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The organization of frontostriatal brain wiring in non-affective early psychosis compared with healthy subjects using a novel diffusion imaging fiber cluster analysis

Molecular Psychiatry volume 28, pages 2301–2311 (2023)Cite this article

Subjects

Abstract

Background

Alterations in brain connectivity may underlie neuropsychiatric conditions such as schizophrenia. We here assessed the degree of convergence of frontostriatal fiber projections in 56 young adult healthy controls (HCs) and 108 matched Early Psychosis-Non-Affective patients (EP-NAs) using our novel fiber cluster analysis of whole brain diffusion magnetic resonance imaging tractography.

Methods

Using whole brain tractography and our fiber clustering methodology on harmonized diffusion magnetic resonance imaging data from the Human Connectome Project for Early Psychosis we identified 17 white matter fiber clusters that connect frontal cortex (FCtx) and caudate (Cd) per hemisphere in each group. To quantify the degree of convergence and, hence, topographical relationship of these fiber clusters, we measured the inter-cluster mean distances between the endpoints of the fiber clusters at the level of the FCtx and of the Cd, respectively.

Results

We found (1) in both groups, bilaterally, a non-linear relationship, yielding convex curves, between FCtx and Cd distances for FCtx-Cd connecting fiber clusters, driven by a cluster projecting from inferior frontal gyrus; however, in the right hemisphere, the convex curve was more flattened in EP-NAs; (2) that cluster pairs in the right (p = 0.03), but not left (p = 0.13), hemisphere were significantly more convergent in HCs vs EP-NAs; (3) in both groups, bilaterally, similar clusters projected significantly convergently to the Cd; and, (4) a significant group by fiber cluster pair interaction for 2 right hemisphere fiber clusters (numbers 5, 11; p = .00023; p = .00023) originating in selective PFC subregions.

Conclusions

In both groups, we found the FCtx-Cd wiring pattern deviated from a strictly topographic relationship and that similar clusters projected significantly more convergently to the Cd. Interestingly, we also found a significantly more convergent pattern of connectivity in HCs in the right hemisphere and that 2 clusters from PFC subregions in the right hemisphere significantly differed in their pattern of connectivity between groups.

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Fig. 1: A model of our method for obtaining cortical and caudate mean distances between the endpoints of streamlines of two frontostriatal fiber clusters.
Fig. 2: Pairwise Distances for Fiber Cluster 5 (Right Hemisphere).
Fig. 3: Graphical representation of the relationship between cortical and caudate distances.
Fig. 4: A mixed model regression analysis of convergence quotients.
Fig. 5: A 3D rendering of fiber clusters 5 and 11.

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Code availability

Statistical analyses were performed using R (www.r-project.org), including the “lme4” and “lmerTest” libraries for mixed model regression. The R code scripts used are available on request. Whole brain white matter tractography was computed using the unscented Kalman filter (UKF) tractography (https://github.com/pnlbwh/ukftractography). Tractography fiber clustering was performed using the whitematteranalysis (WMA) package (https://github.com/SlicerDMRI/whitematteranalysis) and the O’Donnell Research Group (ORG) atlas (http://dmri.slicer.org/atlases/), provided via the SlicerDMRI software (http://dmri.slicer.org). Code for fiber point analysis is available upon request.

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Funding

Funding

R21MH121704 (JJL); U01MH104977 (MES, AB, DO, DH, MKes); R01MH119222 (YR, LJO); R01MH125860 (LJO, YR); P41EB015902 (LJO), R01MH074794 (Mkub, LJO), R21MH116352 (YR, Mkub, MES), NARSAD Young Investigator Award (SC-K), K24 MH110807, R01MH112748 (MKub), VA Merit Award (I01 CX000176-06; MES), R01MH117012 (KEL).

Author information

Authors and Affiliations

  1. Department of Psychiatry, VA Boston Healthcare System, Brockton Division, Brockton, MA, 02301, USA

    J. J. Levitt & P. G. Nestor

  2. Harvard Medical School, Boston, MA, 02115, USA

    J. J. Levitt & P. G. Nestor

  3. Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    J. J. Levitt, Y. Rathi, S. Cetin-Karayumak, M. Kubicki, M. J. Coleman, S. Bouix & M. E. Shenton

  4. Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    F. Zhang, M. Kubicki, M. E. Shenton & L. J. O’Donnell

  5. Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA

    M. Vangel, Y. Rathi, M. Kubicki, D. J. Holt & M. E. Shenton

  6. Department of Psychology, University of Massachusetts, Boston, MA, 02125, USA

    P. G. Nestor

  7. McLean Hospital, Harvard Medical School, Belmont, MA, 02478, USA

    K. E. Lewandowski & D. Öngür

  8. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA

    M. Keshavan

  9. Department of Software Engineering and Information Technology, École de technologie supérieure, Université du Québec, Montréal, QC, H3C 1K3, Canada

    S. Bouix

  10. Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    A. Breier

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Contributions

JJL: conceptualization and design of the study, methodology, data analysis, writing original draft, manuscript review and editing. FZ: conceptualization and design of the study, methodology, software, data analysis, manuscript review and editing. MV: conceptualization and design of the study, methodology, software, statistical analysis, manuscript review and editing. PGN: provided input on science, review of manuscript. YR: conceptualization, methodology, manuscript review and editing. SC-K: provided input on science, methodology, review of manuscript. MK: provided input on science, manuscript review. MJC: data science, QA/QC of clinical database, review of manuscript. KEL: provided input on science, data collection, review of manuscript. DH: provided input on science, data collection, review of manuscript. MKesh: provided input on science, data collection, manuscript review and editing. SB: design and execution of MRI data processing and quality control, review of manuscript. DO: provided input on science, data collection, review of manuscript. AB: provided input on science, data collection, review of manuscript. MES: provided input on science, oversaw collection of data, manuscript review and editing. LJO: conceptualization and design of the study, methodology, software, manuscript review and editing.

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Correspondence to J. J. Levitt.

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Levitt, J.J., Zhang, F., Vangel, M. et al. The organization of frontostriatal brain wiring in non-affective early psychosis compared with healthy subjects using a novel diffusion imaging fiber cluster analysis. Mol Psychiatry 28, 2301–2311 (2023). https://doi.org/10.1038/s41380-023-02031-0

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  • DOI: https://doi.org/10.1038/s41380-023-02031-0

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