[en] Reduced speed of cerebral information processing is a cognitive deficit associated with schizophrenia. Normal information processing speed (PS) requires intact white matter (WM) physiology to support information transfer. In a cohort of 107 subjects (47/60 patients/controls), we demonstrate that PS deficits in schizophrenia patients are explained by reduced WM integrity, which is measured using diffusion tensor imaging, mediated by the mismatch in WM/gray matter blood perfusion, and measured using arterial spin labeling. Our findings are specific to PS, and testing this hypothesis for patient-control differences in working memory produces no explanation. We demonstrate that PS deficits in schizophrenia can be explained by neurophysiological alterations in cerebral WM. Whether the disproportionately low WM integrity in schizophrenia is due to illness or secondary due to this disorder deserves further examination.
Disciplines :
Neurosciences & behavior
Author, co-author :
Wright, Susan N.
Hong, L. Elliot
Winkler, Anderson ; Université de Liège - ULiège > Form. doc. sc. bioméd. & pharma.
Chiappelli, Joshua
Nugent, Katie
Muellerklein, Florian
Du, Xioming
Rowland, Laura M.
Wang, Danny J. J.
Kochunov, Peter
Language :
English
Title :
Perfusion shift from white to gray matter may account for processing speed deficits in schizophrenia.
Publication date :
2015
Journal title :
Human Brain Mapping
ISSN :
1065-9471
eISSN :
1097-0193
Publisher :
John Wiley & Sons, Hoboken, United States - New York
Alba-Ferrara LM, de Erausquin GA (2013): What does anisotropy measure? Insights from increased and decreased anisotropy in selective fiber tracts in schizophrenia. Front Integr Neurosci 7:9
Altamura AC, Bertoldo A, Marotta G, Paoli RA, Caletti E, Dragogna F, Buoli M, Baglivo V, Mauri MC, Brambilla P (2013): White matter metabolism differentiates schizophrenia and bipolar disorder: A preliminary PET study. Psychiatry Res 214:410-414.
Anazodo UC, Thiessen JD, Ssali T, Mandel J, Gunther M, Butler J, Pavlosky W, Prato FS, Thompson RT, St Lawrence KS (2015): Feasibility of simultaneous whole-brain imaging on an integrated PET-MRI system using an enhanced 2-point Dixon attenuation correction method. Front Neurosci 8:434
Ashe J, Georgopoulos AP (1994): Movement parameters and neural activity in motor cortex and area 5. Cereb Cortex 4:590-600.
Asllani I, Borogovac A, Brown TR (2008): Regression algorithm correcting for partial volume effects in arterial spin labeling MRI. Magn Reson Med 60:1362-1371.
Bachman P, Niendam TA, Jalbrzikowski M, Park CY, Daley M, Cannon TD, Bearden CE (2012): Processing speed and neurodevelopment in adolescent-onset psychosis: Cognitive slowing predicts social function. J Abnorm Child Psychol 40:645-654.
Bartzokis G, Cummings JL, Sultzer D, Henderson VW, Nuechterlein KH, Mintz J (2003): White matter structural integrity in healthy aging adults and patients with Alzheimer disease: A magnetic resonance imaging study. Arch Neurol 60:393-398.
Bartzokis G, Lu PH, Tingus K, Mendez MF, Richard A, Peters DG, Oluwadara B, Barrall KA, Finn JP, Villablanca P, Thompson PM, Mintz J (2010): Lifespan trajectory of myelin integrity and maximum motor speed. Neurobiol Aging 31:1554-1562.
Bentourkia M, Bol A, Ivanoiu A, Labar D, Sibomana M, Coppens A, Michel C, Cosnard G, De Volder AG (2000): Comparison of regional cerebral blood flow and glucose metabolism in the normal brain: Effect of aging. J Neurol Sci 181:19-28.
Biagi L, Abbruzzese A, Bianchi MC, Alsop DC, Del Guerra A, Tosetti M (2007): Age dependence of cerebral perfusion assessed by magnetic resonance continuous arterial spin labeling. J Magn Reson Imaging 25:696-702.
Bloemen OJ, de Koning MB, Schmitz N, Nieman DH, Becker HE, de Haan L, Dingemans P, Linszen DH, van Amelsvoort TA (2010): White-matter markers for psychosis in a prospective ultra-high-risk cohort. Psychol Med 40:1297-1304.
Bonner-Jackson A, Grossman LS, Harrow M, Rosen C (2011): Neurocognition in schizophrenia: A 20-year multi-follow-up of the course of processing speed and stored knowledge. Compr Psychiatry 51:471-479.
Borghesani PR, Madhyastha TM, Aylward EH, Reiter MA, Swarny BR, Schaie KW, Willis SL (2013): The association between higher order abilities, processing speed, and age are variably mediated by white matter integrity during typical aging. Neuropsychologia 51:1435-1444.
Brebion G, Amador X, Smith MJ, Gorman JM (1998): Memory impairment and schizophrenia: The role of processing speed. Schizophr Res 30:31-39.
Carletti F, Woolley JB, Bhattacharyya S, Perez-Iglesias R, Fusar Poli P, Valmaggia L, Broome MR, Bramon E, Johns L, Giampietro V, Williams SC, Barker GJ, McGuire PK (2012): Alterations in white matter evident before the onset of psychosis. Schizophr Bull 38:1170-1179.
Cha YH, Jog MA, Kim YC, Chakrapani S, Kraman SM, Wang DJ (2013): Regional correlation between resting state FDG PET and pCASL perfusion MRI. J Cereb Blood Flow Metab 33:1909-1914.
Coyle TR, Pillow DR, Snyder AC, Kochunov P (2011): Processing speed mediates the development of general intelligence (g) in adolescence. Psychol Sci 22:1265-1269.
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. Arch Gen Psychiatry 60:443-456.
Dickinson D, Ragland JD, Gold JM, Gur RC (2008): General and specific cognitive deficits in schizophrenia: Goliath defeats David? Biol Psychiatry 64:823-827.
Ellison-Wright I, Bullmore E (2009): Meta-analysis of diffusion tensor imaging studies in schizophrenia. Schizophr Res 108:3-10.
First MB, Spitzer Robert L, Gibbon, Miriam, and Williams, Janet B.W. (1996): Structured Clinical Interview for DSM-IV Axis I Disorders, Clinical Version (SCID-CV). Washington, DC: American Psychiatric Press, Inc.
Fischl B, Dale AM (2000): Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci USA 97:11050-11055.
Friedman JI, Tang C, Carpenter D, Buchsbaum M, Schmeidler J, Flanagan L, Golembo S, Kanellopoulou I, Ng J, Hof PR, Harvey PD, Tsopelas ND, Stewart D, Davis KL (2008): Diffusion tensor imaging findings in first-episode and chronic schizophrenia patients. Am J Psychiatry 165:1024-1032.
Friston KJ, Frith CD (1995): Schizophrenia: A disconnection syndrome? Clin Neurosci 3:89-97.
Genova HM, DeLuca J, Chiaravalloti N, Wylie G (2013): The relationship between executive functioning, processing speed, and white matter integrity in multiple sclerosis. J Clin Exp Neuropsychol 35:631-641.
Glahn DC, Curran JE, Winkler AM, Carless MA, Kent JW Jr, Charlesworth JC, Johnson MP, Goring HH, Cole SA, Dyer TD, Moses EK, Olvera RL Kochunov P, Duggirala R, Fox PT, Almasy L Blangero J (2011): High dimensional endophenotype ranking in the search for major depression risk genes. Biol Psychiatry 71:6-14.
Glahn DC, Kent JW Jr, Sprooten E, Diego VP, Winkler AM, Curran JE, McKay DR, Knowles EE, Carless MA Goring HH, Dyer TD, Olvera RL Fox PT, Almasy L, Charlesworth J, Kochunov P, Duggirala R Blangero J (2013): Genetic basis of neurocognitive decline and reduced white-matter integrity in normal human brain aging. Proc Natl Acad Sci USA 110:19006-19011.
Harris JJ, Attwell D (2012): The energetics of CNS white matter. J Neurosci 32:356-371.
Hildebrand C, Remahl S, Persson H, Bjartmar C (1993): Myelinated nerve fibres in the CNS. Prog Neurobiol 40:319-384.
Horsfield MA, Jones DK (2002): Applications of diffusion-weighted and diffusion tensor MRI to white matter diseases-A review. NMR Biomed 15:570-577.
Hoyer WJ, Stawski RS, Wasylyshyn C, Verhaeghen P (2004): Adult age and digit symbol substitution performance: A meta-analysis. Psychol Aging 19:211-214.
Imai K, Keele L, Tingley D (2010): A general approach to causal mediation analysis. Psychol Methods 15:309-334.
Jahanshad N, Kochunov P, Sprooten E, Mandl RC, Nichols TE, Almassy L, Blangero J, Brouwer RM, Curran JE, de Zubicaray GI, Duggirala R, Fox PT, Hong LE, Landman BA, Martin NG, McMahon KL, Medland SE, Mitchell BD, Olvera RL, Peterson CP, Starr JM, Sussmann JE, Toga AW, Wardlaw JM, Wright MJ, Hulshoff Pol HE, Bastin ME, McIntosh AM, Deary IJ, Thompson PM, Glahn DC. (2013): Multi-site genetic analysis of diffusion images and voxelwise heritability analysis: A pilot project of the ENIGMA-DTI working group. Neuroimage 81:455-469.
Karlsgodt KH, Niendam TA, Bearden CE, Cannon TD (2009): White matter integrity and prediction of social and role functioning in subjects at ultra-high risk for psychosis. Biol Psychiatry 66:562-569.
Keefe RS, Goldberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L (2004): The brief assessment of cognition in schizophrenia: Reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res 68:283-297.
Knowles EE, David AS, Reichenberg A (2010): Processing speed deficits in schizophrenia: Reexamining the evidence. Am J Psychiatry 167:828-835.
Kochunov P, Lancaster JL, Thompson P, Woods R, Mazziotta J, Hardies J, Fox P (2001): Regional spatial normalization: Toward an optimal target. J Comput Assist Tomogr 25:805-816.
Kochunov P, Ramage AE, Lancaster JL, Robin DA, Narayana S, Coyle T, Royall DR, Fox P (2009a): Loss of cerebral white matter structural integrity tracks the gray matter metabolic decline in normal aging. Neuroimage 45:17-28.
Kochunov P, Robin D, Royall D, Lancaster J, Kochunov V, Coyle T, Schlosser A, Fox P (2009b): Can structural MRI cerebral health markers track cognitive trends in executive control function during normal maturation and adulthood? Hum Brain Mapp 30:2581-2594.
Kochunov P, Coyle T, Lancaster J, Robin DA, Hardies J, Kochunov V, Bartzokis G, Stanley J, Royall D, Schlosser AE, Null M, Fox PT (2010): Processing speed is correlated with cerebral health markers in the frontal lobes as quantified by neuroimaging. Neuroimage 49:1190-1199.
Kochunov P, Williamson DE, Lancaster J, Fox P, Cornell J, Blangero J, Glahn DC (2012): Fractional anisotropy of water diffusion in cerebral white matter across the lifespan. Neurobiol Aging 33:9-20.
Kubicki M, McCarley R, Westin CF, Park HJ, Maier S, Kikinis R, Jolesz FA, Shenton ME (2007): A review of diffusion tensor imaging studies in schizophrenia. J Psychiatr Res 41:15-30.
Lancaster JL, Andrews T, Hardies LJ, Dodd S, Fox PT (2003): Three-pool model of white matter. J Magn Reson Imaging 17:1-10.
Lancaster JL, Cody JD, Andrews T, Hardies LJ, Hale DE, Fox PT (2005): Myelination in children with partial deletions of chromosome 18q. AJNR Am J Neuroradiol 26:447-454.
Laughlin SB, Sejnowski TJ (2003): Communication in neuronal networks. Science 301:1870-1874.
Lee Y, Morrison BM, Li Y, Lengacher S, Farah MH, Hoffman PN, Liu Y, Tsingalia A, Jin L, Zhang PW, Pellerin L, Magistretti PJ, Rothstein JD (2012): Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487:443-448.
Lillrank SM, Lipska BK, Weinberger DR (1995): Neurodevelopmental animal models of schizophrenia. Clin Neurosci 3:98-104.
Llufriu S, Blanco Y, Martinez-Heras E, Casanova-Molla J, Gabilondo I, Sepulveda M, Falcon C, Berenguer J, Bargallo N, Villoslada P, Graus F, Valls-Sole J, Saiz A (2012): Influence of corpus callosum damage on cognition and physical disability in multiple sclerosis: A multimodal study. PLoS One 7:e37167
Loewenstein DA, Czaja SJ, Bowie CR, Harvey PD (2011): Age-associated differences in cognitive performance in older patients with schizophrenia: A comparison with healthy older adults. Am J Geriatr Psychiatry 20:29-40.
Lutz K, Koeneke S, Wustenberg T, Jancke L (2005): Asymmetry of cortical activation during maximum and convenient tapping speed. Neurosci Lett 373:61-66.
Miller DJ, Duka T, Stimpson CD, Schapiro SJ, Baze WB, McArthur MJ, Fobbs AJ, Sousa AM, Sestan N, Wildman DE, Lipovich L, Kuzawa CW, Hof PR, Sherwood CC (2013): Prolonged myelination in human neocortical evolution. Proc Natl Acad Sci USA 109:16480-16485.
Mitkus SN, Hyde TM, Vakkalanka R, Kolachana B, Weinberger DR, Kleinman JE, Lipska BK (2008): Expression of oligodendrocyte-associated genes in dorsolateral prefrontal cortex of patients with schizophrenia. Schizophr Res 98:129-138.
Mori T, Ohnishi T, Hashimoto R, Nemoto K, Moriguchi Y, Noguchi H, Nakabayashi T, Hori H, Harada S, Saitoh O, Matsuda H, Kunugi H (2007): Progressive changes of white matter integrity in schizophrenia revealed by diffusion tensor imaging. Psychiatry Res 154:133-145.
Musiek ES, Chen Y, Korczykowski M, Saboury B, Martinez PM, Reddin JS, Alavi A, Kimberg DY, Wolk DA, Julin P, Newberg AB, Arnold SE, Detre JA (2011): Direct comparison of fluorodeoxyglucose positron emission tomography and arterial spin labeling magnetic resonance imaging in Alzheimer's disease. Alzheimers Dement 8:51-59.
Mutsaerts HJMM, Richard E, Heijtel DFR, van Osch MJP, Majoie CBLM, Nederveen AJ. (2013): Gray matter contamination in arterial spin labeling white matter perfusion measurements in patients with dementia. NeuroImage Clin 4:139-144.
Nazeri A, Mallar Chakravarty M, Felsky D, Lobaugh NJ, Rajji TK, Mulsant BH, Voineskos AN. (2013): Alterations of superficial white matter in schizophrenia and relationship to cognitive performance. Neuropsychopharmacology 38:1954-1962.
Nowicka A, Tacikowski P (2009): Transcallosal transfer of information and functional asymmetry of the human brain. Laterality 16:35-74.
Penke L, Munoz Maniega S, Murray C, Gow AJ, Hernandez MC, Clayden JD, Starr JM, Wardlaw JM, Bastin ME, Deary IJ (2010): A general factor of brain white matter integrity predicts information processing speed in healthy older people. J Neurosci 30:7569-7574.
Perez-Iglesias R, Tordesillas-Gutierrez D, McGuire PK, Barker GJ, Roiz-Santianez R, Mata I, de Lucas EM, Rodriguez-Sanchez JM, Ayesa-Arriola R, Vazquez-Barquero JL, Crespo-Facorro B (2011): White matter integrity and cognitive impairment in first-episode psychosis. Am J Psychiatry167:451-458.
Peters BD, Ikuta T, Derosse P, John M, Burdick KE, Gruner P, Prendergast DM, Szeszko PR, Malhotra AK. (2014): Age-related differences in white matter tract microstructure are associated with cognitive performance from childhood to adulthood. Biol Psychiatry 75:248-256.
Phillips KA, Rogers J, Barrett EA, Glahn DC, Kochunov P (2012): Genetic contributions to the midsagittal area of the corpus callosum. Twin Res Hum Genet 15:315-323.
Pinheiro J, Bates D, DebRoy S, Sarkar D and the R Core Team (2008): nlme: Linear and Nonlinear Mixed Effects Models. R package version 3.1-88.
R-Development-Core-Team (2009): R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing.
Repovs G, Csernansky JG, Barch DM (2011): Brain network connectivity in individuals with schizophrenia and their siblings. Biol Psychiatry 69:967-973.
Salthouse TA (2000): Aging and measures of processing speed. Biol Psychol 54:35-54.
Salthouse TA (2009): When does age-related cognitive decline begin? Neurobiol Aging 30:507-514.
Salthouse TA, Czaja SJ (2000): Structural constraints on process explanations in cognitive aging. Psychol Aging 15:44-55.
Schiavone F, Charlton RA, Barrick TR, Morris RG, Markus HS (2009): Imaging age-related cognitive decline: A comparison of diffusion tensor and magnetization transfer MRI. J Magn Reson Imaging 29:23-30.
Smith SM Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE, Watkins KE Ciccarelli O, Cader MZ, Matthews PM Behrens TE (2006): Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data. Neuroimage 31:1487-1505.
Smith SM Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, Bannister PR, De Luca M, Drobnjak I, Flitney DE Niazy RK, Saunders J, Vickers J, Zhang Y, De Stefano N, Brady JM Matthews PM (2004): Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 23 Suppl 1:S208-S219.
Susuki K (2013): Node of Ranvier disruption as a cause of neurological diseases. ASN Neuro 5:209-219.
Tingley D, Yamamoto T, Hirose K, Keele L, Imai K (2013): Mediation: R Package for Causal Mediation Analysis. R package version 4(3).
Vaishnavi SN Vlassenko AG, Rundle MM, Snyder AZ, Mintun MA Raichle ME (2010): Regional aerobic glycolysis in the human brain. Proc Natl Acad Sci USA 107:17757-17762.
van Gelderen P, de Zwart JA, Duyn JH (2008): Pittfalls of MRI measurement of white matter perfusion based on arterial spin labeling. Magn Reson Med 59:788-795.
van Osch MJ, Teeuwisse WM, van Walderveen MA, Hendrikse J, Kies DA, van Buchem MA (2009): Can arterial spin labeling detect white matter perfusion signal? Magn Reson Med 62:165-173.
Wakana S, Jiang H, Nagae-Poetscher LM, van Zijl PC, Mori S (2004): Fiber tract-based atlas of human white matter anatomy. Radiology 230:77-87.
Wang J, Licht DJ (2006): Pediatric perfusion MR imaging using arterial spin labeling. Neuroimaging Clin N Am 16:149-167, ix.
Wang J, Alsop DC, Li L, Listerud J, Gonzalez-At JB, Schnall MD, Detre JA. (2002): Comparison of quantitative perfusion imaging using arterial spin labeling at 1.5 and 4.0 Tesla. Magn Reson Med 48:242-254.
Wang J, Zhang Y, Wolf RL, Roc AC, Alsop DC, Detre JA (2005): Amplitude-modulated continuous arterial spin-labeling 3.0-T perfusion MR imaging with a single coil: Feasibility study. Radiology 235:218-228.
Waxman SG, Bennett MV (1972): Relative conduction velocities of small myelinated and non-myelinated fibres in the central nervous system. Nat New Biol 238:217-219.
Wechsler D. (1997): Wechsler Adult Intelligence Scale. San Antonio, TX: Psychological Corporation.
Weinberger DR (1996): On the plausibility of "the neurodevelopmental hypothesis" of schizophrenia. Neuropsychopharmacology 14:1S-11S.
Wen Q, Chklovskii DB (2005): Segregation of the brain into gray and white matter: A design minimizing conduction delays. PLoS Comput Biol 1:e78
White T, Magnotta VA, Bockholt HJ, Williams S, Wallace S, Ehrlich S, Mueller BA, Ho BC, Jung RE, Clark VP, Lauriello J, Bustillo JR, Schulz SC, Gollub RL, Andreasen NC, Calhoun VD, Lim KO (2013): Global white matter abnormalities in schizophrenia: A multisite diffusion tensor imaging study. Schizophr Bull 37:222-232.
Wright SN, Kochunov P, Chiappelli J, McMahon RP, Muellerklein F, Wijtenburg SA, White MG, Rowland LM, Hong LE. (2014): Accelerated white matter aging in schizophrenia: Role of white matter blood perfusion. Neurobiol Aging 35:2411-2418.
Yao L, Lui S, Liao Y, Du MY, Hu N, Thomas JA, Gong QY (2013): White matter deficits in first episode schizophrenia: An activation likelihood estimation meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 45:100-106.
