Schizophrenia: from neurochemistry to circuits, symptoms and treatments

Howes, Oliver D.; Bukala, Bernard R.; Beck, Katherine

doi:10.1038/s41582-023-00904-0

Cited by 18 publications

(2 citation statements)

References 186 publications

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“…These findings indicate network-level white matter microstructure alterations as a potential biomarker for CHR/EP. DA's role in psychotic disorders has not clearly been determined besides the fact that most approved treatments focus on blocking D2 action; however, these treatments are not always efficacious 63 . This has set forth the idea that brain networks may modulate and be an essential target to treat psychotic disorders, particularly early in the disease.…”

Section: Discussionmentioning

confidence: 99%

Macro- and Micro-Structural Alterations in the Midbrain in Early Psychosis

Zhou,

Jones,

Ivleva

et al. 2024

Preprint

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Introduction. Early psychosis (EP) is a critical period in the course of psychotic disorders during which the brain is thought to undergo rapid and significant functional and structural changes 1. Growing evidence suggests that the advent of psychotic disorders is early alterations in the brain's functional connectivity and structure, leading to aberrant neural network organization. The Human Connectome Project (HCP) is a global effort to map the human brain's connectivity in healthy and disease populations; within HCP, there is a specific dataset that focuses on the EP subjects (i.e., those within five years of the initial psychotic episode) (HCP-EP), which is the focus of our study. Given the critically important role of the midbrain function and structure in psychotic disorders (cite), and EP in particular (cite), we specifically focused on the midbrain macro- and micro-structural alterations and their association with clinical outcomes in HCP-EP. Methods: We examined macro- and micro-structural brain alterations in the HCP-EP sample (n=179: EP, n=123, Controls, n=56) as well as their associations with behavioral measures (i.e., symptoms severity) using a stepwise approach, incorporating a multimodal MRI analysis procedure. First, Deformation Based Morphometry (DBM) was carried out on the whole brain 3 Tesla T1w images to examine gross brain anatomy (i.e., seed-based and voxel-based volumes). Second, we extracted Fractional Anisotropy (FA), Axial Diffusivity (AD), and Mean Diffusivity (MD) indices from the Diffusion Tensor Imaging (DTI) data; a midbrain mask was created based on FreeSurfer v.6.0 atlas. Third, we employed Tract-Based Spatial Statistics (TBSS) to determine microstructural alterations in white matter tracts within the midbrain and broader regions. Finally, we conducted correlation analyses to examine associations between the DBM-, DTI- and TBSS-based outcomes and the Positive and Negative Syndrome Scale (PANSS) scores. Results: DBM analysis showed alterations in the hippocampus, midbrain, and caudate/putamen. A DTI voxel-based analysis shows midbrain reductions in FA and AD and increases in MD; meanwhile, the hippocampus shows an increase in FA and a decrease in AD and MD. Several key brain regions also show alterations in DTI indices (e.g., insula, caudate, prefrontal cortex). A seed-based analysis centered around a midbrain region of interest obtained from freesurfer segmentation confirms the voxel-based analysis of DTI indices. TBSS successfully captured structural differences within the midbrain and complementary alterations in other main white matter tracts, such as the corticospinal tract and cingulum, suggesting early altered brain connectivity in EP. Correlations between these quantities in the EP group and behavioral scores (i.e., PANSS and CAINS tests) were explored. It was found that midbrain volume noticeably correlates with the Cognitive score of PA and all DTI metrics. FA correlates with the several dimensions of the PANSS, while AD and MD do not show many associations with PANSS or CAINS. Conclusions: Our findings contribute to understanding the midbrain-focused circuitry involvement in EP and complimentary alteration in EP. Our work provides a path for future investigations to inform specific brain-based biomarkers of EP and their relationships to clinical manifestations of the psychosis course.

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Section: Discussionmentioning

confidence: 99%

Macro- and Micro-Structural Alterations in the Midbrain in Early Psychosis

Zhou,

Jones,

Ivleva

et al. 2024

Preprint

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“…Current pharmacotherapies targeting symptom relief in SMI have limited effects on cognition, which may have a different underlying pathophysiology (Howes et al, 2024; McCutcheon et al, 2023). Evidence suggests immune- and inflammatory-related abnormalities, which are well documented across the psychosis spectrum (Andreassen et al, 2023; Benros et al, 2014; Goldsmith et al, 2016; Steen et al, 2023; Webster, 2023), are associated with cognitive impairment (Jovasevic et al, 2024; Morozova et al, 2022; Rosenblat et al, 2015; Wang et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Longitudinal course of inflammatory-cognitive subgroups across first treatment severe mental illness and healthy controls

Sæther,

Ueland,

Haatveit

et al. 2024

Preprint

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Background While inflammation is associated with cognitive impairment in severe mental illnesses (SMI), there is substantial heterogeneity and evidence of transdiagnostic subgroups across schizophrenia (SZ) and bipolar (BD) spectrum disorders. There is however, limited knowledge about the longitudinal course of this relationship. Methods Systemic inflammation (C-Reactive Protein, CRP) and cognition (nine cognitive domains) was measured from baseline to 1 year follow-up in first treatment SZ and BD (n=221), and healthy controls (HC, n=220). Linear mixed models were used to evaluate longitudinal changes separately in CRP and cognitive domains specific to diagnostic status (SZ, BD, HC). Hierarchical clustering was applied on the entire sample to investigate the longitudinal course of transdiagnostic inflammatory-cognitive subgroups. Results There were no case-control differences or change in CRP from baseline to follow-up. We confirm previous observations of case-control differences in cognition at both time-points and domain specific stability/improvement over time regardless of diagnostic status. We identified transdiagnostic inflammatory-cognitive subgroups at baseline with differing demographics and clinical severity. Despite improvement in cognition, symptoms and functioning, the higher inflammation-lower cognition subgroup (75% SZ; 48% BD; 38% HC) had sustained inflammation and lower cognition, more symptoms, and lower functioning (SMI only) at follow-up. This was in comparison to a lower inflammation-higher cognition subgroup (25% SZ, 52% BD, 62% HC), where SMI participants showed cognitive functioning at HC level with a positive clinical course. Conclusions Our findings support heterogenous and transdiagnostic inflammatory-cognitive subgroups that are stable over time, and may benefit from targeted interventions.

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