Brain Imaging and Behavior

, Volume 13, Issue 5, pp 1236–1245 | Cite as

Striato-nigro-striatal tract dispersion abnormalities in patients with chronic schizophrenia

  • Ana María Rivas-Grajales
  • Peter Savadjiev
  • Marek Kubicki
  • Paul G. Nestor
  • Margaret Niznikiewicz
  • Robert W. McCarley
  • Carl-Fredrik Westin
  • Martha E. Shenton
  • James J. LevittEmail author
Original Research


The white matter connections between the midbrain dopamine neurons and the striatum are part of a neural system involved in reward-based learning, a process that is impaired in patients with schizophrenia. The striato-nigro-striatal (SNS) tract, which participates in this process, has not as yet been explored. The present study aimed to use diffusion MRI (dMRI) to delineate the SNS tract, and to compare the application of two dMRI measures, Tract Dispersion (TD), an index of white matter morphology, and Fractional Anisotropy (FA), an index of white matter integrity, to detect group differences between patients with chronic schizophrenia (CSZ) and healthy controls (HC). dMRI scans were acquired in 22 male patients with CSZ and 23 age-matched HC. Two-tensor tractography was used in addition to manually-delineated regions of interest to extract the SNS tract. A mixed-model analysis of variance was used to investigate differences in TD and FA between CSZ patients and HC. The associations between TD and behavioral measures were also explored. Patients and controls differed significantly in TD (P = 0.04), but not in FA (P = 0.69). The group differences in TD were driven by a higher TD in the right hemisphere in the CSZ group. Higher TD correlated significantly with poorer performance in the Iowa Gambling Task (IGT) when combining the scores of both groups. The findings suggest that dysconnectiviy of the SNS tract which is associated with schizophrenia, could arise from abnormalities in white matter morphology. These abnormalities may potentially reflect irregularities in brain development.


Diffusion MRI Reward processing Psychotic symptoms 



This study was supported by The National Institutes of Health (P50MH080272 (RWM (Program Director) MK, PGN, MN, MES), R01AG04252 (MK), R01MH102377 (MK)), the Veterans Affairs Merits Awards (JJL, RWM) (I01CX000176 (MES), and a NARSAD Young Investigator Award (22591 (PS)).

Compliance with ethical standards

Conflict of interest

Ana Maria Rivas-Grajales, Peter Savadjiev, Marek Kubicki, Paul G. Nestor, Margaret Niznikiewicz, Robert W. McCarley, Carl-Fredrik Westin, Martha E. Shenton and James J. Levitt declare that they have no conflicts of interest.

Human and animal rights

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

Informed consent was obtained from all individual participants included in the study.

Supplementary material

11682_2018_9934_MOESM1_ESM.doc (236 kb)
ESM 1 (DOC 236 kb)


  1. Andreasen, N. (1984a). The scale for the assessment of positive symptoms (SAPS). The University of Iowa.Google Scholar
  2. Andreasen, N. C. (1984b). Scale for the assessment of negative symptoms (SANS). The University of Iowa.Google Scholar
  3. Andreasen, N. C. (2010). The lifetime trajectory of schizophrenia and the concept of neurodevelopment. Dialogues in Clinical Neuroscience, 12(3), 409–415.Google Scholar
  4. Basser, P. J., & Pierpaoli, C. (1996). Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. Journal of Magnetic Resonance. Series B, 111(3), 209–219. Retrieved from
  5. Beaulieu, C. (2002). The basis of anisotropic water diffusion in the nervous system - a technical review. NMR in Biomedicine, 15(7–8), 435–455. Scholar
  6. Bechara, A., Damasio, A., Damasio, H., & Anderson, S. (1994). Insensitivity to future consequences following damage to human prefrontal cortex. Cognition, 50, 7–15.CrossRefGoogle Scholar
  7. Bechara, A., Damasio, H., & Damasio, A. (2000). Emotion, decision making and the orbitofrontal cortex. Cerebral Cortex, 10(2000), 295–307. Scholar
  8. Blanchard, J. J., & Cohen, A. S. (2006). The structure of negative symptoms within schizophrenia: Implications for assessment. Schizophrenia Bulletin, 32(2), 238–245. Scholar
  9. Cella, M., Bishara, A. J., Medin, E., Swan, S., Reeder, C., & Wykes, T. (2014). Identifying cognitive remediation change through computational modelling--effects on reinforcement learning in schizophrenia. Schizophrenia Bulletin, 40(6), 1422–1432. Scholar
  10. Dehay, C., Giroud, P., Berland, M., Killackey, H., & Kennedy, H. (1996). Contribution of thalamic input to the specification of cytoarchitectonic cortical fields in the primate: Effects of bilateral enucleation in the fetal monkey on the boundaries, dimensions, and gyrification of striate and extrastriate cortex. Journal of Comparative Neurology, 367(1), 70–89. doi:10.1002/(SICI)1096-9861(19960325)367:1<70::AID-CNE6>3.0.CO;2-G.Google Scholar
  11. Deserno, L., Heinz, A., & Schlagenhauf, F. (2016). Computational approaches to schizophrenia: A perspective on negative symptoms. Schizophrenia Research, In press.
  12. Farreny, A., Del Rey-Mejias, A., Escartin, G., Usall, J., Tous, N., Haro, J. M., & Ochoa, S. (2016). Study of positive and negative feedback sensitivity in psychosis using the Wisconsin card sorting test. Comprehensive Psychiatry, 68, 119–128. Scholar
  13. Friston, K. J. (1998). The disconnection hypothesis. Schizophrenia Research, 30(2), 115–125. Scholar
  14. Gold, J. M. (2012). Negative symptoms and the failure to represent the expected reward value of actions. Archives of General Psychiatry, 69(2), 129. Scholar
  15. Goldman-Rakic, P. S. (1980). Morphological consequences of prenatal injury to the primate brain. Progress in Brain Research, 53, 3–19. Scholar
  16. Goldman-Rakic, P. S., & Rakic, P. (1984). Experimental modification of gyral patterns. In A. M. Geschwind, N., Galaburda (Ed.), Cerebral dominance: The Biological Foundation. (pp. 179–192). Cambridge, MA: Harvard University Press.Google Scholar
  17. Guevara, M., Roman, C., Houenou, J., Duclap, D., Poupon, C., Mangin, J. F., & Guevara, P. (2017). Reproducibility of superficial white matter tracts using diffusion-weighted imaging tractography. NeuroImage, 147, 703–725. Scholar
  18. Haber, S. N., & Behrens, T. E. J. (2014). The neural network underlying incentive-based learning: Implications for interpreting circuit disruptions in psychiatric disorders. Neuron, 83(5), 1019–1039. Scholar
  19. Haber, S. N., & Knutson, B. (2010). The reward circuit: Linking primate anatomy and human imaging. Neuropsychopharmacology.
  20. Haber, S. N., Fudge, J. L., & McFarland, N. R. (2000). Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience, 20(6), 2369–2382 Scholar
  21. Heaton, R. K., Chelune, GJ, Talley, JL, Kay, GG, Curtiss, G. (1993). Wisconsin card sorting test (WCST) manual: Revised and expanded. In Psychological Assessment Resources. Odessa, FL.Google Scholar
  22. Juckel, G., Schlagenhauf, F., Koslowski, M., Wüstenberg, T., Villringer, A., Knutson, B., et al. (2006). Dysfunction of ventral striatal reward prediction in schizophrenia. NeuroImage, 29, 409–416. Scholar
  23. Kaiser, S., Lyne, J., Agartz, I., Clarke, M., Mørch-johnsen, L., & Faerden, A. (2016). Individual negative symptoms and domains – Relevance for assessment , pathomechanisms and treatment. Schizophrenia Research, In Press. doi:
  24. Kapur, S. (2003). Psychosis as a state of aberrant salience: A framework linking biology, phenomenology, and pharmacology in schizophrenia. American Journal of Psychiatry, 160, 13–23. Scholar
  25. Kester, H. M., Sevy, S., Yechiam, E., Burdick, K. E., Cervellione, K. L., & Kumra, S. (2006). Decision-making impairments in adolescents with early-onset schizophrenia. Schizophrenia Research, 85(1–3), 113–123. doi:
  26. Kubicki, M., McCarley, R., Westin, C. F., Park, H.-J., Maier, S., Kikinis, R., et al. (2007). A review of diffusion tensor imaging studies in schizophrenia. Journal of Psychiatric Research, 41(1–2), 15–30. Scholar
  27. Law, A. J., Kleinman, J. E., Weinberger, D. R., & Weickert, C. S. (2007). Disease-associated intronic variants in the ErbB4 gene are related to altered ErbB4 splice-variant expression in the brain in schizophrenia. Human Molecular Genetics, 16(2), 129–141. Scholar
  28. Lee, Y., Kim, Y. T., Seo, E., Park, O., Jeong, S. H., Kim, S. H., & Lee, S. J. (2007). Dissociation of emotional decision-making from cognitive decision-making in chronic schizophrenia. Psychiatry Research, 152(2–3), 113–120. Scholar
  29. Leroux, E., Delcroix, N., & Dollfus, S. (2014). Left fronto-temporal dysconnectivity within the language network in schizophrenia: An fMRI and DTI study. Psychiatry Research - Neuroimaging, 223(3), 261–267. Scholar
  30. Levitt, J. J., Shenton, M. E., McCarley, R. W., Faux, S. F., & Ludwig, A. S. (1994). Premorbid adjustment in schizophrenia: iImplications for psychosocial and ventricular pathology. Schizophrenia Research, 12(2), 159–168. Scholar
  31. Levitt, J. J., Rosow, L. K., Nestor, P. G., Pelavin, P. E., Swisher, T. M., McCarley, R. W., & Shenton, M. E. (2013). A volumetric MRI study of limbic, associative and sensorimotor striatal subregions in schizophrenia. Schizophrenia Research, 145(1–3), 11–19. Scholar
  32. Lewis, D. A., & Levitt, P. (2002). Schizophrenia as a disorder of neurodevelopment. Annual Review of Neuroscience, 25(1), 409–432. Scholar
  33. López-Bendito, G., Cautinat, A., Sánchez, J. A., Bielle, F., Flames, N., Garratt, A. N., et al. (2006). Tangential neuronal migration controls axon guidance: A role for Neuregulin-1 in Thalamocortical axon navigation. Cell, 125(1), 127–142. Scholar
  34. Malcolm, J. G., Shenton, M. E., & Rathi, Y. (2010). Filtered multitensor tractography. IEEE Transactions on Medical Imaging, 29(9), 1664–1675. Scholar
  35. Mucci, A., Dima, D., Soricelli, A., Volpe, U., Bucci, P., Frangou, S., et al. (2015). Is avolition in schizophrenia associated with a deficit of dorsal caudate activity? A functional magnetic resonance imaging study during reward anticipation and feedback. Psychological Medicine, 45(8), 1765–1778. Scholar
  36. Nestor, P. G., Choate, V., Niznikiewicz, M., Levitt, J. J., Shenton, M. E., & McCarley, R. W. (2014). Neuropsychology of reward learning and negative symptoms in schizophrenia. Schizophrenia Research, 159(2–3), 506–508. Scholar
  37. Pettersson-Yeo, W., Allen, P., Benetti, S., McGuire, P., & Mechelli, A. (2011). Dysconnectivity in schizophrenia: Where are we now? Neuroscience and Biobehavioral Reviews.
  38. Prentice, K. J., Gold, J. M., & Buchanan, R. W. (2008). The Wisconsin card sorting impairment in schizophrenia is evident in the first four trials. Schizophrenia Research, 106(1), 81–87. Scholar
  39. Quan, M., Lee, S., Kubicki, M., Kikinis, Z., Rathi, Y., Seidman, L. J., et al. (2013). White matter tract abnormalities between rostral middle frontal gyrus, inferior frontal gyrus and striatum in first-episode schizophrenia. Schizophrenia Research, 145(1–3), 1–10. Scholar
  40. Radua, J., Schmidt, A., Borgwardt, S., Heinz, A., Schlagenhauf, F., McGuire, P., & Fusar-Poli, P. (2015). Ventral striatal activation during reward processing in psychosis: A Neurofunctional meta-analysis. JAMA Psychiatry, 72(12), 1243–1251. Scholar
  41. Rapoport, J. L., Giedd, J. N., & Gogtay, N. (2012). Neurodevelopmental model of schizophrenia: Update 2012. Molecular Psychiatry, 17(12), 1228–1238. Scholar
  42. Rathi, Y., Gagoski, B., Setsompop, K., Grant, P. E., & Westin, C.-F. (2014). Comparing simultaneous multi-slice diffusion acquisitions. In T. Schultz, G. Nedjati-Gilani, A. Venkataraman, L. O’Donnell, & E. Panagiotaki (Eds.), Computational diffusion MRI and brain connectivity (pp. 3–11). Cham: Springer International Publishing.CrossRefGoogle Scholar
  43. Roiser, J. P., Stephan, K. E., den Ouden, H. E. M., Barnes, T. R. E., Friston, K. J., & Joyce, E. M. (2009). Do patients with schizophrenia exhibit aberrant salience? Psychological Medicine, 39(2), 199–209. Scholar
  44. Savadjiev, P., Kindlmann, G., Bouix, S., Shenton, M., & Westin, C. F. (2010). Local white matter geometry from diffusion tensor gradients. Neuroimage, 49(4), 3175–3186. Scholar
  45. Savadjiev, P., Rathi, Y., Bouix, S., Smith, A. R., Schultz, R. T., Verma, R., & Westin, C. F. (2014a). Fusion of white and gray matter geometry: A framework for investigating brain development. Medical Image Analysis, 18(8), 1349–1360. Scholar
  46. Savadjiev, P., Whitford, T. J., Hough, M. E., Clemm Von Hohenberg, C., Bouix, S., Westin, C. F., et al. (2014b). Sexually dimorphic white matter geometry abnormalities in adolescent onset schizophrenia. Cerebral Cortex, 24(5), 1389–1396. Scholar
  47. Savadjiev, P., Seidman, L. J., Thermenos, H., Keshavan, M., Whitfield-Gabrieli, S., Crow, T. J., & Kubicki, M. (2016). Sexual dimorphic abnormalities in white matter geometry common to schizophrenia and non-psychotic high-risk subjects: Evidence for a neurodevelopmental risk marker? Human Brain Mapping, 37(1), 254–261. Scholar
  48. Seitz, J., Zuo, J. X., Lyall, A. E., Makris, N., Kikinis, Z., Bouix, S., et al. (2016). Tractography analysis of 5 white matter bundles and their clinical and cognitive correlates in early-course schizophrenia. Schizophrenia Bulletin, 42(3), 762–771. Scholar
  49. Shurman, B., Horan, W. P., & Nuechterlein, K. H. (2005). Schizophrenia patients demonstrate a distinctive pattern of decision-making impairment on the Iowa gambling task. Schizophrenia Research, 72(2–3), 215–224. Scholar
  50. Somlai, Z., Moustafa, A. A., Kéri, S., Myers, C. E., & Gluck, M. A. (2011). General functioning predicts reward and punishment learning in schizophrenia. Schizophrenia Research, 127(1–3), 131–136. Scholar
  51. Stephan, K. E., Friston, K. J., & Frith, C. D. (2009). Dysconnection in schizophrenia: From abnormal synaptic plasticity to failures of self-monitoring. Schizophrenia Bulletin, 35(3), 509–527. Scholar
  52. Tensaouti, F., Lahlou, I., Clarisse, P., Lotterie, J. A., & Berry, I. (2011). Quantitative and reproducibility study of four tractography algorithms used in clinical routine. Journal of Magnetic Resonance Imaging : JMRI, 34(1), 165–172. Scholar
  53. Wakana, S., Caprihan, A., Panzenboeck, M. M., Fallon, J. H., Perry, M., Gollub, R. L., et al. (2007). Reproducibility of quantitative tractography methods applied to cerebral white matter. NeuroImage, 36(3), 630–644. Scholar
  54. Whitford, T. J., Savadjiev, P., Kubicki, M., O’Donnell, L. J., Terry, D. P., Bouix, S., et al. (2011). Fiber geometry in the corpus callosum in schizophrenia: Evidence for transcallosal misconnection. Schizophrenia Research, 132(1), 69–74. Scholar
  55. Wise, R. A. (2004). Dopamine, learning and motivation. Nature Reviews. Neuroscience, 5(6), 483–494. Scholar
  56. Woodward, N. D., Karbasforoushan, H., & Heckers, S. (2012). Thalamocortical dysconnectivity in schizophrenia. American Journal of Psychiatry, 169(10), 1092–1099. Scholar
  57. Yilmaz, A., Simsek, F., & Gonul, A. S. (2012). Reduced reward-related probability learning in schizophrenia patients. Neuropsychiatric Disease and Treatment, 8, 27–34. Scholar
  58. Ziauddeen, H., & Murray, G. K. (2010). The relevance of reward pathways for schizophrenia. Current Opinion in Psychiatry, 23(2), 91–96. Scholar

Copyright information

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2018

Authors and Affiliations

  • Ana María Rivas-Grajales
    • 1
    • 2
    • 3
  • Peter Savadjiev
    • 1
  • Marek Kubicki
    • 1
    • 2
    • 4
  • Paul G. Nestor
    • 5
  • Margaret Niznikiewicz
    • 6
  • Robert W. McCarley
    • 6
  • Carl-Fredrik Westin
    • 4
  • Martha E. Shenton
    • 1
    • 2
    • 4
    • 7
  • James J. Levitt
    • 1
    • 6
    Email author
  1. 1.Department of Psychiatry, Psychiatry Neuroimaging Laboratory, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA
  2. 2.Department of Psychiatry, Massachusetts General HospitalHarvard Medical SchoolCharlestownUSA
  3. 3.Menninger Department of Psychiatry and Behavioral SciencesBaylor College of MedicineHoustonUSA
  4. 4.Department of Radiology, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA
  5. 5.Department of PsychologyUniversity of MassachusettsBostonUSA
  6. 6.Department of Psychiatry, VA Boston Healthcare System, Brockton DivisionBrocktonUSA
  7. 7.VA Boston Healthcare System, Brockton DivisionBrocktonUSA

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