Skip to main content Accessibility help

Patterns of white matter microstructure in individuals at ultra-high-risk for psychosis: associations to level of functioning and clinical symptoms

  • K. Krakauer (a1) (a2) (a3), B. H. Ebdrup (a2) (a4), B. Y. Glenthøj (a2) (a4), J. M. Raghava (a2) (a3) (a4), D. Nordholm (a1) (a2), L. Randers (a1) (a2), E. Rostrup (a3) and M. Nordentoft (a1) (a2)...



Individuals at ultra-high-risk (UHR) for psychosis present with emerging symptoms and decline in functioning. Previous univariate analyses have indicated widespread white matter (WM) aberrations in multiple brain regions in UHR individuals and patients with schizophrenia. Using multivariate statistics, we investigated whole brain WM microstructure and associations between WM, clinical symptoms, and level of functioning in UHR individuals.


Forty-five UHR individuals and 45 matched healthy controls (HCs) underwent magnetic resonance diffusion tensor imaging (DTI) at 3 Tesla. UHR individuals were assessed with the Comprehensive Assessment of At-Risk Mental States, Scale for the Assessment of Negative Symptoms, and Social and Occupational Functioning Assessment Scale. Partial least-squares correlation analysis (PLSC) was used as statistical method.


PLSC group comparisons revealed one significant latent variable (LV) accounting for 52% of the cross-block covariance. This LV indicated a pattern of lower fractional anisotropy (FA), axial diffusivity (AD), and mode of anisotropy (MO) concomitant with higher radial diffusivity (RD) in widespread brain regions in UHR individuals compared with HCs. Within UHR individuals, PLSC revealed five significant LVs associated with symptoms and level of functioning. The first LV accounted for 31% of the cross-block covariance and indicated a pattern where higher symptom score and lower level of functioning correlated to lower FA, AD, MO, and higher RD.


UHR individuals demonstrate complex brain patterns of WM abnormalities. Despite the subtle psychopathology of UHR individuals, aberrations in WM appear associated with positive and negative symptoms as well as level of functioning.


Corresponding author

*Address for correspondence: K. Krakauer, M.D., Research Unit, Mental Health Centre Copenhagen, Gentofte Hospital, Kildegårdsvej 28, Opgang 15, 4. sal, 2900 Hellerup, Denmark. (Email:


Hide All
Andersson, JL, Jenkinson, M, Smith, S (2007 a). Non-linear optimisation. FMRIB technical report TR07JA1 from ( In (Anonymous).
Andersson, JL, Jenkinson, M, Smith, S (2007 b). Non-linear registration, aka Spatial normalisation FMRIB technical report TR07JA2 from ( In (Anonymous).
Andersson, JL, Skare, S (2002). A model-based method for retrospective correction of geometric distortions in diffusion-weighted EPI. Neuroimage 16, 177199.
Andersson, JL, Skare, S, Ashburner, J (2003). How to correct susceptibility distortions in spin-echo echo-planar images: application to diffusion tensor imaging. Neuroimage 20, 870888.
Andersson, JL, Sotiropoulos, SN (2015). Non-parametric representation and prediction of single- and multi-shell diffusion-weighted MRI data using Gaussian processes. Neuroimage 122, 166176.
Andreasen, NC (1982). Negative symptoms in schizophrenia. Definition and reliability. Archives of General Psychiatry 39, 784788.
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.
Arfanakis, K, Haughton, VM, Carew, JD, Rogers, BP, Dempsey, RJ, Meyerand, ME (2002). Diffusion tensor MR imaging in diffuse axonal injury. AJNR American Journal of Neuroradiology 23, 794802.
Arndt, S, Andreasen, NC, Flaum, M, Miller, D, Nopoulos, P (1995). A longitudinal study of symptom dimensions in schizophrenia. Prediction and patterns of change. Archives of General Psychiatry 52, 352360.
Asami, T, Hyuk, LS, Bouix, S, Rathi, Y, Whitford, TJ, Niznikiewicz, M, Nestor, P, McCarley, RW, Shenton, ME, Kubicki, M (2014). Cerebral white matter abnormalities and their associations with negative but not positive symptoms of schizophrenia. Psychiatry Research 222, 5259.
Ashtari, M, Cervellione, K, Cottone, J, Ardekani, BA, Sevy, S, Kumra, S (2009). Diffusion abnormalities in adolescents and young adults with a history of heavy cannabis use. Journal of Psychiatric Research 43, 189204.
Aung, WY, Mar, S, Benzinger, TL (2013). Diffusion tensor MRI as a biomarker in axonal and myelin damage. Imaging in Medicine 5, 427440.
Baeza-Loya, S, Velasquez, KM, Molfese, DL, Viswanath, H, Curtis, KN, Thompson-Lake, DG, Baldwin, PR, Ellmore, TM, De La Garza, R, Salas, R (2016). Anterior cingulum white matter is altered in tobacco smokers. The American Journal on Addictions 25, 210214.
Basser, PJ, Pierpaoli, C (2011). Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. 1996. Journal of Magnetic Resonance 213, 560570.
Bava, S, Frank, LR, McQueeny, T, Schweinsburg, BC, Schweinsburg, AD, Tapert, SF (2009). Altered white matter microstructure in adolescent substance users. Psychiatry Research 173, 228237.
Bennett, RE, Mac Donald, CL, Brody, DL (2012). Diffusion tensor imaging detects axonal injury in a mouse model of repetitive closed-skull traumatic brain injury. Neuroscience Letters 513, 160165.
Bernard, JA, Orr, JM, Mittal, VA (2015). Abnormal hippocampal-thalamic white matter tract development and positive symptom course in individuals at ultra-high risk for psychosis. NPJ. Schizophrenia 1, 15009.
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. Psychological Medicine 40, 12971304.
Boos, HB, Mandl, RC, van Haren, NE, Cahn, W, van Baal, GC, Kahn, RS, Hulshoff Pol, HE (2013). Tract-based diffusion tensor imaging in patients with schizophrenia and their non-psychotic siblings. European Neuropsychopharmacology 23, 295304.
Bullmore, ET, Suckling, J, Overmeyer, S, Rabe-Hesketh, S, Taylor, E, Brammer, MJ (1999). Global, voxel, and cluster tests, by theory and permutation, for a difference between two groups of structural MR images of the brain. IEE Transactions on Medical Imaging 18, 3242.
Caprihan, A, Jones, T, Chen, H, Lemke, N, Abbott, C, Qualls, C, Canive, J, Gasparovic, C, Bustillo, JR (2015). The paradoxical relationship between white matter, psychopathology and cognition in schizophrenia: a diffusion tensor and proton spectroscopic imaging study. Neuropsychopharmacology 40, 22482257.
Carletti, F, Woolley, JB, Bhattacharyya, S, Perez-Iglesias, R, Fusar, PP, 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. Schizophrenia Bulletin 38, 11701179.
Catani, M, Craig, MC, Forkel, SJ, Kanaan, R, Picchioni, M, Toulopoulou, T, Shergill, S, Williams, S, Murphy, DG, McGuire, P (2011). Altered integrity of perisylvian language pathways in schizophrenia: relationship to auditory hallucinations. Biological Psychiatry 70, 11431150.
Cha, J, Fekete, T, Siciliano, F, Biezonski, D, Greenhill, L, Pliszka, SR, Blader, JC, Roy, AK, Leibenluft, E, Posner, J (2015). Neural correlates of aggression in medication-naive children with ADHD: multivariate analysis of morphometry and tractography. Neuropsychopharmacology 40, 17171725.
Cheung, V, Cheung, C, McAlonan, GM, Deng, Y, Wong, JG, Yip, L, Tai, KS, Khong, PL, Sham, P, Chua, SE (2008). A diffusion tensor imaging study of structural dysconnectivity in never-medicated, first-episode schizophrenia. Psychological Medicine 38, 877885.
Cheung, V, Chiu, CP, Law, CW, Cheung, C, Hui, CL, Chan, KK, Sham, PC, Deng, MY, Tai, KS, Khong, PL, McAlonan, GM, Chua, SE, Chen, E (2011). Positive symptoms and white matter microstructure in never-medicated first episode schizophrenia. Psychological Medicine 41, 17091719.
Choi, H, Kubicki, M, Whitford, TJ, Alvarado, JL, Terry, DP, Niznikiewicz, M, McCarley, RW, Kwon, JS, Shenton, ME (2011). Diffusion tensor imaging of anterior commissural fibers in patients with schizophrenia. Schizophrenia Research 130, 7885.
Cooper, S, Alm, KH, Olson, IR, Ellman, LM (2016). White matter alterations in individuals experiencing attenuated positive psychotic symptoms. Early Intervention in Psychiatry. Epub: doi:10.1111/eip.12306.
Cui, L, Chen, Z, Deng, W, Huang, X, Li, M, Ma, X, Huang, C, Jiang, L, Wang, Y, Wang, Q, Collier, DA, Gong, Q, Li, T (2011). Assessment of white matter abnormalities in paranoid schizophrenia and bipolar mania patients. Psychiatry Research 194, 347353.
Dannevang, AL, Randers, L, Gondan, M, Krakauer, K, Nordholm, D, Nordentoft, M (2016). Premorbid adjustment in individuals at ultra-high risk for developing psychosis: a case-control study. Early Intervention in Psychiatry. Epub: doi: 10.1111/eip.12375.
DeRosse, P, Ikuta, T, Karlsgodt, KH, Peters, BD, Gopin, CB, Szeszko, PR, Malhotra, AK (2016). White matter abnormalities associated with subsyndromal psychotic-like symptoms predict later social competence in children and adolescents. Schizophrenia Bulletin 43, 152159.
Ebdrup, BH, Raghava, JM, Nielsen, MO, Rostrup, E, Glenthoj, B (2016). Frontal fasciculi and psychotic symptoms in antipsychotic-naive patients with schizophrenia before and after 6 weeks of selective dopamine D2/3 receptor blockade. Journal of Psychiatry & Neuroscience 41, 133141.
Ennis, DB, Kindlmann, G (2006). Orthogonal tensor invariants and the analysis of diffusion tensor magnetic resonance images. Magnetic Resonance in Medicine 55, 136146.
Epstein, KA, Cullen, KR, Mueller, BA, Robinson, P, Lee, S, Kumra, S (2014). White matter abnormalities and cognitive impairment in early-onset schizophrenia-spectrum disorders. Journal of the American Academy of Child and Adolescent Psychiatry 53, 362372.
Ersche, KD, Williams, GB, Robbins, TW, Bullmore, ET (2013). Meta-analysis of structural brain abnormalities associated with stimulant drug dependence and neuroimaging of addiction vulnerability and resilience. Current Opinion in Neurobiology 23, 615624.
Filippi, M, Canu, E, Gasparotti, R, Agosta, F, Valsecchi, P, Lodoli, G, Galluzzo, A, Comi, G, Sacchetti, E (2014). Patterns of brain structural changes in first-contact, antipsychotic drug-naive patients with schizophrenia. AJNR American Journal of Neuroradiology 35, 3037.
First, MB, Spitzer, RL, Gibbon, M, Williams, J (2001). Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID I). Psychiatric Institute, Biometrics Research Department: New York State.
First, MB, Spitzer, RL, Gibbon, M, Williams, J, Benjamin, L (1994). Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID II). Biometric Research Department: New York.
Gasparotti, R, Valsecchi, P, Carletti, F, Galluzzo, A, Liserre, R, Cesana, B, Sacchetti, E (2009). Reduced fractional anisotropy of corpus callosum in first-contact, antipsychotic drug-naive patients with schizophrenia. Schizophrenia Research 108, 4148.
Geladi, P, Kowalski, BR (1986). Partial least-squares regression: a tutorial. Analytica Chimica Acta 185, 117.
Gogliettino, AR, Potenza, MN, Yip, SW (2016). White matter development and tobacco smoking in young adults: a systematic review with recommendations for future research. Drug and Alcohol Dependence 162, 2633.
Goldman, HH, Skodol, AE, Lave, TR (1992). Revising axis V for DSM-IV: a review of measures of social functioning. The American Journal of Psychiatry 149, 11481156.
Grady, CL, McIntosh, AR, Horwitz, B, Rapoport, SI (2000). Age-related changes in the neural correlates of degraded and nondegraded face processing. Cognitive Neuropsychology 17, 165186.
Guitart-Masip, M, Salami, A, Garrett, D, Rieckmann, A, Lindenberger, U, Backman, L (2016). BOLD variability is related to dopaminergic neurotransmission and cognitive aging. Cerebral Cortex 26, 20742083.
Guo, W, Liu, F, Liu, Z, Gao, K, Xiao, C, Chen, H, Zhao, J (2012). Right lateralized white matter abnormalities in first-episode, drug-naive paranoid schizophrenia. Neuroscience Letters 531, 59.
Harsan, LA, Poulet, P, Guignard, B, Steibel, J, Parizel, N, de Sousa, PL, Boehm, N, Grucker, D, Ghandour, MS (2006). Brain dysmyelination and recovery assessment by noninvasive in vivo diffusion tensor magnetic resonance imaging. Journal of Neuroscience Research 83, 392402.
Hatton, SN, Lagopoulos, J, Hermens, DF, Hickie, IB, Scott, E, Bennett, MR (2014). White matter tractography in early psychosis: clinical and neurocognitive associations. Journal of Psychiatry & Neuroscience 39, 417427.
Hilsenroth, MJ, Ackerman, SJ, Blagys, MD, Baumann, BD, Baity, MR, Smith, SR, Price, JL, Smith, CL, Heindselman, TL, Mount, MK, Holdwick, DJ Jr. (2000). Reliability and validity of DSM-IV axis V. The American Journal of Psychiatry 157, 18581863.
Hua, K, Zhang, J, Wakana, S, Jiang, H, Li, X, Reich, DS, Calabresi, PA, Pekar, JJ, van Zijl, PC, Mori, S (2008). Tract probability maps in stereotaxic spaces: analyses of white matter anatomy and tract-specific quantification. Neuroimage 39, 336347.
Huang, W, DiFranza, JR, Kennedy, DN, Zhang, N, Ziedonis, D, Ursprung, S, King, JA (2013). Progressive levels of physical dependence to tobacco coincide with changes in the anterior cingulum bundle microstructure. PLoS ONE 8, e67837.
Hubl, D, Koenig, T, Strik, W, Federspiel, A, Kreis, R, Boesch, C, Maier, SE, Schroth, G, Lovblad, K, Dierks, T (2004). Pathways that make voices: white matter changes in auditory hallucinations. Archives of General Psychiatry 61, 658668.
Hudkins, M, O'Neill, J, Tobias, MC, Bartzokis, G, London, ED (2012). Cigarette smoking and white matter microstructure. Psychopharmacology (Berl) 221, 285295.
Jacobsen, LK, Picciotto, MR, Heath, CJ, Frost, SJ, Tsou, KA, Dwan, RA, Jackowski, MP, Constable, RT, Mencl, WE (2007). Prenatal and adolescent exposure to tobacco smoke modulates the development of white matter microstructure. Journal of Neuroscience 27, 1349113498.
James, A, Hough, M, James, S, Winmill, L, Burge, L, Nijhawan, S, Matthews, PM, Zarei, M. (2011). Greater white and grey matter changes associated with early cannabis use in adolescent-onset schizophrenia (AOS). Schizophrenia Research 128, 9197.
Jenkinson, M, Beckmann, CF, Behrens, TE, Woolrich, MW, Smith, SM (2012). FSL. Neuroimage 62, 782790.
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. Biological Psychiatry 66, 562569.
Katagiri, N, Pantelis, C, Nemoto, T, Zalesky, A, Hori, M, Shimoji, K, Saito, J, Ito, S, Dwyer, DB, Fukunaga, I, Morita, K, Tsujino, N, Yamaguchi, T, Shiraga, N, Aoki, S, Mizuno, M (2015). A longitudinal study investigating sub-threshold symptoms and white matter changes in individuals with an ‘at risk mental state’ (ARMS). Schizophrenia Research 162, 713.
Kikinis, Z, Makris, N, Finn, CT, Bouix, S, Lucia, D, Coleman, MJ, Tworog-Dube, E, Kikinis, R, Kucherlapati, R, Shenton, ME, Kubicki, M (2013). Genetic contributions to changes of fiber tracts of ventral visual stream in 22q11.2 deletion syndrome. Brain Imaging and Behavior 7, 316325.
Kim, JH, Loy, DN, Wang, Q, Budde, MD, Schmidt, RE, Trinkaus, K, Song, SK (2010). Diffusion tensor imaging at 3 hours after traumatic spinal cord injury predicts long-term locomotor recovery. Journal of Neurotrauma 27, 587598.
Kindlmann, G, Ennis, DB, Whitaker, RT, Westin, CF (2007). Diffusion tensor analysis with invariant gradients and rotation tangents. IEE Transactions on Medical Imaging 26, 14831499.
Konukoglu, E, Coutu, JP, Salat, DH, Fischl, B (2016). Multivariate statistical analysis of diffusion imaging parameters using partial least squares: application to white matter variations in Alzheimer's disease. Neuroimage 134, 573586.
Krishnan, A, Williams, LJ, McIntosh, AR, Abdi, H (2011). Partial Least Squares (PLS) methods for neuroimaging: a tutorial and review. Neuroimage 56, 455475.
Kumar, J, Iwabuchi, S, Oowise, S, Balain, V, Palaniyappan, L, Liddle, PF (2015). Shared white-matter dysconnectivity in schizophrenia and bipolar disorder with psychosis. Psychological Medicine 45, 759770.
Lane, SD, Steinberg, JL, Ma, L, Hasan, KM, Kramer, LA, Zuniga, EA, Narayana, PA, Moeller, FG (2010). Diffusion tensor imaging and decision making in cocaine dependence. PLoS ONE 5, e11591.
Lee, SH, Kubicki, M, Asami, T, Seidman, LJ, Goldstein, JM, Mesholam-Gately, RI, McCarley, RW, Shenton, ME (2013). Extensive white matter abnormalities in patients with first-episode schizophrenia: a Diffusion Tensor Iimaging (DTI) study. Schizophrenia Research 143, 231238.
Li, J, Li, XY, Feng, DF, Gu, L (2011). Quantitative evaluation of microscopic injury with diffusion tensor imaging in a rat model of diffuse axonal injury. European Journal of Neuroscience 33, 933945.
Li, Y, Xie, S, Liu, B, Song, M, Chen, Y, Li, P, Lu, L, Lv, L, Wang, H, Yan, H, Yan, J, Zhang, H, Zhang, D, Jiang, T (2016). Diffusion magnetic resonance imaging study of schizophrenia in the context of abnormal neurodevelopment using multiple site data in a Chinese Han population. Transl. Psychiatry 6, e715.
Liao, Y, Tang, J, Deng, Q, Deng, Y, Luo, T, Wang, X, Chen, H, Liu, T, Chen, X, Brody, AL, Hao, W (2011). Bilateral fronto-parietal integrity in young chronic cigarette smokers: a diffusion tensor imaging study. PLoS ONE 6, e26460.
Lim, KO, Choi, SJ, Pomara, N, Wolkin, A, Rotrosen, JP (2002). Reduced frontal white matter integrity in cocaine dependence: a controlled diffusion tensor imaging study. Biological Psychiatry 51, 890895.
Lin, F, Wu, G, Zhu, L, Lei, H (2013). Heavy smokers show abnormal microstructural integrity in the anterior corpus callosum: a diffusion tensor imaging study with tract-based spatial statistics. Drug and Alcohol Dependence 129, 8287.
Ling, J, Merideth, F, Caprihan, A, Pena, A, Teshiba, T, Mayer, AR (2012). Head injury or head motion? Assessment and quantification of motion artifacts in diffusion tensor imaging studies. Human Brain Mapping 33, 5062.
Ma, L, Hasan, KM, Steinberg, JL, Narayana, PA, Lane, SD, Zuniga, EA, Kramer, LA, Moeller, FG (2009). Diffusion tensor imaging in cocaine dependence: regional effects of cocaine on corpus callosum and effect of cocaine administration route. Drug and Alcohol Dependence 104, 262267.
Mandl, RC, Pasternak, O, Cahn, W, Kubicki, M, Kahn, RS, Shenton, ME, Hulshoff Pol, HE (2015). Comparing free water imaging and magnetization transfer measurements in schizophrenia. Schizophrenia Research 161, 126132.
McIntosh, AR, Bookstein, FL, Haxby, JV, Grady, CL (1996). Spatial pattern analysis of functional brain images using partial least squares. Neuroimage 3, 143157.
McIntosh, AR, Lobaugh, NJ (2004). Partial least squares analysis of neuroimaging data: applications and advances. Neuroimage 23(Suppl. 1), S250S263.
McLelland, VC, Chan, D, Ferber, S, Barense, MD (2014). Stimulus familiarity modulates functional connectivity of the perirhinal cortex and anterior hippocampus during visual discrimination of faces and objects. Frontiers in Human Neuroscience 8, 117.
Meyer, EC, Carrion, RE, Cornblatt, BA, Addington, J, Cadenhead, KS, Cannon, TD, McGlashan, TH, Perkins, DO, Tsuang, MT, Walker, EF, Woods, SW, Heinssen, R, Seidman, LJ (2014). The relationship of neurocognition and negative symptoms to social and role functioning over time in individuals at clinical high risk in the first phase of the North American Prodrome Longitudinal Study. Schizophrenia Bulletin 40, 14521461.
Mittal, VA, Dean, DJ, Bernard, JA, Orr, JM, Pelletier-Baldelli, A, Carol, EE, Gupta, T, Turner, J, Leopold, DR, Robustelli, BL, Millman, ZB (2014). Neurological soft signs predict abnormal cerebellar-thalamic tract development and negative symptoms in adolescents at high risk for psychosis: a longitudinal perspective. Schizophrenia Bulletin 40, 12041215.
Moeller, FG, Hasan, KM, Steinberg, JL, Kramer, LA, Dougherty, DM, Santos, RM, Valdes, I, Swann, AC, Barratt, ES, Narayana, PA (2005). Reduced anterior corpus callosum white matter integrity is related to increased impulsivity and reduced discriminability in cocaine-dependent subjects: diffusion tensor imaging. Neuropsychopharmacology 30, 610617.
Mori, S, van Zijl, P (2007). Human white matter atlas. The American Journal of Psychiatry 164, 1005.
Morrison, AP, French, P, Stewart, SL, Birchwood, M, Fowler, D, Gumley, AI, Jones, PB, Bentall, RP, Lewis, SW, Murray, GK, Patterson, P, Brunet, K, Conroy, J, Parker, S, Reilly, T, Byrne, R, Davies, LM, Dunn, G (2012). Early detection and intervention evaluation for people at risk of psychosis: multisite randomised controlled trial. British Medical Journal 344, e2233.
Mulert, C, Scarr, E (2012). Editorial: new treatment strategies in schizophrenia beyond dopamine: glutamatergic neurotransmission and more. Current Pharmaceutical Biotechnology 13, 14741475.
Narayana, PA, Herrera, JJ, Bockhorst, KH, Esparza-Coss, E, Xia, Y, Steinberg, JL, Moeller, FG (2014). Chronic cocaine administration causes extensive white matter damage in brain: diffusion tensor imaging and immunohistochemistry studies. Psychiatric Research 221, 220230.
Nestor, PG, O'Donnell, BF, McCarley, RW, Niznikiewicz, M, Barnard, J, Jen, SZ, Bookstein, FL, Shenton, ME (2002). A new statistical method for testing hypotheses of neuropsychological/MRI relationships in schizophrenia: partial least squares analysis. Schizophrenia Research 53, 5766.
Nordholm, D, Poulsen, HE, Hjorthoj, C, Randers, L, Nielsen, MO, Wulff, S, Krakauer, K, Norbak-Emig, H, Henriksen, T, Glenthoj, B, Nordentoft, M (2016). Systemic oxidative DNA and RNA damage are not increased during early phases of psychosis: a case control study. Psychiatry Research 241, 201206.
Ohtani, T, Bouix, S, Lyall, AE, Hosokawa, T, Saito, Y, Melonakos, E, Westin, CF, Seidman, LJ, Goldstein, J, Mesholam-Gately, R, Petryshen, T, Wojcik, J, Kubicki, M (2015). Abnormal white matter connections between medial frontal regions predict symptoms in patients with first episode schizophrenia. Cortex 71, 264276.
Oldfield, RC (1971). The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9, 97113.
Paul, RH, Grieve, SM, Niaura, R, David, SP, Laidlaw, DH, Cohen, R, Sweet, L, Taylor, G, Clark, RC, Pogun, S, Gordon, E (2008). Chronic cigarette smoking and the microstructural integrity of white matter in healthy adults: a diffusion tensor imaging study. Nicotine and Tobacco Research 10, 137147.
Perez-Iglesias, R, Tordesillas-Gutierrez, D, Barker, GJ, McGuire, PK, Roiz-Santianez, R, Mata, I, de Lucas, EM, Quintana, F, Vazquez-Barquero, JL, Crespo-Facorro, B (2010). White matter defects in first episode psychosis patients: a voxelwise analysis of diffusion tensor imaging. Neuroimage 49, 199204.
Peters, BD, de Haan, L, Dekker, N, Blaas, J, Becker, HE, Dingemans, PM, Akkerman, EM, Majoie, CB, van Amelsvoort, TA, den Heeten, GJ, Linszen, DH (2008). White matter fibertracking in first-episode schizophrenia, schizoaffective patients and subjects at ultra-high risk of psychosis. Neuropsychobiology 58, 1928.
Peters, BD, Dingemans, PM, Dekker, N, Blaas, J, Akkerman, E, van Amelsvoort, TA, Majoie, CB, den Heeten, GJ, Linszen, DH, de Haan, L (2010). White matter connectivity and psychosis in ultra-high-risk subjects: a diffusion tensor fiber tracking study. Psychiatry Research 181, 4450.
Peters, BD, Schmitz, N, Dingemans, PM, van Amelsvoort, TA, Linszen, DH, de Haan, L, Majoie, CB, den Heeten, GJ (2009). Preliminary evidence for reduced frontal white matter integrity in subjects at ultra-high-risk for psychosis. Schizophrenia Research 111, 192193.
Pettersson-Yeo, W, Benetti, S, Marquand, AF, Dell'acqua, F, Williams, SC, Allen, P, Prata, D, McGuire, P, Mechelli, A (2013). Using genetic, cognitive and multi-modal neuroimaging data to identify ultra-high-risk and first-episode psychosis at the individual level. Psychological Medicine 43, 25472562.
Protzner, AB, Hargreaves, IS, Campbell, JA, Myers-Stewart, K, van Sophia, H, Goodyear, BG, Sargious, P, Pexman, PM (2016). This is your brain on Scrabble: neural correlates of visual word recognition in competitive Scrabble players as measured during task and resting-state. Cortex 75, 204219.
Reese, TG, Heid, O, Weisskoff, RM, Wedeen, VJ (2003). Reduction of eddy-current-induced distortion in diffusion MRI using a twice-refocused spin echo. Magnetic Resonance in Medicine 49, 177182.
Rigucci, S, Santi, G, Corigliano, V, Imola, A, Rossi-Espagnet, C, Mancinelli, I, De Pisa, E, Manfredi, G, Bozzao, A, Carducci, F, Girardi, P, Comparelli, A (2016). White matter microstructure in ultra-high risk and first episode schizophrenia: a prospective study. Psychiatry Research 247, 4248.
Roalf, DR, Quarmley, M, Elliott, MA, Satterthwaite, TD, Vandekar, SN, Ruparel, K, Gennatas, ED, Calkins, ME, Moore, TM, Hopson, R, Prabhakaran, K, Jackson, CT, Verma, R, Hakonarson, H, Gur, RC, Gur, RE (2016). The impact of quality assurance assessment on diffusion tensor imaging outcomes in a large-scale population-based cohort. Neuroimage 125, 903919.
Savjani, RR, Velasquez, KM, Thompson-Lake, DG, Baldwin, PR, Eagleman, DM, De La Garza, R, Salas, R (2014). Characterizing white matter changes in cigarette smokers via diffusion tensor imaging. Drug and Alcohol Dependence 145, 134142.
Schlosser, DA, Campellone, TR, Biagianti, B, Delucchi, KL, Gard, DE, Fulford, D, Stuart, BK, Fisher, M, Loewy, RL, Vinogradov, S (2015). Modeling the role of negative symptoms in determining social functioning in individuals at clinical high risk of psychosis. Schizophrenia Research 169, 204208.
Schmidt, A, Lenz, C, Smieskova, R, Harrisberger, F, Walter, A, Riecher-Rossler, A, Simon, A, Lang, UE, McGuire, P, Fusar-Poli, P, Borgwardt, SJ (2015). Brain diffusion changes in emerging psychosis and the impact of state-dependent psychopathology. Neurosignals 23, 7183.
Seitz, J, Zuo, JX, Lyall, AE, Makris, N, Kikinis, Z, Bouix, S, Pasternak, O, Fredman, E, Duskin, J, Goldstein, JM, Petryshen, TL, Mesholam-Gately, RI, Wojcik, J, McCarley, RW, Seidman, LJ, Shenton, ME, Koerte, IK, Kubicki, M (2016). Tractography analysis of 5 white matter bundles and their clinical and cognitive correlates in early-course schizophrenia. Schizophrenia Bulletin 42, 762771.
Seok, JH, Park, HJ, Chun, JW, Lee, SK, Cho, HS, Kwon, JS, Kim, JJ (2007). White matter abnormalities associated with auditory hallucinations in schizophrenia: a combined study of voxel-based analyses of diffusion tensor imaging and structural magnetic resonance imaging. Psychiatry Research 156, 93104.
Shergill, SS, Kanaan, RA, Chitnis, XA, O'Daly, O, Jones, DK, Frangou, S, Williams, SC, Howard, RJ, Barker, GJ, Murray, RM, McGuire, P (2007). A diffusion tensor imaging study of fasciculi in schizophrenia. The American Journal of Psychiatry 164, 467473.
Shin, YW, Kwon, JS, Ha, TH, Park, HJ, Kim, DJ, Hong, SB, Moon, WJ, Lee, JM, Kim, IY, Kim, SI, Chung, EC (2006). Increased water diffusivity in the frontal and temporal cortices of schizophrenic patients. Neuroimage 30, 12851291.
Skelly, LR, Calhoun, V, Meda, SA, Kim, J, Mathalon, DH, Pearlson, GD (2008). Diffusion tensor imaging in schizophrenia: relationship to symptoms. Schizophrenia Research 98, 157162.
Smith, SM (2002). Fast robust automated brain extraction. Human Brain Mapping 17, 143155.
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, 14871505.
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), S208S219.
Smith, SM, Nichols, TE (2009). Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. Neuroimage 44, 8398.
Song, SK, Sun, SW, Ramsbottom, MJ, Chang, C, Russell, J, Cross, AH (2002). Dysmyelination revealed through MRI as increased radial (but unchanged axial) diffusion of water. Neuroimage 17, 14291436.
Song, SK, Yoshino, J, Le, TQ, Lin, SJ, Sun, SW, Cross, AH, Armstrong, RC (2005). Demyelination increases radial diffusivity in corpus callosum of mouse brain. Neuroimage 26, 132140.
Spalletta, G, De Rossi, P, Piras, F, Iorio, M, Dacquino, C, Scanu, F, Girardi, P, Caltagirone, C, Kirkpatrick, B, Chiapponi, C (2015). Brain white matter microstructure in deficit and non-deficit subtypes of schizophrenia. Psychiatry Research 231, 252261.
Sun, H, Lui, S, Yao, L, Deng, W, Xiao, Y, Zhang, W, Huang, X, Hu, J, Bi, F, Li, T, Sweeney, JA, Gong, Q (2015). Two patterns of white matter abnormalities in medication-naive patients with first-episode schizophrenia revealed by diffusion tensor imaging and cluster analysis. JAMA Psychiatry 72, 678686.
Sun, SW, Liang, HF, Le, TQ, Armstrong, RC, Cross, AH, Song, SK (2006 a). Differential sensitivity of in vivo and ex vivo diffusion tensor imaging to evolving optic nerve injury in mice with retinal ischemia. Neuroimage 32, 11951204.
Sun, SW, Liang, HF, Trinkaus, K, Cross, AH, Armstrong, RC, Song, SK (2006 b). Noninvasive detection of cuprizone induced axonal damage and demyelination in the mouse corpus callosum. Magnetic Resonance in Medicine 55, 302308.
Szeszko, PR, Robinson, DG, Ashtari, M, Vogel, J, Betensky, J, Sevy, S, Ardekani, BA, Lencz, T, Malhotra, AK, McCormack, J, Miller, R, Lim, KO, Gunduz-Bruce, H, Kane, JM, Bilder, RM (2008). Clinical and neuropsychological correlates of white matter abnormalities in recent onset schizophrenia. Neuropsychopharmacology 33, 976984.
Tyszka, JM, Readhead, C, Bearer, EL, Pautler, RG, Jacobs, RE (2006). Statistical diffusion tensor histology reveals regional dysmyelination effects in the shiverer mouse mutant. Neuroimage 29, 10581065.
Umene-Nakano, W, Yoshimura, R, Kakeda, S, Watanabe, K, Hayashi, K, Nishimura, J, Takahashi, H, Moriya, J, Ide, S, Ueda, I, Hori, H, Ikenouchi-Sugita, A, Katsuki, A, Atake, K, Abe, O, Korogi, Y, Nakamura, J (2014). Abnormal white matter integrity in the corpus callosum among smokers: tract-based spatial statistics. PLoS ONE 9, e87890.
van Dellen, E, Bohlken, MM, Draaisma, L, Tewarie, PK, van Lutterveld, R, Mandl, R, Stam, CJ, Sommer, IE (2016). Structural brain network disturbances in the psychosis spectrum. Schizophrenia Bulletin 42, 782789.
van Ewijk, H, Groenman, AP, Zwiers, MP, Heslenfeld, DJ, Faraone, SV, Hartman, CA, Luman, M, Greven, CU, Hoekstra, PJ, Franke, B, Buitelaar, J, Oosterlaan, J (2015). Smoking and the developing brain: altered white matter microstructure in attention-deficit/hyperactivity disorder and healthy controls. Human Brain Mapping 36, 11801189.
Viswanath, H, Velasquez, KM, Thompson-Lake, DG, Savjani, R, Carter, AQ, Eagleman, D, Baldwin, PR, De La Garza, R, Salas, R (2015). Alterations in interhemispheric functional and anatomical connectivity are associated with tobacco smoking in humans. Frontiers in Human Neuroscience 9, 116.
von Hohenberg, CC, Pasternak, O, Kubicki, M, Ballinger, T, Vu, MA, Swisher, T, Green, K, Giwerc, M, Dahlben, B, Goldstein, JM, Woo, TU, Petryshen, TL, Mesholam-Gately, RI, Woodberry, KA, Thermenos, HW, Mulert, C, McCarley, RW, Seidman, LJ, Shenton, ME (2014). White matter microstructure in individuals at clinical high risk of psychosis: a whole-brain diffusion tensor imaging study. Schizophrenia Bulletin 40, 895903.
Wakana, S, Caprihan, A, Panzenboeck, MM, Fallon, JH, Perry, M, Gollub, RL, Hua, K, Zhang, J, Jiang, H, Dubey, P, Blitz, A, van Zijl, P, Mori, S (2007). Reproducibility of quantitative tractography methods applied to cerebral white matter. Neuroimage 36, 630644.
Wang, C, Ji, F, Hong, Z, Poh, JS, Krishnan, R, Lee, J, Rekhi, G, Keefe, RS, Adcock, RA, Wood, SJ, Fornito, A, Pasternak, O, Chee, MW, Zhou, J (2016). Disrupted salience network functional connectivity and white-matter microstructure in persons at risk for psychosis: findings from the LYRIKS study. Psychological Medicine 46, 27712783.
Wechsler, D (1997). Administration and Scoring Manual for the Wechsler Adult Intelligence Scale–3rd Revision (WAIS-III), Psychological Corporation: San Antonio.
Whitford, TJ, Kubicki, M, Schneiderman, JS, O'Donnell, LJ, King, R, Alvarado, JL, Khan, U, Markant, D, Nestor, PG, Niznikiewicz, M, McCarley, RW, Westin, CF, Shenton, ME (2010). Corpus callosum abnormalities and their association with psychotic symptoms in patients with schizophrenia. Biological Psychiatry 68, 7077.
Wigand, M, Kubicki, M, Clemm von, HC, Leicht, G, Karch, S, Eckbo, R, Pelavin, PE, Hawley, K, Rujescu, D, Bouix, S, Shenton, ME, Mulert, C (2015). Auditory verbal hallucinations and the interhemispheric auditory pathway in chronic schizophrenia. The World Journal of Biological Psychiatry 16, 3144.
Wing, JK, Babor, T, Brugha, T, Burke, J, Cooper, JE, Giel, R, Jablenski, A, Regier, D, Sartorius, N (1990). SCAN. Schedules for clinical assessment in neuropsychiatry. Archives of General Psychiatry 47, 589593.
Wolkin, A, Choi, SJ, Szilagyi, S, Sanfilipo, M, Rotrosen, JP, Lim, KO (2003). Inferior frontal white matter anisotropy and negative symptoms of schizophrenia: a diffusion tensor imaging study. The American Journal of Psychiatry 160, 572574.
Woolrich, MW, Jbabdi, S, Patenaude, B, Chappell, M, Makni, S, Behrens, T, Beckmann, C, Jenkinson, M, Smith, SM (2009). Bayesian analysis of neuroimaging data in FSL. Neuroimage 45, S173S186.
Xie, M, Tobin, JE, Budde, MD, Chen, CI, Trinkaus, K, Cross, AH, McDaniel, DP, Song, SK, Armstrong, RC (2010). Rostrocaudal analysis of corpus callosum demyelination and axon damage across disease stages refines diffusion tensor imaging correlations with pathological features. Journal of Neuropathology and Experimental Neurology 69, 704716.
Yendiki, A, Koldewyn, K, Kakunoori, S, Kanwisher, N, Fischl, B (2014). Spurious group differences due to head motion in a diffusion MRI study. Neuroimage 88, 7990.
Yu, D, Yuan, K, Zhang, B, Liu, J, Dong, M, Jin, C, Luo, L, Zhai, J, Zhao, L, Zhao, Y, Gu, Y, Xue, T, Liu, X, Lu, X, Qin, W, Tian, J (2016). White matter integrity in young smokers: a tract-based spatial statistics study. Addiction Biology 21, 679687.
Yucel, M, Zalesky, A, Takagi, MJ, Bora, E, Fornito, A, Ditchfield, M, Egan, GF, Pantelis, C, Lubman, DI (2010). White-matter abnormalities in adolescents with long-term inhalant and cannabis use: a diffusion magnetic resonance imaging study. Journal of Psychiatry & Neuroscience 35, 409412.
Yung, AR, Phillips, LJ, Yuen, HP, Francey, SM, McFarlane, CA, Hallgren, M, McGorry, PD (2003). Psychosis prediction: 12-month follow up of a high-risk (“prodromal”) group. Schizophrenia Research 60, 2132.
Yung, AR, Yuen, HP, McGorry, PD, Phillips, LJ, Kelly, D, Dell'Olio, M, Francey, SM, Cosgrave, EM, Killackey, E, Stanford, C, Godfrey, K, Buckby, J (2005). Mapping the onset of psychosis: the comprehensive assessment of at-risk mental states. Australian & New Zealand Journal of Psychiatry 39, 964971.
Zalesky, A, Solowij, N, Yucel, M, Lubman, DI, Takagi, M, Harding, IH, Lorenzetti, V, Wang, R, Searle, K, Pantelis, C, Seal, M (2012). Effect of long-term cannabis use on axonal fibre connectivity. Brain 135, 22452255.
Zeng, B, Ardekani, BA, Tang, Y, Zhang, T, Zhao, S, Cui, H, Fan, X, Zhuo, K, Li, C, Xu, Y, Goff, DC, Wang, J (2016). Abnormal white matter microstructure in drug-naive first episode schizophrenia patients before and after eight weeks of antipsychotic treatment. Schizophrenia Research 172, 18.
Zhang, XY, Fan, FM, Chen, DC, Tan, YL, Tan, SP, Hu, K, Salas, R, Kosten, TR, Zunta-Soares, G, Soares, JC (2016). Extensive white matter abnormalities and clinical symptoms in drug-naive patients with first-episode schizophrenia: a voxel-based diffusion tensor imaging study. Journal of Clinical Psychiatry 77, 205211.
Zhu, J, Zhuo, C, Qin, W, Wang, D, Ma, X, Zhou, Y, Yu, C (2015). Performances of diffusion kurtosis imaging and diffusion tensor imaging in detecting white matter abnormality in schizophrenia. Neuroimage: Clinical 7, 170176.
Ziegler, G, Dahnke, R, Winkler, AD, Gaser, C (2013). Partial least squares correlation of multivariate cognitive abilities and local brain structure in children and adolescents. Neuroimage 82, 284294.


Type Description Title
Supplementary materials

Krakauer supplementary material
Krakauer supplementary material 1

 Unknown (1.6 MB)
1.6 MB


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