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Abstract Altered hippocampal morphology and metabolic pathology, but also hippocampal circuit dysfunction, are established phenomena seen in psychotic disorders. Thus, we tested whether hippocampal subfield volume deficits link with deviations in glucose metabolism commonly seen in early psychosis, and whether the glucose parameters or subfield volumes change during follow-up period using one-year longitudinal study design of 78 first-episode psychosis patients (FEP), 48 clinical high-risk patients (CHR) and 83 controls (CTR). We also tested whether hippocampal morphology and glucose metabolism relate to clinical outcome. Hippocampus subfields were segmented with Freesurfer from 3T MRI images and parameters of glucose metabolism were determined in fasting plasma samples. Hippocampal subfield volumes were consistently lower in FEPs, and findings were more robust in non-affective psychoses, with strongest decreases in CA1, molecular layer and hippocampal tail, and in hippocampal tail of CHRs, compared to CTRs. These morphometric differences remained stable at one-year follow-up. Both non-diabetic CHRs and FEPs had worse glucose parameters compared to CTRs at baseline. We found that, insulin levels and insulin resistance increased during the follow-up period only in CHR, effect being largest in the CHRs converting to psychosis, independent of exposure to antipsychotics. The worsening of insulin resistance was associated with deterioration of function and symptoms in CHR. The smaller volume of hippocampal tail was associated with higher plasma insulin and insulin resistance in FEPs, at the one-year follow-up. Our longitudinal study supports the view that temporospatial hippocampal subfield volume deficits are stable near the onset of first psychosis, being more robust in non-affective psychoses, but less prominent in the CHR group. Specific subfield defects were related to worsening glucose metabolism during the progression of psychosis, suggesting that hippocampus is part of the circuits regulating aberrant glucose metabolism in early psychosis. Worsening of glucose metabolism in CHR group was associated with worse clinical outcome measures indicating a need for heightened clinical attention to metabolic problems already in CHR.

Abstract The persecutory delusion is the most common symptom of psychosis, yet its underlying neurobiological mechanisms are poorly understood. Prior studies have suggested that abnormalities in medial temporal lobe-dependent associative learning may contribute to this symptom. In the current study, this hypothesis was tested in a non-clinical sample of young adults without histories of psychiatric treatment (n = 64), who underwent classical Pavlovian fear conditioning while fMRI data were collected. During the fear conditioning procedure, participants viewed images of faces which were paired (the CS+) or not paired (the CS−) with an aversive stimulus (a mild electrical shock). Fear conditioning-related neural responses were measured in two medial temporal lobe regions, the amygdala and hippocampus, and in other closely connected brain regions of the salience and default networks. The participants without persecutory beliefs (n = 43) showed greater responses to the CS− compared to the CS+ in the right amygdala and hippocampus, while the participants with persecutory beliefs (n = 21) failed to exhibit this response. These between-group differences were not accounted for by symptoms of depression, anxiety or a psychosis risk syndrome. However, the severity of subclinical psychotic symptoms overall was correlated with the level of this aberrant response in the amygdala (p = .013) and hippocampus (p = .033). Thus, these findings provide evidence for a disruption of medial temporal lobe-dependent associative learning in young people with subclinical psychotic symptoms, specifically persecutory thinking.

Abstract Background Major depressive disorder (MDD) is a prevalent mental health condition affecting millions worldwide, leading to disability and reduced quality of life. MDD poses a global health priority due to its early onset and association with other disabling conditions. Available treatments for MDD exhibit varying effectiveness, and a substantial portion of individuals remain resistant to treatment. Repetitive transcranial magnetic stimulation (rTMS), applied to the left and/or right dorsolateral prefrontal cortex (DLPFC), is an alternative treatment strategy for those experiencing treatment-resistant MDD. The objective of this study is to investigate whether this newer form of rTMS, namely theta burst stimulation (TBS), when performed unilaterally or bilaterally, is efficacious in treatment-resistant MDD. Methods In this naturalistic, randomized double-blinded non-inferiority trial, participants with a major depressive episode will be randomized to receive either unilateral (i.e., continuous TBS [cTBS] to the right and sham TBS to the left DLPFC) or bilateral sequential TBS (i.e., cTBS to the right and intermittent TBS [iTBS] to the left DLPFC) delivered 5 days a week for 4–6 weeks. Responders will move onto a 6-month flexible maintenance phase where TBS treatment will be delivered at a decreasing frequency depending on degree of symptom mitigation. Several clinical assessments and neuroimaging and neurophysiological biomarkers will be collected to investigate treatment response and potential associated biomarkers. A non-inferiority analysis will investigate whether bilateral sequential TBS is non-inferior to unilateral TBS and regression analyses will investigate biomarkers of treatment response. We expect to recruit a maximal of 256 participants. This trial is approved by the Research Ethics Board of The Royal's Institute of Mental Health Research (REB# 2,019,071) and will follow the Declaration of Helsinki. Findings will be published in peer-reviewed journals. Discussion Comprehensive assessment of symptoms and neurophysiological biomarkers will contribute to understanding the differential efficacy of the tested treatment protocols, identifying biomarkers for treatment response, and shedding light into underlying mechanisms of TBS. Our findings will inform future clinical trials and aid in personalizing treatment selection and scheduling for individuals with MDD. Trial registration The trial is registered on https://clinicaltrials.gov/ct2/home (#NCT04142996).

Background: The functional outcomes of patients with a psychotic disorder have been associated with several overlapping clinical, neuropsychological and developmental factors. Aim: In a prospective study, we aimed to predict functional outcomes in patients with first-episode psychosis or clinically high risk for psychosis by sociodemographic, clinical, neuropsychological and premorbid factors and follow-up symptomatology. Methods: Altogether, 130 first-episode psychosis and 60 clinical high-risk patients were recruited, and their functioning was assessed at baseline and at 9- and 18-month follow-ups. The total follow-up functioning was predicted by baseline characteristics and factorized dimensions of baseline clinical symptoms, premorbid adjustment, childhood adversities, neuropsychological tests and follow-up symptoms. Results: Emotional Poverty and Disorganized Thinking, premorbid Sociability and Scholastic Performance, social support, baseline functioning, follow-up Depression/Anxiety and Psychoticism correlated significantly with follow-up functioning. In the regression model, follow-up functioning was significantly associated with Sociability and Scholastic Performance, Disorganized Thinking, work and marital status in the entire sample and in psychotic patients separately. In clinical high-risk patients, Emotional Poverty and follow-up depression/anxiety symptomatology were significantly associated with poor followup functioning. The effects of Sociability and School Performance on follow-up functioning were mediated via Emotional Poverty in both patient groups. Conclusion: In psychotic patients, poor premorbid adjustment, disorganized thinking, poor baseline work status and being single predicted poor follow-up functioning. The effect of premorbid adjustment on follow-up functioning was partly mediated via emotional poverty. In clinical high-risk patients, basic disturbances were affective disorders, and attenuated psychotic symptoms represented their severity.

Neurotransmitter receptors modulate signaling between neurons. Thus, neurotransmitter receptors and transporters play a key role in shaping brain function. Due to the lack of comprehensive neurotransmitter receptor/transporter density datasets, microarray gene expression measuring mRNA transcripts is often used as a proxy for receptor densities. In the present report, we comprehensively test the spatial correlation between gene expression and protein density for a total of 27 neurotransmitter receptors, receptor binding-sites, and transporters across 9 different neurotransmitter systems, using both PET and autoradiography radioligand-based imaging modalities. We find poor spatial correspondences between gene expression and density for all neurotransmitter receptors and transporters except four single-protein metabotropic receptors (5-HT1A, CB1, D2, and MOR). These expression-density associations are related to gene differential stability and can vary between cortical and subcortical structures. Altogether, we recommend using direct measures of receptor and transporter density when relating neurotransmitter systems to brain structure and function.