz J, Ventura J, Casaus LR, Luo JS, Subotnik KL, Nuechterlein KH (2012) Impact on intracortical myelination trajectory of long acting injection versus oral risperidone in first-episode schizophrenia. Schizophr Res 140(1–3):122–128. doi:10.1016/j.schres.2012.06.036

    Article  PubMed  PubMed Central  Google Scholar 

  12. Rowley CD, Bazin PL, Tardif CL, Sehmbi M, Hashim E, Zaharieva N, Minuzzi L, Frey BN, Bock NA (2015) Assessing intracortical myelin in the living human brain using myelinated cortical thickness. Front Neurosci 9:396. doi:10.3389/fnins.2015.00396

    Article  PubMed  PubMed Central  Google Scholar 

  13. Tatebayashi Y, Nihonmatsu-Kikuchi N, Hayashi Y, Yu X, Soma M, Ikeda K (2012) Abnormal fatty acid composition in the frontopolar cortex of patients with affective disorders. Transl Psychiatry 2:e204. doi:10.1038/tp.2012.132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Uranova NA, Vostrikov VM, Orlovskaya DD, Rachmanova VI (2004) Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium. Schizophr Res 67(2–3):269–275. doi:10.1016/S0920-9964(03)00181-6

    Article  PubMed  Google Scholar 

  15. Hayashi Y, Nihonmatsu-Kikuchi N, Yu X, Ishimoto K, Hisanaga SI, Tatebayashi Y (2011) A novel, rapid, quantitative cell-counting method reveals oligodendroglial reduction in the frontopolar cortex in major depressive disorder. Mol Psychiatry 16(12):1155–1158. doi:10.1038/mp.2011.84

    Article  CAS  PubMed  Google Scholar 

  16. Uranova N, Orlovskaya D, Vikhreva O, Zimina I, Kolomeets N, Vostrikov V, Rachmanova V (2001) Electron microscopy of oligodendroglia in severe mental illness. Brain Res Bull 55(5):597–610

    Article  CAS  PubMed  Google Scholar 

  17. Tkachev D, Mimmack ML, Ryan MM, Wayland M, Freeman T, Jones PB, Starkey M, Webster MJ, Yolken RH, Bahn S (2003) Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 362(9386):798–805. doi:10.1016/S0140-6736(03)14289-4

    Article  CAS  PubMed  Google Scholar 

  18. Hof PR, Haroutunian V, Friedrich VL Jr, Byne W, Buitron C, Perl DP, Davis KL (2003) Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biol Psychiatry 53(12):1075–1085

    Article  CAS  PubMed  Google Scholar 

  19. Aston C, Jiang L, Sokolov BP (2005) Transcriptional profiling reveals evidence for signaling and oligodendroglial abnormalities in the temporal cortex from patients with major depressive disorder. Mol Psychiatry 10(3):309–322. doi:10.1038/sj.mp.4001565

    Article  CAS  PubMed  Google Scholar 

  20. Kluver H, Barrera E (1953) A method for the combined staining of cells and fibers in the nervous system. J Neuropathol Exp Neurol 12(4):400–403

    Article  CAS  PubMed  Google Scholar 

  21. Torrey EF, Webster M, Knable M, Johnston N, Yolken RH (2000) The stanley foundation brain collection and neuropathology consortium. Schizophr Res 44(2):151–155. doi:10.1016/S0920-9964(99)00192-9

    Article  CAS  PubMed  Google Scholar 

  22. Nieuwenhuys R (2013) The myeloarchitectonic studies on the human cerebral cortex of the Vogt-Vogt school, and their significance for the interpretation of functional neuroimaging data. Brain Struct Funct 218(2):303–352. doi:10.1007/s00429-012-0460-z

    Article  PubMed  Google Scholar 

  23. Petrides M (2000) The role of the mid-dorsolateral prefrontal cortex in working memory. Exp Brain Res 133(1):44–54

    Article  CAS  PubMed  Google Scholar 

  24. Duncan J, Owen AM (2000) Common regions of the human frontal lobe recruited by diverse cognitive demands. Trends Neurosci 23(10):475–483

    Article  CAS  PubMed  Google Scholar 

  25. Rock PL, Roiser JP, Riedel WJ, Blackwell AD (2014) Cognitive impairment in depression: a systematic review and meta-analysis. Psychol Med 44(10):2029–2040. doi:10.1017/S0033291713002535

    Article  CAS  PubMed  Google Scholar 

  26. Bora E, Yucel M, Pantelis C (2009) Cognitive endophenotypes of bipolar disorder: a meta-analysis of neuropsychological deficits in euthymic patients and their first-degree relatives. J Affect Disord 113(1–2):1–20. doi:10.1016/j.jad.2008.06.009

    Article  PubMed  Google Scholar 

  27. Heinrichs RW, Zakzanis KK (1998) Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 12(3):426–445

    Article  CAS  PubMed  Google Scholar 

  28. Annese J, Pitiot A, Dinov ID, Toga AW (2004) A myelo-architectonic method for the structural classification of cortical areas. NeuroImage 21(1):15–26

    Article  CAS  PubMed  Google Scholar 

  29. Grydeland H, Walhovd KB, Tamnes CK, Westlye LT, Fjell AM (2013) Intracortical myelin links with performance variability across the human lifespan: results from T1- and T2-weighted MRI myelin mapping and diffusion tensor imaging. J Neurosci official J Soc Neurosci 33(47):18618–18630. doi:10.1523/JNEUROSCI.2811-13.2013

    Article  CAS  Google Scholar 

  30. Wu M, Kumar A, Yang S (2016) Development and aging of superficial white matter myelin from young adulthood to old age: mapping by vertex-based surface statistics (VBSS). Hum Brain Mapp. doi:10.1002/hbm.23134

    PubMed Central  Google Scholar 

  31. Liu J, Dietz K, DeLoyht JM, Pedre X, Kelkar D, Kaur J, Vialou V, Lobo MK, Dietz DM, Nestler EJ, Dupree J, Casaccia P (2012) Impaired adult myelination in the prefrontal cortex of socially isolated mice. Nat Neurosci 15(12):1621–1623. doi:10.1038/nn.3263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Grydeland H, Westlye LT, Walhovd KB, Fjell AM (2015) Intracortical Posterior Cingulate Myelin Content Relates to Error Processing: results from T1- and T2-Weighted MRI Myelin Mapping and Electrophysiology in Healthy Adults. Cereb Cortex. doi:10.1093/cercor/bhv065

    PubMed Central  Google Scholar 

  33. Peters A, Sethares C (2002) Aging and the myelinated fibers in prefrontal cortex and corpus callosum of the monkey. J Comp Neurol 442(3):277–291

    Article  PubMed  Google Scholar 

  34. Shafee R, Buckner RL, Fischl B (2015) Gray matter myelination of 1555 human brains using partial volume corrected MRI images. NeuroImage 105:473–485. doi:10.1016/j.neuroimage.2014.10.054

    Article  PubMed  Google Scholar 

  35. Glasser MF, Goyal MS, Preuss TM, Raichle ME, Van Essen DC (2014) Trends and properties of human cerebral cortex: correlations with cortical myelin content. NeuroImage 93(Pt 2):165–175. doi:10.1016/j.neuroimage.2013.03.060

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are grateful to the Stanley Foundation for postmortem tissue donations and to Dr. William Regenold for his helpful suggestions.

Funding

This project was supported by a 2014 NARSAD Independent Investigator Grant from the Brain & Behavior Research Foundation (Dr. Frey).

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Authors and Affiliations

  1. Imaging Research, Sunnybrook Research Institute, Toronto, ON, Canada

    Evelyn M. R. Lake

  2. Department of Psychology, Neuroscience and Behaviour, McMaster University, Psychology Complex, Room 304, 1280 Main Street West, Hamilton, ON, L8S 4K1, Canada

    Eric A. Steffler, Christopher D. Rowley & Nicholas A. Bock

  3. Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada

    Manpreet Sehmbi, Luciano Minuzzi & Benicio N. Frey

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  1. Evelyn M. R. Lake
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Correspondence to Nicholas A. Bock.

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Lake, E.M.R., Steffler, E.A., Rowley, C.D. et al. Altered intracortical myelin staining in the dorsolateral prefrontal cortex in severe mental illness. Eur Arch Psychiatry Clin Neurosci 267, 369–376 (2017). https://doi.org/10.1007/s00406-016-0730-5

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  • DOI: https://doi.org/10.1007/s00406-016-0730-5

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