Brain capillary structures of schizophrenia cases and controls show a correlation with their neuron structures

Abstract

Brain blood vessels constitute a micrometer-scale vascular network responsible for supply of oxygen and nutrition. In this study, we analyzed cerebral tissues of the anterior cingulate cortex and superior temporal gyrus of schizophrenia cases and age/gender-matched controls by using synchrotron radiation microtomography or micro-CT in order to examine the three-dimensional structure of cerebral vessels. Over 1 m of cerebral blood vessels was traced to build Cartesian-coordinate models, which were then used for calculating structural parameters including the diameter and curvature of the vessels. The distribution of vessel outer diameters showed a peak at 7-9 μm, corresponding to the diameter of the capillaries. Mean curvatures of the capillary vessels showed a significant correlation to the mean curvatures of neurites, while the mean capillary diameter was almost constant, independent of the cases. Our previous studies indicated that the neurites of schizophrenia cases are thin and tortuous compared to controls. The curved capillaries with a constant diameter should occupy a nearly constant volume, while neurons suffering from neurite thinning should have reduced volumes, resulting in a volumetric imbalance between the neurons and the vessels. We suggest that the observed structural correlation between neurons and blood vessels is related to neurovascular abnormalities in schizophrenia.

Figure 1

Rendering of three-dimensional image of BA22 cerebral tissue of schizophrenia case S1 and Cartesian-coordinate model of its vessel network. The pial surface is toward the top. (A) Three-dimensional image of the tissue. Linear attenuation coefficients of 8–50 cm⁻¹ were rendered in gray scale with the maximum projection method of the VG Studio software. Scale bar: 100 μm. (B) Cartesian-coordinate model of vessel network built by tracing the three-dimensional image. The model is viewed from nearly the same direction as the rendering. The vessel models of the other 23 samples were built in the same manner (Supplementary Figures S1–S17). The model was drawn with the MCTrace software. Model constituents are color-coded. The vessels magnified in panels C–E are indicated with boxes. (C–E) Cartesian-coordinate models of capillary vessels (red) superposed on cage representations of the three-dimensional image (gray) contoured at 6 times the standard deviation of the image from its mean intensity. Blood cells were visualized in the vessel lumen as low-intensity bodies. Positions of these vessels are indicated with boxes in (B). Scale bar: 10 μm.

Figure 2

Vessel diameter distribution. The frequency distribution in each 0.4-μm diameter bin is represented by the length fraction, which was calculated by dividing the vessel length per bin by the total vessel length. Insets show magnifications of capillary peaks. Schizophrenia cases S1–S4 and controls N1–N4 are color-coded. Solid lines represent BA22 distributions, and dashed lines represent BA24 distributions. (A) Diameter distribution of the schizophrenia cases. (B) Diameter distribution of the control cases.

Figure 3

Vessel structures in (A) tissue of schizophrenia S3-22 and (B) tissue of control N4-22B. The capillary vessels of S3-22 had curved structures, whereas those of N4-22B were rather straight. The pial surface is toward the top. The structures are drawn to the same scale using MCTrace. Nodes composing each vessel are indicated with octagons. The color coding and structural orientation are the same as in Supplementary Figures S2 and S7. Scale bar: 50 μm.

Figure 4

(A) Relationship between mean capillary curvature and mean neurite curvature of the BA22 or BA24 area of each case. The dashed line indicates a linear regression. Schizophrenia cases S1–S4 and controls N1–N4 are color-coded. (B) Relationship between mean capillary diameter and mean neurite thickness radius. Cases are color-coded as in (A).