Skip to main content Accessibility help
×
Home

Increased MRI-based cortical grey/white-matter contrast in sensory and motor regions in schizophrenia and bipolar disorder

  • K. N. Jørgensen (a1) (a2), S. Nerland (a1) (a2), L. B. Norbom (a1), N. T. Doan (a2) (a3), R. Nesvåg (a4), L. Mørch-Johnsen (a1) (a2), U. K. Haukvik (a1) (a2), I. Melle (a2) (a3), O. A. Andreassen (a2) (a3), L. T. Westlye (a2) (a3) (a5) and I. Agartz (a1) (a2)...

Abstract

Background

Schizophrenia and bipolar disorder share genetic risk factors and one possible illness mechanism is abnormal myelination. T1-weighted magnetic resonance imaging (MRI) tissue intensities are sensitive to myelin content. Therefore, the contrast between grey- and white-matter intensities may reflect myelination along the cortical surface.

Method

MRI images were obtained from patients with schizophrenia (n = 214), bipolar disorder (n = 185), and healthy controls (n = 278) and processed in FreeSurfer. The grey/white-matter contrast was computed at each vertex as the difference between average grey-matter intensity (sampled 0–60% into the cortical ribbon) and average white-matter intensity (sampled 0–1.5 mm into subcortical white matter), normalized by their average. Group differences were tested using linear models covarying for age and sex.

Results

Patients with schizophrenia had increased contrast compared to controls bilaterally in the post- and precentral gyri, the transverse temporal gyri and posterior insulae, and in parieto-occipital regions. In bipolar disorder, increased contrast was primarily localized in the left precentral gyrus. There were no significant differences between schizophrenia and bipolar disorder. Findings of increased contrast remained after adjusting for cortical area, thickness, and gyrification. We found no association with antipsychotic medication dose.

Conclusions

Increased contrast was found in highly myelinated low-level sensory and motor regions in schizophrenia, and to a lesser extent in bipolar disorder. We propose that these findings indicate reduced intracortical myelin. In accordance with the corollary discharge hypothesis, this could cause disinhibition of sensory input, resulting in distorted perceptual processing leading to the characteristic positive symptoms of schizophrenia.

Copyright

Corresponding author

*Address for correspondence: K. N. Jørgensen, Department of Psychiatric Research, Diakonhjemmet Hospital, N-0319 Oslo, Norway. (Email: k.n.jorgensen@medisin.uio.no)

References

Hide All
Agartz, I, Andersson, JL, Skare, S (2001). Abnormal brain white matter in schizophrenia: a diffusion tensor imaging study. Neuroreport 12, 22512254.
Andreasen, NC, Pressler, M, Nopoulos, P, Miller, D, Ho, BC (2010). Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs. Biological Psychiatry 67, 255262.
Anticevic, A, Cole, MW, Repovs, G, Murray, JD, Brumbaugh, MS, Winkler, AM, Savic, A, Krystal, JH, Pearlson, GD, Glahn, DC (2014). Characterizing thalamo-cortical disturbances in schizophrenia and bipolar illness. Cerebral Cortex 24, 31163130.
Anticevic, A, Haut, K, Murray, JD, Repovs, G, Yang, GJ, Diehl, C, McEwen, SC, Bearden, CE, Addington, J, Goodyear, B, Cadenhead, KS, Mirzakhanian, H, Cornblatt, BA, Olvet, D, Mathalon, DH, McGlashan, TH, Perkins, DO, Belger, A, Seidman, LJ, Tsuang, MT, van Erp, TG, Walker, EF, Hamann, S, Woods, SW, Qiu, M, Cannon, TD (2015). Association of thalamic dysconnectivity and conversion to psychosis in youth and young adults at elevated clinical risk. JAMA Psychiatry 72, 882891.
Baker, JT, Holmes, AJ, Masters, GA, Yeo, BT, Krienen, F, Buckner, RL, Ongur, D (2014). Disruption of cortical association networks in schizophrenia and psychotic bipolar disorder. JAMA Psychiatry 71, 109118.
Bansal, R, Hao, X, Liu, F, Xu, D, Liu, J, Peterson, BS (2013). The effects of changing water content, relaxation times, and tissue contrast on tissue segmentation and measures of cortical anatomy in MR images. Magnetic Resonance Imaging 31, 17091730.
Bartzokis, G (2002). Schizophrenia: breakdown in the well-regulated lifelong process of brain development and maturation. Neuropsychopharmacology 27, 672683.
Bartzokis, G (2011). Neuroglialpharmacology: white matter pathophysiologies and psychiatric treatments. Frontiers in Bioscience 16, 26952733.
Baumann, N, Pham-Dinh, D (2001). Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiological Reviews 81, 871927.
Blackmon, K, Halgren, E, Barr, WB, Carlson, C, Devinsky, O, DuBois, J, Quinn, BT, French, J, Kuzniecky, R, Thesen, T (2011). Individual differences in verbal abilities associated with regional blurring of the left grey and white matter boundary. Journal of Neuroscience 31, 1525715263.
Bodatsch, M, Brockhaus-Dumke, A, Klosterkotter, J, Ruhrmann, S (2014). Forecasting psychosis by event-related potentials – systematic review and specific meta-analysis. Biological Psychiatry 77, 951958.
Castle, D, Sham, P, Murray, R (1998). Differences in distribution of ages of onset in males and females with schizophrenia. Schizophrenia Research 33, 179183.
Chen, C-MA, Mathalon, DH, Roach, BJ, Cavus, I, Spencer, DD, Ford, JM (2010). The corollary discharge in humans is related to synchronous neural oscillations. Journal of Cognitive Neuroscience 23, 28922904.
Crapse, TB, Sommer, MA (2008). Corollary discharge across the animal kingdom. Nature Reviews: Neuroscience 9, 587600.
Dale, AM, Fischl, B, Sereno, MI (1999). Cortical surface-based analysis: I. Segmentation and surface reconstruction. Neuroimage 9, 179194.
Dale, AM, Sereno, MI (1993). Improved localizadon of cortical activity by combining EEG and MEG with MRI cortical surface reconstruction: a linear approach. Journal of Cognitive Neuroscience 5, 162176.
Davis, KL, Stewart, DG, Friedman, JI, Buchsbaum, M, Harvey, PD, Hof, PR, Buxbaum, J, Haroutunian, V (2003). White matter changes in schizophrenia: evidence for myelin-related dysfunction. Archives of General Psychiatry 60, 443456.
Du, F, Cooper, AJ, Thida, T, Shinn, AK, Cohen, BM, Ongur, D (2013). Myelin and axon abnormalities in schizophrenia measured with magnetic resonance imaging techniques. Biological Psychiatry 74, 451457.
Eickhoff, S, Walters, NB, Schleicher, A, Kril, J, Egan, GF, Zilles, K, Watson, JD, Amunts, K (2005). High-resolution MRI reflects myeloarchitecture and cytoarchitecture of human cerebral cortex. Human Brain Mapping 24, 206215.
Engh, JA, Friis, S, Birkenaes, AB, Jonsdottir, H, Klungsoyr, O, Ringen, PA, Simonsen, C, Vaskinn, A, Opjordsmoen, S, Andreassen, OA (2010). Delusions are associated with poor cognitive insight in schizophrenia. Schizophrenia Bulletin 36, 830835.
Feinberg, I (1978). Efference copy and corollary discharge: implications for thinking and its disorders. Schizophrenia Bulletin 4, 636640.
First, MB, Spitzer, RL, Gibbon, M, Williams, JB (2002). Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition. Biometric Research, New York State Psychiatric Institute: New York.
Fischl, B (2012). FreeSurfer. Neuroimage 62, 774781.
Fischl, B, Dale, AM (2000). Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proceedings of the National Academy of Sciences USA 97, 1105011055.
Foong, J, Maier, M, Barker, GJ, Brocklehurst, S, Miller, DH, Ron, MA (2000). In vivo investigation of white matter pathology in schizophrenia with magnetisation transfer imaging. Journal of Neurology, Neurosurgery and Psychiatry 68, 7074.
Fornito, A, Bullmore, ET (2015). Connectomics: a new paradigm for understanding brain disease. European Neuropsychopharmacology 25, 733748.
Friston, KJ, Frith, CD (1995). Schizophrenia: a disconnection syndrome? Clinical Neuroscience 3, 8997.
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, 165175.
Glasser, MF, Van Essen, DC (2011). Mapping human cortical areas in vivo based on myelin content as revealed by T1- and T2-weighted MRI. Journal of Neuroscience 31, 1159711616.
Goodwin, DW, Rosenthal, R (1971). Clinical significance of hallucinations in psychiatric disorders: a study of 116 hallucinatory patients. Archives of General Psychiatry 24, 7680.
Goudriaan, A, de Leeuw, C, Ripke, S, Hultman, CM, Sklar, P, Sullivan, PF, Smit, AB, Posthuma, D, Verheijen, MH (2014). Specific glial functions contribute to schizophrenia susceptibility. Schizophrenia Bulletin 40, 925935.
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. Journal of Neuroscience 33, 1861818630.
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. Cerebral Cortex. Published online: 2 April 2015. doi:10.1093/cercor/bhv065.
Haijma, SV, Van Haren, N, Cahn, W, Koolschijn, PC, Hulshoff Pol, HE, Kahn, RS (2013). Brain volumes in schizophrenia: a meta-analysis in over 18 000 subjects. Schizophrenia Bulletin 39, 11291138.
Hakak, Y, Walker, JR, Li, C, Wong, WH, Davis, KL, Buxbaum, JD, Haroutunian, V, Fienberg, AA (2001). Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proceedings of the National Academy of Sciences USA 98, 47464751.
Heinks-Maldonado, TH, Mathalon, DH, Houde, JF, Grey, M, Faustman, WO, Ford, JM (2007). Relationship of imprecise corollary discharge in schizophrenia to auditory hallucinations. Archives of General Psychiatry 64, 286296.
Javitt, DC, Freedman, R (2015). Sensory processing dysfunction in the personal experience and neuronal machinery of schizophrenia. American Journal of Psychiatry 172, 1731.
Kaufmann, T, Skatun, KC, Alnaes, D, Doan, NT, Duff, EP, Tonnesen, S, Roussos, E, Ueland, T, Aminoff, SR, Lagerberg, TV, Agartz, I, Melle, IS, Smith, SM, Andreassen, OA, Westlye, LT (2015). Disintegration of sensorimotor brain networks in Schizophrenia. Schizophrenia Bulletin 41, 13261335.
Kay, SR, Fiszbein, A, Opler, LA (1987). The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261276.
Koenig, SH (1991). Cholesterol of myelin is the determinant of grey-white contrast in MRI of brain. Magnetic Resonance in Medicine 20, 285291.
Koenig, SH, Brown, RD III, Spiller, M, Lundbom, N (1990). Relaxometry of brain: why white matter appears bright in MRI. Magnetic Resonance in Medicine 14, 482495.
Kong, L, Herold, C, Stieltjes, B, Essig, M, Seidl, U, Wolf, RC, Wüstenberg, T, Lässer, MM, Schmid, LA, Schnell, K, Hirjak, D, Thomann, PA (2012). Reduced grey to white matter tissue intensity contrast in schizophrenia. PLoS ONE 7, e37016.
Kong, L, Herold, CJ, Zöllner, F, Salat, DH, Lässer, MM, Schmid, LA, Fellhauer, I, Thomann, PA, Essig, M, Schad, LR, Erickson, KI, Schröder, J (2015). Comparison of grey matter volume and thickness for analysing cortical changes in chronic schizophrenia: a matter of surface area, grey/white matter intensity contrast, and curvature. Psychiatry Research: Neuroimaging 231, 176183.
Lichtenstein, P, Yip, BH, Björk, C, Pawitan, Y, Cannon, TD, Sullivan, PF, Hultman, CM (2009). Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 373, 234239.
Lutti, A, Dick, F, Sereno, MI, Weiskopf, N (2014). Using high-resolution quantitative mapping of R1 as an index of cortical myelination. Neuroimage 93, 176188.
Magnaldi, S, Ukmar, M, Vasciaveo, A, Longo, R, Pozzi-Mucelli, RS (1993). Contrast between white and grey matter: MRI appearance with ageing. European Radiology 3, 513519.
McGhie, A, Chapman, J (1961). Disorders of attention and perception in early schizophrenia. British Journal of Medical Psychology 34, 103116.
Merkler, D, Klinker, F, Jurgens, T, Glaser, R, Paulus, W, Brinkmann, BG, Sereda, MW, Stadelmann-Nessler, C, Guedes, RC, Bruck, W, Liebetanz, D (2009). Propagation of spreading depression inversely correlates with cortical myelin content. Annals of Neurology 66, 355365.
Moran, LV, Tagamets, MA, Sampath, H, O'Donnell, A, Stein, EA, Kochunov, P, Hong, LE (2013). Disruption of anterior insula modulation of large-scale brain networks in schizophrenia. Biological Psychiatry 74, 467474.
Mottershead, JP, Schmierer, K, Clemence, M, Thornton, JS, Scaravilli, F, Barker, GJ, Tofts, PS, Newcombe, J, Cuzner, ML, Ordidge, RJ, McDonald, WI, Miller, DH (2003). High field MRI correlates of myelin content and axonal density in multiple sclerosis–a post-mortem study of the spinal cord. Journal of Neurology 250, 12931301.
Nelson, B, Thompson, A, Yung, AR (2012). Basic self-disturbance predicts psychosis onset in the ultra high risk for psychosis ‘prodromal’ population. Schizophrenia Bulletin 38, 12771287.
Nesvag, R, Schaer, M, Haukvik, UK, Westlye, LT, Rimol, LM, Lange, EH, Hartberg, CB, Ottet, MC, Melle, I, Andreassen, OA, Jonsson, EG, Agartz, I, Eliez, S (2014). Reduced brain cortical folding in schizophrenia revealed in two independent samples. Schizophrenia Research 152, 333338.
Nutt, DJ, Need, AC (2014). Where now for schizophrenia research? European Neuropsychopharmacology 24, 11811187.
Pettersson-Yeo, W, Allen, P, Benetti, S, McGuire, P, Mechelli, A (2011). Dysconnectivity in schizophrenia: where are we now? Neuroscience and Biobehavioral Reviews 35, 11101124.
Poulet, JFA, Hedwig, B (2006). The cellular basis of a corollary discharge. Science 311, 518522.
Reuter, M, Rosas, HD, Fischl, B (2010). Highly accurate inverse consistent registration: a robust approach. Neuroimage 53, 11811196.
Rietkerk, T, Boks, MP, Sommer, IE, de Jong, S, Kahn, RS, Ophoff, RA (2009). Network analysis of positional candidate genes of schizophrenia highlights myelin-related pathways. Molecular Psychiatry 14, 353355.
Rimol, LM, Hartberg, CB, Nesvag, R, Fennema-Notestine, C, Hagler, DJ Jr., Pung, CJ, Jennings, RG, Haukvik, UK, Lange, E, Nakstad, PH, Melle, I, Andreassen, OA, Dale, AM, Agartz, I (2010). Cortical thickness and subcortical volumes in schizophrenia and bipolar disorder. Biological Psychiatry 68, 4150.
Rimol, LM, Nesvag, R, Hagler, DJ Jr., Bergmann, O, Fennema-Notestine, C, Hartberg, CB, Haukvik, UK, Lange, E, Pung, CJ, Server, A, Melle, I, Andreassen, OA, Agartz, I, Dale, AM (2012). Cortical volume, surface area, and thickness in schizophrenia and bipolar disorder. Biological Psychiatry 71, 552560.
Salat, DH, Chen, JJ, van der Kouwe, AJ, Greve, DN, Fischl, B, Rosas, HD (2011). Hippocampal degeneration is associated with temporal and limbic grey matter/white matter tissue contrast in Alzheimer's disease. Neuroimage 54, 17951802.
Salat, DH, Lee, SY, van der Kouwe, AJ, Greve, DN, Fischl, B, Rosas, HD (2009). Age-associated alterations in cortical grey and white matter signal intensity and grey to white matter contrast. Neuroimage 48, 2128.
Schaer, M, Cuadra, MB, Tamarit, L, Lazeyras, F, Eliez, S, Thiran, JP (2008). A surface-based approach to quantify local cortical gyrification. IEEE Transactions on Medical Imaging 27, 161170.
Schmierer, K, Scaravilli, F, Altmann, DR, Barker, GJ, Miller, DH (2004). Magnetization transfer ratio and myelin in postmortem multiple sclerosis brain. Annals of Neurology 56, 407415.
Schmierer, K, Wheeler-Kingshott, CA, Tozer, DJ, Boulby, PA, Parkes, HG, Yousry, TA, Scaravilli, F, Barker, GJ, Tofts, PS, Miller, DH (2008). Quantitative magnetic resonance of postmortem multiple sclerosis brain before and after fixation. Magnetic Resonance in Medicine 59, 268277.
Schneider, DM, Nelson, A, Mooney, R (2014). A synaptic and circuit basis for corollary discharge in the auditory cortex. Nature 513, 189194.
Segonne, F, Dale, A, Busa, E, Glessner, M, Salat, D, Hahn, H, Fischl, B (2004). A hybrid approach to the skull stripping problem in MRI. Neuroimage 22, 10601075.
Shergill, SS, White, TP, Joyce, DW, Bays, PM, Wolpert, DM, Frith, CD (2014). Functional magnetic resonance imaging of impaired sensory prediction in schizophrenia. JAMA Psychiatry 71, 2835.
Stuber, C, Morawski, M, Schafer, A, Labadie, C, Wahnert, M, Leuze, C, Streicher, M, Barapatre, N, Reimann, K, Geyer, S, Spemann, D, Turner, R (2014). Myelin and iron concentration in the human brain: a quantitative study of MRI contrast. Neuroimage 93, 95106.
Sullivan, PF, Kendler, KS, Neale, MC (2003). Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Archives of General Psychiatry 60, 11871192.
Sun, L, Castellanos, N, Grützner, C, Koethe, D, Rivolta, D, Wibral, M, Kranaster, L, Singer, W, Leweke, MF, Uhlhaas, PJ (2013). Evidence for dysregulated high-frequency oscillations during sensory processing in medication-naïve, first episode schizophrenia. Schizophrenia Research 150, 519525.
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, 798805.
Uhlhaas, PJ, Mishara, AL (2007). Perceptual anomalies in schizophrenia: integrating phenomenology and cognitive neuroscience. Schizophrenia Bulletin 33, 142156.
Uhlhaas, PJ, Singer, W (2015). Oscillations and neuronal dynamics in schizophrenia: the search for basic symptoms and translational opportunities. Biological Psychiatry 77, 10011009.
Uranova, NA, Vikhreva, OV, Rachmanova, VI, Orlovskaya, DD (2011). Ultrastructural alterations of myelinated fibers and oligodendrocytes in the prefrontal cortex in schizophrenia: a postmortem morphometric study. Schizophr Res Treatment 2011, 325789.
Wechsler, D (2007). Wechsler Abbreviated Scale of Intelligence (WASI). Norwegian Manual Supplement. Harcourt Assessment: Stockholm, Sweden.
Westlye, LT, Walhovd, KB, Dale, AM, Bjornerud, A, Due-Tonnessen, P, Engvig, A, Grydeland, H, Tamnes, CK, Ostby, Y, Fjell, AM (2010). Differentiating maturational and aging-related changes of the cerebral cortex by use of thickness and signal intensity. Neuroimage 52, 172185.
Westlye, LT, Walhovd, KB, Dale, AM, Espeseth, T, Reinvang, I, Raz, N, Agartz, I, Greve, DN, Fischl, B, Fjell, AM (2009). Increased sensitivity to effects of normal aging and Alzheimer's disease on cortical thickness by adjustment for local variability in grey/white contrast: a multi-sample MRI study. Neuroimage 47, 15451557.
Whitford, TJ, Ford, JM, Mathalon, DH, Kubicki, M, Shenton, ME (2012). Schizophrenia, myelination, and delayed corollary discharges: a hypothesis. Schizophrenia Bulletin 38, 486494.
Yu, H, Bi, W, Liu, C, Zhao, Y, Zhang, D, Yue, W (2014). A hypothesis-driven pathway analysis reveals myelin-related pathways that contribute to the risk of schizophrenia and bipolar disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry 51, 140145.

Keywords

Related content

Powered by UNSILO
Type Description Title
WORD
Supplementary materials

Jørgensen supplementary material
Figures S1-S10 and Tables S1-S2

 Word (7.7 MB)
7.7 MB

Increased MRI-based cortical grey/white-matter contrast in sensory and motor regions in schizophrenia and bipolar disorder

  • K. N. Jørgensen (a1) (a2), S. Nerland (a1) (a2), L. B. Norbom (a1), N. T. Doan (a2) (a3), R. Nesvåg (a4), L. Mørch-Johnsen (a1) (a2), U. K. Haukvik (a1) (a2), I. Melle (a2) (a3), O. A. Andreassen (a2) (a3), L. T. Westlye (a2) (a3) (a5) and I. Agartz (a1) (a2)...

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed.