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The potential influence of astrocytes on neuronal circuitry and psychotic symptoms in schizophrenia have recently been highlighted. Human postmortem studies have observed reduced astrocyte numbers in schizophrenia, but whether this pathology is present at disease onset or accumulates progressively with further psychotic episodes remains unclear. Therefore, we analysed serum levels of the astrocyte-derived proteins glial fibrillary acidic protein (GFAP) and fatty acid-binding protein 7 (FABP7) in acutely ill first-episode (n = 60) and relapsed (n = 34) schizophrenia patients compared to 94 matched controls. Measurements were taken before and 6 weeks after antipsychotic treatment. We found significantly lower levels of GFAP (p < 0.001) and FABP7 (p < 0.001) in patients compared to controls, with no significant differences between first-episode and relapsed patients or changes after treatment. FABP7 negatively correlated with age in controls (r = -0.319, p = 0.002), but not in patients (r = -0.251, p = 0.015). In contrast, GFAP showed no correlation with age. Our findings suggest that lowered GFAP and FABP7 may serve as trait markers of astrocyte pathology in schizophrenia, even prior to antipsychotic treatment. The absent correlation between FABP7 and age in schizophrenia patients, in contrast to controls, may be related to premature brain aging in schizophrenia. Long-term studies are needed to explore the relationship between chronic disease and astrocyte pathology in schizophrenia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Research has focused on identifying neurobiological risk factors associated with aggressive behavior in order to improve prevention and treatment efforts. This study aimed to characterize microstructural differences in white matter (WM) integrity in individuals prone to aggression. We hypothesized that altered cerebral WM microstructure may underlie normal individual variability in aggression and tested this using a case-control design in healthy individuals. Diffusion tensor imaging (DTI) was used to examine WM changes in martial artists (n = 29) and age-matched controls (n = 31). We performed tract-based spatial statistics (TBSS) to identify differences in axial diffusivity (AD), fractional anisotropy (FA) and mean diffusivity (MD) between the two groups at the whole-brain level. Martial artists were significantly more aggressive than controls, with increased MD in parietal and occipital areas and increased AD in widespread fiber tracts in the frontal, parietal and temporal areas. Positive associations between AD/MD and (physical) appetitive aggression were identified in several clusters, including the corpus callosum, the superior longitudinal fasciculus and the corona radiata. Our study found evidence for WM microstructural changes associated with aggressiveness in a community case-control sample. Longitudinal studies with larger cohorts, taking into account the dimensional nature of aggressiveness, are needed to better understand the underlying neurobiology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Direct electrical stimulation has been used for decades as a gold standard clinical tool to map cognitive function in neurosurgery patients 1-8 . However, the molecular impact of electrical stimulation in the human brain is unknown. Here, using state-of-the-art transcriptomic and epigenomic sequencing techniques, we define the molecular changes in bulk tissue and at the single-cell level in the human cerebral cortex following direct electrical stimulation of the anterior temporal lobe in patients undergoing neurosurgery. Direct electrical stimulation surprisingly had a robust and consistent impact on the expression of genes related to microglia-specific cytokine activity, an effect that was replicated in mice. Using a newly developed deep learning computational tool, we further demonstrate cell type-specific molecular activation, which underscores the effects of electrical stimulation on gene expression in microglia. Taken together, this work challenges the notion that the immediate impact of electrical stimulation commonly used in the clinic has a primary effect on neuronal gene expression and reveals that microglia robustly respond to electrical stimulation, thus enabling these non-neuronal cells to sculpt and shape the activity of neuronal circuits in the human brain., Competing Interests: Competing interests T.A. is a scientific advisor to Aditum Bio and Radius Health and serves on the scientific advisory board of Embark Neuro. The other authors declare no conflicting interests.

Genome-wide association studies (GWASs) of major depressive disorder (MDD) have recently achieved extremely large sample sizes and yielded substantial numbers of genome-wide significant loci. Because of the approach to ascertainment and assessment in many of these studies, some of these loci appear to be associated with dysphoria rather than with MDD, potentially decreasing the clinical relevance of the findings. An alternative approach to MDD GWAS is to focus on the most severe forms of MDD, with the hope that this will enrich for loci of larger effect, rendering their identification plausible, and providing potentially more clinically actionable findings. Here we review the genetics of severe depression by using clinical markers of severity including: age of onset, recurrence, degree of impairment, and treatment with ECT. There is evidence for increased family-based and Single Nucleotide Polymorphism (SNP)-based estimates of heritability in recurrent and early-onset illness as well as severe functional impariment. GWAS have been performed looking at severe forms of MDD and a few genome-wide loci have been identified. Several whole exome sequencing studies have also been performed, identifying associated rare variants. Although these findings have not yet been rigorously replicated, the elevated heritability seen in severe MDD phenotypes suggests the value of pursuing additional genome-wide interrogation of samples from this population. The challenge now is generating a cohort of adequate size with consistent phenotyping that will allow for careful and robust classifications and distinctions to be made. We are currently pursuing such a strategy in our 50-site worldwide Gen-ECT-ics consortium., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Formal thought disorder (FTD) is a clinical key factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, the relationship between FTD symptom dimensions and patterns of regional brain volume loss in schizophrenia remains to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles by enrolling a large multi-site cohort acquired by the ENIGMA Schizophrenia Working Group (752 schizophrenia patients and 1256 controls), to unravel the neuroanatomy of FTD in schizophrenia and using virtual histology tools on implicated brain regions to investigate the cellular basis. Based on the findings of previous clinical and neuroimaging studies, we decided to separately explore positive, negative and total formal thought disorder. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but positive and negative FTD demonstrated a dissociation: negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD also showed associations with microglial cell types. These results provide an important step towards linking FTD to brain structural changes and their cellular underpinnings, providing an avenue for a better mechanistic understanding of this syndrome., (© 2024. The Author(s).)

Glioblastoma (GBM) is the most commonly occurring and most aggressive primary brain tumor. Transcriptomics-based tumor subtype classification has established the mesenchymal lineage of GBM (MES-GBM) as cancers with particular aggressive behavior and high levels of therapy resistance. Previously it was show that Trihexyphenidyl (THP), a market approved M1 muscarinic receptor-targeting oral drug can suppress proliferation and survival of GBM stem cells from the classical transcriptomic subtype. In a series of in vitro experiments, this study confirms the therapeutic potential of THP, by effectively suppressing the growth, proliferation and survival of MES-GBM cells with limited effects on non-tumor cells. Transcriptomic profiling of treated cancer cells identified genes and associated metabolic signaling pathways as possible underlying molecular mechanisms responsible for THP-induced effects. In vivo trials of THP in immunocompromised mice carry orthotopic MES-GBMs showed moderate response to the drug. This study further highlights the potential of THP repurposing as an anti-cancer treatment regimen but mode of action and d optimal treatment procedures for in vivo regimens need to be investigated further., Competing Interests: Authors JA and WW were employed by Experimental Pharmacology and Oncology Berlin-Buch GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Du, Sanin, Shi, Huang, Nickel, Vargas-Toscano, Huo, Nickl-Jockschat, Dumitru, Hu, Duan, Sandalcioglu, Croner, Alcaniz, Walther, Berndt and Kahlert.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.