Cutting‐edge morphological studies of post‐mortem brains of patients with schizophrenia and potential applications of X‐ray nanotomography (nano‐CT)

Abstract

Kraepelin expected that the neuropathological hallmark of schizophrenia would be identified when he proposed the concept of dementia praecox 120 years ago. Although a variety of neuropathological findings have been reported since then, a consensus regarding the pathology of schizophrenia has not been established. The discrepancies have mainly been ascribed to limitations in the disease definition of schizophrenia that accompanies etiological heterogeneity and to the incompleteness of the visualization methodology and technology for biochemical analyses. However, macroscopic structural changes in the schizophrenia brain, such as volumetric changes of brain regions, must entail structural changes to cells composing the brain. This paper overviews neuropathology of schizophrenia and also summarizes recent application of synchrotron radiation nanotomography (nano‐CT) to schizophrenia brain tissues. Geometric parameters of neurites determined from the 3‐D nano‐CT images of brain tissues indicated that the curvature of neurites in schizophrenia cases is significantly higher than that of controls. The schizophrenia case with the highest curvature carried a frameshift mutation in the glyoxalase 1 gene and exhibited treatment resistance. Controversies in the neuropathology of schizophrenia are mainly due to the difficulty in reproducing histological findings reported for schizophrenia. Nano‐CT visualization using synchrotron radiation and subsequent geometric analysis should shed light on this long‐standing question about the neuropathology of schizophrenia.

Basal-Forebrain Cholinergic Nuclei Alterations are Associated With Medication and Cognitive Deficits Across the Schizophrenia Spectrum

“… 53–56 Conversely, postmortem findings revealed overall reduced GM volume, especially in the limbic system and thalamus, and decreased cell density in schizophrenia. 57 , 58 Therefore, the observed differences in anterior BFCN MRI-signal might result from a combination of decreased lipid levels due to both long-term treatment with antipsychotics and actual reduction in GM tissue.…”

Schizophrenia-Mimicking Layers Outperform Conventional Neural Network Layers

“…Neural networks were first developed by incorporating biological findings, but until now, the structural aspects of neurons of patients with psychiatric disorders have not been incorporated in studies on artificial intelligence. This is probably because the neuropathology of psychiatric disorders had not been three-dimensionally delineated (Itokawa et al, 2020 ) before our recent reports regarding the nanometer-scale structure of neurons of schizophrenia cases (Mizutani et al, 2019 , 2021 ). A method called “optimal brain damage” (Le Cun et al, 1990 ) has been proposed to remove unimportant weights to reduce the number of parameters, although its relation to biological findings, such as those regarding brain injuries, has not been explicitly described.…”

Three-dimensional architecture of human diabetic peripheral nerves revealed by X-ray phase contrast holographic nanotomography

“…We showed degeneration in the single patient with type 1 diabetes, which is in agreement with an earlier study on the same nerve biopsies 29 , but due to the small number of nerve specimens it was not relevant to make any quantitative measurements and analysis of the morphometry here. Interestingly, analyses of single specimens in post-mortem brains from a few patients with schizophrenia have also been utilized in detection of certain structural changes at high resolution by the use of X-ray nanotomography 35,36 . As in previously published work by Bartels et al 17 from mouse sciatic nerve, the 3D details of human myelinated nerve fibres, such as nodes of Ranvier, including the paranode, and Schmidt-Lanterman incisures, were observed in the present study.…”