The psychiatric symptoms of schizophrenia suggest the structural alteration of neurons. This review summarizes our structural studies of brain tissues from schizophrenia patients and control cases using synchrotron radiation. We found that the geometry of neurites differs among individuals and becomes abnormal in schizophrenia. Synchrotron radiation is electromagnetic radiation covering a broad spectrum from X-rays to infrared light. The highly brilliant X-rays enable the analysis of nanometer-scale three-dimensional structures of objects such as asteroid samples returned by the Hayabusa mission. The principle of three-dimensional visualization is the same as that of clinical CT, but its spatial resolution is three- to four-fold higher. Thus, this method is called nanotomography (nano-CT) or microtomography (micro-CT). We applied nano-CT for the structural analysis of brain tissues from schizophrenia and control subjects. Nano-CT was performed at the third-generation synchrotron radiation facilities of SPring-8 in Japan and the Advanced Photon Source of Argonne National Laboratory in the United States. Biopsied brain tissues of the anterior cingulate cortex were stained by Golgi impregnation in order to visualize neurons in the X-ray images. The obtained three-dimensional images were analyzed by tracing their neuronal networks using automated machine recognition algorithms. As the traced models are represented by Cartesian coordinates, we can quantitatively evaluate the geometry of the neurites. The neurites visualized in the three-dimensional image can be regarded as three-dimensional curves. A three-dimensional curve is represented by two geometric parameters: curvature and torsion. The curvature corresponds to the reciprocal of the radius of the curve, and the torsion represents the deviation of the curve from a plane. Analysis of a total of 2592 schizophrenia and 2069 control neurites revealed the median curvature to be significantly different among individuals, even among controls (P<2.2×10^-16). The anterior cingulate cortex analyzed in this study has been reported to be responsible for emotion and recognition functions, and is associated with psychiatric disorders, including schizophrenia. Therefore, the differences in neurite geometry observed among individuals may represent mental individuality. We further analyzed the differences in neurite geometry between the 4 schizophrenia and 4 control subjects, and found that the mean neurite curvatures in the schizophrenia subjects were 1.5-times higher than those in the controls (P=0.020). The schizophrenia subject with the highest neurite curvature had a frame-shift mutation in the glyoxalase 1 gene. This suggests that the carbonyl stress due to the mutation caused structural changes in the neurons, resulting in the reported treatment resistance. We also analyzed the dendritic spine spinal structure using the same strategy, but no significant differences were observed between the schizophrenia and control subjects. The spine density was highly correlated with the postmortem time, suggesting that the spinal changes related to schizophrenia should be re-evaluated considering the postmortem time. Whether the neuronal structure changes in schizophrenia continues to be a topic of discussion, and controversies remain regarding the structural changes due to the difficulty in reproducing the reported changes. The nano-CT visualization technique using synchrotron radiation and subsequent geometrical analysis may shed light on this long-standing question about microstructural changes in the schizophrenic brain.
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