Miswiring of Frontostriatal Projections in Schizophrenia

Abstract

We investigated brain wiring in chronic schizophrenia and healthy controls in frontostriatal circuits using diffusion magnetic resonance imaging tractography in a novel way. We extracted diffusion streamlines in 27 chronic schizophrenia and 26 healthy controls connecting 4 frontal subregions to the striatum. We labeled the projection zone striatal surface voxels into 2 subtypes: dominant-input from a single cortical subregion, and, functionally integrative, with mixed-input from diverse cortical subregions. We showed: 1) a group difference for total striatal surface voxel number (P = .045) driven by fewer mixed-input voxels in the left (P = .007), but not right, hemisphere; 2) a group by hemisphere interaction for the ratio quotient between voxel subtypes (P = .04) with a left (P = .006), but not right, hemisphere increase in schizophrenia, also reflecting fewer mixed-input voxels; and 3) fewer mixed-input voxel counts in schizophrenia (P = .045) driven by differences in left hemisphere limbic (P = .007) and associative (P = .01), but not sensorimotor, striatum. These results demonstrate a less integrative pattern of frontostriatal structural connectivity in chronic schizophrenia. A diminished integrative pattern yields a less complex input pattern to the striatum from the cortex with less circuit integration at the level of the striatum. Further, as brain wiring occurs during early development, aberrant brain wiring could serve as a developmental biomarker for schizophrenia.

Keywords: brain wiring; diffusion magnetic resonance imaging; prefrontal cortex; schizophrenia; striatum; tractography.

Fig. 1.

A. Mixed-input voxel (<0.7 threshold; left and right blue and yellow boxes represent different cortical functional subregions). B. Dominant-input voxel (>0.70% threshold; left and right blue and yellow boxes represent different cortical functional subregions). C. Model of frontostriatal connections. Parallel, segregated streamlines (4 black arrows) are shown, as well as convergent, integrative streamlines (2 red arrows). Far right voxel is representative of an overlapping-input striatal surface voxel; left and middle voxels are representative of dominant-input voxels. CTX: Cortex; DLPFC: dorsolateral prefrontal cortex; VLPFC: ventrolateral prefrontal cortex.

Fig. 2.

3D rendering of FreeSurfer frontal cortical ROIs. DLPFC is light blue; VLPFC is dark blue; Motor cortex is Red; Limbic cortex (rACG & OFC) is green. Only OFC is shown. DLPFC: dorsolateral prefrontal cortex; VLPFC: ventrolateral prefrontal cortex; rACG: rostral anterior cingulate gyrus; OFC: orbitofrontal cortex.

Fig. 3.

Panel A scatter plot shows fewer mixed voxels in the left hemisphere on striatal surface in CSZ vs HCs. Panel B scatter plot shows an interaction between hemisphere and group; follow-up t-test shows larger VTR quotient in the LH in SZ vs HCs. * < .05. VTR (voxel type ratio).