Neuroimaging in schizophrenia: an overview of findings and their implications for synaptic changes

Abstract

Over the last five decades, a large body of evidence has accrued for structural and metabolic brain alterations in schizophrenia. Here we provide an overview of these findings, focusing on measures that have traditionally been thought to reflect synaptic spine density or synaptic activity and that are relevant for understanding if there is lower synaptic density in the disorder. We conducted literature searches to identify meta-analyses or other relevant studies in patients with chronic or first-episode schizophrenia, or in people at high genetic or clinical risk for psychosis. We identified 18 meta-analyses including over 50,000 subjects in total, covering: structural MRI measures of gyrification index, grey matter volume, grey matter density and cortical thickness, neurite orientation dispersion and density imaging, PET imaging of regional glucose metabolism and magnetic resonance spectroscopy measures of N-acetylaspartate. We also review preclinical evidence on the relationship between ex vivo synaptic measures and structural MRI imaging, and PET imaging of synaptic protein 2A (SV2A). These studies show that schizophrenia is associated with lower grey matter volumes and cortical thickness, accelerated grey matter loss over time, abnormal gyrification patterns, and lower regional SV2A levels and metabolic markers in comparison to controls (effect sizes from ~ −0.11 to −1.0). Key regions affected include frontal, anterior cingulate and temporal cortices and the hippocampi. We identify several limitations for the interpretation of these findings in terms of understanding synaptic alterations. Nevertheless, taken with post-mortem findings, they suggest that schizophrenia is associated with lower synaptic density in some brain regions. However, there are several gaps in evidence, in particular whether SV2A findings generalise to other cohorts.

Progressive brain abnormalities in schizophrenia across different illness periods: a structural and functional MRI study

“…In chronic schizophrenia, gray matter density reduction was observed in extensive brain regions 7 . In a recent review article, Howes et al concluded gray matter density is lower relative to controls in a network of regions, including the bilateral insular cortex, anterior cingulate gyrus, left parahippocampal gyrus, middle frontal gyrus, postcentral gyrus, and the thalamus and the abnormalities progress from first episode to chronic stage in schizophrenia 8 . However, most studies have recruited patients with chronic schizophrenia lasting less than 20 years of ill duration, and the illness's progression beyond this point has rarely been investigated 9,10 .…”

Evidence for embracing normative modeling

“…In the raw data models, which were residualized of covariates including site, sex, and linear +quadratic effects of age and head motion (only included for functional models), we observe no group differences after multiple comparison corrections. The lack of any group differences in the raw data was initially a puzzling finding due to reported group differences in the literature ( Arbabshirani et al, 2013 ; Cetin et al, 2015 ; Cetin et al, 2016 ; Cheon et al, 2022 ; Dansereau et al, 2017 ; Howes et al, 2023 ; Lei et al, 2020a ; Lei et al, 2020b ; Meng et al, 2017 ; Rahim et al, 2017 ; Rosa et al, 2015 ; Salvador et al, 2017 ; Shi et al, 2021 ; van Erp et al, 2018 ; Venkataraman et al, 2012 ; Wannan et al, 2019 ; Yu et al, 2012 ), however, upon the investigation of the uncorrected statistical maps, we observe that the raw data follows a similar pattern to the deviation group difference map ( Figure 4 ), but these results do not withstand multiple comparison correction. For full statistics including the corrected and uncorrected p-values and test-statistic of every ROI, see Supplementary files 3 and 4 .…”

Evidence for Embracing Normative Modeling

“…In the raw data models, which were residualized of covariates including site, sex, and linear plus quadratic effects of age and head motion (only included for functional models), we observe no group differences after multiple comparison correction. The lack of any group differences in the raw data was initially a puzzling finding due to reported group differences in the literature Arbabshirani et al (2013 ); Cetin et al (2015 , 2016); Dansereau et al (2017 ); Howes et al (2022 ); Lei et al (2020b ,a); Meng et al (2017 ); Rahim et al (2017 ); Rosa et al (2015 ); Salvador et al (2017 ); Shi et al (2021 ); van Erp et al (2018 ); Venkataraman et al (2012 ); Wannan et al (2019 ); Yu et al (2012 ), however, upon investigation of the uncorrected statistical maps, we observe that the raw data follows a similar pattern to the deviation group difference map, but these results do not withstand multiple comparison correction.…”